to the full program book with all educational
Louisiana Society of Health-System Pharmacists 2015 Annual Meeting May 21-23, 2015 Hyatt Regency 601 Loyola Ave., New Orleans, LA Program Book Louisiana Society of Health-System Pharmacists Board of Directors & Committee Chairs Officers & Directors Fancy Manton— President Edward Stemley — Past President Shawn Manor— President Elect Helen Calmes— Secretary Tommy Mannino— Treasurer Kristian Fruge— Director at Large Camtu Ho— Director at Large Frank McCloy—Director at Large Chapter Presidents Teresa Nash— Director at Large Liz Lafitte— NLSHP President vacant—NELSHP President Jennifer Smith— SCLSHP President LaKeisha Williams— SELSHP President vacant—SWLSHP President Joseph Gary LeBlanc— CLSHP President Committee Chairs Jamie Terrell — Education & Workforce Development Chair Michael Loftin & Michael Dorman— Pharmacy Management Chair William Kirchain & Jeff Evans — Public Policy Chairs Jay Schwab & Helen Calmes— Programming & Practitioner Education Chairs Tammy Belleau—Pharmacy Practice Chairs Dana Jamero—Publications Editor Lisa Ross— Membership & Marketing Chair Anne LaVance —Technician Activities Helen Calmes—Organization Affairs & Documents Chair Jessica Brady— University of Louisiana at Monroe Liaison Iman Borghol— Xavier University Liaison Liz Lafitte and Amanda Storer—Mid Year Meeting Coordinators New Practitioner Committee—Alexis Horace Louisiana Society of Health-System Pharmacists Past Presidents 1944-45 Gracie A. Barr* 1945-46 Hebert J. Mang* 1946-47 Guy L. Leefe* 1947-48 John F. Thompson* 1948-51 Valerie C. Armbruster (Bobear) 1951-52 Troy L. Carter, Jr.* 1952-53 William P. O‘Brien* 1953-54 Ernest B. Simnacher 1954-55 Frances C. Pizzolato (Polizzi) 1955-56 Herbert J. Mang* 1956-57 Albert P. Lauve* 1957-58 Joseph P. Crisalli* 1958-59 Joseph P. Crisalli*/ Frank Hollister 1959-60 Frank W. Hollister 1960-62 Gladys M. Hebert 1962-63 John F. Kellerman 1963-64 Malcolm Claus*/ Henry Derewicz 1964-65 Henry J. Derewicz/ Lowell Pfau 1965-66 Lowell Pfau 1966-67 Troy L. Carter, Jr.* 1967-68 Willard L. Harrison 1968-69 Joseph A. Maggio, Jr. 1969-70 W. Clark Wherritt* 1970-71 Daniel H. Yeoman 1971-72 Thomas B. Himel* 1972-73 W. James Inbau, Jr. 1973-74 Jon J. Tanja 1974-75 Paul J. Comeaux 1975-76 Charles G. Eberhardt 1976-77 Thomas G. Alexander 1977-78 JoBeth Baggett 1978-79 Wesley R. Gladhart, Jr. 1979-80 Claudine J. Lackey 1980-81 Shelton E. McBride 1981-82 Michael L. Louviere * Deceased 1982-83 John D. ―Jack‖ Harris, III* 1983-84 Andrew L. Wilson 1984-85 T. Morris Rabb 1985-86 Paul S. Knecht 1986-87 F. B. ―Brad‖ Belding 1987-88 Michael W. Walker 1988-89 Malcolm J. Broussard 1989-90 Theresa M. Miller 1990-91 Ruth A.C. ―Cookie‖ Jean 1991-92 Darryl Gould 1992-93 Myra Thomas 1993-94 Susan Webber 1994-95 Michael C. Loftin 1995-96 James Witchen 1996-97 Deborah U. Carpenter 1997-98 Janet B. Schmitt 1998-99 Charles W. Jastram 1999-00 Helen M. Calmes 2000-01 Ernest Terry 2001-02 Jay Schwab 2002-03 Mathew Thomas 2003-04 David Loftin 2004-05 Tommy Mannino 2005-06 Michael Cockerham 2006-07 Christopher Betz 2007-08 Barries Leung 2008-09 Marty Steffenson 2009-10 Keturah Robinson 2010-11 Teresa Nash 2011-12 Scott Dantonio 2012-13 Roxie Stewart 2013-14 Edward Stemley 2014-15 Fancy Manton Table of Contents General Information & Activities 1 Hotel Meeting Room Diagram 3 Annual Meeting Program 4 Sponsors 7 Syllabus (listed chronologically) Trends in Prescribing in Pediatric Psychopharmacology Mary Margaret Gleason, MD 8 Application of Epidemiology, Study Design & Methodology, and Biostatistics for Specialty Board Preparation or Use in Literature Evaluation Larry W. Segars, PharmD, DrPH, FCCP, FACE, BCPS, RPh 18 New and Emerging Strategies for the Treatment of Advanced Melanoma R. Donald Harvey, PharmD, FCCP, BCOP 55 Special Situations in Patients with Type 2 Diabetes Susan Ann Cornell, PharmD, CDE, FAPhA, FAADE 72 The Future is Yours—Advancing Practice Christene Jolowsky, MS, RPh, FASHP, ASHP President 78 Technician Advancement: How can I Climb the Ladder? (TECHNICIAN SESSION) Richard Ponder, MBA, CMRP, CPhT, CPP, CEPP 88 Sterile Compounding: USP <800> Hazardous Drugs Anne P. LaVance, BS, CPhT 95 A Pharmacists Guide to Using Fluids, Vasopressors, and Inotropes in Shock Craig Worby, PharmD, BCPS 100 Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing 124 Antifungal Therapy Kevin W. Garey, Pharm.D., M.S., FASHP Emerging Technologies to Decrease Opioid Abuse: An Update for Pharmacists/Technicians Gregory L. Holmquist, PharmD, CPE 139 Sterile Compounding: USP <797> Update Anne P. LaVance, BS, CPhT 156 Trends in Pharmacy Law and Regulation William R. Kirchain, PharmD, CDE Jeffery D. Evans, PharmD 162 General Information & Activities Registration The Annual Meeting Registration and Information Desk is located on the third floor of the Hyatt Regency. Registration will be open Thursday from 12:00-5:30 p.m., Friday from 7:30 a.m.-12:30 p.m. & 2:00-5:30 p.m., and Saturday from 7:30 a.m.-12:00 p.m. Information Updates Please read through your meeting packet, particularly the program-at-a-glance. It contains updated meeting information as well as meeting locations. Badges Badges must be worn at all times. Badges are required for admittance to all Annual Meeting functions. Registrants, staff, guests and speakers have white badges. Exhibitors have blue badges. Meeting Locations Most meeting sessions will be held in the Celestin Ballroom on the third floor of the Hyatt Regency. On Friday, the student session will take place in Foster 2 and the technician session will be in Foster 1 Room on the second floor. Welcome Reception Come join us for the Thursday Welcome Reception from 7:00—9:30 p.m. at Rock ‗n‘ Bowl. Rock ‘n‘ Bowl is located at 3016 S. Carrollton Ave. in New Orleans. Transportation will be provided. There will be a mini bus that will begin picking up at 6:30 pm at the rear entrance of the hotel. Exhibit Program & Lunch The exhibit program is located in the Storyville Hall on the third floor from 12:00-3:00 p.m. on Friday. Please take time to visit our exhibitors and express your thanks for their participation. Additionally, please thank your local representatives. Friday‘s lunch is provided for all paid registrants and exhibitors. Lunch will be served in Storyville Hall for exhibitors only beginning at 11:00 a.m. Lunch begins for registrants at 11:30 a.m. Seating and lunch service ends at 12:30 p.m. Please see the handouts in your packet for a list of exhibitors and exhibit hall layout. Door Prize Drawings Cash Drawing– Four $50 cash drawings will be held throughout the exhibit hours on Friday. All registrants are automatically entered, but you must be present to win! Exhibitor Drawing- A door prize drawing card can be found in your meeting packet. In order to qualify for the drawing, you must have an exhibitor from each company on your card sign or initial the appropriate space on the card. After completing your card, sign it and return it to the registration desk. The drawing will be held at 2:45 p.m. Friday in the Exhibit Hall. You must be present to win. New Mentorship Program We are developing a mentorship program to aid in the professional growth of new practitioners. The New Practitioner Committee is formalizing this program state-wide to provide consistent oversight and leadership. The goal of the program is to provide mentorship opportunities to leaders and future leaders of the society through a program designed to develop, inspire, and encourage involvement in the profession. In doing so, this will allow new practitioners, students and their mentoring pharmacists to expand their professional network, share and learn from experience, and develop the future generation of our profession. The Mentorship Program is available to both students and New Practitioners. Mentors and their mentees will have an opportunity to meet face-to-face at the Annual Meeting at 4:00 pm on Friday, May 22 after the Student Session in Foster 2 room. LSHP Annual Pharmacy Student Ice Cream Social Moderator: Lisa M. DiGioia-Ross ,Pharm. D. Sponsor: Robert D. Ross ,M.D., APMC All students are invited to attend the student listening session and reception at 4:30 p.m. on Friday (immediately following the Mentorship Program.) This will be held in Foster 2 Room on the second floor. Ice cream will be served. Awards All awards will be presented at the General Membership Meeting on Friday, May 22 from 9:00-10:00 am. Past Presidents’ Breakfast The Past Presidents‘ Breakfast has been scheduled for Saturday from 7:00-8:00 a.m. in the in Foster 1 Room. This function is by invitation only. 1 General Information & Activities, continued Activity Evaluations Activity evaluations are extremely important in the development of educational needs assessment for future activities. Please take a moment to evaluate each activity you attend; we appreciate and value your input. A booklet of evaluations was included in your registration packet. Please turn in your evaluation packet at the end of the activity, or after attending your last activity. Please also fill out the Annual Meeting Survey, which helps us know what you enjoyed or didn‘t enjoy about the meeting and the facility. Thank you in advance for your participation! Continuing Education Credit The Louisiana Society of Health-System Pharmacists, American Society of Health-System Pharmacists, and the American Association of Diabetes Educators are accredited by the Accreditation Council for Pharmacy Education as providers of continuing pharmacy education. Certification of Continuing Education Hours/ How to Receive Credit: To receive credit for continuing education activities at the Annual Meeting registrants must: 1. Register and pay all applicable fees. 2. Attend the activity. 3. Complete the Continuing Education Credit Report included in the registration packet. 4. Initial next to each activity that you attend. PARTIAL CREDIT WILL NOT BE GIVEN FOR ANY ACTIVITY. (For example, if you attended only 1 hour of a 2 hour activity, then you will not get any credit for it.) 5. Complete and sign the form and submit to the registration desk at the end of the conference or after attending your last activity. Include on the form your month of birth in ―MM‖ format (for example, January is ―01‖) and day of birth in ―DD‖ format (for example, the 3rd of the month is ―03‖). Also include your NABP eProfile ID. Due to ACPE credit recordation requirements, LSHP no longer issues statements of credit. Your CE credit will be recorded by the LSHP office electronically via CPE Monitor (see details below) within 60 days after the meeting. CPE Monitor is a national, collaborative effort by ACPE and the National Association of Boards of Pharmacy (NABP) to provide an electronic system for pharmacists and pharmacy technicians to track their completed continuing pharmacy education (CPE) credits. All pharmacists and pharmacy technicians must obtain their NABP e-Profile ID by going to www.nabp.net. Your NABP e-Profile ID is required to receive credit for the LSHP Annual Meeting. After the Annual Meeting, LSHP will send to NABP and ACPE (via the CPE Monitor) the amount of credit you received (using your e-Profile ID) at the Annual Meeting. Once this information is received by NABP, pharmacists and pharmacy technicians will be able to log in to access information about their completed CPE. To receive credit, registrants must attend activities designated for their credential. Activities acceptable for pharmacists are indicated by a ―P‖ suffix in the activity number. Programs acceptable for pharmacy technicians are indicated by a ―T‖ suffix in the activity number. ACPE credit will not be given by LSHP for the following activities. Information will be given to participants at these sessions on how to receive credit. Friday, May 22: 8:00—9:00 am: New and Emerging Strategies for the Treatment of Advanced Melanoma (0204-0000-15-413-L01-P) Friday, May 22: 10:00—11:30 am: Special Situations in Patients with Type 2 Diabetes (0069-9999-14-148-L01-P) Saturday, May 23: 8:00—9:00 am: Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing Antifungal Therapy (0204-0000-15-412-L01-P) 2 Hyatt Regency Layout Second floor Legend: Foster 1 (second floor) Technician Session on Friday; and Past President‘s Breakfast on Saturday Foster 2 (second floor) Student sessions on Friday ♠ Celestin Foyer (third floor) Registration ♥ ♣ Celestin A-C (third floor) General Session Storyville Hall (third floor) Exhibit Hall and Friday lunch Celestin D (third floor) Reverse Expo Strand 13 (second floor) Pharmacy Directors Forum Third floor ♣ ♥ ♠ 3 Program Thursday, May 21, 2015 Schedule 12:00—5:30 p.m. Registration open Celestin Foyer 1:00—3:00 p.m. Pharmacy Directors Forum (for pre-registered pharmacy directors and clinical managers only) Strand 13 3:00—5:00 p.m. Reverse Expo (for pre-registered pharmacy directors, clinical managers, and exhibitor reps only) Celestin D 2:45—3:00 p.m. Welcome & Announcements Celestin A-C 3:00—4:00 p.m. Trends in Prescribing in Pediatric Psychopharmacology Mary Margaret Gleason, MD 0179-0000-15-003-L04-P / 0179-0000-15-003-L04-T 1 contact hour (0.1 CEU) Celestin A-C 4:00—5:30 p.m. Application of Epidemiology, Study Design & Methodology, and Biostatistics for Specialty Board Preparation or Use in Literature Evaluation Larry W. Segars, PharmD, DrPH, FCCP, FACE, BCPS, RPh 0179-0000-15-004-L04-P 1.5 contact hours (0.15 CEUs) Celestin A-C 7:00—9:30 p.m. LSHP Welcome Reception at Rock ‘n’ Bowl 3016 South Carrollton Ave., New Orleans, LA 70118 Sponsored by: FFF ENTERPRISES Transportation will be provided. A mini bus will arrive at 6:30 pm at the rear entrance to the hotel. Thank you to MORRIS & DICKSON for being an educational sponsor! Program continued on next page. 4 Program (continued) Friday, May 22, 2015 Schedule 7:30 a.m.—12:30 p.m. and 2:00—5:30 p.m. Registration Open Celestin Foyer 7:30—8:00 a.m. Breakfast Celestin Foyer 8:00—9:00 a.m. New and Emerging Strategies for the Treatment of Advanced Melanoma R. Donald Harvey, PharmD, FCCP, BCOP 0204-0000-15-413-L01-P 1 contact hour (0.1 CEU) This activity is planned and conducted by ASHP Advantage and supported by an educational grant from Merck. Celestin A-C 9:00—10:00 a.m. General Membership Meeting Celestin A-C 10:00—11:30 a.m. Special Situations in Patients with Type 2 Diabetes Susan Ann Cornell, PharmD, CDE, FAPhA, FAADE 0069-9999-14-148-L01-P 1.5 contact hours (0.15 CEU) This program is supported by an educational grant from Novo Nordisk Inc. Celestin A-C 11:30—12:30 p.m. Lunch Sponsored by a grant from NOVO NORDISK, INC. Storyville Hall 12:00—3:00 p.m. Exhibits Storyville Hall 2:00—3:00 p.m. Poster Session: Focus on Patient Safety 0179-0000-15-010-L05-P / 0179-0000-15-010-L05-T 1.0 contact hour (0.1 CEU) Storyville Hall 3:00—4:00 p.m. The Future is Yours—Advancing Practice Christene Jolowsky, MS, RPh, FASHP, ASHP President 0179-0000-15-005-L04-P / 0179-0000-15-005-L04-T 1.0 contact hour (0.1 CEU) Celestin A-C 5 TECHNICIAN BREAKOUT SESSION 3:00—4:00 p.m. Technician Advancement: How can I Climb the Ladder? Richard Ponder, MBA, CMRP, CPhT, CPP, CEPP 0179-0000-15-011-L04-T 1.0 contact hour (0.1 CEU) Foster 1—2nd floor STUDENT SESSION 3:00-4:00 p.m. Financial Planning Scott LaCaze, CPA Foster 2 Room—2nd floor 4:00—4:30 p.m. Mentorship Program Foster 2 Room—2nd floor 4:30 p.m. LSHP Annual Pharmacy Student Ice Cream Social Moderator: Lisa M. DiGioia-Ross ,Pharm. D. Sponsor: Robert D. Ross ,M.D., APMC All students are invited to attend Foster 2 Room—2nd floor Program continued on next page. Program (continued) 4:00—5:00 p.m. Sterile Compounding: USP <800> Hazardous Drugs Anne P LaVance, BS, CPhT 0179-0000-15-006-L04-P / 0179-0000-15-006-L04-T 1.0 contact hour (0.1 CEU) Celestin A-C 5:00—7:00 p.m. A Pharmacists Guide to Using Fluids, Vasopressors, and Inotropes in Shock Craig Worby, PharmD, BCPS 0179-0000-15-008-L01-P / 0179-0000-15-008-L01-T 2.0 contact hours (0.2 CEUs) Celestin A-C Saturday, May 23, 2015 Schedule 7:30 a.m. —12:00 p.m. Registration Open Celestin Foyer 7:30—8:00 a.m. Continental Breakfast 8:00—9:00 a.m. Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing Antifungal Therapy Kevin W. Garey, Pharm.D., M.S., FASHP 0204-0000-15-412-L01-P 1.0 contact hour (0.1 CEU) This activity is planned and conducted by ASHP Advantage and supported by an educational grant from Merck. Celestin A-C 9:00—11:00 a.m. Emerging Technologies to Decrease Opioid Abuse: An Update for Pharmacists/Technicians Gregory L. Holmquist, PharmD, CPE 0179-0000-15-009-L01-P / 0179-0000-15-009-L01-T 2.0 contact hours (0.2 CEUs) Celestin A-C 11:00 a.m.—12:00 p.m. Sterile Compounding: USP <797> Update Anne P LaVance, BS, CPhT 0179-0000-15-007-L04-P / 0179-0000-15-007-L04-T 1.0 contact hour (0.1 CEU) Celestin A-C 12:00—1:00 p.m. Trends in Pharmacy Law and Regulation William R. Kirchain, PharmD, CDE and Jeffery D. Evans, PharmD 0179-0000-15-012-L03-P / 0179-0000-15-012-L03-T 1.0 contact hour (0.1 CEU) Celestin A-C 6 Sponsors The success of LSHP‘s Annual Meeting depends, in large part, on the participation and support of pharmaceutical and related interests. LSHP is very appreciative of the companies listed below that have generously supported the 2015 Annual Meeting by educational or event sponsorship. ASHP Advantage Merck Novo Nordisk Program Management Services, Inc. 7 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Thursday, May 21 3:00—4:00 p.m. Trends in Prescribing in Pediatric Psychopharmacology Mary Margaret Gleason, MD Associate Professor, Psychiatry and Behavioral Sciences Tulane University School of Medicine 0179-0000-15-003-L04-P / 0179-0000-15-003-L04-T 1 contact hour (0.1 CEU) Knowledge-based activity Technician Objectives: Discuss trends in prescribing psychotropic medications for young children nationally Discuss trends in prescribing psychotropic medications for young children in Louisiana Pharmacist Objectives: Describe trends in prescribing psychotropic medications for young children nationally Describe trends in prescribing psychotropic medications for young children in Louisiana Recognize medication classes with FDA indications or empirical evidence for use in children Speaker has disclosed that she has no relevant financial relationships. 8 Abramson Preschool Psychopharmacology Working Group Louisiana Society of Health System Pharmacists Mary Margaret Gleason MD FAAP [email protected] Tulane University School of Medicine Graham J. Emslie, MD Helen L. Egger, MD Laurence L. Greenhill, MD Robert A. Kowatch, MD PhD Alicia Lieberman, PhD Joan Luby, MD Judith Owens, MD Lawrence D. Scahill, MSN PhD Michael S. Scheeringa, MD MPH Brian Stafford, MD MPH Brian Wise, MD MPH Charles H. Zeanah, MD Louisiana’s Early Childhood Supports and Services Teams Tulane Institute of Infant and Early Childhood Mental Health Patients and parents who teach us Mary Margaret Gleason MD [email protected] Will No be discussing off label medications financial conflicts of interest Be familiar with pediatric psychotropic prescription patterns Nationally in Louisiana Be able to recognize medication classes with FDA indications or empirical evidence for use in children. Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] A state of well-being in which every individual realizes his or her own potential can cope with the normal stresses of life can work productively and fruitfully and is able to make a contribution to her or his community. WHO 2014 Provide overview of pediatric indications for psychopharmacologic treatment Present prescribing trends in pediatric psychopharmacology especially in young children Review developmentally-specific issues in preschool mental health Review evidence supporting psychopharmacological interventions in young children Mary Margaret Gleason MD [email protected] 9 A state of well-being in which every individual realizes his or her own potential can cope with the normal stresses of life can work productively and fruitfully and is able to make a contribution to her or his community. WHO 2014 and Statistical Manual (US) Classification of Diseases (UK and billing) Diagnostic Classification: 0-3R (children under 36 months) International These are just parenting problems (or school problems or our culture in the 21st century) Psychiatric illnesses are just created by PHARMA to increase sales Diagnostic Quality research demonstrates that psychiatric disorders have high heritabillity, that diagnostic criteria can differentiate healthy from non-healthy children, and that there is stability over time Best practices recommend non-pharmacologic treatment for many disorders If we just disciplined children more, they wouldn’t have these problems These are just phases Many psychiatric illnesses have biological correlates Rates of disorders are more similar across the globe than different Prevalence of psychiatric disorders increases with age Most adults with psychiatric illness had onset in childhood or adolescence Mary Margaret Gleason MD [email protected] Corporal punishment is associated with higher rates of aggression Mary Margaret Gleason MD [email protected] 16 14 12 10 8 6 4 2 0 Anxiety Disorders Depressive disorder ADHD Disruptive Any disorder behavior Polanczyk et al 2015 JCPP Verlust et al 2003 AJP 10 14 16 13.5 14 12 12.5 Prevalence (%) Prevalence (%) 13 10 Diagnosis 12 Severe Emotional Disability 11.5 Diagnosis 8 Severe Emotional Disability 6 4 11 2 10.5 0 Preschool School age Preschool Adolescent Egger 2006 JAACAP ; Merkingas 2014 Pediatrics School age Adolescent Egger 2006 JAACAP ; Merkingas 2014 Pediatrics 18 16 Lack of empathy 14 Impulse control Attention Prevalence (%) 12 Diagnosis 10 8 Psychosis Severe Emotional Disability 6 Social impairm ent 4 2 0 Preschool School age Mood (sad/irrit able) Problems Anxiety Substance use disorder Adolescent Egger 2006 JAACAP ; Merkingas 2014 Pediatrics Strong validity ADHD Oppositional Defiant Disorder Conduct Disorder Anxiety disorders Posttraumatic stress disorder Depression Bipolar disorder (in adolescence) Autism Tic disorders Eating Disorders Strong Moderate validity Limited data Strong validity Schizophrenia/Schizophr eniform Intermittent explosive disorder Moderate ADHD Oppositional Defiant Disorder Conduct Disorder Anxiety disorders Posttraumatic stress disorder Depression Bipolar disorder (in adolescence) Autism Tic disorders Eating Disorders Strong Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] 11 Moderate validity Schizophrenia/Schizophr eniform Limited data Intermittent explosive disorder Moderate Strong validity ADHD Oppositional Defiant Disorder Conduct Disorder Posttraumatic stress disorder Depression Autism Moderate validity 80% Anxiety disorders Eating/Feeding disorders 60% 10 20% Intermittent explosive disorder Bipolar disorder Tic disorders (Psychosis) ** 8 No diagnosis 6 Diagnosis 4 40% Limited data 12 ** No diagnosis Diagnosis 2 0 0% Percent Impaired Impairment Score Children Strong who meet criteria for a disorder are more impaired than those who do not Moderate ** p<0.01, Egger et al 2006 Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Multiple informants (child and parent minimally) sessions for younger children Multiple modes of assessment (interview, observations, structured measures of symptoms and development) Consider biological, developmental, family, social, and environmental factors Fluoxetine, sertraline, (es)citalopram (paroxetine) Uses: Anxiety, depressive disorders FDA Indications: Anxiety disorders, OCD, MDD Multiple (lower limit age range 6-8; case reports in preschoolers) Clinically important adverse effects Increased suicidality (Black box) Mania FDA.gov Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Methylphenidate, amphetamines Uses: ADHD, severe, impulsive aggression FDA Indications Guanfacine, Uses: Methylphenidate (> 6; explicitly warns against preschool use) Amphetamines (> 3 yo) Empirical support clonidine ADHD, aggression, sleep (clonidine) FDA indications: Hypertension (immediate release), ADHD (extended release, children > 6) Empirical support 1 major RCT for mph in preschoolers Extensive RCT’s in school age and adolescents Clinically important adverse effects Clinically Anorexia Sleep disturbance Emotionality Does NOT increase risk of substance abuse Mary Margaret Gleason MD [email protected] RCT’s in children > 6 Case reports (guanfacine) in preschoolers FDA.gov; parentsmedguide.org important adverse effects Hypotension/death in overdose Sedation Rebound hypertension Mary Margaret Gleason MD [email protected] 12 FDA.gov Atomoxetine Uses: ADHD (anxiety) FDA indication: ADHD (> 6) Empirical support: RCT’s in children 4+ Clinically important adverse effects Buproprion Uses: Depression, ADHD FDA indication • • • • • Emotionality Appetite suppression Liver failure Mary Margaret Gleason MD [email protected] • • FDA.gov FDA.gov 18 Depression, (ADHD) FDA indication: None in youth Empirical support: RCT for ADHD, Depression Clinically important adverse effects Sedation Obesity Lipid and glucose problems Hyperprolactinemia Mary Margaret Gleason MD [email protected] Uses: Aripiprazole, asenpine, olanzapine, olanzapine/fluoxetine, quetiapine, risperidone, ziprasidone (iloperidone; paliperidone, lurasidone) Uses: psychosis, bipolar disorder (aggression, eating disorder) FDA indications: Bipolar disorder (> 10), schizophrenia (> 14 yo); irritability in children with autism (> 5) Important adverse effects • 16 14 12 1995-1998 1999-2002 2003-2006 2007-2010 10 Seizures suicidality 8 6 4 2 0 Visit for psychotropic FDA.gov Mary Margaret Gleason MD [email protected] Visit for psychotherapy Visit to psychiatrist Mary Margaret Gleason MD [email protected] 7 6 girls 0-5 boys 0-5 girls 6-10 boys 6-10 girls 11-14 boys 11-14 girls 15-18 boys 15-18 5 4 3 2 1 Figure Legend: 0 1998 1999 2000 JAMA Psychiatry. 2014;71(1):81-90. doi:10.1001/jamapsychiatry.2013.3074 Date of download: 4/11/2015 Olfson et al 2014 JAMA Psychiatry Mary Margaret Gleason MD [email protected] 13 2001 2002 (Delate 2004) Represents 64% of children 4-18 in LA received medication for ADHD 10 yo white boys highest rates 35.8% Children born in September were 26% more likely to receive medication for ADHD 12.9% Visser 2015 presentation to LA DHH Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Bilbo DHH 2015 Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Most preschoolers with a psychiatric diagnosis do not receive any treatment Children receiving prescriptions are impaired Prescriber profession varies Pediatricians, psychiatrists, child psychiatrists, and family practitioners Class Mary Margaret Gleason MD [email protected] of medications Stimulant rates have plateaued Antipsychotic agent rates are increasing dramatically (Debar et al., 2003; Lavigne et al 2009, Luby et al 2007; Zito et al 2007, Patel et al 2005, Olfson et al 2011) Mary Margaret Gleason MD [email protected] 14 Parent Beliefs Perception of the problem Acceptability of treatment options Race/Ethnicity Socioeconomic status Geography Central > North= South= West > Northeast X2=398.7, p<0.001 Complex associations Higher rates of use in Medicaid population DosReis et al., 2003; Gleason et al 2011; Krain et al., 2005a; Zito 2000; Bennett 1996; Brinkman 2009; Gage and Wilson, 2000; Harrison and Saronoff, 2002 ; Hoza et al., 2000; Hughes and Wingard, 2008; Liu 1991; Owens et al., 2003; Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Child mental health workforce shortage Limitations of mental health care by insurers Stigma Regulatory approval Impact of out of home care Mary Margaret Gleason MD [email protected] Preschoolers Bilbo DHH 2015 Mary Margaret Gleason MD [email protected] Optimal Development are different Development Parent-child relationship Systems Evidence Adverse outcome 0 Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] 15 5 Healthy CNS development Normal IQ Decreased IQ Hyperactivity •Lead toxicity 5 0 Low IQ Thyroxin 5 0 Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Fisher J PEDS 2000) Normal Cortisol diurnal rhythm Increased IQ Low IQ Quality foster care 5 0 Extreme cortisol diurnal rhythm Dyadic therapy 5 0 Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Healthy CNS development Adverse outcome ? Healthy CNS development Adverse outcome ? ? ? 5 0 5 0 Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] 16 Healthy CNS development Adverse outcome Healthy CNS development ? ? ? 5 0 Mary Margaret Gleason MD [email protected] Relationship quality can buffer biological and environmental risk Symptoms may be relationship specific If first line medication fails Reassess diagnosis and level of impairment Track symptoms systematically using structured measures Plan discontinuation trial Practice within the scope of training and experience Parent-child Teacher-child Parent 5 0 Mary Margaret Gleason MD [email protected] Adverse outcome ? attributions What do the symptoms mean about the child? What do the symptoms mean about the parent? What does the medication mean? Mary Margaret Gleason MD [email protected] Mary Margaret Gleason MD [email protected] Researchers to examine safety and efficacy of psychopharmacological and psychotherapeutic interventions for preschoolers Funders (private and public) to fund this research Clinicians and parents to advocate for improved access to quality assessment and treatment Vocal advocate for access to appropriate evidence based treatments through insurance advocacy, legislative and other policy interventions Mary Margaret Gleason MD [email protected] 17 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Thursday, May 21 4:00-5:30 p.m Application of Epidemiology, Study Design & Methodology, and Biostatistics for Specialty Board Preparation or Use in Literature Evaluation 0179-0000-15-004-L04-P Larry W. Segars, PharmD, DrPH, FCCP, FACE, BCPS, RPh Associate Dean, College of Biosciences, and Associate Professor of Pharmacology, Dept. of Pharmacology/Microbiology, College of Osteopathic Medicine Kansas City University of Medicine and Biosciences Kansas City, Missouri 1.5 contact hours (0.15 CEUs) Application-based activity Pharmacist Objectives Delineate and differentiate the various study designs and methodologies commonly utilized in observational and interventional studies. Strengths and weaknesses of each design will be reviewed. Delineate, calculate and interpret common elements associated with medical screenings, measures of disease frequency and measures of association for diseases and practice their interpretations. Delineate and demonstrate the selection process for appropriate statistical tests for data comparisons. Speaker has disclosed that he has no relevant financial relationships. 18 Specialty Board Review: Screenings in Medicine Practice Board‐style Questions Measures of Association & Disease Frequency (Epi.) Practice Board‐style Questions Biostatistics Practice Board‐style Questions Study Designs & Methodology Practice Board‐style Questions Larry W. Segars, PharmD, DrPH, FCCP, FACE, BCPS, RPh Associate Dean of the College of Biosciences Associate Professor of Pharmacology Kansas City University of Medicine & Biosciences 3 4 Possible Outcomes to Screening Screening Test Result Screenings in Medicine 4 Possible Outcomes to Screening “Truth” Disease Presence Yes No Total Positive A B A + B Negative C D C + D Total A + C B + D A + B + C + D 4 Possible Outcomes to Screening • True Positive (TP) – Test is positive and the patient does have the disease • True Negative (TN) – Test is negative and the patient does not have the disease 19 4 Possible Outcomes to Screening 4 Possible Outcomes to Screening • False Positive (FP) – Test is positive but the patient does not have the • False Negative (FN) – Test is negative but the patient does have the disease disease 10 SUMMARY 5 Knowledge Elements of Screenings • • • • • • Calculation of the 5 primary elements associated with medical screenings is straight forward • Understanding how to explain/describe each (and their converse) is the more advance skill to acquire Sensitivity Describes accuracy of TEST RESULT (from known disease status) Specificity Positive Predictive Value Predicts accuracy of DIAGNOSIS (from known test result) Negative Predictive Value Diagnostic Accuracy Describes Total Accuracy of CORRECT TEST RESULTS (from total study population) 11 12 QUESTIONS? Measures of Association 20 Measures of Association Measures of Disease Frequency Absolute Risk Reduction (ARR) [a.k.a. Attributable Risk (AR)] o Example: 14.0% – 17.8% = 3.8% absolute risk difference Building a Mental Understanding of Risks The AR defines the excess risk of the outcome among the group with the exposure being studied Risk: Relative Risk Reduction (RRR) o (ARR) Runexposed o Example: 3.8% ÷ 17.8% = 21.35% relative reduction in risk o PROBABILITY of outcome Risk is a PROPORTION…a simple PERCENTAGE…“part over whole” Risk Ratio (RR) (a.k.a. Relative Risk (RR)) o RATIO of the RISKS from 2 different groups The measure‐of‐choice commonly utilized in COHORT studies NEJM 2000;342(3):145‐153. Measures of Disease Frequency Measures of Association Number Needed to Treat (NNT) / Number Needed to Harm (NNH) Building a Mental Understanding of Odds o “# of patients needed to be treated to receive the stated benefit/harm” 1 ÷ Absolute Risk Reduction (ARR; in decimal format) Odds: o Example: 1 ÷ 0.038 (3.8%) = 27 patients will need to be treated with ramipril to reduce 1 AMI/CVA/Death from CV causes o FREQUENCY of an outcome occurring vs. it NOT occurring Odds is a RATIO, NOT a percentage/proportion Odds Ratio (OR) o RATIO of the ODDS from 2 different groups The measure‐of‐choice commonly utilized in CASE‐CONTROL studies Measures of Association Measures of Association Interpreting Ratio’s – Risk (RR), Odds (OR), Hazard (HR): When Interpreting Ratio’s [RR/OR/HR], look for…: o =1.0 = no difference (no increase/decrease) in risk/odds/hazard o >1.0 = Increased Ratio (RR/OR/HR) 1. Direction of words a. Increased / Decreased +1.0001 to +1.99 = use decimal value and convert to % for interpretation 2. Magnitude a. 80% (1.8 times) / 20% (0.8 times) • If RR = 1.53, then a 53% INCREASED (GREATER) risk in the comparator group RR = 1.8 3. Group Comparison Orientation o ≥2.0 = use phrase “x” times greater for interpretation a. Ramipril vs. Placebo / Placebo vs. Ramipril +2.0 to ∞ • If OR = 6.18, then comparator group is 6.18 times GREATER odds o <1.0 = Decreased Ratio (RR/OR/HR) When looking at the CI for “Ratio’s” (RR/OR/HR), if both values are on the SAME SIDE of 1.0, it is always statistically significant! 0.00001 to 0.99 = subtract decimal value from 1, then convert answer to % for interpretation • If HR = 0.73, then a 27% LOWER probability of the hazard outcome 21 19 Example Board Question Measures of Disease Frequency • Incidence – New occurrences of an outcome/disease • Prevalence – Existing occurrences of an outcome/disease • Includes old and new cases, collectively Both are a PROPORTION…a simple PERCENTAGE…“part over whole” Epidemiology 2012;23:677‐85. Both frequencies are customarily compared to the “at risk” (incidence) or “base” (prevalence) population, to provide a reference Interpret this OR Measures of Disease Frequency Measures of Disease Frequency Incidence (a.k.a.; Risk, Attack Rate, Cumulative Incidence): o [# new cases of the outcome (during a defined time period) # persons at risk of the outcome (during the same time period)] https://www.youtube.com/watch?v=2_qKgbLOlyY • ALWAYS subtract out (from the starting population), those who already have the disease or are immune to the disease (not “at risk”) https://www.youtube.com/watch?v=1jzZe3ORdd8g Measures of Disease Frequency Measures of Disease Frequency Prevalence: • Incidence Rate (a.k.a. Incidence Density): o [# existing cases of outcome # persons in population] – [# new cases of the outcome person‐time (a.k.a., total (net) time) people were at risk The denominator includes those with the outcome and those at risk of getting the outcome of the disease] • Appropriate for dynamic populations o Point Prevalence Prevalence at a given point in time • e.g., on Dec. 31st o Period Prevalence Prevalence over a given period of time • e.g.; during 2012 (1 year) 22 25 26 QUESTIONS? SUMMARY • Risk and Odds are easily determined from 2x2 tables – although not mathematically calculated the same • RR and OR are simply ratio’s of 2 risks or odds and interpreted exactly the same (as is HR) • Measures of association are commonly determined from Observational studies or statistical analyses (regression’s) • Measures of disease frequency are easily determined by focusing on values included in the denominator & numerator of each Biostatistics It’s All About the Data! 2 Key Attributes of Data Measurement (variables) 1. Magnitude (or Dimensionality) Bigger is more, Lower is less 2. Consistency of scale (or Fixed Interval) Equal, measurable spacing between units 3. Rational/Absolute Zero No negative numbers Each attribute can be assessed with a “Yes” or “No” response Algorithm‐style 23 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? a. Does the data have MAGNITUDE? (yes/no) b. Does the data have a fixed, measureable INTERVAL along the entire scale? (yes/no) (units?) Flow Sheet‐style 3 Key Levels of Measurement 3 Key Levels of Measurement Nominal (Dichotomous/Binary; Non‐ Ranked/Ordered Categories) Ordinal (Ranked Categories; Non‐Equal‐Distance) o Yes Magnitude / No Consistency of scale / No Rational Zero o No Magnitude / No Consistency of scale / No Rational Zero (usually just names of groups/categories) Level of Intimidation Can you describe others? Gender & Death & Pharma. companies Can you describe others? 3 Key Levels of Measurement Interval Data Interval/Ratio (Order/Magnitude & Equal Intervals‐of‐scale) Required Assumptions for Interval/Ratio: o Normally‐distributed (around a known mean) o Equal variance (SD) o Yes Magnitude / Yes Consistency of scale / No or Yes Rational Zero (No‐Interval; Yes‐Ratio) • Use Bartlett, Levene, or Kolmogorov‐Smirnov tests to assess for equal variances Number of Days Hospitalized & Age (years) Can you describe others? o Randomly derived and Independent 24 Key Levels of Measurement Changing Levels of Measurement of Data o After data is collected, we can appropriately go down in specificity/detail of data measurement (levels), but never up! Flow Sheet‐style Can you provide examples of converting data to other levels? 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? a. Does the data have MAGNITUDE? (yes/no) b. Does the data have a fixed, measureable INTERVAL along the entire scale? (yes/no) Algorithm‐style The remaining 3 QUESTIONS get you around the other portions of each individual sheet 4 KEY QUESTIONS to Selecting the Correct Statistical Test 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is a. Does the data have MAGNITUDE? (yes/no) b. Does the data have a fixed, measureable INTERVAL along the entire scale? (yes/no) desired? 2. What TYPE OF COMPARISON/ASSESSMENT is desired? – Outcome Prediction/Association (OR) – Predicting Future Outcome/Group Membership a regression – Correlation a correlation test – Time‐to‐Event (Survival)/Event‐Occurrence a survival test 25 regression 4 KEY QUESTIONS to Selecting the Correct Statistical Test Regressions Regressions 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is o Provide a measure of the relationship between variables by allowing the prediction about the dependent, or outcome, variable (DV) knowing the value/rank of others independent variables (IV’s) o Also able to calculate OR for a Measure of Association desired? – Outcome Prediction/Association (OR) regression – Nominal Regression test = Logistic Regression – Ordinal Regression test = Multinomial Logistic Regression – Interval Regression test = Linear Regression 4 KEY QUESTIONS to Selecting the Correct Statistical Test 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is desired? – Correlation desired? correlation test – Correlation correlation test – Provides a quantitative measure of the strength & direction of a relationship between variables 4 KEY QUESTIONS to Selecting the Correct Statistical Test 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is desired? – Correlation desired? correlation test – Time‐to‐Event / Event‐Occurrence – Nominal Correlation test = Contingency Coefficient – Ordinal Correlation test = Spearman Correlation – Interval Correlation test = Pearson Correlation – NOTE: p>0.05 for a Pearson Correlation just means there is no linear correlation; there may still be non‐linear correlations present! All Correlations can be run as a “partial correlation” to control for confounders 26 survival test 4 KEY QUESTIONS to Selecting the Correct Statistical Test “Survival” tests Compares the proportion of, or time‐to, event occurrences between groups (over time) 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is o Commonly represented by a Kaplan‐Meier curve desired? – Time‐to‐Event / Event‐Occurrence survival test – Nominal Survival test = Log‐Rank test – Ordinal Survival test = Cox‐Proportional Hazards test – Interval Survival test = Kaplan‐Meier test All can be represented by a Kaplan‐Meier curve 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? 2. What TYPE OF COMPARISON/ASSESSMENT is desired? – Frequencies/Counts/Proportions* 3. *HOW MANY GROUPS are being compared? o 2 or 3 or more groups 4. *Is the data INDEPENDENT or RELATED (PAIRED)? o Data from different groups (independent) or the same (paired) *KEY WORDS FOR “PAIRED” or “RELATED” DATA: “Pre‐ vs. Post‐”, “Before vs. After”, “Baseline vs. End”, etc… 4 KEY QUESTIONS to Selecting the Correct Statistical Test 1. What TYPE OF DATA is being collected/evaluated? a. Does the data have MAGNITUDE? (yes/no) b. Does the data have a fixed, measureable INTERVAL along the entire scale? (yes/no) 2. What TYPE OF COMPARISON/ASSESSMENT is desired? – – – – Correlation a correlation test Time‐to‐Event (Survival)/Event‐Occurrence a survival test Predicting Future Outcome/Group Membership a regression Frequencies/Counts/Proportions* 3. *HOW MANY GROUPS are being compared? o 2 or 3 or more groups 4. *Is the data INDEPENDENT or RELATED (PAIRED)? Large, individual versions available at end of slide set o Data from the same (paired) or different groups (independent) 27 Accepting or Rejecting Hypothesis Type 1 & Type 2 Errors o An error can be made when incorrectly accepting or rejecting the Null Hypothesis TRUTH Statistical Test Do NOT reject H0 (p>0.05) DO reject H0 Large, individual blank‐versions available at end of slide set for practice, if desired (p<0.05) p value H0 True H1 True CORRECT Type 2 Error Type 1 Error CORRECT Statistical Significance Statistical tests compare differences in variables or to evaluate relationships between them If the p value is lower than the pre‐selected a priori value (customarily 5% (0.05))* then we say it’s statistically significant 1. A test statistic value is calculated, then 2. The test statistic value is compared to the appropriate table of probabilities for that test, then 3. A probability (p) value is obtained; based on the probability of observing, due to chance alone, a test statistic value as extreme or more extreme than actually observed if the groups were equal (not different) o Based on an acceptably‐low probability (less than 5%) that the value of the test statistic could be as large as it is by chance alone if the groups were similar if < the a priori percentage‐risk of error, we REJECT the Null Hypothesis The risk of experiencing a Type 1 error is acceptably low (less than 5%) The probability is selected by investigators before the study starts (a priori) Statistical Significance Statistical Significance Interpretation of a pre‐set (a priori) p value: Comparisons of groups generates only a statistical estimate of the “true” yet unknown difference between groups (a point estimate) o The probability of making a Type 1 error if the Null Hypothesis is rejected o The probability of erroneously claiming a difference between groups if one does not really exist o The probability of the outcome of the group’s differences occurring by chance o The probability of obtaining group differences as great or greater if the groups were actually the same/equal The probability of obtaining a test statistic as high/higher if the groups were actually the same/equal 28 QUESTIONS? Statistical Significance Interpretation of a 95% CI o We are 95% confident that the “true” difference between the groups is contained within the confidence interval range. 63 64 Research Design & Methodology Quantitative vs. Qualitative Study Design & Methodology Numbers used to Represent Data Words used to Represent Data Interventional vs. Observational Forced allocation to study groups 2 KEY QUESTIONS No forced allocation to study groups 2 KEY QUESTIONS 65 to Selecting the Correct Study Design 66 to Selecting the Correct Study Design 1. Is researcher FORCING GROUP ALLOCATION? 1. Is researcher FORCING GROUP ALLOCATION? a. Yes – Interventional (sample size/focus) b. No – Observational (‘outcome’/‘exposure’) a. Yes – Interventional (sample size/focus) b. No – Observational (‘outcome’/‘exposure’) 2. For Observational studies, how were groups Considering OUTCOME vs. EXPOSURE……, Look for what is KNOWN vs. being SOUGHT ORGANIZED? Considering OUTCOME vs. EXPOSURE……, Look for what is KNOWN vs. being SOUGHT a. By Disease Status – Case‐Control/Nested Case‐Control b. By Exposure Status – Cohort c. By Common Factor – Cohort or Cross‐Sectional 29 Study Designs Research Evidence Pyramid Pre-Clinical Cases* (Reports/Series) Phase 1 Ecological* Phase 2 Cross-Sectional Phase 3 Case-Control Phase 4 Pragmatic Trials Randomized Trials Cohort Case‐Control Cross‐Sectional Ecological Case Series Case Reports Increasing Strength of Evidence * Meta‐Analyses Systematic Reviews Increasing Evidence Increasing Evidence Interventional Observational Animal Research Cohort In vitro (test‐tube) Research 69 70 Case‐Control Study Cohort Study Commonly utilized 2x2 Table for study summary: Exposure Disease Presence Yes No Total Yes A B A+B No C D C+D B+D A+B+ C+D Total Commonly utilized 2x2 Table for study summary: A+C Exposure Yes No Total Yes A B A+B No C D C+D B+D A+B+ C+D Total CASE‐CONTROL design useful when studying a rare disease Disease Presence A+C COHORT design useful when studying a rare exposure 71 72 Study Designs Research Design & Methodology • Observational Studies: • Study Methodology: Group allocation based on EXPOSURE status (presence/absence) • Definition: A group with something in common Birth / Inception / Exposure 30 Interventional Observational Pre-Clinical Phase 1 Phase 2 Cases (Reports/Series) Cross-Sectional Ecological Phase 3 Case-Control Phase 4 Cohort Increasing Evidence Increasing Evidence – Cohort Study (a.k.a. Longitudinal & Follow‐up Study) DEFINITION vs. STUDY METHODOLOGY 73 74 Research Design & Methodology Research Design & Methodology • Observational Studies Cont’d: • Observational Studies Cont’d: – Nested Case‐Control • A Case‐Control study derived out of a completed Cohort – Cross‐Sectional Study (a.k.a.; Prevalence study) • Purpose: Examines relationships between disease AND study exposure (simultaneously) among individuals in a defined study population at a point in time The diseased study subjects determined from the Cohort study becoming the Cases of a different, subsequent study » Includes new subjects without disease, called Controls, who may A “snap‐shot” in time (across the entire study population) Patient selection: based on inclusion in study population or may not have necessarily come from the original Cohort study Think of a cross‐sectional study when the information gathered represents what is going on with disease AND exposures (at the same time) a‐cross the entire (a large) study population 75 76 Study Strengths/Weaknesses (Broad) Study Strengths/Weaknesses (Broad) • Ability to prove Causation • Patient Selection • Applicability (External Validity) – Inclusion / Exclusion criteria • Others… (Ethics / Cost / Time requirement) – Inclusion / Exclusion criteria • Validity (Accuracy/Precision/Consistency) – Measurements / Assessments / Classifications Induction Period / Latency Period 77 78 QUESTIONS? SUMMARY • Appropriate study design based on study question, purpose, and group allocation format • Every study has its unique strengths & weaknesses • For boards, be able to select the study design delineated in the stem and understand definitions of study‐related terms 31 Learning Objectives for Biostatistics Topics 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Be able to define, explain, and differentiate the 3 common characteristics of research data. Magnitude Interval Rational Zero Be able to define, differentiate and give multiple examples of the common categories of research data. Nominal Ordinal Interval/Ratio These 3 categories can also be transformed into, or thought of in terms of, 2 broader categories: o Categorical o Continuous Q: Can you place each of the initial 3 categories into its appropriate broader category? Be able to define, differentiate and calculate the 3 common measures of central tendency for research data. Mean Median Mode Be able to define, differentiate & calculate the 2 common measures of variation (spread/dispersion) for research data. Standard Deviation (SD) Variance Be able to interpret multiple forms of visual presentations for data (e.g. pie charts, histograms, scatter and box plots, etc…). Be able to define and differentiate the terms descriptive statistics versus inferential statistics. Be able to identify and describe a data distribution curve as normally distributed or positively/negatively skewed especially as it relates to the mean and median values of a research data set. Be able to cite and list the percentages of a population represented by 1, 2 and 3 standard deviations (SDs) from the mean of a normally-distributed data set. Be able to define and differentiate the statistical terms skewness and kurtosis and be able to interpret values for each. Be able to define and differentiate the following common statistical terms. Alpha Type 1 error Power Beta Type 2 error Q: How does sample size affect Power? Be able to define and appropriately interpret the statistical terms p value and 95% confidence interval (95% CI). Be able to list and delineate the elements used to determine sample size for a research study. Be able to describe and discuss how sample size affects power and the ability to detect a difference between populations, if a difference truly exists. Be able to define and differentiate between independent vs. non-independent (paired/repeated measures) data. Be able to delineate and list the key questions to answer to determine which statistical test is most appropriate when analyzing research data. What “type” of data needs to be analyzed (nominal, ordinal, or interval)? Is the data independent or non-independent (paired/repeated measures)? How many groups are being compared? Be able to select the most appropriate statistical test based on the research data being analyzed. [NOTE: Two different styles/versions of how to select the most appropriate statistical test for research data is provided as an additional Appendix at the end of this document] Comparisons of Frequencies or Proportions: o Chi-square / Fisher’s Exact o Mann-Whitney o Kruskal-Wallis o McNemar o Cochran o Wilcoxon-Signed Rank o Student t-test o Friedman / Kendall o Paired t-test o Analysis of Variance (ANOVA) / Analysis of Co-Variance (ANCOVA) o Repeated Measures ANOVA / Repeated Measures ANCOVA o Multiple ANOVA (MANOVA) / Multiple ANCOVA (MANCOVA) Post-hoc tests for 3 or more groups where an initial significance was detected: o Student-Newman-Keul o Dunnett o Scheffe o Dunn o Tukey o Bonferroni adjustment Correlations: o Pearson Correlation o Contingency Coefficient o Spearman/Kendall Correlation Regressions: o Logistic Regression o Linear Regression o Multinomial Logistic Regression Survival tests: o Kaplan-Meier o Log-Rank o Cox Proportional Hazards Kappa (the amount of agreement between 2 or more elements (e.g., evaluators/raters/investigators)) Coefficient of Determination (the fraction of total variability predicted by a regression model) Bartlett or Levene or Kolmogorov-Smirnov tests (tests for equal variances of interval data) 32 Learning Objectives for Epidemiology Topics 1. 2. 3. 4. 5. 6. 7. 8. 9. Be able to define and differentiate the 2 main stages of disease prevention. Primary Secondary Be able to define and differentiate the following epidemiological terms: Outbreak Endemic Internal Validity Cluster Pandemic External Validity Epidemic Reliability Generalizability Be able to calculate a ratio and proportion as measures of disease frequency. Be able to define, differentiate and calculate each of the following terms associated with medical screenings: True Positive (TP) Positive Predictive Value (PPV) (a.k.a., Predictive Value Positive (PVP)) True Negative (TN) Negative Predictive Value (NPV) (a.k.a., Predictive Value Negative (PVN)) False Positive (FP) Positive Likelihood Ratio (LR+) False Negative (FN) Negative Likelihood Ratio (LR-) Sensitivity Diagnostic Accuracy Specificity Task: Given the first 4 elements, be able to complete a customary epidemiological 2x2 table to calculate all remaining terms. Be able to define, differentiate and calculate the following measures of disease frequency terms: Incidence (a.k.a. Attack or Risk) Prevalence o Incidence Density o Point Prevalence o Incidence Rate o Period Prevalence o Cumulative Incidence o Prevalence Rate Q: How does disease duration affect the Prevalence of a disease? Be able to define, differentiate and calculate the following epidemiological terms associated with comparing groups based on measures of association for disease: Absolute Difference Absolute Risk Reduction (ARR) (a.k.a. Absolute Risk Difference) Relative Difference Relative Risk Reduction (RRR) (a.k.a. Relative Risk Difference) Attributable Difference Number Needed to Treat/Harm (NNT/NNH) Incidence Risk (IR) Odds Risk (Rate) Ratio/Relative Risk (RR) Odds Ratio (OR) Attributable Risk (AR) Task: Given frequencies of exposure & disease (for 2 groups), complete a customary epidemiological 2x2 table to calculate all remaining terms. Be able to define and differentiate each of the following common types of bias: Recall bias Hawthorne effect Healthy-Worker effect Compliance bias Selection bias Withdrawal/Lost-to-Follow-up bias Participation/Responder bias Be able to define and differentiate the following epidemiological terms: Association Confounding Categories of Associations: Types of Causal Relationships: o Artifactual Association o Sufficient Cause o Non-Causal Association o Necessary Cause o Causal Association o Component Cause (a.k.a., Risk Factor) Misclassification Interaction (a.k.a., Effect Modification) o Differential Misclassification o Non-Differential Misclassification Q: Can you differentiate between the terms causation and association? Which study designs can demonstrate each term? Be able to define and differentiate the following common techniques to control for bias and confounding: Study Design stage: Data Analysis stage: o Randomization o Stratification o Restriction o Multivariate Analysis o Matching 33 Learning Objectives for Study Design & Methodology Topics 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Be able to delineate and describe the difference between Observational and Interventional (Experimental) study designs. Be able to list, describe and differentiate the methodology of the common types of Observational study designs (specifically their purpose/design, and patient allocation techniques). Case Report/Case Series Case-Control (and Nested Case-Control) Cohort Cross-Sectional Be able to describe and differentiate between the common types of perspectives utilized by Observational studies. Prospective Retrospective Ambidirectional Be able to list, describe and differentiate the common types of Interventional study designs (specifically their purpose, sample size, and duration). Pre-Clinical Phase Phase 3 Phase 1 Phase 4 Phase 2 Q: Which “phase” occurs after a new medication/device receives FDA approval? Be able to recite the common elements needed in the determination of a study’s sample size. Margin of Error [Alpha (p-value)] Confidence Levels (usually 90%-99%) Estimated Population Size Standard Deviation (usually 0.5 if unknown) Be able to describe and differentiate between the common types of study reviews. Systematic Reviews Meta-Analysis Be able to list, in increasing order of strength of evidence, the common Observational and Interventional study designs. Be able to describe and differentiate a population and a sample. Be able to describe and differentiate each of the following sampling terms: Probabilistic Sampling: Non-Probabilistic Sampling Simple Random Sample Convenience Sample Systematic Random Sample Stratified Random Sample Be able to describe the process and purpose of Randomization (a.k.a. group allocation/assignment). Q: How might you determine if a study’s randomization technique was successful and met its primary goal? Be able to describe and differentiate between the 3 common forms of Randomization. Simple Blocked Stratified Be able to describe and differentiate between, and draw examples of, each of the following Interventional study designs. Simple vs. Factorial Parallel vs. Cross-Over Be able to define the process and purpose of Blinding (a.k.a. Masking). Be able to describe and differentiate between the 3 main levels of Blinding. Single-Blind Double-Blind Triple-Blind Be able to describe and differentiate the following terms associated with Interventional studies. Placebo/Dummy/Double-Dummy Wash-out period Run-in/Lead-in period Hawthorne-effect Be able to describe and differentiate the purpose/responsibilities of the following entities associated with Interventional studies. Investigational Review Board (IRB) Data & Safety Monitoring Board (DSMB) Be able to describe and differentiate the common methods of handling lost-to-follow up/drop-outs associated with Interventional and Observational studies. Intent-to-Treat Per Protocol Be able to define and develop examples of the common statements of research hypothesis used by researchers. Null Hypothesis Alternative Hypothesis 34 APPENDIX Glossary of Example Terms Related to Study Methodology, Epidemiology & Biostatistics AMBIDIRECTIONAL: A study conducted using both a retrospective and a prospective focus (See Retrospective and Prospective). This type of study looks back in time for occurrences/events, and then looks forward in time for future occurrences/events. ARTIFACTUAL (FALSE) ASSOCIATION: A false, incorrect relationship or connection between an exposure and a disease (See Association). ASSOCIATION: A relationship or connection between an exposure and a disease. Associations can be categorized as Artifactual (false), Non-Causal, or Causal (See Artifactual Association, Non-Causal Association and Causal Association). BASELINE: Information gathered from or about the study subject at the initial time point in a clinical trial, just before a participant starts to receive their assigned study intervention. BIAS: The introduction of any factor, process, or information in the design or execution of a study that leads to a spurious (false) result. Bias is considered as a systemic distortion of the truth. In clinical studies, bias can be minimized by use of the blinding and randomization techniques. Most biases are associated with the Selection and Information-Gathering/Measurement processes. Example biases are selection bias and recall bias (See Blinding, Randomization and Selection Bias, Recall Bias). BLINDING: A research technique by which one or more individuals (study subject, study clinician, study researcher) is prevented from being informed or know which of the intervention each study subject has been assigned (also called Masked). (See Single-Blind and Double-Blind). BLOCKED RANDOMIZATION: A randomization process that attempts to assure a balance number of study subjects within each of the study groups in the study (See Randomization). BOOLEAN: Technique in database (literature) searching using the terms “and”, “or”, “not”; web-based presentations can be found at the following websites (http://lib.colostate.edu/tutorials/advboolean.html and http://lib.colostate.edu/tutorials/boolean.html). CAUSAL ASSOCIATION: A relationship or connection in which the antecedent event, characteristic or condition must be present prior to the occurrence of disease (the exposure comes before the disease) (See Association). There are 3 types of causal relationships: Sufficient Cause, Necessary Cause, and Component Cause (a.k.a., Risk Factor) (See Sufficient Cause, Necessary Cause, and Component Cause). CLINICAL TRIAL: A research study involving humans to answer specific questions regarding specific interventions (e.g., medications, procedures, etc…). Clinical trials can be conducted in one of four phases (See Phase 1, Phase 2, Phase 3, and Phase 4 Trials). COHORT: In epidemiology, a group of individuals with some characteristics in common (employment, exposure, birth place, birth year, residence (e.g., zip code)). COMPONENT CAUSE (a.k.a. RISK FACTOR): A characteristic that if present increases the probability (risk) of disease occurring (See Causal Association). In other words, if the component cause is present then the disease is more likely to occur than if it is present, but just because the component cause is present doesn’t mean the disease can’t occur of that if it is present it will occur (e.g., cholesterol level and coronary heart disease). COMPOSITE OUTCOME: The combining of two or more outcomes (primary, secondary, or tertiary), into a single, combined outcome (e.g., death OR myocardial infarction OR stroke). CONFIDENCE INTERVAL: An interval between which researchers are confident (to a preset percentage (e.g., 95%)) that the true association or difference between groups lies. CONFOUNDER: A 3rd variable that distorts the real, observed relationship (association) between two other variables (e.g., exposure and disease). To be a confounder, the 3rd variable must be associated (correlated) with both of the other 2 variables (e.g., associated with the exposure and associated with the disease) (See Correlation and Association). CONTROL: Also known as “the comparator” to which the experimental intervention/observation is compared. (See Control Group). In an interventional study, the control may either be an active, useful intervention or a placebo. In an observational study, a control is a person without the exposure (in a Cohort study) or disease (in a Case-Control study). CONTROL GROUP: The standard by which observational and interventional studies are conducted and in which other groups are compared. In clinical trials, there is always a “comparator” group, whether they are receiving an active, known effective intervention or a placebo, from which the experimental interventional group is compared (See Placebo and Standard Deviation). CORRELATION: A statistical test which evaluates the degree to which one variable changes in relationship with another variable and relates the magnitude and direction of this change and relationship (association) (See Association). CROSS-OVER STUDY: A study in which subjects are initially randomly assigned to one of the intervention groups and during the study are switched from their initially-assigned group to another treatment group, after a wash-out period. Switching intervention groups can occur more than once during a study (See Wash-Out, Randomization, and Intervention). 35 DATA SAFETY AND MONITORING BOARD (DSMB): An independent committee of researchers (statisticians, clinicians, nonclinicians, etc…) and non-researchers (community advocates) organized with the sole purpose of ensuring a clinical trial is ethical and that the rights (ethical and legal) and safety of study participants are protected after the study begins (while it is being conducted) (See Clinical Trial). A DSMB may recommend that a trial be stopped or procedures/processes changed if there are safety concerns. These concerns could include too much risk of harm in one or more groups (not all) or too great of a benefit in one or more groups (not all). DIFFERENTIAL MISCLASSIFICATION: Unequal/Unbalanced error in classifying study subjects in an observational study, based on their exposure or disease status (misclassification related to study subjects disease or exposure status) (See Misclassification). DIGITAL OBJECT IDENTIFIER (DOI): Provides an actionable, interoperable, persistent link to electronic resources; Can be found at www.doi.org to locate articles and other electronically-based documents. DIRECT ENDPOINT: An outcome of a study which is most clinically relevant and useful for patient quality of life/health (e.g., a disease such as death, stroke, MI; or a patient-relevant event, such as hospitalization, prevention of dialysis). This is different from surrogate endpoints (See Surrogate Endpoint). DOUBLE-BLIND: A clinical trial design in which neither the participating study subjects nor the study researchers know which intervention each study participant is receiving; also called double-masked study (See Blinding, Single-Blind, and Placebo). DOI: See Digital Object Identifier. DOUBLE-DUMMY INTERVENTION: Use of two placebos so that each group is receiving more than one intervention at a time. Useful when the two (or more) interventions are customarily administered via different routes (oral, inhaled, injected, rectal, etc…). This reduces the risk of subjects or an investigator knowing which intervention is the “active” intervention and which intervention is the placebo. DSMB: See Data Safety and Monitoring Board. DUMMY INTERVENTION: See Placebo. EFFECT MODIFIER: A 3rd variable that distorts the real, observed relationship (association) between two other variables (e.g., exposure and disease) by varying the relationship (association) within different layers (strata) of this 3 rd variable. (Note: It is this underlined portion that differentiates an Effect Modifier with a Confounder). (See Correlation, Confounder, Strata and Association). EFFICACY ANALYSIS: See Per-Protocol Analysis. ELIGIBILITY CRITERIA: See Inclusion Criteria. ENDEMIC: The occurrence of disease at a level that is constantly and consistently elevated for a given population compared to the occurrence level in other populations/countries. ENDPOINT: A time-point in which a study ends (a date or duration). Outcome variable(s) the study protocol is designed to assess/evaluate (answers research question) (synonymous with study Outcome) (See Outcome, Direct Endpoint, Surrogate Endpoint and Protocol). EPIDEMIC: The occurrence of disease at a level that is clearly in excess of normal expectancy; Interpreted by most as having a larger scope/distribution than an outbreak (See Outbreak). EQUIPOISE: The genuine belief and confidence that an intervention may be worthwhile (risks vs. benefits) if utilized in humans; therefore, the defense for acceptable use in interventional studies. EXCLUSION CRITERIA: Predetermined criteria, set by investigators, that delineate the characteristics that patients may have the will cause them to not be eligible to participate in a clinical study. EXTERNAL VALIDITY: Extent to which results are applicable to other, non-studied, populations who also have the disease/condition being studied. (See Generalizability). GENERALIZABILITY: Taking the results of a study, in which only a sample of the complete study population it utilized, and confer the same results and outcomes to the entire (full) population (external to the study’s sample population). HAWTHORNE EFFECT: Psychological or physiological change simply due to being cared for and managed as part of a study. Commonly considered a reason for any ‘changes’ seen/perceived from use of a placebo (See Placebo and Placebo-Effect). HEALTHY-WORKER EFFECT: A common bias in Cohort studies where study subjects are selected only from the currentlyemployed cohort; excluding all of the existing and past ill/dead subjects who may have been exposed and may have been harmed by disease but are no longer able to be employed (See Bias). HYPOTHESIS: A supposition, assumption, or perspective on which to base the rationale for conducting a research study. A statement of outcome the researcher expects to find from conducting the research study (See Null Hypothesis). INCLUSION CRITERIA: Predetermined criteria set by investigators, which delineates the characteristics that patients need to have to allow them to be eligible to participate in a clinical study. INDUCTION PERIOD: Time interval between exposure which may cause a disease and the onset of the disease (could be undiagnosable at this stage). 36 INFERENTIAL STATISTICS: Use of statistical tests to reach conclusions that extend beyond the immediate data derived from the study’s sample population; using statistics to draw conclusions, generalizations, predictions, and estimations about the general population based on data from samples (See Generalizability). INFORMED CONSENT: The process potential study subjects undergo to learn the key facts (risks, benefits, processes, requirements, costs, compensation, etc…) about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants. To help someone decide whether or not to participate, the doctors and nurses involved in the trial explain the details of the study and document in detail each step of this process. INSTITUTIONAL REVIEW BOARD (IRB): An independent committee of researchers (statisticians, clinicians, non-clinicians, etc…) and non-researchers (community advocates) organized with the sole purpose of ensuring a clinical trial is ethical and that the rights (ethical and legal) and safety of study participants are protected before the study begins. All clinical trials in the U.S. must be approved, prior to study initiation, by an IRB (See Clinical Trial). INTENT-TO-TREAT: Analysis of clinical trial results that includes all data from participants in the groups to which they were randomized (See Randomization) even if they never received the intervention, withdrew from the study or were lost to further follow-up. Considered the most conservative way to manage patients who are lost-to-follow-up (See Lost to Follow-up). Missing data is commonly treated as the last-assessment carried forward for all missed assessments, or use of the study subject’s baseline assessment for all missed assessments going forward. INTERACTION: See Effect Modifier. INTERNAL VALIDITY: Extent to which results accurately reflect the true situation of the study population (study sample). INTERVAL DATA: Data that has magnitude, a fixed, consistent spacing (interval) between all observable points, yet does not have an absolute zero (allows negative values). Adequately described by the descriptive statistics of mean, median and mode (See Ratio Data, Mean, Median and Mode). INTERVENTION: A “treatment” provided to the patient as part of a clinical trial. The treatments may be medications, placebo, device, health program, exercise or other element the study subjects will be asked to undertake. IRB: See Institutional Review Board. KAPPA STATISTIC: A statistical test useful in comparing assessments from two or more raters/evaluators. It looks at “agreement” between multiple opinions/determinations. Statistic varies between +1.0 (perfect agreement) and -1.0 (perfect disagreement). LATENCY PERIOD: Time interval between disease onset of the disease and clinical diagnosis of disease. LEAD-IN PHASE: See Run-In Phase. LOST TO FOLLOW-UP: Patients not completing all aspects of a study, regardless of reason(s). MATCHING: Process of selecting pre-determined patient characteristic(s) used to select and enroll subjects enrolled in different study groups to make them more equal on that key characteristic(s). A key way to control or adjust for confounders (See Confounder). MASKED: See Blinding. MAXIMUM: The highest value in a set of values. MEAN: Average. Calculated by taking the sum of all values and dividing the sum by the total number of values. Useful for describing Interval/Ratio data variables (See Interval Data and Ratio Data). MEDIAN: The middle value of a group of values listed from lowest to highest. Found in an odd number of values by listing all values in the data set from lowest to highest and finding the middle-most value (where there is the same number of values above and below this middle value). Found in an even number of values by listing all values in the data set from lowest to highest and finding the average of the middle two values. Useful for describing Ordinal and Interval/Ratio data variables (See Ordinal Data, Interval Data and Ratio Data). MEDICAL SUBJECT HEADING (MeSH): MeSH is the National Library of Medicine's controlled vocabulary thesaurus. It consists of sets of terms which name descriptors in a hierarchical structure that permits literature searching at various levels of specificity. MeSH descriptors are arranged in an alphabetic and a hierarchical structure. At the basic level of the hierarchical structure, are very broad headings (e.g., "Anatomy" or "Mental Disorders”). More specific headings are found at more narrow levels of the twelve-level hierarchy, (e.g., "Ankle" and "Conduct Disorder”). There are 27,149 descriptors in the current MeSH network. There are also over 218,000 entry terms that assist in finding the most appropriate MeSH Heading, (e.g., "Vitamin C" is an entry term to "Ascorbic Acid”). In addition to these headings, there are more than 219,000 headings called Supplementary Concept Records (formerly Supplementary Chemical Records) within a separate thesaurus. MeSH: See Medical Subject Heading. MINIMUM: The lowest value in a set of values (dataset). MISCLASSIFICATION: Error in classifying study subjects in an observational study in terms of exposure status or disease status. The two common types of misclassification are Differential and Non-Differential (See Differential Misclassification and Non-Differential Misclassification). 37 MODE: The most common value in a set of values. Useful for describing Nominal, Ordinal, and Interval/Ratio data variables (See Nominal Data, Ordinal Data, Interval Data and Ratio Data). NECESSARY CAUSE: A condition/event which must be present prior to the onset of disease for the disease to occur yet may also be present without causing the disease (See Causal Association). In other words, if disease occurs then the necessary cause must have been present prior to the onset of disease, but just because the cause is present doesn’t necessary mean that disease will absolutely occur (e.g., Mycobacterium tuberculosis and Tuberculosis disease). NOMINAL DATA: Data that has does not have magnitude. Classically represented by categories that do not express magnitude. Adequately described by the descriptive statistics of mode (See Mode). NON-CAUSAL ASSOCIATION: A relationship or connection in which the disease induces the exposure (rather than the exposure inducing the disease) or from a confounding variable (See Association and Confounder). NON-DIFFERENTIAL MISCLASSIFICATION: Equal and balanced error in classifying study subjects in an observational study, regardless of exposure or disease status (misclassification unrelated to study subjects disease or exposure status) (See Misclassification). NON-PARAMETRIC DATA: Data which is not known to meet the criteria for parametric data. Non-parametric data does not have a normal distribution, is not randomly or independently obtained, does not contain equal variances between groups, and is not adequately described by a mean, median and mode. (See Parametric Data, Mean, Median, Mode, Randomization & Sampling and Variance). NON-PROBABILITY SAMPLING: A sample obtained without a non-zero probability of inclusion in the study. An example is Convenience Sampling (just taking the first 20 people you come in contact with or willing to participate) NULL HYPOTHESIS: Perspective taken by researchers at the start of human studies that there will be no difference between the study groups. At the conclusion of the study, the researchers use the outcome data to either accept this perspective or reject it because they found a statistically significant difference between groups (See Statistically Significant). OPEN-LABEL: A clinical trial in which all participants (study researchers, clinicians, and subjects) know which intervention is being administered to each study subject. ORDINAL DATA: Data that has magnitude, yet does not have a fixed, consistent spacing (interval) between all observable points. Classically represented by categories/ranges that express magnitude. Adequately described by the descriptive statistics of median and mode (See Median and Mode). OUTBREAK: The increase in occurrence of a disease (epidemic) that is limited in time and scope/distribution (local) (See Epidemic). OUTCOME: A variable (assessment) which answers the study purpose/intent (answers a research question). Outcomes can either be Primary, Secondary, Tertiary, or Composite. (See Primary Outcome, Secondary Outcome and Composite Outcome). PANDEMIC: The occurrence of disease at a level that is clearly in excess of normal expectancy and that is also very widespread; classically across multiple countries/continents. PARAMETRIC DATA: Data which is known to have a normal distribution, randomly and independently obtained, contain equal variances between groups, and is adequately described by a mean, median and mode. (See Mean, Median, Mode, Randomization & Sampling and Variance). PER-PROTOCOL ANALYSIS (a.k.a. EFFICACY ANALYSIS): Analysis of clinical trial results that includes only the data from participants that completed a pre-determined percentage/fraction (e.g., 80%) of the study’s requirements (treatments, evaluations, followup, etc…) (See Randomization). It ignores the data collected to date on the patients that never received their assigned intervention, withdrew from the study, or were lost to further follow-up before the study was completed. PHASE 1 TRIAL: A clinical study conducted in a small number (10-30) of health individuals to determine the pharmacokinetics/pharmacology and short-term safety of an intervention. PHASE 2 TRIAL: A clinical study conducted in a slightly larger number of diseased subjects (compared to Phase 1 studies; 50-150) to determine the effectiveness and short-term safety of an intervention. PHASE 3 TRIAL: A clinical study conducted in an even larger number of diseased subjects (compared to Phase 1 & 2 studies; 150300+) to determine the effectiveness and short-to-intermediate-term safety of an intervention. This phase is intended to gather additional information in a larger diseased population (over the Phase 2 study) to evaluate the overall benefit-risk relationship of the intervention and is required by the FDA for intervention approval/labeling. PHASE 4 TRIAL: Also called Post-Marketing trial and is a clinical interventional study or documentation registry (observational data collection), conducted after a drug is approved by the FDA and marketed/sold by one or more companies. Post-marketing (Phase 4) studies are customarily utilized to delineate additional information including the drug's longer-term risks, benefits, and optimal use when used in a very large population. PLACEBO: A placebo is an inactive ingredient administered in any form (tablet, capsule, liquid, inhalation, etc…) that has no known/inherent interventional value. In clinical trials, interventions are often compared with a placebo to assess the intervention's effectiveness. (See Placebo-Controlled). PLACEBO CONTROLLED: A study in which a placebo is utilized (See Placebo). 38 PLACEBO EFFECT: A physical or emotional change derived from the use of a placebo. Due to the power of suggestion or the Hawthorne Effect (See Hawthorne Effect) POWER: The ability of a study to detect a true difference between group measurements if one actually exists (See Sample Size). PRE-CLINICAL: Refers to the testing of experimental interventions (medications, techniques, materials, etc…) in the test tube or in animals - testing that occurs in before trials in humans are carried out. PRIMARY OUTCOME: The main purpose of the study. It is what the researchers consider the most important element to assess/evaluate from the study. PRIMARY PREVENTION: An intervention used to prevent a disease from occurring (before it occurs or becomes established). PROBABILITY SAMPLING: A sample obtained with a known, non-zero probability of inclusion in the study. Examples include Simple Random Sampling (e.g., using random number generator), Systematic Sampling (e.g., using all persons who last name begins with “M”) and Stratified Sampling (e.g., random sampling by layers (strata) of a given variable (e.g., age, disease severity, etc…)) (See Strata, Sampling and Randomization) PROPORTION: The division of two numbers that are related (i.e., the numerator is a part, or subset, of the denominator). PROSPECTIVE: Forward looking for study outcome (e.g., disease, as assessed in a Cohort study). At the time of study initiation, the outcome (disease) is not known. All clinical trials are prospective in nature. Cohort studies can also be conducted retrospectively. CaseControl studies are always considered retrospective (See Retrospective). PROTOCOL: A procedural plan-of-action on which all studies are based, planned and conducted. The plan is carefully designed describe exactly how the study will be conducted and how the researchers plan to strive to answer specific research questions. A protocol describes what types of people may and may not participate in the study (inclusion/exclusion criteria); the schedule of tests/procedures/medications and their related protocols/instructions; and the length of the study (including post-study follow-up) (See Inclusion Criteria and Exclusion Criteria). RANDOMIZATION: A method of study subject allocation based on a known probability for study group selection. The goal/purpose of the randomization process is to make all study groups as equal as possible (in number and characteristics) and to reduce the occurrence of confounding/bias. Examples of the types of randomization include Simple Randomization, Blocked Randomization, and Stratified Randomization (See Simple Randomization, Blocked Randomization and Stratified Randomization). RANDOMIZED TRIAL: A study in which participants are randomly assigned, with a known probability of selection, to one of the study groups (arms) of a clinical trial. (See Randomization). RANGE: The difference (subtraction) between the lowest value and the highest value in a set of values. RATE: The division of two numbers with time as an element of the denominator. RATIO: The division of two numbers that are unrelated (i.e., the numerator is not a part, or subset, of the denominator). RATIO DATA: Data that has magnitude, a fixed, consistent spacing (interval) between all observable points and contains an absolute zero. Adequately described by the descriptive statistics of mean, median and mode (See Mean, Median and Mode). RECALL BIAS: A difference in the way study subjects in the different study groups recall information which has occurred in the past (See Bias). RETROSPECTIVE: Backward looking for study outcome (e.g., exposure, as assessed in a Case-Control study or disease, as assessed in a Cohort study). At the time of study initiation, patient disease status is already known but is not the primary focus of the observational study. Case-Control studies are always considered retrospective. Cohort studies are either retrospective (disease status already known at time of study initiation (yet being a Cohort study, the subjects will initially be divided based on exposure status) or prospective (disease status (outcome) not yet known at start of study) (See Prospective). RESTRICTION: Pre-set patient characteristics set by researchers which will not be allowed to participate in a study. A key way to control or adjust for confounders (See Exclusion Criteria and Confounder). RISK FACTOR: See Component Cause. RUN-IN PHASE: The pre-defined time period prior to the start of the official interventional stage of a clinical study in which participants are asked to limit, reduce or eliminate certain interventions or practices in order to determine a intervention-free (new) baseline. Many studies utilize one or more placebo interventions during this phase to determine if the study subject can be compliant with the study requirements prior to the start of the more important (“real”) intervention phase under study (Synonymous with Lead-In Phase). SAMPLE: A number of individuals selected from all of the subjects in a particular group (population) (See Sampling, Probability Sampling and Non-Probability Sampling). SAMPLE SIZE: The total number of individuals needed/selected for a study (See Sample and Power). SAMPLING: The process of selecting a pre-determined number of individuals from all of the subjects in a particular group (population) (See Probability Sampling and Non-Probability Sampling). The goal of sampling is to draw a representative smaller number of study subjects from the full, total population being studied. 39 SECONDARY PREVENTION: An intervention used to interrupt/minimize a disease process from progressing, more symptomatic or from reoccurring. SECONDARY OUTCOME: An evaluation that is not considered the most important element to assess/evaluate from the study (See Primary Outcome), but is none-the-less still evaluable and useful to address/evaluate. SELECTION BIAS: A non-equitable, non-balanced difference between study groups in the way study subjects are selected by the researcher for study participation (See Bias). This bias could also be due to actions of the study subject (called Self-Selection bias). SELF-SELECTION BIAS: A non-equitable, non-balanced difference between study groups in the way study subjects determine their interest in study participation (See Bias). SIMPLE RANDOMIZATION: See Randomization. SINGLE-BLIND: A study that classically keeps the study subject unaware of what intervention the participant is receiving; also called single-masked study (See Blinding and Double-Blind). STANDARD DEVIATION (SD): One way to represent the spread of a data set and is calculated by taking the square root of the variance (See Variance). STATISTICAL SIGNIFICANCE: The probability that an event or difference occurred by chance alone; also interpreted as the probability of making a Type 1 error if the null hypothesis is rejected (See Null Hypothesis and Type 1 Error). STRATA: Layers or levels (categories) of a given variable or patient characteristic. STRATIFIED RANDOMIZATION: A randomization process that attempts to assure balance in the number of study subjects within individual layers/levels (categories) on pre-determined variable(s) or patient characteristic(s). Useful in controlling for possible confounders (e.g., Gender (Male/Female), Disease severity (Low/Moderate/High), etc…). (See Randomization and Strata). SUFFICIENT CAUSE: A set of minimum conditions/events required to be present to inevitably produce disease (See Causal Association). In other words, if disease occurs then the sufficient cause must have been present prior to the onset of disease, and if the cause is not present the disease will not occur (e.g., homozygous gene alterations and Tay-Sachs disease). SURROGATE ENDPOINT: An outcome of a study which is an alternative to detecting disease and may be less clinically relevant and useful for patient quality of life/health, but useful as a substitute (alternative) for disease or other patient-relevant outcomes. Examples include cholesterol level, blood pressure, or serum creatinine. These are considered different from direct endpoints (See Direct Endpoint). TYPE 1 ERROR: Incorrectly rejecting the null hypothesis when in fact there really is no difference between the groups and it should have been accepted (See Null Hypothesis). TYPE 2 ERROR: Incorrectly accepting the null hypothesis when in fact there really is a difference between the groups and it should have been rejected (See Null Hypothesis). VALIDITY: The quality of being factually sound (accurate); the extent to which a concept, conclusion or measurement is well-founded and corresponds accurately to the real world; “Determining the Truth” (See Internal Validity and External Validity). VARIANCE: One way to represent the spread of a data set and is calculated by finding the difference in each individual value and the mean value of the group/data set, adding these differences together and then dividing by the number of values in the data set (See Mean). WASH-OUT: The period of time during a clinical, interventional study in which study subjects have their initially-assigned intervention stopped. This time period allows the effects of the initial intervention to be eliminated, after which the study subjects are then given an alternative intervention and its affects assessed (See Cross-Over Study). 40 Exposure Outcome Yes No Total Yes No Total Exposure Outcome Yes No Total Yes No Total Exposure Outcome Yes No Yes No Total 41 Total Test Disease Present Absent Total Positive Negative Total Test Disease Present Absent Total Positive Negative Total Test Disease Present Absent Positive Negative Total 42 Total Data Type NOMINAL 2 Groups Independent Related ≥3 Groups Independent Proportion of Events (Survival) Related Log-Rank (Pearson’s) Chi-square Fisher’s Exact McNemar Chi-square Fisher’s Exact Bonferroni test of Inequality 43 Cochran Measure of Correlation Prediction or Association Contingency Coefficient Logistic Regression Data Type ORDINAL 2 Groups Independent Related ≥3 Groups Independent Proportion with Event (Survival) Related Cox Proportional Hazards MannWhitney Wilcoxon Signed Rank KruskalWallis Friedman Student-Newman-Keul Dunnett Dunn 44 Measure of Correlation Prediction or Association Spearman Correlation Multinomial Logistic Regression Data Type INTERVAL 2 Groups ≥3 Groups Independent Independent Related Student t or ANOVA or MANOVA Paired t or Repeated Measures ANOVA or Repeated Measures MANOVA NonParametric Alternative MannWhitney NonParametric Alternative Wilcoxon Signed Rank ANOVA or MANOVA Non-Parametric Alternative Kruskal-Wallis If Confounder is present ANCOVA or MANCOVA Bonferroni t or Tukey or Scheffe or Dunn or Student-Newman-Keul or Dunnett Time to Event or Survival Measure of Correlation Kaplan-Meier product-limit estimate Pearson Correlation NonParametric Alternative Cox Proportional Hazards NonParametric Alternative Spearman Correlation Related Repeated Measures ANOVA or Repeated Measures MANOVA NonParametric Alternative Friedman If Confounder is present Repeated Measures ANCOVA or Repeated m45 easures MANCOVA Membership Prediction or Association Linear Regression NonParametric Alternative (Multinomial) Logistic Regression Is the data Nominal? Figure 1 No Do you wish to check for correlation? Yes No Do you wish to assess for associations or predict group membership? No Yes Log Rank Yes Logistic Regression How many groups? 2 Are groups or their assessments independent Yes Does any cell have an expected frequency of <5? No Chi-square Yes No Yes Contingency Coefficient Do you wish to assess for proportion to event (survival)? Do you wish to compare frequencies or proportions? Report Results ≥3 No Does any cell have an expected frequency of <5? Chi-square No 46 Is test significant? No Is the Data Interval? Yes Go to Figure 3 No Yes McNemar Fisher’s Exact Go to Figure 2 Are groups or their assessments independent? No Yes Yes Is the Data Ordinal? Cochran Yes Fisher’s Exact Yes Bonferroni test of Inequality Is the data Ordinal? Figure 2 No Do you wish to check for correlation? No Do you wish to assess for proportion with event (survival)? Yes Yes Spearman Correlation Cox Proportional H a z a r ds Do you wish to assess for associations or predict group membership? Do you wish to compare frequencies or proportions? No Yes No No Is the Data Nominal? Yes How many groups? Yes Multinomial Logistic Regression 2 Are groups or their assessments independent? Yes MannWhitney No Wilcoxon Signed Rank Yes KruskalWallis Yes Student-Newman-Keul Dunnett Dunn 47 Go to Figure 1 No Yes Yes Go to Figure 3 ≥3 Are groups or their assessments independent? Is the Data Interval? Friedman Is test significant No Report Results Figure 3 No Do you wish to assess for a correlation? Yes Pearson Correlation No Do you wish to assess for associations or predict group membership? No Linear Regression Yes No Are groups or their assessments independent? Paired t [or Repeated Measures ANOVA or Repeated Measures MANOVA] No ANOVA; IF Confounding is present use ANCOVA Yes Is there >1 DV? MANOVA; IF Confounding is present use MANCOVA Is test No significant? 48 Go to Figure 1 Is there >1 DV? No Yes Report Results Is the Data Nominal? Yes No Yes Student t [or ANOVA or MANOVA] Yes Go to Figure 2 ≥3 No Yes Is the Data Ordinal? No How many groups? Are groups or their assessments independent? Bonferroni t Tukey Scheffe Student-Newman-Keul Dunnett Dunn No Is data normally distributed? 2 Yes Is the data Interval? Yes Yes Do you wish to assess for time to event or survival? Kaplan-Meier product-limit estimate Do you wish to compare means? Yes Repeated Measures ANOVA; IF Confounding is present use Repeated Measures ANCOVA Yes Repeated Measures MANOVA; IF Confounding is present use Repeated Measures MANCOVA Data Type NOMINAL 2 Groups Independent Related ≥3 Groups Independent 49 Proportion of Events (Survival) Related Measure of Correlation Prediction or Association Data Type ORDINAL 2 Groups Independent Related ≥3 Groups Independent Related 50 Proportion with Event (Survival) Measure of Correlation Prediction or Association Data Type INTERVAL 2 Groups ≥3 Groups Independent Independent Measure of Correlation Membership Prediction or Association NonParametric Alternative NonParametric Alternative NonParametric Alternative Related Non-Parametric Alternative NonParametric Alternative Related Time to Event or Survival NonParametric Alternative NonParametric Alternative If Confounder is present If Confounder is present 51 Is the data Nominal? Figure 1 No Do you wish to assess for associations or predict group membership? No 2 Yes How many groups? Are groups or their assessments independent No Yes Yes No Report Results No No 52 Go to Figure 2 ≥3 Does any cell have an expected frequency of <5? Is test significant? Is the Data Ordinal? No Is the Data Interval? Yes No Yes No Yes Yes Are groups or their assessments independent? Does any cell have an expected frequency of <5? No Yes Yes Yes Do you wish to check for correlation? Do you wish to assess for proportion to event (survival)? Do you wish to compare frequencies or proportions? Yes Yes Go to Figure 3 Is the data Ordinal? Figure 2 No No Do you wish to check for correlation? Do you wish to assess for proportion with event (survival)? Do you wish to assess for associations or predict group membership? Do you wish to compare frequencies or proportions? No Yes No No Is the Data Nominal? Yes How many groups? Yes 2 Yes Are groups or their assessments independent? Yes Yes No Yes Go to Figure 1 No Yes Yes Is test significant No Report Results 53 Yes Go to Figure 3 ≥3 Are groups or their assessments independent? Is the Data Interval? Figure 3 No Do you wish to assess for a correlation? Do you wish to assess for associations or predict group membership? Do you wish to compare means? No Is the data Interval? No Yes Is data normally distributed? Yes Yes Yes No 2 Are groups or their assessments independent? Do you wish to assess for time to event or survival? Are groups or their assessments independent? Is there >1 DV? Yes Is test No significant? 54 Yes Report Results Go to Figure 1 Is there >1 DV? No Is the Data Nominal? Yes No Yes No Yes Go to Figure 2 ≥3 No Yes Is the Data Ordinal? No How many groups? No Yes Yes Yes Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May 22 8:00—9:00 a.m. New and Emerging Strategies for the Treatment of Advanced Melanoma R. Donald Harvey, PharmD, FCCP, BCOP 0204-0000-15-413-L01-P 1 contact hour (0.1 CEU) Please see the following pages for educational materials for this activity and instructions on how to receive credit. This activity is planned and conducted by ASHP Advantage and supported by an educational grant from Merck. 55 New and Emerging Strategies for the Treatment of Advanced Melanoma LSHP Annual Meeting 2015 – New Orleans, LA – May 22, 2015 Planned and conducted by ASHP Advantage and supported by an educational grant from Merck 56 Activity Overview According to the National Cancer Institute and the American Cancer Society, over 75,000 people will be diagnosed with melanoma in the United States in 2014, with 9710 deaths. The increasing number of people in the US over 65 along with longer life expectancy generally will lead to greater numbers of patients diagnosed with melanoma over the coming decade. Although knowledge about prevention of melanoma has become more prevalent, death due to advanced disease has doubled over the past 30 years. Inevitably, the aging US population and improvement in treatments will increase the number of patients with melanoma and present new challenges. A number of novel treatments have been approved and are in development for patients with melanoma. Oral agents that target molecular drivers of the disease have produced robust response rates, however, they come with a number of challenges for patients and providers, specifically drug interactions, food effects, and unique side effects. Along with new oral agents, drugs that activate the immune system have also been approved for use, with impressive activity. These agents also have specific adverse event profiles that all pharmacists should be familiar with. Faculty will discuss current agents and regimens used to treat melanoma, highlighting recently approved agents and treatment controversies. Management principles and key resources for pharmacists will also be discussed. Learning Objectives At the conclusion of this application-based educational activity, participants should be able to • • • • • Review the pathophysiology of BRAF-mutant melanoma. Design a first- line therapeutic plan for a patient who has BRAF-mutated metastatic melanoma. Compare and contrast the mechanism of action and toxicity profile of interleukin 2, ipilimumab, and pembrolizumab. Describe common adverse effects associated with immunotherapy as well as strategies for managing them. Discuss future directions in the treatment of melanoma therapy with regard to treatment options and tumor genomic sequencing. Continuing Education Accreditation The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #02040000-15-413-L01-P). Participants will process CPE credit online at http://elearning.ashp.org/my-activities, with the option of printing a CE certificate. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity. 57 New and Emerging Strategies for the Treatment of Advanced Melanoma Activity Faculty R. Donald Harvey, Pharm.D., FCCP, BCOP Associate Professor, Hematology/Medical Oncology Director, Phase 1 Clinical Trials Section Winship Cancer Institute Emory University Atlanta, Georgia R. Donald Harvey, Pharm.D., FCCP, BCOP is Director, Phase 1 Clinical Trials Section at Winship Cancer Institute of Emory University and Associate Professor, Department of Hematology and Medical Oncology at the Emory University School of Medicine in Atlanta, Georgia. Dr. Harvey also serves as Co-chair of the Data Safety and Monitoring Committee and as a Pharmacology representative on the Clinical and Translational Research Committee for the cancer center, as well as preceptor for the Emory PGY-2 oncology residency. He received his Bachelor of Science in Pharmacy and Doctor of Pharmacy degrees from the University of North Carolina (UNC) in Chapel Hill. He subsequently completed a pharmacy practice residency at the University of Kentucky Medical Center and College of Pharmacy and a Hematology/Oncology specialty residency at UNC Hospitals and School of Pharmacy. Dr. Harvey is a board certified oncology pharmacist and a fellow of the American College of Clinical Pharmacy (ACCP). He has authored or co-authored over 40 peer-reviewed publications, and is section editor for original research for the Journal of Hematology Oncology Pharmacy. He serves as a reviewer for the British Journal of Cancer, Journal of Pharmaceutical and Biomedical Analysis, Cancer, Annals of Oncology, Pharmacotherapy, and the Journal of Clinical Pharmacology. Dr. Harvey was President of the Hematology/Oncology Pharmacy Association (HOPA) from 2010-2013 and now serves as Vice Chair of the HOPA Research Foundation. 358 Disclosure Statement In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations. All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity. • The faculty and planners report no financial relationships relevant to this activity. 59 Disclosures New and Emerging Strategies for the Treatment of Advanced Melanoma • The faculty and planners report no financial relationships relevant to this activity. R. Donald Harvey, Pharm.D., FCCP, BCOP Associate Professor, Hematology/Medical Oncology Director, Phase 1 Clinical Trials Section Winship Cancer Institute Emory University Atlanta, Georgia Planned and conducted by ASHP Advantage and supported by an educational grant from Merck Learning Objectives At the conclusion of this activity, participants should be able to • Review the pathophysiology of BRAF‐mutant melanoma. • Design a first‐line therapeutic plan for a patient who has BRAF‐mutated metastatic melanoma. • Compare and contrast the mechanism of action and toxicity profile of interleukin 2, ipilimumab, and pembrolizumab. • Describe common adverse effects associated with immunotherapy as well as strategies for managing them. • Discuss future directions in the treatment of melanoma therapy with regard to treatment options and tumor genomic sequencing. Pathophysiology of Melanoma and Drug Approval Risk Factors Melanoma Epidemiology • UV Radiation • Previous sunburns • 3% of skin cancer cases – 80% of skin cancer deaths • • • • – > 4 severe by 15 yr ~60,000 new US cases each year ~8,000 will die High cure rates if treated early 14% of patients with metastatic melanoma have 5‐year survival rate • Outdoor lifestyles • • • • • • • • Miller AJ et al. N Engl J Med. 2006; 355: 51-65. Age Male Gender Past hx of melanoma Xeroderma pigmentosum Dysplastic nevi Fair skin Family History of melanoma Immunosuppressed Miller AJ et al. N Engl J Med. 2006; 355: 51‐65. 60 ABCDEs of Melanoma Patient Presentation A B C D E • Median Age of diagnosis 45‐55 years • Diagnosis at presentation – 82‐85% present with localized disease – 10‐13% regional disease – 2‐5% with metastatic disease Evolution of existing mole www.skincancer.org accessed 2014 October 30 2014. Miller AJ et al. N Engl J Med. 2006; 355: 51‐65. Further Work Up Biopsy • History and physical exam • Further dermatologic examination indicating other lesions • >1mm thick • Indicated for a suspicious lesion • Full thickness excisional biopsy with 1‐3mm margins into normal skin – Not always feasible (i.e. face, feet, large lesions) – Full thickness incisional biopsy or punch – Baseline CXR and LFTs • Lactate dehydrogenase (LDH) • Suspected lymph node involvement confirmation • Radiographic evaluation at baseline based on site of symptoms Lymph Node Involvement Clark Level • Important prognostic factor • Complete lymph node dissection • How deep the tumor has penetrated base histology • Directly related to risk of metastasis to nodes • Level I‐V – Labor intensive – Unable to stain every section of node and may miss area showing metastasis – Level I is restricted to epidermis (in situ) – Level V is metastatic • Only 20% of patients with an intermediate thickness regional nodal involvement – 80% are at risk for a bad outcome from the complete dissection of the LN • Sentinel LN = First node that melanoma spreads to – Melanoma follows an orderly nodal distribution Morton DL et al. Ann Surg. 2005; 242: 302‐313. 61 Breslow Thickness Staging and 5 Year Survival Rates • A: < 1mm thick, no ulceration, Clark II‐III • B: < 1 mm thick with ulceration, Clark IV‐V • Similar to Clark level but uses a micrometer to measure tumor invasion through a microscope • 0.75 mm (Clark Level II) • > 0.75 ‐ 1.5 mm (Clark Level III) • > 1.5 ‐ 4.0 mm (Clark Level IV) • > 4.0 mm (Clark Level V) Stage I • 5yr OS: 90‐95% • > 1 mm thick with any characteristic Stage II • 5yr OS: 45‐78% • Lymph node involvement Stage III • 5yr OS: 28‐70% (depends on # of nodes) • Metastatic Disease Stage IV • 5yr OS: 18% (though may be increasing) http://training.seer.cancer.gov/module_staging_cancer/unit03_sec04_part05_melanoma.html Melanoma Molecular Subsets Immunotherapy and Targeted Treatment and Future of Melanoma Treatment Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved. Sosman, J: 2011 Education Book American Society of Clinical Oncology 2011: 367-72. Treatment Overview Stage I or II Cancer and Immune Evasion Surgical removal and observation • Individual cells and tumors have capacity to avoid immune surveillance from early in development • Methods used Surgical removal and observation Stage III Lymph Node Positive Diagnosis – Production of immunosuppressive cytokines (e.g., TGF‐β, IL‐4, IL‐6, IL‐10) – Increase number and function of immune suppressor cells (e.g., macrophages, regulatory T cells [Tregs] – Changes in cell signaling that leads to cancer cell death (e.g., increased IDO, reduced MHC receptors) – Limit immune effectors and create inhibitory checkpoints Surgical removal and IFN If BRAF positive, vemurafenib, dabrafenib +/‐trametinib or immunotherapy or trial Stage IV Metastatic If BRAF negative, Ipilimumab first line, HD‐IL2, or trial IFN=interferon HD-IL2=high-dose interleukin-2 IDO=indoleamine 2,3-dioxygenase MHC=major histocompatibility complex NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2015. NCCN.org http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.Accessed November 2014. 62 Current Immunotherapies in Melanoma General Immunotherapy Approaches • Active • Direct immune stimulation – Vaccination – Interleukin‐2 (IL‐2) used for metastatic disease – Interferon alfa‐2B (IFN) for adjuvant therapy • Autologous • Allogenic • Inhibition of immune checkpoints – Cytokines • Interferon, interleukin‐2, GM‐CSF, denileukin diftitox – Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) • Passive • Ipilimumab approved for metastatic melanoma in 2011 – Conventional naked (e.g., rituximab) and loaded (e.g., ado‐trastuzumab emtansine) monoclonal antibodies – Programmed cell death protein 1 (PD‐1) receptor • Pembrolizumab approved for patients who failed ipilimumab in 9/4/2014 • Nivolumab approved for same indication 12/22/2014 • Passive leading to active – Ipilimumab, pembrolizumab, nivolumab HD IL‐2 Therapy: Durable Responses • • • Metastatic Melanoma (N = 270) 0.8 0.6 0.4 0.2 0.0 0 • High‐dose IL‐2 benefits patients, but: – Toxic – Impractical: must be delivered as an inpatient • Use remains limited to selected patients treated at experienced centers • Efforts to develop more tolerable IL‐2 based regimens unsuccessful • Efforts to better select patients who might benefit from HD IL‐2 therapy have produced modest advances • Proof of principle that immunotherapy can produce durable benefit in patients with solid tumor malignancies Metastatic RCC (N = 255) 1.0 CR (n = 17) PR (n = 26) CR + PR (n = 43) 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of Response (Months) Probability of Continuing Response 1.0 CR PR All 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Duration of Response (Months) Atkins MB et al. J Clin Oncol. 1999;17:2105‐2116. McDermott DF et al. Expert Opin Biol Ther. 2004;4:455‐468. Ipilimumab in Metastatic Melanoma: Durable Survival Comparison of CTLA‐4 vs PD‐1 CTLA‐4 pathway PD‐1 pathway Exclusively on T cells On T, B, and NK cells Ligands: CD80 and CD86 Ligands: PD‐L1 and PD‐L2 Ligands only expressed on APCs Ligand expressed on APCs and tumor cells CTLA‐4–deficient mice suffer early, fatal autoimmune syndrome PD‐1–deficient mice develop strain‐specific autoimmunity late in life Previously Treated Patients Median OS, Mos Ipi + gp100 10.0 Ipi 10.1 gp100 6.4 100 Previously Untreated Patients HR P Value 0.68 < .001 0.66 .003 80 60 40 Blockade enhances CD8+ T cells greater than Blockade enhances proliferation of CD4+ and CD8+ T cells with increase in ratio to regulatory CD4+ with increase of CD8+ to Tregs and T cells cytotoxicity of CD8+ 20 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Ipilimumab + dacarbazine Placebo + dacarbazine 40 20 Ipilimumab + gp100 vs OS=Overall survival 0 4 8 12 16 20 24 28 32 36 40 44 48 Mos Mos Greenwald RJ et al. Ann Rev Immunol. 2005; 23:515-548. Chambers CA et al. Ann Rev Immunol. 2001;19:565-594. Dong H et al. Nat Med. 2002; 8:793-800. Curran MA et al. Proc Natl Acad Sci U S A. 2010; 107:4275-80. Pilon-Thomas S et al. J Immunol. 2010;184:3442-3449. 80 0 0 APC=antigen presenting cells Est 1, 2, 3-Yr P Median Survival, % OS, Mos HR Value 47.3, 28.5, 20.8 0.72 < .001 11.2 Ipi + D 36.3, 17.9, 12.2 Placebo + D 9.1 100 Patients Survival (%) Probability of Continuing Response HD IL‐2 Therapy in Melanoma and RCC HD IL‐2 produces durable responses in 6% to 10% of patients with advanced melanoma or renal cell carcinoma (RCC) Few relapses in patients responding for over 2.5 years (therefore, can be considered cured) FDA approval in 1992 (RCC) and 1997 (melanoma) gp100[1] Ipilimumab vs Placebo[2] Adapted from Hodi FS et al. N Engl J Med. 2010; 363:711-723. Robert C et al. N Engl J Med. 2011;364:2517-2526. 63 Ipilimumab: Immune‐Related Adverse Events System GI tract Skin Symptoms Management Diarrhea Abdominal pain Dark, bloody stools Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory patients Rash (± itching) Blistering/peeling Oral sores Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids Jaundice Nausea/vomiting Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory patients Weakness in extremities Numbness/tingling Sensory changes Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the patient Liver CNS Endocrine Eyes Vision problems Irritation Ipilimumab Adverse Effects #2 #3 #4 Monitor for redness suggesting uveitis, treat with topical steroidal eye drops Ipilimumab adverse reaction management guide. Available at: http://hcp.yervoy.com/pages/rems.aspx. Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved. Weber JS et al. J Clin Oncol. 2012; 30:2691-7. CTLA‐4 and PD‐1 Pathways Nivolumab Phase I Trial Design Phase 1 Dose Escalation of anti-PD-1 antibody N=296 patients Melanoma (n = 104) NSCLC (n = 122) Renal cell carcinoma (n = 34) Prostate cancer (n = 17) Colorectal cancer (19) BMS-936558 All patients had a ECOG performance status of < 2 and measurable disease Ipilimumab 0.1 to 10 mg/kg IV every 2 weeks for up to 12 cycles or until disease progression or complete response where therapy could continue Tumor samples analyzed for PD-L1 expression using immunohistochemistry (IHC) • Cohorts of 3‐6 patients enrolled in each cohort – 0.1, 0.3, 1.0, 3.0, and 10 mg/kg • Expansion groups enrolled after no maximum tolerated dose was found Nivolumab Pembrolizumab Brahmer JR. J Clin Oncol. 2013; 31:1021-8. Topalian S et al. N Engl J Med. 2012; 366:2443-54. Selected Toxicity Summary of Results Toxicity • Antitumor activity was seen at all dose levels • Objective response rate (complete or partial) – 28% in melanoma – 27% in renal cell carcinoma – 18% in NSCLC • 65% of the responses were durable for 1 year or more in patients with > 1 year follow up • IHC staining for PD‐L1 predicted response rate Anti‐PD‐1 Antibody all dose levels All grade Grade 3 and 4 Diarrhea 11% 1% Infusion reaction 3% 1% Hypothyroidism 2% 1% Increased AST 4% 1% Pneumonitis 3% 1% (3 deaths) Skin Toxicity – 0 of 17 responses in PD‐L1 negative tumors – 9 of 25 responses in PD‐L1 positive tumors Topalian S et al. N Eng J Med. 2012; 366:2443-54. Rash 12% 0% Pruritus 29% 1% Vitiligo 8% 0% Urticaria 2% 0% Topalian S et al. N Eng J Med. 2012; 366:2443-54. 64 Clinical Development of Inhibitors of the PD‐1 Immune Checkpoint Target PD‐1 Antibody Molecule Development Stage Nivolumab (BMS‐936558) Fully human IgG4 Approved Pembrolizumab (MK‐3475) Humanized IgG4 Approved Pidilizumab (CT‐011) Humanized IgG1 BMS‐936559 Fully human IgG4 MedI‐4736 Engineered human IgG1 Phase I MPDL‐3280A Engineered human IgG1 Phase I‐II PD‐L1 Activity of Anti‐PD‐1/PD‐L1 in Patients With Advanced Melanoma 6‐Mo PFS, % 12‐Mo PFS, % Median PFS, Mos 1‐Yr OS, % 2‐Yr OS, % 41 36 3.7 62 43 NA NA > 7 81 NA Pts, n ORR (at Optimal Dose), % Grades 3/4 Tx‐Related AEs, % Nivolumab (anti‐PD‐1)[1‐3] 104 31 (41) 22 Pembrolizumab (anti‐PD‐1)[4,5] 135 38 (52) 13 Phase II multiple tumors BMS 936559 (anti‐PD‐L1)[6] 55 17 5 NA NA NA NA NA Phase I MPDL3280A (anti‐PD‐L1)[7] 44 29* 36 43 NA NA NA NA Agent *Includes 4 patients with UM without a response. 1. Topalian SL et al. J Clin Oncol. 2014; 32:1020-30. 2. Sznol M et al. ASCO 2013. Abstract 9006. 3. Topalian SL et al. N Engl J Med. 2012; 366:2443-54. 4. Ribas A et al. ASCO 2013. Abstract 9009. 5. Hamid O et al. N Engl J Med. 2013; 369:134-44. 6. Brahmer JR et al. N Engl J Med. 2012; 366:2455-65. 7. Hamid O et al. ASCO 2013. Abstract 9010. Nivolumab + Ipilimumab: Phase I Study Comparison of Anti‐PD‐1 Agents FDA Approval Date Type of Antibody Approved Dosing Dose forms Approved Indication Pembrolizumab Nivolumab September 4, 2014 December 22, 2014 Humanized, , IgG4 kappa immunoglobulin Human, IgG4 kappa immunoglobulin 2 mg/kg over 30 minutes every 3 weeks 3 mg/kg IV over 60 minutes every 2 weeks 50 mg lyophilized powder in single use vial and 100mg/4mL solution in single use vial 40 mg/4mL and 100 mg/10mL solution in single‐use vial • Concurrent therapy study design: Patients with stage III or IV melanoma with ≤ 3 previous therapies (n = 53) Weeks 0-9 Ipilimumab + Nivolumab q3w x 4 cycles Weeks 24-108 Ipilimumab + Nivolumab q12w x 8 cycles Weeks 12-21 Nivolumab q3w x 4 cycles Escalating doses of nivolumab (0.3‐10 mg/kg) and ipilimumab (1‐10 mg/kg) • Sequenced therapy study design Patients with stage III or IV melanoma with ≥ 3 previous doses of ipilimumab (n = 33) FDA accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Nivolumab (1 or 3 mg/kg) q2w for up to 48 doses Wolchok JD et al. N Engl J Med. 2013; 369:122-33. Wolchok JD et al. ASCO 2013. Abstract 9012. Nivolumab + Ipilimumab Adverse Events Nivolumab + Ipilimumab: Tumor Response With Concurrent Therapy Treatment-Related AE, Number of Patients (%) Change in Target Lesions From Baseline (%) 250 200 150 100 ORR: 40% Highest dose ORR: 53% (by investigator-assessed irRC with confirmation) 50 0 -50 -100 Patients Objective responses were observed in patients with either PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–negative tumor samples (9 of 22) (P > .99) irRC=immune-related response criteria Wolchok JD et al. N Engl J Med. 2013; 369:122-33. Concurrent All Cohorts (n = 53) Sequenced All Cohorts (n = 33) All Grades Grades 3/4 Al Grades Grades 3/4 Any adverse event 49 (93) 28 (53) 24 (73) 6 (18) Rash 29 (55) 2 (4) 3 (9) 0 Pruritus 25 (47) 0 6 (18) 0 Fatigue 20 (38) 0 3 (9) 0 Diarrhea 18 (34) 3 (6) 3 (9) 0 Nausea 11 (21) 0 1 (3) 0 Pyrexia 11 (21) 0 1 (3) 0 AST increase 11 (21) 7 (13) 0 0 ALT increase 11 (21) 6 (11) 1 (3) 0 Lipase increase 10 (19) 7 (13) 4 (12) 2 (6) 1 (3) Amylase increase 8 (15) 3 (6) 1 (3) Cough 7 (13) 0 2 (6) Vomiting 6 (11) 1 (2) 0 0 Vitiligo 6 (11) 0 0 0 Headache 6 (11) 0 0 0 0 Wolchok JD et al. N Engl J Med. 2013;369:122-33. 65 Combining Immunotherapy and Targeted Therapy for Melanoma Improved Survival With Ipilimumab[1] Ipi + gp100 Ipi gp100 Vemurafenib (n = 336) 6 mos OS: 84% 80 60 40 12 20 28 Mos 36 44 52 0 0 1 2 3 4 5 6 7 8 9 101112 Mos Immunotherapy Combination??? Percent Alive Percent Alive Targeted Therapy 0 1 Yrs 2 3 0 1 Yrs 2 3 Doses of Ipilimumab Before ALT-AST Elevation, n Time to Onset of ALT-AST Elevation After First Dose Ipilimumab, Days Treatment Time to Resolution of ALT-AST Elevation, Days Toxicity Relapse With Repeated Ipilimumab 4 1 21 Vem discontinued for 5 days then restarted with dose reduction; Ipi permanently discontinued 4 NA 5 2 26 Vem discontinued for 4 days then restarted with dose reduction; Ipi continued (2 doses) 6 No 6† 1 21 Vem discontinued for 5 days then restarted with dose reduction; Ipi continued (1 dose) 6 No 8 1 19 Vem discontinued for 4 days then restarted with dose reduction; Ipi continued (1 dose) 12 Yes 10 1 15 Vem discontinued for 7 days then restarted with dose reduction; Ipi permanently discontinued (1 dose) 10 NA 16§ 1 13 Vem and Ipi permanently discontinued 20 NA Cohort 1* Dacarbazine (n = 336) 6 mo OS: 64% 20 0 4 Patient Number Improved Survival With Vemurafenib[2] 100 OS (%) 100 80 60 40 20 0 Ipilimumab + Vemurafenib Liver Toxicities in Phase I Testing Cohort 2‡ 0 1 Yrs 2 *Cohort 1: 1-month run-in of single-agent vemurafenib 960 mg BID followed by 4 infusions of ipilimumab 3 mg/kg every 3 wks plus vemurafenib. †Patient also had grade 2 increase in total bilirubin. ‡Cohort 2: vemurafenib 760 mg BID plus ipilimumab 3 mg/kg every 3 wks. §Patient also had grade 3 increase in total bilirubin. Ribas A et al. N Engl J Med. 2013;368:1365-1366. 3 Adapted from Hodi FS et al. N Engl J Med. 2010; 363:711-723. Chapman PB et al. N Engl J Med. 2011; 364:2507-2516. Which of the following is true regarding single agent immunotherapy in melanoma? Adverse events seen with ipilimumab and PD‐1 antagonism include: a. High response rates are commonly seen, but are of short duration a. Rash, cardiotoxicity, and myelosuppression b. All produce low response rates of short duration c. Cardiotoxicity, hepatotoxicity, and myelosuppression c. Long‐term responses can be seen, but are in less than 20% of patients d. Diarrhea, hepatotoxicity, and myelosuppression b. Rash, hepatotoxicity, and diarrhea d. Responses are seen in over 50% and are very durable Treatment Overview Stage I or II BRAF Mutant Melanoma Surgical removal and observation • Found in 40‐50% of cutaneous melanoma – Nearly 60% of melanoma in skin without chronic sun‐ induced damage – 80‐90% are the V600E and 5‐12% are V600K – Generally non‐overlapping with other mutations Surgical removal and observation Stage III Lymph Node Positive Diagnosis Surgical removal and IFN • Results in enhanced BRAF kinase activity and subsequent MAPK activation If BRAF positive, vemurafenib, dabrafenib +/‐trametinib or immunotherapy or trial Stage IV Metastatic • Current FDA approved therapies: If BRAF negative, Ipilimumab first line, HD‐IL2, or trial – BRAF inhibitors: Vemurafenib and Dabrafenib – MEK inhibitor: Trametinib IFN=interferon HD-IL2=high-dose interleukin-2 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2015. NCCN.org http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed November 2014. 66 Phase III Vemurafenib vs. Dacarbazine R A N D O M I Z A T I O N N = 675 Previously untreated, unresectable Stage IIIC or IV melanoma with BRAF V600E mutations Phase III Vemurafenib vs. Dacarbazine • Overall Survival (6 months) Vemurafenib 960 mg PO BID – Vemurafenib: 84% (95% CI, 78%‐89%) – Dacarbazine: 64%(95% CI, 56%‐73%) – HR: 0.37 (0.26‐0.55), p< 0.001 Dacarbazine 1000 mg/m2 IV every 3 weeks • Estimated Progression‐Free Survival – Vemurafenib: 5.3 months – Dacarbazine: 1.6 months – HR: 0.26 (0.20‐0.33), p< 0.001 • Co‐primary endpoints: Progression‐free survival (PFS) and overall survival (OS) • Secondary endpoints: Response rate (RR), response duration and safety • Stratification by stage, performance status, LDH level and geographic region • Enrolled January 2010 to December 2010 in 12 countries Chapman PB et al. N Engl J Med. 2011; 364:2507-2516. Chapman PB et al. N Engl J Med. 2011; 364:2507-2516. BRAF Inhibitor Dermatologic Effects Vemurafenib and Dacarbazine Toxicity Toxicity Vemurafenib Arthralgia Maculopapular rash with keratoacanthomas Dacarbazine Grade 2 Grade 3 Grade 2 Grade 3 18% 3% < 1% < 1% Nausea 7% 1% 11% 2% Fatigue 11% 2% 12% 2% Diarrhea 5% < 1% 1% < 1% Keratoacanthoma 2% 6% 0% 0% Hyperkeratosis 5% 1% 0% 0% Cutaneous SqCC N/A 12% N/A < 1% Pustular “white head” reactions treated like traditional acne The majority of all toxicities were grade 2 or less. Most common events in the vemurafenib arm were cutaneous events, arthralgia and fatigue. N/A = not applicable sqCC=squamous cell carcinoma Photo courtesy of Dr. Walko, used with patient permission Chapman PB et al. N Engl J Med. 2011; 364:2507-2516. Vemurafenib Relapse BRAF + MEK vs. BRAF alone N = 704 Previously untreated, unresectable Stage IIIC or IV melanoma with BRAF V600E or V600K mutations Baseline before therapy 15 weeks of therapy with vemurafenib R A N D O M I Z A T I O N Dabrafenib 150 mg PO BID + Trametinib 2 mg PO daily Vemurafenib 960 mg PO BID • Primary endpoint: Overall survival • Secondary endpoint: Progression free survival • Preplanned interim survival analysis performed after 77% of the total number of expected events 23 weeks of therapy with vemurafenib Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved. Wagle N et al. J Clin Oncol. 2011; 29:3085-96. Robert C et al. N Engl J Med. 2015; 372:30-9. 67 BRAF + MEK vs. BRAF alone BRAF‐Targeted Selected Toxicities • Median overall survival at 12 months Toxicity – Dabrafenib + trametinib: 72% – Vemurafenib: 65% – HR 0.69 (95% CI 0.53‐0.89), p = 0.005 • Median progression free survival – Dabrafenib + trametinib: 11.4 months – Vemurafenib: 7.3 months – HR 0.56 (95% CI 0.46‐0.69), p < 0.001 Vemurafenib Grade 3 and 4 All grade Grade 3 and 4 Pyrexia 21% 1% 53% 4% Rash 43% 9% 22% 1% Diarrhea 38% < 1% 32% 1% Hand Foot Syndrome 25% < 1% 4% 0% Hyperkeratosis 25% 1% 4% 0% Cutaneous SqCC 18% 17% 1% 1% Decreased ejection fraction 0% 0% 8% 4% Robert C et al. N Engl J Med. 2015; 372:30-9. Robert C et al. N Engl J Med. 2015; 372:30-9. Patient Case BRAF Mutated Melanoma: Summary • Resistance to BRAF inhibitors typically occurs after 6‐7 months in most BRAF mutant metastatic melanoma patients • Combination of a BRAF and MEK inhibitors may suppress downstream resistance mechanisms • WK is a 38 yo female who was initially diagnosed with stage IIIC melanoma of the neck – Modified radical neck dissection – 2 months of adjuvant interferon before stopping due to toxicity – Combination therapy had longer mPFS compared with monotherapy – Median overall survival not yet reached • PET scan at 6 months shows numerous sites compatible with metastatic disease • Pathology notable for the 1799 T>A (V600E) mutation in the BRAF gene • She is willing to travel for a clinical trial. • Combination therapy resulted in higher occurrence of pyrexia, chills, nausea and vomiting but less skin toxicities • Potential place in therapy: – First line for BRAF positive metastatic melanoma mPFS=median progression free survival Dabrafenib + Trametinib All grade Flaherty KT et al. N Engl J Med. 2012; 367:1694-703. What therapy would be most beneficial for this patient? Compared to a BRAF inhibitor alone, which toxicity is LESS likely with combination BRAF + MEK inhibition? a. Single agent trametinib a. Pyrexia b. Single agent vemurafenib b. Rash c. Combination dabrafenib and trametinib c. Peripheral edema d. Combination vemurafenib and dabrafenib d. Squamous cell carcinoma 68 Future Challenges and Directions Genetic Assessment: Patient Case • 71 yo man diagnosed with metastatic melanoma in April 2013 when he presented with a lesion on the left chin and also had nodal involvement. • Treatment Hx • Optimal sequencing of therapy for BRAF‐ positive patients • Optimal use of PD‐1 or PD‐L1 inhibitors – Surgical resection of primary site and lymphadenectomy – Ipilimumab x 3 doses 11/2013 – complicated by ipilimumab ‐induced colitis requiring high‐dose steroids and infliximab – Radiation therapy to the neck area and left lung from 11/2013 ‐1/2014 – CT scan in July 2014 demonstrated recurrent disease – Sequential therapy – Combination immunotherapy – Combination with BRAF inhibitors • Somatic genetic analysis: • Managing drug resistance – Lymph node from 08/11/2014 • Clinical Question – Genetic tumor profiling – Future treatment options Somatic Genetic Analysis Gene Variant Notes NRAS Amplification • NRAS activating mutations have been reported to activate the RAF/MEK/ERK and PI3K pathways leading to hyperactivation of CDK4/6. • Numerous clinical trials available targeting this pathway with various combinations of inhibitors CDK4 Amplification • Amplification of CDK4 may lead to excessive protein expression and activity, resulting in unrestricted cell cycle progression. • Several CDK4/6 inhibitors are currently being studied in clinical trials MDM2 amplification • This gene encodes a nuclear‐localized E3 ubiquitin ligase and regulates the tumor suppressor p53. Controls entry into S‐phase and ultimately mitosis • Putative amplification of MDM2 has been reported in 4% of cases in the Skin Cutaneous Melanoma TCGA dataset. • Phase I clinical trial with MDM2 inhibitor currently enrolling Potential Trial Considerations NCT ID Title A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With NCT01781572 MEK162 in Adult Patients With NRAS Mutant Melanoma A Phase Ib Study of MEK162 Plus BYL719 in NCT01449058 Adult Patients With Selected Advanced Solid Tumors Modular Phase II Study to Link Targeted Therapy to Patients With Pathway NCT02187783 Activated Tumors: Module 8 ‐ LEE011 for Patients With CDK4/6 Pathway Activated Tumors A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and NCT02065063 Anti‐Cancer Activity of Trametinib in Combination With Palbociclib in Subjects With Solid Tumors Conclusions • Genetic testing is a standard part of the metastatic melanoma work up – BRAF V600E or K positive patients are eligible for treatment with BRAF‐inhibitors with or without MEK‐inhibitor directed therapy – Patients lacking the BRAF mutation should be directed towards immunotherapy with HD‐IL2, ipilimumab or PD‐1 therapy • Novel targeted and immunotherapy agents have unique side effect profiles that provide opportunities for pharmacists in terms of patient education and supportive care • Ongoing clinical trials are aimed at addressing optimal sequencing and combinations of therapy for both BRAF‐ positive and negative patients. 69 Target Compound MEK, CDK4/6 LEE011 and MEK162 MEK, PI3K BYL719 and MEK162 CDK4/6 LEE011 MEK, CDK4/6 Trametinib Palbociclib New and Emerging Strategies for the Treatment of Advanced Melanoma Self-assessment Questions 1. Which of the following is true regarding single agent immunotherapy in melanoma? a. High response rates are commonly seen, but are of short duration b. All produce low response rates of short duration c. Long-term responses can be seen, but are in less than 20% of patients d. Responses are seen in over 50% and are very durable 2. Adverse events seen with ipilimumab and PD-1 antagonism include: a. Rash, cardiotoxicity, and myelosuppression b. Rash, hepatotoxicity, and diarrhea c. Cardiotoxicity, hepatotoxicity, and myelosuppression d. Diarrhea, hepatotoxicity, and myelosuppression 3. What therapy would be most beneficial for this patient? a. Single agent trametinib b. Single agent vemurafenib c. Combination dabrafenib and trametinib d. Combination vemurafenib and dabrafenib 4. Compared to a BRAF inhibitor alone, which toxicity is LESS likely with combination BRAF + MEK inhibition? a. Pyrexia b. Rash c. Peripheral edema d. Squamous cell carcinoma Answers 1. 2. 3. 4. c b c d 70 Instructions for Processing CE Credit with Enrollment Code Pharmacists and Technicians: Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity. All ACPE accredited activities which are processed on the eLearning site will be reported directly to CPE Monitor. To claim pharmacy credit, you must have your NABP e-Profile ID, birth month, and birth day. If you do not have an NABP e-Profile ID, go to www.MyCPEMonitor.net for information and application. Please follow the instructions below to process your CPE credit for this activity. 1. The ASHP eLearning site allows participants to obtain statements of continuing education credit conveniently and immediately using any computer with an internet connection. Type the following link into your web browser to access the e-Learning site: http://elearning.ashp.org/my-activities 2. If you already have an account registered with ASHP, log in using your username and password. If you have not logged in to any of the ASHP sites before and/or are not a member of ASHP, you will need to set up an account. Click on the Register link and follow the registration instructions. 3. Once logged in to the site, enter the enrollment code for this activity in the field provided and click Redeem. Note: The Enrollment Code was announced at the end of the live activity. Please record the Enrollment Code in the grid below for your records. 4. The title of this activity should now appear in a pop-up box on your screen. Click on the Go button or the activity title. 5. Complete all required elements. A green You can now claim your credit. should appear as each required element is completed. 6. Available credit(s) will appear beneath the completed required activities. Look for your profession in the list of available credits and click the appropriate Claim button. You might have to click to see more credit options if you don’t see your profession listed. CPE Credit for Pharmacists and Technicians: To claim continuing pharmacy education (CPE) credit, you will need to enter your NABP e-Profile ID, birth month, and birth day. Once you have entered this information the first time, it will auto fill in the future. Please note: All CPE credit processed on the eLearning site will be reported directly to CPE Monitor. 7. Review the information for the credit you are claiming. If all information appears to be correct, check the box at the bottom and click Claim. You will see a message if there are any problems claiming your credit. 8. After successfully claiming credit, you may print your statement of credit by clicking on Print. If you require a reprint of a statement of credit, you can return here at any time to print a duplicate. Please note that for CPE credit, printed statements may not be necessary because your credit will be reported directly to CPE Monitor. Date of Activity 5/22/15 Activity Title Enrollment Code New and Emerging Strategies for the Treatment of Advanced Melanoma NEED HELP? Contact [email protected]. 71 16 Credit Hours 1.0 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May 22 10:00—11:30 a.m. Special Situations in Patients with Type 2 Diabetes Susan Ann Cornell, PharmD, CDE, FAPhA, FAADE 0069-9999-14-148-L01-P 1.5 contact hours (0.15 CEU) Please see the following pages for educational materials for this activity and instructions on how to receive credit. This program is supported by an educational grant from Novo Nordisk, Inc. 72 Special Situations in Patients with Type 2 Diabetes A knowledge-based CE program for nurses, dietitians, and pharmacists Disclosures to Participants It is the policy of the American Association of Diabetes Educators and Scherer Clinical Communications to ensure independence, balance, objectivity, scientific rigor, and integrity in all of their continuing education activities. The planning team and faculty must disclose to the participants any significant relationships with the commercial companies whose products or devices may be mentioned in the activity or with the supporter of this continuing education activity. The information is for participant information; it is not assumed that these relationships will have a negative impact on the content of the activity. Activity Speaker Susan Ann Cornell, BS, PharmD, CDE, FAPhA, FAADE, has no disclosures to report. Activity Planning Team Members Jerry Meece, RPh, CDE, FACA, FAADE, reports that he is a speaker for Lilly, Novo Nordisk Inc, J&J, Pfizer, Lifescan, and Janssen Pharmaceuticals. He consults for Novo Nordisk Inc, J&J, and Lifescan. Mr. Meece also receives grants from Novo Nordisk Inc, Pfizer, and Lifescan. Virginia Peragallo-Dittko, APRN, BC-ADM, MA, CDE, FAADE, has no actual, potential or perceived conflict of interest to report. Gretchen Youssef, MS, RD, CDE, reports that she is on an advisory committee for Janssen Pharmaceuticals Marguerite K. York, PhD, has no actual, potential or perceived conflict of interest to report. Peter Macholdt, BS, has no actual, potential or perceived conflict of interest to report. Non-Endorsement of Products: Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity. Off-Label Use: Speakers will notify participants about any product used for a purpose not approved by the US Food and Drug Administration. This program is supported by an educational grant from Novo Nordisk Inc. 73 Special Situations in Patients with Type 2 Diabetes This activity is intended for nurses, dietitians and pharmacists involved in Date: May 22, 2015 Time: 9:30 AM - 12:30 PM Location: Hyatt Regency 601 Loyola Avenue New Orleans, LB 70112 Schedule Of Events 9:30 AM - 10:00 AM : Registration To Register On-Line Click the link below or open your browser and go to: http://www.mycecenter.com 1) Click on the orange colored Registration button that says: "Click Here To Register For CE Programs" 2) Click on the Register link for the program you wish to attend 3) Please make sure you are selecting the correct program For problems or questions regarding online registration, contact us at: 800-232-4422 Speaker: Susan Ann Cornell, PharmD, CDE, FAPhA, FAADE Susan Cornell, BS, Pharm.D, CDE, FAPhA, FAADE is the associate director of experiential education and an associate professor in the department of pharmacy practice at Midwestern University Chicago College of Pharmacy in Downers Grove, Illinois. Dr. Cornell is also a clinical pharmacy consultant and certified diabetes educator, specializing in community and ambulatory care practice. Dr. Cornell’s current clinical practice is with the Access Community Health Network in Chicago. Dr. Cornell received her bachelor of pharmacy at the University of Illinois, College of Pharmacy and her Doctor of Pharmacy at Midwestern University. She has received numerous awards and recognitions, including the 2014 Bowl of Hygeia, 2011 Outstanding Faculty Advisor Award, and 2010 Teacher of the Year Award, to list a few. She is an active member of the American Diabetes Association, and the American Association of Diabetes Educators, where she served on their board of directors from 2004 to 2007. Dr. Co Target Audience: This activity is intended for nurses, dietitians and pharmacists involved in Program Goal: The goal of this knowledge-based activity is to provide participants with the skills necessary to manage special situations that may arise in patients using insulin therapy. 74 Special Situations in Patients with Type 2 Diabetes This activity is intended for nurses, dietitians and pharmacists involved in Program Objectives Identify special situations that necessitate lifestyle modifications and individually tailored glucose-lowering regimes for adults with type 2 diabetes 2. Describe monitoring, lifestyle modifications, and glucose-lowering regimen changes that are important for maintaining glucose control in special situations 3. Discuss resources that provide guidance for making lifestyle modifications and glucose-lowering regimen changes in special situations Important Notice To obtain continuing education contact hours for this event, be sure to obtain the “Instruction Page” from the program planner. This Instruction Page will outline the process for completing online fulfillment and printing of your CE Statement of Credit. There are no fees for this program. 75 Special Situations in Patients with Type 2 Diabetes This activity is intended for nurses, dietitians and pharmacists involved in This continuing nursing education activity was approved by the American Association of Diabetes Educators, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. This program 2014-055-RN is approved for 1.50 contact hours. American Association of Diabetes Educators, (AM001) is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). Registered dietitians (RD) and dietetic technicians, registered (DTR) will receive 1.50 continuing professional education units (CPEU) for completion of this program. Continuing Professional Education Provider Accreditation does not constitute endorsement by CDR of a provider, program, or materials. The American Association of Diabetes Educators is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.50 contact hours (0.15 CEU’s) of continuing education credit. ACPE Universal Program Number: 0069-9999-14-148-L01-P Program Release Date: 10/1/2014 Program Expiration Date: 10/1/2016 The approval of this educational offering by AADE does not imply endorsement of specific therapies, treatments, or products discussed in the presentation. This program is supported by an educational grant from Novo Nordisk Inc. 76 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May 22 2:00 – 3:00 p.m. Focus on Patient Safety Interactive Poster Session 1.0 contact hours (0.1 CEU) 0179-0000-15-010-L05-P / 0179-0000-15-010-L05-T Knowledge-based activity Pharmacist Objectives: Describe the concepts of patient safety. Review outstanding health-system pharmacy practices or best practices in health-system pharmacy. Describe the impact of patient safety and safe medication practices. Discuss Continuous Quality Improvement and processes utilize to achieve quality in Pharmaceutical Care. Utilize national standards, evidenced-based medicine and pharmacy literature to improve safety and efficacy. List the ways that national accreditation agencies may positively impact the overall practice of pharmacy in health-systems. List what the high-risk drugs are and how to handle them throughout the continuum of care. Describe the impact of educational programs on safety and pharmacy practice improvement. Review the impact pharmacist or pharmacy technicians may have in patient safety. Technician Objectives: Review the concept of Patient Safety List what the high-risk drugs are and how to handle them throughout the continuum of care Review programs in insulin, chemotherapy, anticoagulation and sedatives and introduce the safety practices into your practice setting Outline how technicians may assist the pharmacist in identifying opportunities to improve medication safety. To earn ACPE credit for the poster session, you must: 1. Attend the interactive portion of the poster session. 2. Complete the questions for each program in the poster packet provided. 3. Submit the completed poster packet to the registration desk by the end of the Annual Meeting. 4. Indicate your attendance for the poster session on your Continuing Education Report Form. 77 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May 22 3:00 – 4:00 p.m. The Future is Yours—Advancing Practice Christene Jolowsky, MS, RPh, FASHP Executive Director, Applied and Experiential Education University of Minnesota College of Pharmacy President, ASHP 0179-0000-15-005-L04-P / 0179-0000-15-005-L04-T 1.0 contact hour (0.1 CEU) Knowledge-based activity Technician Objectives: Describe changes roles and practice for Describe the roles and scope of practice pharmacy technicians for pharmacists, based on patient needs. Identify expanded roles for pharmacy Compare how practice in an acute care technicians setting may differ from an ambulatory care Identify resources that are available to support setting. expanded services and roles Pharmacist Objectives: Identify activities and resources that you have available to expand services. Focus on the transition to ambulatory care, identifying challenges and changes. Speaker has disclosed that she has no relevant financial relationships. 78 Disclosure: The Future Is Yours Advancing Practice I have nothing to disclose commercially regarding this presentation. Louisiana Society of Health System Pharmacists – 2015 Annual Meeting Christene Jolowsky, MS, RPh, FASHP President – ASHP Executive Director, Applied and Experiential Education University of Minnesota College of Pharmacy Learning Objectives for Pharmacists Objectives • Describe the scope of practice for pharmacists, • Trends that will affect our future • ASHP initiatives to position pharmacy for a key based on patient needs. • Compare how practice in an acute care setting role in health care may differ from an ambulatory care setting. • ASHP strategic plan • PPMI update • Identify metrics that could be used to demonstrate outcomes of expanded services Focus on the transition to ambulatory care, identifying challenges and changes • Hospital • Amb Care • Think about practice Learning Objectives for Technicians Practice Will Change • Describe changes in the roles and practice for Code of Ethics prior to 1969 “The pharmacist does not discuss the therapeutic effects or composition of a prescription with a patient. When such questions are asked, he suggests that the qualified practitioner is the proper person with whom such matters should be discussed” (APhA, 1952, p. 722). pharmacy technicians. • Identify expanded roles for pharmacy technicians. • Identify resources that are available to support expanded services and roles 79 Trends That Will Change Our Practice Practice Will Change “ To bring about change within a diverse profession such as pharmacy, one needs a large number of people pulling in the same direction. Before one can get folks pulling in the same direction, one needs general agreement about the best direction in which to move.” … • Technological revolution • Health care reform • Evolution of pharmacy workforce • Growing complexity and cost of medications and medication use systems • Further move to corporate governance William A. Zellmer Our Patients and Their Care ASHP Strategic Plan • • • • • • • • • • • Three sections, which focus on professional, operational, and leadership & management PPMI Provider Status Expand Pharmacy Practice in Ambulatory Clinics and Other Primary Care Settings Advance Patient Care and Pharmacy Practice in Small, Rural, and Underserved Settings (new 2015) Address the Needs and Interests of Pharmacists Who Practice in Multihospital Systems (new 2015) Address Issues Related to Specialty Pharmacy (new 2015) Compounding Medication Safety Drug Shortages Expansion of Residencies New Programs, Products, and Services • • • • Tech Portal Certification Expansion of Residency Meetings PPMI • Hospital Self ‐ Assessment • • • • Ambulatory Care Growth and its Impact on Pharmacy Practice State Grants Large health systems engagement Messaging • • • Communications plan Presentations at state meetings, health systems, and others Social media National Dashboard 80 Overview • State of the ambulatory care environment • Challenges and opportunities in ambulatory care • The ASHP Ambulatory Care Conference and Summit 2013 AAMI/FDA Healthcare Technology in Nonclinical Settings Summit Source: Alvere Health analysis of American Hospital Association Annual Survey data, 2011, for community hospitals. Available at: http://www.aha.org/research/reports/tw/chartbook/2013/table4‐2.pdf CDC, NCHS Data Brief, Multiple Chronic Conditions Among Adults Aged 45 and Over: Trends Over the Past 10 Years, http://www.cdc.gov/nchs/data/databriefs/db100.htm, Accessed January 3, 2014 Marketplace Trends Health Care Reform • 40% of physicians are employed or practice is owned 2010‐2013 ‐ Initiation by health system. • Growth in the number of NCQA recognized medical homes: 38 in 2008 to 6,000 in 2013 • Ambulatory care pharmacy related services on the rise. • “Aging in place” will drive home health care industry (Impact on home infusion?) • Specialty pharmacy growth • Other trends? 2014‐2017 – Market Expansion •Medicare market basket reductions •Payer Reform—new insurance rules •Medicare and Medicaid sponsor earliest payment innovations •Rapid coverage expansion •New federal money for new Medicaid eligibles •Capacity constraints emerge in ED, primary care, discretionary specialty services 81 ASHP Strategic Plan Identifying and Addressing Challenges and Opportunities in Ambulatory Care 4. Convene a consensus conference to study and make recommendations to enhance the ambulatory care services provided by pharmacists. Ambulatory Care Feedback: Challenges • #1 – Efficiency in documentation EMRs don’t meet amb care needs • Effectively place pharmacists on the health care team Not just physicians, case managers, care navigators… • Address community pharmacists moving from a dispensing • • environment into a cognitive environment Training, other opportunities Demonstrate pharmacists’ value in ACOs and PCMHs State‐level information – to advance roles for pharmacists http://www.ashp.org/amcare New Opportunity: Medicare Wellness Visits Wellness Visits • Supplement to the “Welcome to Medicare Visit” • Provided by “…other licensed practitioner… working Yearly "Wellness" visits/ steps: • • • • • • • • under the direct supervision of a physician.” • ASHP members are providing and billing for these Patient has had Part B for longer than 12 months Patient completes “Health Risk Assessment” as part of visit. Develop a personalized prevention plan Develop/ update a list of current providers and prescriptions Take height, weight, blood pressure, other routine measurements Review potential risk for depression and level of safety Develop a list of risk factors and treatment options Visit is covered once every 12 months • 11 full months must have passed since the last visit services: • • 82 HCPCS code G0438 for first Annual Medicare Wellness Visit • Medicare payment approximately $172 in 2011 HCPCS code G0439 for subsequent visits • Medicare payment approximately $111 in 2011 Medicare Wellness Visits Resources: • • • http://www.ajhp.org/content/71/1/44.full.pdf http://www/cms.gov/Outreach‐and‐education/medicare‐ learning‐network‐ mln/mlnprodcuts/downloads/awv_chart_icn905706.pdf http://www.cms.gov/outreach‐and‐education/medicare‐ learning‐network‐ mln/mlnproducts/downloads/annualwellnessvisit‐ icn907786.pdf http://connect.ashp.org/ambulatorycareconference14/ The Conference • • • • Outcomes of the Summit • Consensus: important step for ASHP & ASHP Navigating the Future: Patient Care Delivery and Integration Develop the Possibilities: Sustainable Business Models Make It Matter: Outcomes Evaluation It Starts with Us: Defining and Advancing Ambulatory Care Foundation Pharmacy Practice Model Initiative • Post‐Summit follow‐up survey to all ASHP members • Input on the Summit recommendations • Final report published in AJHP August 15, 2014 • Ambulatory Self‐Assessment (Spring 2015) • ASHP meeting presentations and discussions (Summer meetings!) • Inclusion of Ambulatory Pharmacy Practice Model in ASHP Foundation‐supported research Provider Status Other ASHP Initiatives • ASHP: Member of the Patient Access to Pharmacists' Care Coalition • Bi‐partisan Legislation: H.R. 592 and S. 314 introduced • Amend the Social Security Act • Recognize pharmacists as providers in medically underserved areas under Medicare Part B 83 Drug Shortages Compounding • ASHP in collaboration with the University of • ASHP has been a leader in developing Utah and FDA – leading provider of information and advocacy for over 10 years • Legislation was passed in 2012 giving FDA enhanced authority • ASHP continuing to working with various stakeholders to find long‐term solutions guidelines and advocating on this issue for over 20 years • Legislation recently passed clarifying and increasing FDA authority • ASHP working with stakeholders to influence regulations Expansion of Residencies • Residency capacity stakeholders conference in 2011 • Offering workshops on starting a residency at ASHP meetings • Tools and resources on starting residency programs Center for Pharmacy Practice Accreditation (CPPA) • Partnership between APhA, NABP, and ASHP • Develops and implements comprehensive programs of pharmacy practice site accreditation • Initial focus on community pharmacy accreditation • Other ongoing explorations In 2014 appx 20% of graduates (2411) are seeking PGY1 positions And 5% (129) are graduates before 2014 84 Technician Portal Pharmacy Technicians • Pharmacytechce.org • Pharmacy Technician Accreditation • Individual or group subscriptions • 20 hours of “T designated” CE • Live webinars plus online anytime Commission (PTAC) • Partnership between ACPE and ASHP • Task: Assure and advance the quality of pharmacy •Podcasts •Live webinars •On‐Demand •CE Monographs technician education and training programs • PTAC will conduct document reviews and site surveys • Pharmacy Technician Certification Board • PTCB’s new requirements • Group subscription with admin function • ASHP, NABP, APhA, ICHP, MPA •Tracking completion of CE Transforming how pharmacists care for patients PPMI is a profession‐led initiative that is empowering the pharmacy team to take responsibility for patient outcomes. Care Team Integration • Promotes a team‐ based approach to health care • Shifts the roles of the health care team to enable pharmacists to optimize their time with patients across the continuum of care • Goal 1 Goal 2 Goal 3 Goal 4 Goal 5 Pharmacist roles, practices, and activities will improve medication use and optimize medication related outcomes. Pharmacy technicians will prepare and distribute medications and perform other functions that do not require a pharmacist's professional judgment. Pharmacists and pharmacy technicians will have appropriate training and credentials for the activites performed within their scope of practice. Pharmacy departments utilize available automation and technology to improve patient safety and improve efficiency. Pharmacists will demonstrate leadership in exercising their responsibility for medication use systems and will be accountable for medicationrelated patient outcomes. 2014: 20 40 50 60 70 30 80 90 10 0 100 64% 2011 59% 50 60 40 60 70 30 40 20 80 90 10 0 100 20 40 506060 70 30 40 80 90 10 0 100 30 20 40 50 60 60 40 50 60 70 3040 20 80 70 80 90 10 0 0 100 XX% 17% 27% 64% 17% 24% 44% 90 10 100 48% 41 50% 85 • Elevates the reputation of the pharmacy team • Ensures pharmacists, residents, and students have training and credentials for activities performed within their scope of practice now and in the future • Empowers the pharmacy team to ensure that pharmacy technicians perform all traditional preparation and distribution activities • Urges technicians to handle non‐traditional and advanced responsibilities and activities to allow • pharmacists to take greater responsibility for direct patient care Enhances the relationship between pharmacists and patients by positioning pharmacists as providers • PPMI National Dashboard Pharmacist Credentialing & Training Leveraging Pharmacy Technicians Promotes technician training and certification requirements, such as the need for uniform standards for advanced technician roles Promotes the use of credentials to provide services at the top of the scope of practice Leadership in Medication Use Technology • Evaluates the available technologies to support patient safety and quality of care • Encourages use of available automation and technology to improve patient safety, quality and efficiency, while also reducing costs • Identifies emerging technologies to improve pharmacy practice • Empowers pharmacists to take responsibility for patient outcomes • Positions pharmacists to promote health and wellness, optimize therapeutic outcomes, and prevent adverse medication events • Emphasizes that given their extensive education and training, pharmacists are integral in helping achieve the best outcomes Challenge… Support… • Complete the survey • Students: ask at your site • Use this in department planning • Be a member • Be involved • Think Locally! • Support initiatives Research and Education Foundation (REF) ASHP Foundation Focus: Leadership Development/Practice Advancement Research & Tools for Pharmacists Key Leadership Programs ASHPFoundation.org • Student Leadership Speakers Bureau • Whitney Lectures/Conversations Videos • Residents Visiting Leaders Program • Pharmacy Leadership Academy • Pharmacy Leadership Institute • Leadership Resource Center • Pharmacy Forecast 2015‐2019 • C‐Suite Toolkit ASHP Foundation PAC (Political Action Committee) Focus: Leadership Development/Practice Advancement Research & Tools for Pharmacists Research/Practice Advancement Programs • Legislative Issues • Provider Status • Drug Shortages Bill • Compounding • Supporting Pharmacy Practice • ASHP.org Advocacy • Residents Research Tips/Webinars • PGY1 & Master’s Residents Grant Programs • New Investigator Grants & Residency Expansion Grants • Complexity Index Research‐ 23 preventable ADEs • Traineeships‐ Crit. Care/Oncol./Pain/Med. Home/Anticoag • Practice Tools‐ Insourcing/Outsourcing/Antithrombotic Assessment/Insulin Safety 86 Audience Questions Audience Question Why is obtaining provider status important? • For Technicians? • For Pharmacists? As you are looking at advancing practice, what are some of the criteria you would take into account in expanding into an ambulatory setting? Audience Question Bring It Home – Practice Model Initiatives What are some differences in pharmacist roles in an ambulatory care setting v. an acute care setting? • Care for the patients • Role at transition points • Assessment of your practice • Personal plan • Work plan • Know your resources What are some roles that technicians can perform to support ambulatory‐based pharmacy services? What are your questions? (and thank you … again) [email protected] [email protected] 87 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May 22 3:00 – 4:00 p.m. **Technician Session** Technician Advancement: How can I Climb the Ladder? Richard Ponder, MBA, CMRP, CPhT, CPP, CEPP Senior Advisor, Advisory Services VHA 0179-0000-15-011-L04-T 1.0 contact hour (0.1 CEU) Knowledge-based activity Technician Objectives: Discuss background information related to technician career ladders, benefits and challenges Describe how to design a technician advancement program, ladder levels, criteria for advancement, advancing beyond a ladder Discuss implementation of technician advancement program Speaker has disclosed that he has no relevant financial relationships. 88 Objectives • Describe background information related to technician career ladders, benefits and challenges. • Describe how to design a technician advancement program, ladder levels, criteria for advancement and advancing beyond a ladder. Technician Advancement: How can I Climb the Ladder? • Discuss implementation of technician advancement program. Richard Ponder, MBA, CMRP, CPhT, CPP, CEPP Senior Advisor, Advisory Services VHA LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting When you think about a traditional Pharmacy Technician role, what comes to mind? LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting Current “Technician” Role • Varies significantly among hospitals When you think about an advance Pharmacy Technician, what roles comes to mind? • Traditional functions: – – – – – – – – – – – – – Fill prescriptions Compound products Prepare IVs Restock automated dispensing cabinets Order medications and supplies Receive order/invoices Restocking and repackaging Maintain inventory area Borrow/Loan Billing – departments, pt. charges, coding, etc Reports, Audits, Analytical task Work with automation systems Perform any and all tasks assigned LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting 89 Current “Advanced” Roles Barriers • Advance roles: • Human Resource Department – – – – – – – – – – – Medication Reconciliation Transition of Care Technician Patient Assistance Program Research Technician 340B Program Management Decentralized Nursing Liaison Informaticists Tech-Check-Tech Pharmacy Concierge Technician Specialty Pharmacy Technician Business/Operation Manager/Director – value, background, knowledge, and skills • “Don’t we have a department for that?” • “Why would we want a technician to do that, doesn’t pharmacist, nurse, etc. already do that?” LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting Barriers Continued Barriers Continued • Pharmacy Support • Professional Development – value, perception – Education, certifications, additional training • “Do you want that technician to interact with a patient?” – Lack of Pharmacy and/or Healthcare specific training • “The technician did not go to school for that.” • “All you do is play on the computer and talk on the phone.” • “How did you get a promotion/pay increase when we never have anything on the shelves?” LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting A Pharmacy Purchasing Professional An individual working with pharmacy who leverages his/her knowledge and experience in the purchasing of products and services required to provide all customers with quality cost effective healthcare. Advanced Role - Pharmacy Purchasing Professional LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting 90 Pharmacy Purchasing Professional’s Role Justification – How? • Traditional functions • Professional – more work & documentation – – – – – • Provides Pharmacy with expertise in: – – – – – – – – – Business Contracts Logistics and Distribution Project Management Process Improvement Quality Controls Supplier Relations Customer Relations Technology Position description vs. current responsibilities What do I need to know? What do I need know how to do? “What have you done for me lately?” Internal Proposal • Management – ROI – Executive Summary, Background & Description, Market Analysis, Clinical and Quality Requirements, Operational Structure & Processes, Financial Projections, Critical Risk and Opportunities – Job Function Analysis – Salary, Wages and Benefits LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting Career Development: Pharmacy Purchasing Professional Career Levels Advancement, Security and Value • SMART – Specific, measurable, agreed upon, realistic and time-bound 1 Technician, Senior/Lead Technician 2 Buyer 3 Supervisor, Coordinator, Agent, Analyst 4 Manager, Regional, Corporate, GPOs, Beyond • FAMIC – Few in number and focused, aligned internally and organizationally, intended to build mastery; incremental; and controllable • FITEMA (AFITME) – Fairly determined, individual, task-focused, errortolerant, matched with the cadence of work and action-oriented LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting Scope Pharmacy Purchasing Professional Position Elements 1 Scope of practice 2 Education, certification, and training 3 Experience 4 Knowledge, skills and abilities LSHP 2015 Annual Meeting Technician Buyer Supervisor Manager Performs a variety of duties in addition to purchasing. Competent in the core elements of purchasing addendums. Fully competent in all elements of the operational addendums. Fully competent in all elements of the operational and financial addendums. Task Driven Inventory Management Supply Chain Management Strategic Management LSHP 2015 Annual Meeting 91 Education/Certification/Training Technician Buyer High School diploma (or GED). Must comply with state specific pharmacy technician regulations and requirements. Nationally Certified Technician required. 2 year college degree preferred. Nationally Certified Technician preferred. Supervisor Experience Manager Technician Nationally Certified Nationally Certified Technician required. Technician required. 4 year college degree 2 or 4 year college in related area required. degree in related area required. Certification and additional training in Certification and related area required. additional training in related area Masters preferred. preferred. 0 to 2 years of pharmacy technician experience. Buyer Supervisor 3+ years of hospital 2 to 3 years of hospital pharmacy pharmacy technician experience. technician experience. 2 to 3 years of pharmacy purchasing Purchasing experience in multiple experience acute care hospitals preferred. preferred. LSHP 2015 Annual Meeting Manager 5+ years of pharmacy purchasing experience in mid to large size hospitals or health systems. Established success in operational and financial arenas. LSHP 2015 Annual Meeting Job Overview Job Overview • Essential Functions • Essential Functions Continued – Establish and maintain appropriate cost effective on hand product availability – Conducts audits and analysis of contract compliance, invoices, charge master and department finances – Implement and maintain best practice in pharmacy supply chain operations – Prepare presentations, reports and other documents as needed relative to cost and assigned projects – Work with management, purchasing, accounts payable, business operations, clinical departments and hospital customers to identify opportunities of cost savings or clinical value – Maintain compliance LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting How can I become a Pharmacy Purchasing Professional? Resources • No Cost • Personal Assessment, Goals and Plan • KSA - ABCs – Social Media: industry specific topics/groups • Training Agenda – Library: books/article on supply chain, finance, operations – Analytics, Business and Communications – – – – – Determine needs: personal and employer Decide on type/style Negotiate commitment Document training Document new skills in action – Publications: Pharmacy related for trends/industry news – Employer: PowerPoint, communication skills, excel, etc – GPO & Wholesaler: educational offerings LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting 92 “The” Pharmacy Purchasing Professional of Tomorrow Resources • Low Cost • Nationally Certified Pharmacy Technician – Membership: NPPA, ASHP, AHRMM, APICS, PMI – Books, podcast, book summaries – Training/certificate courses – Certification – Conferences/Meetings • Bachelor's in Business Administration or Supply Chain Management with a minor in Management Information Systems • Certification in supply chain, healthcare supply chain, project management, business analyst, etc • High Cost • Diverse experience – internships, volunteering, organization involvement, etc – Formal education – Training programs • Master’s in Healthcare Administration or Business Administration LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting A “CPhPP” Future Hospital I now have options. Advanced Role - Medication Reconciliation Technician Business Manager Operation Manager Supply Chain Finance/Revenue Analyst Industry Regulatory Sales GPO Consulting Insurance Instructor Automation Policy Patient Safety Leadership cGMP LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting Med Rec Selection & Training Med Rec Financial Justification • Technician Candidate for Med Rec Program Average # of discrepancies / med errors per patient Adaptation of a template based on data at Northwestern Memorial Hospital – – – – – Strong communication skills Attention to detail Self motivated Hospital work experience Knowledge of commonly prescribed outpatient medications 43,312 Potential medication errors per year that can be avoided 95,286 % of medications that were potentially harmful to patient during hospitalization Number of harmful medication errors avoided per year $11,434,320 Avg pharmacist time requirement per admission One on One Pharmacist lead training Overview of program and EHR Role observation Responsibility and procedure review Instruction in patient interview techniques and EHR documentation 2.5% 2,382 Annual gross savings to Hospital ($4,800 per harmful error) • Training might include: – – – – – 2.2 Number of inpatient admission per year 21 minutes Additional pharmacist FTE needed to provide service (based on 115 admission daily) ~ 5 FTE Cost of additional pharmacist FTE (salary = benefits) $625,000 Annual Net Savings/Cost Avoidance $11.4M Replacing Rx for Tech could expand service at no net increase 1rx = 2 tech Source: Part of this template was presented by Steve Rough, MS, RPh at ASHP Summer meeting, 6/6/06. LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting 93 Technician Resources Conclusion • Associations/Boards/Societies • Organizations should support the hiring, development and retaining of quality Pharmacy Technicians – American Society of Health-System Pharmacists • www.ashp.org – American Association of Pharmacy Technicians • www.pharmacytechnician.com • Continuous education and training is needed for the advancement of the profession – Healthcare Information and Management Systems Society • www.himss.org – Louisiana Society of Health-System Pharmacists • www.lshp.org • Each Pharmacy Technician is responsible for the promotion and advancement of their profession – National Pharmacy Technician Association • www.pharmacytechnician.com – National Pharmacy Purchasing Association • www.pharmacypurchasing.com – Pharmacy Technician Educators Council • www.pharmacytecheducators.com – Pharmacy Technician Certification Board • www.PTCB.org LSHP 2015 Annual Meeting LSHP 2015 Annual Meeting Any Questions? Email: [email protected] 94 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May, 22 4:00—5:00 p.m. Sterile Compounding: USP <800> Hazardous Drugs Anne P. LaVance, BS, CPhT Director - Pharmacy Technician Program Delgado Community College New Orleans, LA 0179-0000-15-006-L04-P / 0179-0000-15-006-L04-T 1.0 contact hour (0.1 CEU) Knowledge-based activity Pharmacist Objectives: Identify the primary areas of focus for the health and safety management system for HDs Describe Primary and Secondary Engineering Controls for compounding HD Identify requirements for training personnel who handle HDs Identify Pharmacists responsibilities for handling hazardous drugs Discuss elements of a medical surveillance program Technician Objectives: Identify the primary areas of focus for the health and safety management system for HDs Describe Primary and Secondary Engineering Controls for compounding HD Identify requirements for training personnel who handle HDs Identify Pharmacy Technician responsibilities for handling hazardous drugs Discuss elements of a medical surveillance program Speaker has disclosed that she has no relevant financial relationships. 95 Learning Objectives: Pharmacist USP Chapter <800>: Hazardous Drugs • Review components of USP Chapter <797> pertaining to the Compounding of Hazardous Drugs (HDs) Pharmacy Technician Program Director – • List Facility requirements for • List requirements for training of • List requirements for training of personnel 1 Chapter <797> pertaining to the Compounding of HDs • Identify key USP Chapter Compounding HDs Delgado Community College • Review components of USP • Identify key USP Chapter <800>Sections involved in the Compounding of HDs Anne P LaVance, BS, CPhT Pharmacy Technician <800>Sections involved in the Compounding of HDs personnel • Review purpose and • Review purpose and requirements of Medical Surveillance ACPE Certified Trainer: requirements of Medical Surveillance 2 Sterile Compounding and Aseptic Technique USP <797> Hazardous Drugs as CSPs Change from USP <797> • Drugs are classified as hazardous if studies in • <797>: Allows facilities that prepare a low animals or humans indicate that exposures to them have a potential for causing cancer, development or reproductive toxicity, or harm to organs. volume of HDs to place BSC or CACI in a nonnegative pressure room • <800>(Proposed): Requires all HD • Occupational exposure to hazardous drugs can result in (1) acute effects, such as skin rashes; (2) chronic effects, including adverse reproductive events; and (3) possibly cancer. Source: 2015 USP Compounding Compendium compounding to be done in a separate area designated for HD compounding 3 4 USP<800>: Handling Hazardous Drugs Section 1: Introduction and Scope • Receipt • Storage • Compounding • Dispensing • Administration • Practice and Quality Standards for handling Hazardous Drugs (HDs) • Applies to sterile and non-sterile compounding • 19 sections • Purpose: protect healthcare personnel and patients 5 6 96 Section 2: List of Hazardous Drugs Health and Safety Management System / Occupational Safety Plan • • • • • • Engineering Controls • Competent personnel • Safe work practices • Proper use of appropriate PPE • Policies for HD waste and disposal NIOSH List of HDs1 Original List: 2004 Updated: 2010, 2012, and 2014 Table 1: Currently 96 Antineoplastic Drugs Table 2: Non-Neoplastic Drugs • Manufactures’ safe-handling recommendations (MSHG):10 drugs 7 8 Engineering Controls Section 5: Facilities • C-PEC • Designed to promote patient safety, worker safety, environmental protection, and infection prevention. • BSC or CACI • Designated areas for: • Receipt of HDs • Storage • Compounding • C-SEC • Negative Pressure room • Externally vented • 152 Air changes per hour • Supplemental Engineering Controls 9 Most Current Update 10 Containment Supplemental Engineering Controls: CSTD • Containment Segregated Compounding Area C-SCA • Separate, negative pressure room with at least 12 air changes per hours • Low/Medium-Risk • Prepared in BSC or CACI in a C-SCA • BUD cannot exceed 12 hours BD PhaSeal Equashield ChemoClave/ChemoLock (ICUMedical) 11 12 97 Section 6: Environmental Quality and Control Section 7: PPE • Wipe sampling – every 6 months • Interior or the C-PEC and equipment within • Staging / work areas near the C-PEC • Areas adjacent to C-PEC • Gloves: 2 pairs; change every 30 minutes • Gowns: non-absorbent, back closing, long sleeved, closed cuffs; changed every 2-3 hours • Head, Hair, Shoe, and Sleeve Covers • Face shield and/or goggles 13 14 Section 9: Personnel Training Section 10: Receiving • Training must be completed prior to handling HDs • Validated every 12 months or when new or significant changes in process or SOP occurs • List of HDs and their Risks • Review of SOPs related to HDs • Proper use of PPE • Proper use of equipment and devices • Spill management • Response to known or suspected HD exposure • Separate from other drugs in supplier sealed impervious plastic • Moved to HD receiving area • Chemo gloves • Accessibility to Spill Kit 15 16 Section 13: Compounding Section 15: Decontamination and Cleaning • USP <797> • Clean and Deactivate/Decontaminate areas where HDs are handled, and all reusable equipment and devices. • Clean between compounding different HDs, when there is a spill • Clean under work tray monthly • Decontamination: sodium hypochlorite, surfactant, and thiosulfate neutralizer • Chemo mat • Prime tubing before compounding • If not using a CTSD, use negative pressure • Use ¾ rule for selecting syringe 17 18 98 Section 18: Documentation and SOPs Section 18: Documentation and SOPs • SOPs must be reviewed annually • • • • • • • SOPs must be reviewed annually (con’t) Hazard communication program Occupational safety program Labeling of HDs Procurement of HDs Use of proper engineering controls Use of PPE based on activity • Decontamination/Deactivation, cleaning and • • • • disinfection Transport Environmental Monitoring Spill Control Medical Surveillance 19 20 Section 19: Medical Surveillance USP <800> • General purpose: • minimize adverse health effects in personnel potentially exposed to HDs • Current revision of proposed USP General Chapter • Initial baseline assessment of health status <800> was posted in Dec 2014 on the USP website and published March-April issue of the Pharmacopeial Forum. and medical history • Assessment and documentation of symptom • Open for public comment until May 31, 2015 complaints, physical findings, and lab values • Follow up plan • Maintained according to OSHA regulations 21 22 RESOURCES • 1NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, (Sept. 2104) http://www.cdc.gov/niosh/docs/2014-138/default.html • McCarney,Lisa, BAAS, CPhT, PhTR (2012). Sterile Compounding and Aseptic Techniques; St. Paul, MN: Paradigm Publishing Inc. • Ochoa, Pamella S., and Vega, Jose’ A. (2015). Concepts in Sterile Preparations and Aseptic Technique. Burlington, MA: Jones & Bartlett Learning. • The United States Pharmacopeial Convention (2015). 2015 USP Compounding Compendium; Update Feb 2015: <797> 43-87 • USP Briefing: (800) Hazardous Drugs – Handling in Health care Settings, PF 40(3) [May-Jun. 2013] http://www.usp.org/sites/default/files/usp_pdf/EN/m7808_pre-post.pdf 23 99 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Friday, May 22 5:00—7:00 p.m. A Pharmacists Guide to Using Fluids, Vasopressors, and Inotropes in Shock Craig Worby, PharmD, BCPS Clinical Assistant Professor University of New England 0179-0000-15-008-L01-P / 0179-0000-15-008-L01-T 2.0 contact hours (0.2 CEUs) Knowledge-based activity Pharmacist Objectives: Differentiate between hypovolemic shock, cardiogenic shock, and distributive shock Compare and contrast options for fluid resuscitation Discuss the pharmacology, dosing, adverse effects, and place of therapy for vasopressors and inotropes Examine the primary literature for fluids, vasopressors, and inotropes influencing current and future practice Describe an appropriate, individualized vasopressor/inotrope regimen for a patient in shock Technician Objectives: Recognize the importance of administration of fluids, vasopressors, and inotropes during shock Explain the pharmacology and common uses of fluids, vasopressors, and inotropes Identify common formulations and concentrations of vasopressors and inotropes Speaker has disclosed that he has no relevant financial relationships. 100 Disclosures • Nothing to disclose • No conflicts of interest A Pharmacist’s Guide to Using Fluids, Vasopressors, and Inotropes in Shock Craig Worby, PharmD, BCPS Clinical Assistant Professor University of New England College of Pharmacy Clinical Pharmacist – Cardiothoracic ICU Maine Medical Center Pharmacist Objectives Technician Objectives • Differentiate between hypovolemic shock, cardiogenic shock, and distributive shock • Compare and contrast options for fluid resuscitation • Explain the pharmacology, dosing, adverse effects, and place of therapy for vasopressors and inotropes • Examine the primary literature for fluids, vasopressors, and inotropes influencing current and future practice • Choose an appropriate, individualized vasopressor/inotrope regimen for a patient in shock • Recognize the importance of administration of fluids, vasopressors, and inotropes during shock • Explain the pharmacology and common uses of fluids, vasopressors, and inotropes • Identify common formulations and concentrations of vasopressors and inotropes Outline Vascular Terminology 1. 2. 3. 4. 5. • Mean Arterial Pressure (MAP) Hemodynamic Principles Shock States Fluid Resuscitation Using Vasopressors Using Inotropes – Mean pressure in central arterial bed – Determined by CO and SVR – MAP = ((2*DBP) + SBP)/3 • Systemic Vascular Resistance (SVR) – Measure of impedance applied by systemic vascular system to systolic effort of left ventricle – SVR = ((MAP‐CVP)/CO) * 80 • Afterload – Ventricular wall tension developed during systole – Determined by resistance or impedance the ventricle must overcome to eject end‐diastolic volume Hoffman EW. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64. 101 Cardiac Terminology Volume Status Terminology • Heart Rate (HR) • Preload – Number of myocardial contractions per minute – End diastolic fiber length before contraction • Stroke Volume (SV) – Amount of blood ejected from the ventricle with each systolic contraction • Pulmonary capillary wedge pressure (PCWP) – Measures pressure distal to pulmonary artery – Reflects left ventricular filling pressures • Cardiac Output (CO) – Amount of blood ejected from the left ventricle per minute – CO = SV x HR • Central venous pressure (CVP) • Cardiac Index (CI) – Measures mean pressure in right atrium and reflects right ventricular filling process – Amount of blood ejected from the left ventricle adjusted for size of the patient – CI = CO/BSA Hoffman EW. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64. Hoffman EW. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64. Normal Values MAP = SVR * CO Parameter Value Blood pressure (BP) 120‐140/80‐90 mm Hg Mean Arterial Pressure (MAP) 80‐100 mm Hg Cardiac Output (CO) 4‐7 L/min Cardiac Index (CI) 2.8‐3.6 L/min/m2 Central Venous Pressure (CVP) 2‐6 mm Hg Cardiac Output CO = SV * HR MAP Heart Rate (HR) 60‐80 BPM Pulmonary Capillary Wedge Pressure (PCWP) 5‐12 mm Hg Stroke Volume (SV) 60‐130 mL/beat Systemic Vascular Resistance (SVR) 800‐1400 dyne/sec/m2 Stroke Volume SVR Hoffman EW. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64. MAP = SVR * CO Inotropes (CO) Monitoring CO = SV * HR • Central Venous Catheter – Ends in the superior vena cava or right atrium – Measures CVP • Pulmonary Artery Catheter (Swan‐Ganz) MAP Vasopressors (SVR) – Measures pulmonary capillary wedge pressure, cardiac output, SVR, and other parameters Fluids (SV, CVP, PCWP) 102 Outline 1. 2. 3. 4. 5. Shock Hemodynamic Principles Shock States Fluid Resuscitation Using Vasopressors Using Inotropes • A syndrome in which the circulatory system fails to maintain adequate cellular perfusion • Typically accompanied by persistent hypotension Pathophysiology Classic Presentation • Insult triggers cascade of events ultimately leading to organ dysfunction and cell death • Common pathways • Systolic blood pressure < 90 mm Hg or change in baseline > 60 mm Hg • Tachycardia (HR > 90 BPM) • Tachypnea (respiratory rate > 20 breaths per minute) • Signs and symptoms of hypoperfusion – Ischemia endogenous inflammatory cytokine release generation of oxygen free radicals – Prolonged ischemia triggers initiation of anaerobic metabolism • Decreased ATP stores • Build up of lactic acid and other toxic substances – Irreversible cellular damage, multi‐organ failure, death Clinical Signs of Hypoperfusion Types of shock • Altered mental status • Serum creatinine increase > 0.5 mg/dL • Oliguria (urine output < 0.5 mL/kg/hr for 2 hours despite fluid resuscitation) • Ileus • Cold, clammy, mottled skin (exception: distributive shock) • Metabolic acidosis (elevated lactate) • Hypovolemic shock • Distributive shock – Septic shock – Anaphylaxis – Neurogenic • Cardiogenic shock 103 Hypovolemic Shock Distributive Shock • Reduction in intravascular volume • Causes: • Loss of vascular tone causing acute tissue hypoperfusion • Causes: – External loss of fluid • Trauma, bleeding – Sepsis – Anaphylaxis – Neurogenic – Third spacing • Compensatory mechanisms – Increased HR, contractility, and SVR • Treatment: administration of fluids and/or blood products Erstad BL. Hypovolemic Shock. Pharmacotherapy: A Pathophysiologic Approach. 2008; p 441‐454. Pathophysiology Septic Shock • Pathophysiology – Proinflammatory molecules upregulate adhesion molecules in neutrophils and endothelial cells – Inflammatory mediators released by neutrophils damage endothelial cells – Endothelial cells release nitric oxide to promote vasodilation • Hemodynamic changes – Decreased SVR – Decreased PCWP – Compensatory increase in CO, followed by decrease Russell JA. N Engl J Med. 2006 Oct 19;355(16):1699‐713. Cardiogenic Shock Cardiogenic Shock • “Persistent hypotension and tissue hypoperfusion due to cardiac dysfunction in the presence of adequate intravascular volume and left ventricular filling pressure.” • Causes • Pathophysiology – Impaired left ventricular function, reduced systolic contractility, decreased cardiac output and arterial blood pressure – Compensatory responses • RAAS activated • Systemic vasoconstriction – Nonmechanical • Myocardial infarction • Acute exacerbations of heart failure • Progressive deterioration of myocardial function, worsening ischemia – Mechanical – Increased left ventricular filling pressures – Pulmonary congestion and edema • Pericardial tamponade • Tension pneumothorax 104 Cardiogenic Shock Hemodynamic Changes In Shock • Hemodynamic changes Hypovolemic Distributive Heart Rate Blood Pressure / Cardiac Output / PCWP (Preload) SVR (Afterload) – Decreased cardiac index • CI < 2.2 L/min/m2 – Elevated pulmonary capillary wedge pressure • PCWP > 25 mm Hg – Systolic BP < 90 mm Hg for ≥ 30 minutes MAP = SVR * CO General Treatment Principles Cardiogenic CO = SV * HR Choosing an Agent • Does the patient have a Swan‐Ganz catheter? 1. Individualized care – Does the patient have a Swan‐Ganz catheter? – Treat the patient, not the number – Correct abnormalities • What is the cause of hypoperfusion? 2. Identify and treat the underlying cause – Hypovolemia vs. sepsis vs. STEMI – Hypovolemia – stop hemorrhage, volume repletion – Sepsis – antibiotics – STEMI – cardiac reperfusion • Literature and guidelines – Surviving Sepsis – AHA STEMI – AHA Heart Failure 3. Restore volume – Caution in cardiogenic shock • Patient specific concerns 4. Hemodynamic support – Tachycardia – Arrhythmias – Vasopressors – Inotropes Treatment of Cardiogenic Shock Secondary to Myocardial Infarction Septic Shock Treatment • Pulmonary Artery Catheter? • Fluid Challenge • Initial resuscitation (within 6 hours) – CVP 8‐12 mm Hg – MAP ≥ 65 mm Hg – Urine output ≥ 0.5 mL/kg/hr – Central venous oxygen saturation ≥ 70% – No more than 100‐250 mL at a time – Severe LV impairment – increased intravascular volume can worsen pulmonary congestion • Inotropes or vasopressors should be used to increase MAP and reestablish coronary perfusion • Alternative: mixed venous oxygen saturation ≥ 65% – May exacerbate ventricular arrhythmia and increase oxygen consumption – Goal of therapy – MAP: 65‐70 mmHg – Early administration of antibiotics • Hemodynamic support/adjunctive may be needed to reach goals • Cardiac catheterization or revascularization • IABP or VAD Dellinger RP. Crit Care Med. 2013 Feb;41(2):580‐637. 105 MAP = SVR * CO AMI, ADHF Inotropes (CO) Patient Case: SM CO = SV * HR SM is an 80 year old male 5’8” 98 kg who was transferred to the ICU an hour ago after undergoing a successful aortic valve replacement with a Magna‐Ease valve. HPI: SM presented to the hospital this morning to undergo an elective aortic valve replacement. He reports that he has been having problems walking for a year. An echo shows LV dysfunction with mild dilatation, EF = 30%, and aortic valve stenosis. MAP Allergies: spironolactone Sepsis Vasopressors (SVR) Hypovolemia Fluids (SV, CVP, PCWP) PMH: Hyperlipidemia, coronary artery disease, aortic valve stenosis, CHF, atrial fibrillation Patient Case: SM Home Meds: Warfarin 2 mg daily Atorvastatin 40 mg daily Furosemide 80 mg twice daily Lisinopril 2.5 mg daily Carvedilol 6.25 mg twice daily General Treatment Principles 1. Individualized care – Does the patient have a Swan‐Ganz catheter? – Treat the patient, not the number 2. Identify and treat the underlying cause – Hypovolemia – Sepsis – Cardiogenic 3. Restore volume 4. Hemodynamic support – Vasopressors – Inotropes Fluid Compartments Intracellular Fluid (ICF) 60% Total Body Water Fluid Resuscitation Interstitial Fluid 75% ECF Intravascular space 25% ECF Extracellular Fluid (ECF) 40% Total Body Water 106 The Ideal Fluid Fluids • Predictable and sustained increase of intravascular volume • Chemical composition resembles extracellular fluid • Metabolized and excreted without accumulation • No adverse effects • Cheap • Crystalloid fluids – Isotonic sodium containing fluids • Normal Saline (NS) • Lactated ringers (LR) • Plasma‐Lyte, Normosol‐R • Colloids – Large molecular weight solutions • Albumin • Hetastarches (Voluven, Hespan, Hextend) • Dextran No such fluid exists Myburgh JA. N Engl J Med. 2013 Sep 26;369(13):1243‐51. Myburgh JA. N Engl J Med. 2013 Sep 26;369(13):1243‐51. Crystalloid vs. Colloid Intravascular Space • Distribution – Isotonic crystalloids – freely distribute to extracellular fluid compartments 0.9% Saline • 3:1 ratio crystalloid volume to colloid volume • Clinically the ratio is lower 1.4:1 – Colloids – expand intravascular space with minimal loss to interstitial spaces 5% Albumin • Less volume needed to resuscitate • Longer duration of action • Allergic/hypersensitivity reactions Interstitial Space Myburgh JA. N Engl J Med. 2013 Sep 26;369(13):1243‐51. Finfer S. N Engl J Med. 2004 May 27;350(22):2247‐56. Adapted from: Erstad BL. Hypovolemic Shock. Pharmacotherapy: A Pathophysiologic Approach. 2008; p 441‐454. Fluid Principles • Crystalloids preferred over colloids • Multicenter, blinded, randomized controlled trial • Adult patients admitted to the ICU • Voluven vs. 0.9% saline – Colloids show no clinical benefits over crystalloids – Colloids are more expensive than crystalloids – Colloids may provide a faster hemodynamic response BUT this does not correspond to improved clinical outcomes like mortality – Hetastarches are associated with a higher risk of acute kidney injury – 3315 received Voluven – 3336 received 0.9% saline • Results – No differences in 90 day mortality – Increased need for RRT in Voluven (7.0% vs 5.8%, RR = 1.21 95% CI 1‐1.45, p=0.04) – Patients who received Voluven had a higher SCr • Conclusion – No clinical benefit to justify use of HES Myburgh JA. N Engl J Med. 2013 Sep 26;369(13):1243‐51. Finfer S. N Engl J Med. 2004 May 27;350(22):2247‐56. Myburgh JA. N Engl J Med. 2012 Nov 15;367(20):1901‐11. 107 Hetastarches SAFE Trial (2004) • Multisite, double‐blind, RCT • Adult patients predominantly trauma and sepsis • 4% albumin vs. saline 0.9% – 3473 patients received albumin – 3460 patients received saline • Primary outcome: 28 day mortality • Results – No difference in mortality • Albumin vs saline: 20.9% vs. 21.1%, p=0.99 – No difference survival time, length of hospital and ICU stay – Patients in albumin group required less fluid on day 1 and 2 • No clinical difference in hemodynamics – Albumin may have slight mortality benefit in severe sepsis http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm Finfer S. N Engl J Med. 2004 May 27;350(22):2247‐56. ALBIOS Trial (2014) Bottom Line Albumin may have slight mortality benefit in severe sepsis (SAFE 2004) No evidence colloids are better over crystalloids – ALBIOS – No difference in 28 day or 90 day mortality Crystalloids preferred due to cost • 28 day mortality = 31.8% albumin vs 32.0% crystalloid (RR = 1.00, 95% CI 0.87‐1.14, p=0.94) • 90 day mortality = 41.1% albumin vs 43.6% crystalloid (RR = 0.94, 95% CI 0.85‐1.05, p=0.29) But does choice of crystalloid matter? Finfer S. N Engl J Med. 2004 May 27;350(22):2247‐56. Caironi P, Tognoni G, Masson S. N Engl J Med. 2014 Apr 10;370(15):1412‐21. • Primary outcome • Prospective open label sequential pilot study – Increase in SCr from baseline to peak – Incidence of AKI – February 2008 – August 2008: Chloride rich solution • NS, gelatin solutions, 4% albumin – August 2008 – February 2009: Chloride poor solution • Secondary outcomes • Hartmann solution, Plasma‐Lyte, 20% albumin – Need for dialysis – ICU length of stay – Mortality • 1533 patients – 760 patients during control period – 773 patients during intervention period Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72. Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72. 108 Hartog Hamburger – Father of “Normal Saline” • Erroneously suggested 0.9% was the concentration of salt in human blood • Results – Data derived from IN VITRO experiments involving RBC lysis (1882‐1883) – Never intended for clinical use – Intervention group lower SCr increase (14.8 μmol/L) than control group (22.6 μmol/L) P = 0.03 – Lower risk of dialysis with intervention group (OR = 0.52 95% CI 0.33‐0.81, p = 0.004) • Fewer intervention patients classified as at risk of AKI (3.0% vs 6.3% P = 0.002) • No differences ICU length of stay • No differences mortality Hartog Hamburger – Dutch physiologist • Term “Normal Saline” historically referred to solutions of varying compositions NOT Hamburger’s solution • Mystery as to how Hamburger’s solution made its way into clinical practice – easy to formulate? Inexpensive? Awad S. Clin Nutr. 2008 Apr;27(2):179‐88. Myburgh JA. N Engl J Med. 2013 Sep 26;369(13):1243‐51. Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72. Human Plasma Chloride Containing Solutions • Supraphysiologic doses of chloride may be detrimental • Can lead to a hyperchloremic metabolic acidosis • Possible mechanisms of AKI – Renal vasoconstrictive effect of tubular chloride reabsorption – Activation of tubuloglomerular feedback triggers arterial vasoconstriction and decrease in GFR – Enhances responsiveness to vasoconstrictor agents such as angiotension II Albumin 5% Voluven Normal Saline Ringer’s Lactate Plasmalyte Colloid Colloid Crystalloid Crystalloid Crystalloid Osmolarity (mOsm/L) 291 309 308 308 280.6 294 Sodium (mmol/liter) 135‐145 130‐160 154 154 131 140 Potassium (mmol/liter) 4.5‐5.0 5.4 5.0 Calcium (mmol/liter) 2.2‐2.6 2.0 Magnesium (mmol/liter) 0.8‐1.0 Chloride (mmol/liter) 94‐111 3.0 130‐160 154 154 111 Acetate (mmol/liter) Lactate (mmol/liter) 1‐2 Bicarbonate (mmol/liter) 23‐27 29 Gluconate (mmol/liter) Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72. • Retrospective cohort study using claims data • 53,448 adult patients with sepsis treated with vasopressors and crystalloids • Patients were stratified into quintiles based on the percentage of total crystalloids that was a balanced fluid • Primary outcome: in‐hospital mortality occurring after day 2 • Secondary outcomes: acute renal failure 98 27 23 • Results – Balanced fluids had a lower mortality than non‐balanced fluids • 19.6% vs. 22.8% (RR = 0.86, 95% CI 0.78‐0.94, p=0.001) • For each 10% increase in proportion of balance fluid used, mortality decreased on average by 3.4% – No difference in acute renal failure between balanced and non‐balanced fluids • With dialysis – 4.52% vs 4.74% (RR = 0.953, 95% CI = 0.761‐1.150) • Without dialysis – 7.12% vs. 7.50% (RR = 0.950, 95% CI = 0.784‐ 1.150) – No difference hospital or ICU LOS Raghunathan K. Crit Care Med. 2014 Jul;42(7):1585‐91. Raghunathan K. Crit Care Med. 2014 Jul;42(7):1585‐91. 109 Fluids Clinical Pearls Patient Case: SM SM received 500 mL lactated ringer’s solution, 1500 mL isotonic saline, 500 mL albumin. A Swan‐ganz catheter is placed • No difference in clinical outcomes between crystalloids and colloids • Crystalloids preferred over colloids due to cost – Chloride‐rich solutions = increased nephrotoxicity? • Avoid hetastarch due to association with increased nephrotoxicity What intervention would be most appropriate for the treatment of SM’s hemodynamic instability? α1 agonism Location Post synaptic‐ smooth muscle, small amounts on heart muscle α2 agonism β1 agonism Cardiac muscle Pre synaptic regulating norepinephrine release into the synaptic cleft Using Vasopressors Physiologic effects Constrict Vasodilation, arteries & veins sedation ↑ SVR Hemo‐ dynamic effect ↑ MAP Location β2 agonism Dopamine agonism V1 agonism Vascular and bronchial smooth muscle, small amounts on cardiac muscle Smooth muscle in renal, splanchnic, coronary, and cerebral vascular beds Smooth muscle in blood vessels, hepatocytes, and platelets Vasodilation Vasodilate & increase blood flow to the kidneys Vasoconstriction Increase urine output ↑ SVR ↑ MAP Physiologic effects ↓ SVR Hemo‐ dynamic effect ↓ SVR Inotropic effect Chronotropic effect ↑ HR, ↑ CO Vasopressin Epstein FH. N Engl J Med 2001;345:589. 110 Vasopressor Treatment Principles: Common Adverse Drug Effects Vasopressor Use Guidelines • Ensure adequate trial of fluid resuscitation (30 mL/kg) prior to initiating vasopressors • Administer through a central line if able • All vasopressors that have alpha‐1 agonism – Excessive vasoconstriction/organ ischemia – Tissue necrosis – Bradycardia – Extravasation through peripheral line can cause localized skin necrosis • All vasopressors that have beta‐1 agonism • Titrate to the lowest possible dose to maintain adequate tissue perfusion – Tachycardia – Potential for arrhythmias – Many vasopressors increase cardiac oxygen demand – Treat the patient not the number Dellinger RP. Crit Care Med. 2013 Feb;41(2):580‐637. Norepinephrine Septic Shock – Hemodynamic Support • Vasopressors – – – – • Neurotransmitter of the sympathetic nervous system 1st – Norepinephrine 2nd – Epinephrine 3rd – Vasopressin Alternatives: phenylephrine, dopamine – Precursor of epinephrine • Catecholamine with both alpha and beta effects • Inotropes (if decreased CO in the setting of adequate PCWP) – Alpha effects > beta effects – Dobutamine • Causes vasoconstriction of arterioles • Corticosteroids – For relative adrenal insufficiency/blood pressures unresponsive to fluids and vasopressors – Hydrocortisone 50 mg IV q6h – Constricts both renal afferent and efferent arteriole Dellinger RP. Crit Care Med. 2013 Feb;41(2):580‐637. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Norepinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Norepinephrine Norepinephrine • Hemodynamic effects • Usual dose – Alpha 1: Vasoconstriction – increased SVR – Beta 1: Mild increases in contractility and heart rate – no effect on CO – Starting infusion rate: 0.01 – 0.05 mcg/kg/min – May titrate up to 2 mcg/kg/min • Dosage forms • Increased myocardial oxygen consumption – 1 mg/mL (4 mL) vial • Dilute 4 mg in 250 mL (16 mcg/mL) or 8 mg in 250 mL (32 mcg/mL) in D5W or NS • D5W protective against oxidation and degradation Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Norepinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Norepinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. 111 Norepinephrine Adverse Effects • Alpha effects • Multisite, double blind RCT • Comparison of dopamine vs norepinephrine as first line vasopressor in various shock states • 1679 patients enrolled – Excessive vasoconstriction • Compromise of organ perfusion – Worsening of ventricular function • Increased afterload – 858 received dopamine – 821 received norepinephrine – Tissue necrosis and sloughing • Beta effects – Cardiac arrhythmias Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Norepinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. De Backer D. N Engl J Med. 2010 Mar 4;362(9):779‐89. • No significant difference in 28 day mortality (52.5% dopamine, 48.5% norepinephrine, OR 1.17 (0.97‐1.42), p = 0.10) • Arrhythmias occurred in 24.1% dopamine patients vs 12.4% norepinephrine patients (p < 0.001) • Statistically significant higher 28 day mortality in cardiogenic shock subgroup with dopamine use • 1360 patients from 11 trials – 5 trials observational – 6 trials interventional • No difference in mortality with dopamine in observational trials – RR = 1.09 (95% CI 0.84‐1..41, p = 0.72) – Significant heterogeneity in outcomes, vasopressors used • Increased mortality with dopamine in interventional trials – RR = 1.12 (95% CI 1.01‐1.20; p = 0.035) – Only two trials had 28 day mortality as the primary endpoint De Backer D. N Engl J Med. 2010 Mar 4;362(9):779‐89. De Backer D. Crit Care Med. 2012 Mar;40(3):725‐30. Epinephrine Epinephrine • Hemodynamic effects • Endogenous hormone synthesized by norepinephrine • Circulating hormone produced and released by adrenal glands in response to stress • α1, β1, and β2 adrenergic agonist – Low doses (0.01 ‐0.05 mcg/kg/min) • Activates β1 and β2 receptors – Beta 1: Increases heart rate and contractility – increased CO – Beta 2: Vasodilatory – Moderate‐high doses (0.05‐3 mcg/kg/min) • Activates α1, β1, and β2 receptors – Primary vasoconstriction effect on small arterioles and precapillary sphincters – Beta 1: Increases heart rate and contractility –increased CO – Alpha 1: Vasoconstriction – increased SVR • The most potent alpha receptor activator Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Epinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. 112 Epinephrine Epinephrine Adverse Effects • • • • • • Usual Dose – 0.05‐0.2 mcg/kg/min – Max dose: 0.8 mcg/kg/min • Dosage forms: Hyperglycemia Lactic acidosis Restlessness Headache Alpha effects Effects are transient, resolve after 24 hours – Excessive vasoconstriction • Compromise of organ perfusion – 1 mg/mL (1 mL) vial – Extravasation • Dilute 1 mg in 250 mL (4 mcg/mL) or 4 mg in 250 mL (16 mcg/mL) of D5W or NS • Beta effects – Tachycardia – Tachyarrhythmias – Anginal pain Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Epinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Epinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. • Prospective, multisite, randomized controlled trial in Australia • 277 patients enrolled • No difference in time to achieve MAP goal, vasopressor free days • No difference in mortality in any group, subgroup • Epinephrine associated with significant increases in tachycardia and lactic acidosis which resolved in the first 24 hours – 139 received epinephrine – 138 received norepinephrine • 66% of patients not on vasopressors at enrollment – Higher withdrawal from study due to adverse effects than norepinephrine (12.9% vs 2.8%, p = 0.002) • No difference in supraventricular arrhythmias Myburgh JA. Intensive Care Med. 2008 Dec;34(12):2226‐34. Epub 2008 Jul 25. Myburgh JA. Intensive Care Med. 2008 Dec;34(12):2226‐34. Epub 2008 Jul 25. • Prospective, multicentered, randomized, double blind study • 330 patients enrolled • No difference observed in any mortality outcome (13 deaths NE+DOB, 13 deaths EPI) • Epinephrine patients had a higher arterial pH through day 4 and higher arterial lactate concentration at day 1 • No significant differences in adverse events – 169 received norepinephrine + dobutamine – 161 received epinephrine – Included patients refractory to high dose dopamine, or any dose of norepinephrine or epinephrine • Primary Endpoints – 28 day all cause mortality • Secondary endpoints – Mortality rates at day 7, 14, 90 ICU discharge, hospital discharge – Systemic hemodynamics – Arterial pH and lactate Annane D. Lancet. 2007 Aug 25;370(9588):676‐84. Annane D. Lancet. 2007 Aug 25;370(9588):676‐84. 113 Vasopressin Vasopressin • Dosing • Endogenous peptide hormone • Agonist at V1 and V2 receptors – VASST Trial: 0.01‐0.03 units/min – Surviving Sepsis: 0.03 units/min fixed dose adjunctive – Vasostrict® PI: 0.01 units/min, titrate up by 0.005 units/min at 10‐15 minute intervals (Max dose: 0.07 units/min) – Higher affinity V2 than V1 • Septic shock – relative vasopressin deficiency • Hemodynamic effects – Vasoconstriction – Associated with lower heart rates • Dosage forms – 20 units/mL (1 mL) vial – 2.5 mL vasopressin in 500 mL NS or D5W (0.1 units/mL) – Fluid restricted: 5 mL vasopressin in 100 mL NS or D5W (1 unit/mL) • Discard unused diluted solution after 18 hours room temp or 24 hours refrigerated • Unpunctured vials can be stored up to 12 months at room temperature Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Vasopressin. In: DRUGDEX® System [Internet database]. Updated periodically. Vasotrict(R) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies Inc. 2014 Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Vasopressin. In: DRUGDEX® System [Internet database]. Updated periodically. Vasotrict(R) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies Inc. 2014 Vasopressin • Multicenter, randomized, stratified, double‐blind trial • Included patients in septic shock unresponsive to 500 mL bolus of fluid and 5 mcg/min norepinephrine • 778 patients randomized • Adverse events – Increased incidence of cardiac arrest? – Decreased cardiac output? – Hyponatremia – Mesenteric ischemia – Skin necrosis – Digital ischemia – 396 patients: vasopressin – 382 patients: norepinephrine • No difference 28 day mortality (35.4% vaso, 39.3% norepi) – Trend favoring vasopressin in less severe septic shock • No difference secondary outcomes – No difference 90 day mortality – No difference rate of organ dysfunction • Vasopressin allowed for rapid decrease in norepinephrine dose while maintaining MAP (“catecholamine sparing”) Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Vasopressin. In: DRUGDEX® System [Internet database]. Updated periodically. Vasotrict(R) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies Inc. 2014 Russell JA. N Engl J Med. 2008 Feb 28;358(9):877‐87. VASST Sub‐Group Analyses • Single center, randomized controlled, open label trial • Included patients with vasodilatory shock due to sepsis, SIRS, or cardiac surgery • Reduced mortality in patients at risk for AKI • Reduced mortality in patients with less severe shock • Reduced mortality if vasopressin administered early (within 12 hours) than late • Vasopressin + steroids use led to decreased mortality than norepinephrine + steroids • No increase in myocardial ischemia or decreased cardiac output – Required NE > 0.6 mcg/kg/min • 50 patients randomized – 25 received vasopressin 0.033 units/min • Dose range: 2‐16 mcg/min – 25 received vasopressin 0.067 units/min • Primary outcome – Hemodynamic response • Secondary outcomes – Differences in organ function and lab values – AVP and prolactin levels – ADE rate Gordon AC. Intensive Care Med. 2010 Jan;36(1):83‐91. Epub 2009 Oct 20. Gordon AC. Chest. 2012 Apr 19. [Epub ahead of print] Mehta S. Crit Care. 2013 Jun 20;17(3):R117. Torgersen C. Intensive Care Med. 2010 Jan;36(1):57‐65. 114 Dose Baseline 1 hour 12 hour 24 hours 48 hours P value 0.033 units 65 +/‐ 9 71 +/‐ 12 71 +/‐ 11 71 +/‐ 10 75 +/‐ 7 P = 0.06 0.067 units 65 +/‐ 9 78 +/‐ 13 69 +/‐ 14 71 +/‐ 7 75 +/‐ 7 • Results – Mortality similar in both groups MAP • 6 patients in low dose, 4 patients in high dose (p=0.73) – ADEs comparable in both groups (LD vs. HD) • • • • NE dose (mcg/kg/min) 0.033 units 0.98 +/‐ 0.6 0.94 +/‐ 0.82 0.85 +/‐ 0.96 0.57 +/‐ 0.39 0.4 +/‐ 0.31 0.067 units 0.86 +/‐ 0.34 0.64 +/‐ 0.37 0.69 +/‐ 0.78 0.65 +/‐ 1.4 0.22 +/‐ 0.16 P = 0.06 Decrease CI (25% vs. 50%, p=0.26) Elevated LFTs (47.6% vs. 65.2%, p = 0.36) Increased bilirubin (19% vs. 26.1%, p=0.72) Decreased platelets (71.4% vs. 73.9%, p=1) Torgersen C. Intensive Care Med. 2010 Jan;36(1):57‐65. Torgersen C. Intensive Care Med. 2010 Jan;36(1):57‐65. Phenylephrine Phenylephrine • Pure alpha agonist • Usual dose: 0.2‐0.5 mcg/kg/min • Dosage form – Causes vasoconstriction of most vascular beds • Alternative in patients who cannot tolerate tachycardia or arrhythmias from dopamine or norepinephrine • Hemodynamic effect – 10 mg/mL (1 mL, 5 mL, 10 mL) vials – Vazculep® ‐ 10 mg/mL (1 mL, 5 mL, 10 mL) vials – Dilute to 10 mg in 500 mL (20 mcg/mL), 50 mg in 500 mL (100 mcg/mL), or 100 mg in 500 mL (200 mcg/mL) D5W or NS – Increases systolic, diastolic pressure and MAP Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Phenylephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Phenylephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Phenylephrine Dopamine • Endogenous neurotransmitter in CNS and PNS • Adverse effects – precursor of norepinephrine – Alpha effects • Direct and indirect effects • Excessive vasoconstriction – Compromise of organ perfusion – Direct – stimulates alpha, beta, and dopamine receptors – Indirect – stimulates release of norepinephrine from sympathetic nerves • Extravasation • Reflex bradycardia – Caution in patients with decreased CO » Impaired preload + bradycardia = worsen CO • Stimulates dopaminergic receptors in the splanchnic, renal, and coronary vascular beds • Low concentration solutions at high doses = large amounts of fluid administered – Produces vasodilation, improved renal blood flow Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Phenylephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dopamine. In: DRUGDEX® System [Internet database]. Updated periodically. 115 Dopamine Dopamine • Hemodynamic effects • Dosing – 2 – 5 mcg/kg/min – 0.5 – 3 mcg/kg/min • Increases cardiac contractility and cardiac output • No changes in heart rate, blood pressure, SVR • Activates D1 receptors in renal vascular beds • “Renal sparing dose” – > 10 mcg/kg/min – 3 – 10 mcg/kg/min • Increases blood pressure, mean arterial pressure – increased SVR • Activates β1‐adernergic receptors • Minimal activation of α1‐adernergic receptors • Inotropic, chronotropic, vasoactive properties – 10 – 20 mcg/kg/min • Mixed β1 and α1 adrenergic response – Effects are dose dependent – > 20 mcg/kg/min • Stimulates dopaminergic receptors in the splanchnic, renal, and coronary vascular beds • Predominant stimulation of peripheral α1‐adernergic receptors Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dopamine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dopamine. In: DRUGDEX® System [Internet database]. Updated periodically. Dopamine “Low‐Dose” Dopamine • In healthy volunteers, increases renal blood flow and induces naturesis and diuresis • Attenuates renal injury? • Bellomo, etal – Lancet 2000 • Dosage Forms – Premix – 200 mg/250 mL, 400 mg/250 mL, 800 mg/250 mL in D5W – 40 mg/mL (5 mL, 10 mL), 80 mg/mL (5 mL), 160 mg/ mL (5 mL) vials – Double blind, placebo controlled RCT – 328 patients with at least 1 indicator of renal dysfunction • 163 – “low‐dose” dopamine (2 mcg/kg/min) • 165 – Placebo • dilute 400 mg or 800 mg in 250 mL NS or D5W – Results • Protect from light • No difference in peak serum creatinine, increase in creatinine, # of patients acute renal failure, or # of patients requiring hemodialysis • No differences in length of stay, mortality – Do not use if yellow‐brown discoloration • • • • • • “Low‐Dose” dopamine cannot be recommended Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dopamine. In: DRUGDEX® System [Internet database]. Updated periodically. Bellomo R. Lancet. 2000 Dec 23‐30;356(9248):2139‐43. Dopamine ADRs Midodrine • Prodrug of desglymidodrine, a pure alpha 1 agonist Headache Nausea/vomiting May impair resistance to infection Tachyphylaxis Alpha Effects – Causes vasoconstriction of arteriolar and venous vasculature • Clinical use: – Hypertension – Vasoconstriction – Extravasation – ORAL agent for patients who are unable to be weaned off LOW doses of vasopressors • Ischemic necrosis and sloughing • Hemodynamic effect: • Beta Effects – Increases systolic, diastolic pressure and MAP – Tachycardia – Arrhythmias – Anginal pain • Usual dose: 5 mg three times daily – Up to 10 mg three times daily may be used Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dopamine. In: DRUGDEX® System [Internet database]. Updated periodically. Midodrine. In: DRUGDEX® System [Internet database]. Updated periodically. 116 Midodrine Pharmacokinetics Midodrine Adverse Effects • Absorption • • • • – Rapid and complete – Onset of action: 1 hour • Metabolism – Midodrine – prodrug converted through hydrolysis in systemic circulation to desglymidodrine – Desglymidodrine – active metabolite, responsible for therapeutic activity Bradycardia Piloerection (goosebumps) Pruritus Urinary urgency, retention, and frequency • Excretion – Renal – Duration of action: 2‐6 hours • Dose adjustment – Renal impairment: consider lower initial dose (2.5 mg) Midodrine. In: DRUGDEX® System [Internet database]. Updated periodically. Midodrine. In: DRUGDEX® System [Internet database]. Updated periodically. Usual Dosing and Concentrations Receptor Affinity Usual Dose Range Max Dose Adult Concentrations Solution Norepinephrine Norepinephrine 0.01‐0.6 mcg/kg/min 3 mcg/kg/min 16‐32 mcg/mL D5W or NS Epinephrine Epinephrine 0.1‐0.5 mcg/kg/min 0.8 mcg/kg/min 4‐40 mcg/mL D5W or NS 0.01‐0.05 mcg/kg/min Vasopressin 01‐0.7 units/min 0.7 units/min 0.2‐1 unit/mL D5W or NS Phenylephrine 0.2‐0.5 mcg/kg/min 9.1 mcg/kg/min 20‐200 mcg/mL NS Dopamine 1‐20 mcg/kg/min 50 mcg/kg/min 1600‐3200 mcg/mL D5W or NS Dobutamine 2.5‐20 mcg/kg/min 40 mcg/kg/min 500‐4000 mcg/mL D5W or NS Milrinone 0.375‐0.75 mcg/kg/min 200 mcg/mL D5W 0.05‐3 mcg/kg/min α1 α2 Β1 β2 D V +++ +++ +++ +/++ 0 0 ++ ++ ++++ +++ 0 0 ++++ ++++ +++ + 0 0 Dopamine 0.05‐3 mcg/kg/min 0 0 + 0 ++++ 0 3‐10 mcg/kg/min 0/+ 0 ++++ + ++++ 0 > 10‐20 mcg/kg/min +++ 0 ++++ + 0 0 + 0 ++++ ++ 0 0 +++ + + 0 0 0 0 0 0 0 0 +++ Dobutamine Phenylephrine Vasopressin Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Epinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Extravasation General Management • Leakage of vasopressor into soft tissue causing necrosis • Due to large gauge needles inserted peripherally in smaller veins or areas of lower circulation • Adrenergic agents – induce venous and arterial vasospasm reducing distal blood flow • STOP THE INFUSION • Leave catheter or needle in place to attempt to aspirate drug (3‐5 mL blood) • Administer reversal agent • Remove needle • Elevate affected limb • Apply WARM compresses • Wound care – Blanching, swelling, skin sloughing, dermal necrosis Reynolds PM. Pharmacotherapy. 2014 Le A. Ann Pharm. 2014 117 Phentolamine Terbutaline • Standard of Care – only FDA approved antidote • MoA: Competitively blocks alpha receptors • Dose: 1 mg in 10 mL NS – Administer SQ around extravasation site • MoA: Beta 2 receptor agonist – Antagonizes norepinephrine, epinephrine, phenylephrine, dopamine – Vasodilates vasculature • Case reports for treating extravasation of dobutamine, dopamine, epinephrine finger pricks • No commercially available product – Discontinued by West‐Ward in early January 2015 http://www.ashp.org/menu/DrugShortages/DrugsNoLongerAvailable/Bulletin.aspx?id=349 Stier P. Am J Emerg Med. 1999 Jan;17(1):91‐4. Terbutaline Evidence Nitroglycerin Study Type Extravasation Dose Administration Efficacy Stier P, 1999 1 Case – 65 y/o adult Dopamine + dobutamine 1 mg in 10 mL NS 10 mL infiltrated into blanched areas within 1 hour Immediate return of blood flow, no ADRs • Dose: 4 mm/kg (up to 1 inch) of 2% topical ointment applied to sides of extravasation • MoA: vasodilates capillaries • Case reports of use in dopamine extravasation in infants • Monitor for hypotension Stier P. Am J Emerg Med. 1999 Jan;17(1):91‐4. Denkler KA. Plast Reconstr Surg. 1989 Nov;84(5):811‐3. Wong AF. J Pediatr. 1992 Dec;121(6):980‐3. Nitroglycerin Evidence Nitroglycerin Evidence Study Patient Extravasation Dose Study Denkler, 1989 Infant 34 weeks gestation Dopamine 10 mcg/kg/min 2% nitroglycerin ointment Wong, 1992 Infant 15 days old Dopamine 12‐20 mcg/kg/min Wong, 1992 infant 4 day old, Dopamine 24 mcg/kg/min Administration Efficacy Denkler, 1989 2% nitroglycerin ointment 1 inch strip applied to each site of extravasation 2% nitroglycerin ointment Blanching resolved within minutes, normal appearance within 6.5 hours Wong, 1992 2% nitroglycerin ointment 4 mm/kg applied to affect area every 8 hours x 3 doses Some improvement noted after 8 hours, full resolution after 24 hours 2% nitroglycerin ointment Wong, 1992 2% nitroglycerin ointment 4 mm/kg applied to affected area NTG administered 1 hour after phentolamine failure. Improvement within 15 minutes, full resolution in 2 hours Denkler KA. Plast Reconstr Surg. 1989 Nov;84(5):811‐3. Wong AF. J Pediatr. 1992 Dec;121(6):980‐3. Dose Denkler KA. Plast Reconstr Surg. 1989 Nov;84(5):811‐3. Wong AF. J Pediatr. 1992 Dec;121(6):980‐3. 118 Vasopressor Clinical Pearls Patient Case: SM • Do not start vasopressors until adequate trial of fluids (30 mL/kg) • Administer through a central line SM received 500 mL lactated ringer’s solution, 1500 mL isotonic saline, 500 mL albumin. A Swan‐ganz catheter is placed – Extravasations may be treated with terbutaline or nitroglycerin ointment • Norepinephrine 1st line for septic shock • Vasopressors that agonize alpha – Increase SVR – Reflex bradycardia • Vasopressors that agonize beta – Increase CO – Tachycardia, arrhythmias What intervention would be most appropriate for the treatment of SM’s hemodynamic instability? Patient Case: SM Norepinephrine is initiated at 0.03 mcg/kg/min, but we still need to address the low CI. Using Inotropes What intervention would be most appropriate for the treatment of SM’s hemodynamic instability? Cardiogenic Shock Dobutamine • ACC/AHA STEMI Guidelines 2013 • Synthetic catecholamine designed for selective inotropic activity with minimal vascular effect • Selective β1, β2 agonist – “Medical support with inotropes and vasopressor agents should be individualized and guided by invasive hemodynamic monitoring” – Only specific recommendation – avoid dopamine • Inotropes – Dobutamine – Epinephrine – Milrinone – Weak β2, α1 effects • Vasopressors • β2 >>> α1 – Norepinephrine • Reserved for severe hypotension – Dopamine – No longer recommended (DeBacker 2010) Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dobutamine. In: DRUGDEX® System [Internet database]. Updated periodically. O'Gara PT. J Am Coll Cardiol. 2013;61(4):e78‐e140. 119 Dobutamine Dobutamine • Hemodynamic effects • Usual dose: 2.5‐20 mcg/kg/min • Dosage forms – Increases contractility, stroke volume, heart rate – increased CO – Decreased to minimal effect on SVR, CVP, PCWP – Premix – 250 mg/250 mL (1 mg/mL), 500 mg/250 mL (2 mg/mL), 1000 mg/250 mL (4 mg/mL) – 250 mg/20 mL, 500 mg/40 mL vials – Dilute vials to to premix concentrations in D5W or NS • Effects may diminish over time due to down‐ regulation of beta receptors Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dobutamine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dobutamine. In: DRUGDEX® System [Internet database]. Updated periodically. Dobutamine Milrinone • Adverse Effects • Inhibits cAMP phosphodiesterase found in cardiac and vascular muscles – Beta agonism – Increase intracellular ionized calcium and contractile force in heart muscle • Tachycardia • Arrhythmias • Ischemia • May be useful in patients who CO does not increase in response to catecholamines • Hemodynamic effects – Nausea – Anxiety – Tremors – Positive inotrope • Long term use • Increases myocardial work, oxygen consumption – Decline in CO and HR as body downregulates β1 receptors – Vasodilation • decreases PVR/SVR Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Dobutamine. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Milrinone. In: DRUGDEX® System [Internet database]. Updated periodically. Milrinone Milrinone Dose Adjustments • Usual dose – 0.1‐0.75 mcg/kg/min infusion • Eliminated via kidney – Reduce infusion rate in renal insufficiency – T1/2 = 1‐3 hours • Dosage forms Creatinine Clearance 5 Infusion Rate (mcg/kg/min) 0.2 10 0.23 20 0.28 30 0.33 40 0.38 50 0.43 – Premix – 20 mg/100 mL, 40 mg/200 mL – 10 mg/10 mL, 20 mg/20 mL, 50 mg/50 mL vials Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Milrinone. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Milrinone. In: DRUGDEX® System [Internet database]. Updated periodically. 120 Milrinone Usual Dosing and Concentrations • Adverse effects – Arrhythmias • Ventricular arrhythmias (12.1%) – 8.5% Non‐sustained ventricular tachycardia – 2.8% Sustained ventricular tachycardia – 1% Ventricular fibrillation – Hypotension (2.9%) – Headache (2.9%) Usual Dose Range Max Dose Adult Concentrations Solution Norepinephrine 0.01‐0.6 mcg/kg/min 3 mcg/kg/min 16‐32 mcg/mL D5W or NS Epinephrine 0.1‐0.5 mcg/kg/min 0.8 mcg/kg/min 4‐40 mcg/mL D5W or NS Vasopressin 0.3 units/min 0.2‐1 unit/mL D5W or NS Phenylephrine 0.2‐0.5 mcg/kg/min 9.1 mcg/kg/min 20‐200 mcg/mL NS Dopamine 1‐20 mcg/kg/min 50 mcg/kg/min 1600‐3200 mcg/mL D5W or NS Dobutamine 2.5‐20 mcg/kg/min 40 mcg/kg/min 500‐4000 mcg/mL D5W or NS Milrinone 0.1‐0.75 mcg/kg/min 200 mcg/mL D5W Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Milrinone. In: DRUGDEX® System [Internet database]. Updated periodically. Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56. Epinephrine. In: DRUGDEX® System [Internet database]. Updated periodically. Mechanical Options Inotropes Clinical Pearls • Intraaortic Balloon Pump • Administer through a central line • Avoid dopamine in cardiogenic shock • Watch for arrhythmias – may require treatment or change in inotrope • Many inotropes decrease SVR – Improves short term hemodynamic profile – May not improve outcomes unless combined with coronary revascularization • Ventricular Assist Devices (VADs) – Consider for patients with very low cardiac output (< 1.2 L/min/m2) who have failed to respond to IABP and reperfusion – Device and catheter inserted percutaneously into the left atrium – Dobutamine – Milrinone Thiele H. N Engl J Med. 2012 Oct 4;367(14):1287‐96. O'Connor CM. N Engl J Med. 2012 Oct 4;367(14):1349‐50. Patient Case: SM Patient Case: SM The PA initiates SM on epinephrine at 0.04 mcg/kg/min and norepinephrine at 0.03 mcg/kg/min. An hour later, the nurse pulls a reading from the Swan‐ Ganz catheter. Norepinephrine is initiated at 0.03 mcg/kg/min, but we still need to address the low CI. Continuous Infusions Epinephrine 0.04 mcg/kg/min Norepinephrine 0.03 mcg/kg/min What intervention would be most appropriate for the treatment of SM’s hemodynamic instability? 121 Areas of Future Research Summary • Treat the patient not the number • Fluids, fluids, and more fluids! • Choice of vasopressor or inotrope: • Do physiologically balanced crystalloids have better outcomes than normal saline? • Can vasopressin be used as first line for septic shock? – Swan‐Ganz: what values are abnormal? – Pathophys: what is the cause of patients instability? • Sepsis or low SVR: Norepinephrine • Cardiogenic or low CO: consider side effect profile when choosing agent – VANISH trial currently underway • Further study of vasopressors in specific disease states – Can patient tolerate an agent that will decrease SVR? – Avoid dopamine • Use the lowest possible dose to maintain perfusion • Terbutaline or nitroglycerin ointment may be used to treat extravasation Additional References 1. 2. 3. Questions? 4. 5. 6. 7. Additional References Hoffman EW. Basics of cardiovascular hemodynamic monitoring. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64. Barnes AD, Lee SH. Shock. In: Koda‐Kimble MA, Young LY, Kradjan WA, editors. Applied Therapeutics: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins. 2005; p 22‐1‐22‐36. MacLaren R, Rudis MI, Dasta JF. Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock. In: Dipiro JT, Talbert JL, editors. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill. 2008; p 417‐440. Erstad BL. Hypovolemic Shock. In: Dipiro JT, Talbert JL, editors. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill. 2008; p 441‐454. Russell JA. Management of sepsis. N Engl J Med. 2006 Oct 19;355(16):1699‐713. Hollenberg SM. Inotrope and vasopressor therapy of septic shock. Crit Care Clin. 2009 Oct;25(4):781‐802, ix. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock 2012. Crit Care Med. 2013 Feb;41(2):580‐637. Additional References 15. Raghunathan K, Shaw A, Nathanson B, etal. Association between the choice of IV crystalloid and in‐hospital mortality among critically ill adults with sepsis. Crit Care Med. 2014 Jul;42(7):1585‐91. 16. Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. 2008 Sep 2;118(10):1047‐56. 17. Norepinephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 18. De Backer D, Biston P, Devriendt J, etal. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779‐ 89. 19. Epinephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 20. Annane D, Vignon P, Renault A, etal. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 Aug 25;370(9588):676‐84. 21. Myburgh JA, Higgins A, Jovanovska A, etal. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008 Dec;34(12):2226‐ 34. Epub 2008 Jul 25. 8. Topalian S, Ginsberg F, Parrillo JE. Cardiogenic shock. Crit Care Med. 2008 Jan;36(1 Suppl):S66‐74. 9. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588‐95. 10. Myburgh JA, Finfer S, Bellomo R, etal. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901‐11. 11. Finfer S, Bellomo R, Boyce N, etal. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247‐ 56. 12. Caironi P, Tognoni G, Masson S, etal. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412‐21. 13. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013 Sep 26;369(13):1243‐51. 14. Yunos NM, Bellomo R, Hegarty C, etal. Association between a chloride‐liberal vs chloride‐restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566‐72. 122 Additional References Additional References 22. Levy B, Perez P, Perny J, etal. Comparison of norepinephrine‐dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med. 2011 Mar;39(3):450‐5. 23. Vasopressin. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 24. Vasotrict(R) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies Inc. 2014 25. Landry DW, Levin HR, Gallant EM, etal. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997 Mar 4;95(5):1122‐5. 26. Russell JA, Walley KR, Singer J, etal. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877‐87. 27. Gordon AC, Wang N, Walley KR, etal. The Cardiopulmonary Effects of Vasopressin Compared With Norepinephrine in Septic Shock. Chest. 2012 Apr 19. [Epub ahead of print] 28. Gordon AC, Russell JA, Walley KR, etal. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010 Jan;36(1):83‐91. Epub 2009 Oct 20. 29. Patel BM, Chittock DR, Russell JA, etal. Beneficial effects of short‐term vasopressin infusion during severe septic shock. Anesthesiology. 2002 Mar;96(3):576‐82. 30. Torgersen C, Dünser MW, Wenzel V, etal. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open‐ label trial. Intensive Care Med. 2010 Jan;36(1):57‐65. 31. Phenylephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 32. Dopamine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 33. Bellomo R, Chapman M, Finfer S, etal. Low‐dose dopamine in patients with early renal dysfunction: a placebo‐controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23‐ 30;356(9248):2139‐43. 34. Midodrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 35. Le A, Patel S. Extravasation of Noncytotoxic Drugs: A Review of the Literature. Ann Pharmacother. 2014 Apr 8;48(7):870‐886. Additional References 36. 37. 38. 39. 40. 41. 42. 43. 44. Reynolds PM, MacLaren R, Mueller SW, etal. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014 Jun;34(6):617‐32. Stier PA, Bogner MP, Webster K, etal. Use of subcutaneous terbutaline to reverse peripheral ischemia. Am J Emerg Med. 1999 Jan;17(1):91‐4. Denkler KA, Cohen BE. Reversal of dopamine extravasation injury with topical nitroglycerin ointment. Plast Reconstr Surg. 1989 Nov;84(5):811‐3. Wong AF, McCulloch LM, Sola A. Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates. J Pediatr. 1992 Dec;121(6):980‐3. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST‐ Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78‐e140. Dobutamine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. Milrinone. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. Thiele H, Zeymer U, Neumann FJ, etal. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1287‐96. doi: 10.1056/NEJMoa1208410. Epub 2012 Aug 26. O'Connor CM, Rogers JG. Evidence for overturning the guidelines in cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1349‐50. doi: 10.1056/NEJMe1209601. Epub 2012 Aug 26. 123 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Saturday, May 23 8:00—9:00 a.m. Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing Antifungal Therapy Kevin W. Garey, Pharm.D., M.S., FASHP 0204-0000-15-412-L01-P 1.0 contact hour (0.1 CEU) Please see the following pages for educational materials for this activity and instructions on how to receive credit. This activity is planned and conducted by ASHP Advantage and supported by an educational grant from Merck. 124 Maanaggem ment of In nvassive Funggal Infec I ction ns: A Applyyingg Evid dencce‐ bassed Straategiies aand Indiividu ualizzing A Antiifunggal Th heraapy LSHP Annuaal Meetin ng 2015 –– New Orlleans, LA – May 23 3, 2015 Planned and cond ducted by ASHP Advantag ge and supported by an educational grant fro om Merck. 125 Activity Overview As the 3rd most common cause of bloodstream infections in the intensive care unit, and the fourth most common cause of nosocomial bloodstream infections, invasive candidiasis is common and deadly. While C. albicans remains the most prevalent species in the USA, the prevalence of non-albicans Candida species has increased since 2004, and C. parapsilosis and C. glabrata each comprise approximately 15% of all Candida isolates. The wider availability and use of newer agents over the past decade has resulted in additional choices of agents, but also in the incidence of antifungal resistance, in particular for C. glabrata to azoles and (of recent concern) to echinocandins. Faculty will discuss current antifungal therapies for the treatment of candidemia, focusing on recent studies that affect the interpretation and use of treatment guidelines and the importance of using local epidemiology and resistance patterns. Management principles for the identification, monitoring, and management of antifungal adverse effects, drug interactions, and therapeutic drug monitoring will also be highlighted. Learning Objectives At the conclusion of this knowledge-based educational activity, participants should be able to • • • • Review rapid diagnostics and their roles for diagnosis and treatment of systemic Candida infections. Discuss therapeutic drug monitoring for azole antifungals. Recommend treatment options for patients with systemic candidiasis or candidemia infections. Describe evolving resistance mechanisms and changing paradigms for treating systemic candidiasis or candidemia infections. Continuing Education Accreditation The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #02040000-15-412-L01-P). Participants will process CPE credit online at http://elearning.ashp.org/my-activities, with the option of printing a CE certificate. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity. 126 Management of Invasive Fungal Infections: Applying Evidence‐based Strategies and Individualizing Antifungal Therapy Activity Faculty Kevin W. Garey, Pharm.D., M.S., FASHP Professor and Chair Department of Clinical Sciences and Administration University of Houston College of Pharmacy Houston, Texas Kevin W. Garey, Pharm.D., M.S., FASHP is Professor at the University of Houston College of Pharmacy and Chair of the Department of Clinical Sciences and Administration at the University of Houston College of Pharmacy in Houston, Texas. Dr. Garey is an Adjunct Professor at the University of Texas School of Public Health and a Clinical Specialist and Researcher at Baylor St. Luke’s Medical Center in Houston, Texas. He received a Bachelor of Science in Pharmacy degree from Dalhousie University in Halifax, Nova Scotia, Canada, a Doctor of Pharmacy from the State University of New York in Buffalo, New York, and Master of Science in Biometry from the University of Texas School of Public Health in Austin, Texas. He completed a pharmacy practice residency at Bassett Healthcare, Cooperstown, NY and infectious disease specialty residency and fellowship training at the University of Illinois at Chicago College of Pharmacy in Chicago, Illinois. Dr. Garey has numerous publications in infectious diseases topics and has presented extensively at national and international professional conferences. He has received numerous professional awards including the ASHP Drug Therapy Research Award, ASHP Best Practices Award in Health‐System Pharmacy, the Society of Infectious Diseases Pharmacists Impact Paper in Infectious Diseases Pharmacotherapy Award and the University of Houston Faculty Leadership award. He is a Fellow of ASHP. Dr. Garey's research interests involve clinical and translational research involving healthcare‐associated infections including post‐surgical infections, candidemia, and Clostridium difficile infection. 127 3 Disclosure Statement In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations. All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity. • Peggy L. Carver, Pharm.D., FCCP, serves on the speakers bureau for Merck and Astellas, Inc. • Kevin W. Garey, Pharm.D., M.S., FASHP, has received research grants from Astellas, Inc. and T2 Biosystems. • All other planners report no financial relationships relevant to this activity. 128 Disclosures • Peggy L. Carver, Pharm.D., FCCP, serves on the speakers bureau for Merck and Astellas, Inc. Management of Invasive Fungal Infections: Applying Evidence‐based Strategies and Individualizing Antifungal Therapy • Kevin W. Garey, Pharm.D., M.S., FASHP, has received research grants from Astellas, Inc. and T2 Biosystems. Kevin W. Garey, Pharm.D., M.S., FASHP • All other planners report no financial relationships relevant to this activity. Professor and Chair Department of Clinical Sciences and Administration University of Houston College of Pharmacy Houston, Texas Planned and conducted by ASHP Advantage and supported by an educational grant from Merck Systemic Candida Infections Learning Objectives • Review rapid diagnostics and their roles for diagnosis and treatment of systemic Candida infections. 67 year old white male past admission acute pancreatitis Vitals: 102.3F, 100/50, 101, 23 WBC: 13,000 Baseline Cr: 1.4 Current Cr: 1.8 • Recommend treatment options and describe evolving resistance mechanisms and changing paradigms for treating systemic candidiasis or candidemia infections. Pharmacy is Phabulous • Discuss indications for antifungal therapeutic drug monitoring. Central venous catheter associated for TPN Also received antibiotics for pancreatitis • Identify current therapeutic options for the diagnosis and treatment of aspergillosis infections. Central venous catheter Send Blood samples Start therapy (micafungin) Diagnosis: Suspected systemic candidiasis!!! A delay in echinocandins also is associated with poor outcomes A delay in the initiation of antifungals increases bad outcomes in patients with candidemia Multicenter study of 169 patients with candidemia given caspofungin Morrell M et al. Antimicrobial Agents Chemother. 2005; 49: 3640-5. Garey KW et al. Clin Infect Dis. 2006; 43:25 31. Hsu D. J Antimicrob Chemother. 2010; 65(8):1765‐70. 129 Blood cultures take a long time to identify Candida BC drawn Yeast 2.4 days T2 Magnetic resonance We would like to start antifungals here Speciation 2.2 days • I think ID/antimicrobial stewardship pharmacists are going to become “react to positive diagnostic test” pharmacists Antifungal Susceptibilities Culture + (time 0) Implications for pharmacy practice SPECIFIC Antifungal Rx initiated EMPIRIC Antifungal Rx initiated 0.5 days Rapid test : MALDI‐TOF MS or PNA‐FISH … but we usually start them here ….and many times, we wont get it right until here But, when a stewardship pharmacist is involved, good things happen! Systemic Candida Infections 67 year old white male‐ past admission acute pancreatitis Vitals: 102.3F, 100/50, 101, 23 • PNA‐FISH and Candida WBC: 13,000 Baseline Cr: 1.4 Current Cr: 1.8 – Pharmacist reacted to results – $1729 saved per patient – Forrest GN et al. J Clin Microb. 2006; 44:3381‐3. Central venous catheter associated for TPN Pharmacy is Phabulous Also received antibiotics for pancreatitis • MALDI‐TOF and (Gram‐negative) – Pharmacist reacted to results – Approximately $12k saved per patient – Perez KK et al. Arch Pathol Lab Med. 2012; 137: 1247‐54. Send Blood samples using a rapid diagnostic Diagnosis: Systemic Candida infection!!! Which antifungal regimen would you choose to treat the patient? How do we make our decision about what antifungal to use? If you were choosing using general susceptibility to antifungals Candida species a. Fluconazole 400mg IV once daily b. Fluconazole 6 mg/kg IV once daily c. An echinocandin (your choice) FDA indicated fixed dose FLUC ECHINO AMB C. albicans S S S C. tropicalis S S S C. parapsilosis S S to R S C. glabrata C. krusei d. An echinocandin (your choice) using a mg/kg once daily dose S = susceptible; S‐DD to R S S to I R S S to I S‐DD = susceptible dose – dependent; R = resistant FLUC = fluconazole; AMP B = amphotericin B; ECH = caspofungin, micafungin, anidulafungin Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35 130 IDSA Guideline Recommendations: Initial therapy with fluconazole vs. an echinocandin Fluconazole An Echinocandin Less critically ill Moderately severe to severe illness IDSA guidelines recommendation on management of candidemia in non‐neutropenic patients Initial (empiric) therapy options Fluconazole No recent azole exposure An Echinocandin Caspofungin Loading dose of 70 mg 50 mg daily Loading dose of 800 mg (12 mg/kg) 400 mg (6 mg/kg) daily Recent azole exposure Micafungin 100 mg daily Anidulafungin Loading dose: 200 mg 100 mg daily Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35. Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35. How long to continue treatment for candidemia? Fluconazole • Human evidence suggests that the appropriate dose of fluconazole is associated with: – Better treatment outcomes – Reduced mortality – Decreased resistance 2 weeks* * No obvious metastatic complications • Dose: 6 mg/kg (C. glabrata: 12 mg/kg) • Pharmacodynamics When to start counting treatment days? – Dose: MIC or AUC:MIC – Animal models support an AUC/MIC breakpoint of 25‐50 After documented clearance of Candida species from bloodstream • Thus: appropriate dosing should affect outcomes Lewis RE. Mayo Clin Proc. 2011; 86: 805-17. Andes D et al. Antimicrob Agents Chemother. 1999; 43:2116‐20. Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35 Inappropriate doses of fluconazole are associated with increased risk of antifungal resistance. Patients (%) with pre‐exposure to fluconazole An inappropriate fluconazole dose increases hospital costs Total hospital costs stratified by adequate fluconazole dose given at the onset of symptoms (Day 0) or later. Initial dose (mg/kg) of prior fluconazole therapy 100% 8 (89%) 90% 80% 70% 60% 4 (44%) 50% 40% 30% 2 (22%) 20% 3 (33%) 1(11%) 10% 0% Lower risk ≤2 mg/kg Total hospital costs stratified by adequate fluconazole dose given at the onset of symptoms (Day 0) or later. Fluconazole-susceptible Fluconazole-resistant Garey KW et al. Int J Antimicrob Agents. 2007; 29:557-62. Higher risk 3‐5 mg/kg Fluconazole dose range (mg/kg) Lower risk ≥6 mg/kg A dose in the 3‐5 mg/kg range was associated with a subsequent increased risk of fluconazole resistant Candida (p‐value=0.049) Shah DN et al. Antimicrob Agents Chemother. 2012; 56:3239‐43. 131 Highlights of Recent Studies and European Candida Guidelines Echinocandins inhibit glucan synthase – For moderately or severely ill patients mannoproteins • Start with an echinocandin or amphotericin B if catheters cannot be removed • Inhibit β‐1,3‐glucan synthase enzyme – Severity of illness and choice of antifungal predict response in patients with C. glabrata fungemia, but do not influence mortality 1,3 1,6 glucans – Catalytic subunit PPL (Fks1p/2p) bilaye r – Encoded by 3 FKS related genes in Candida spp. (FKS1, FKS2, FKS3) • When there is improvement, switch to fluconazole (if the pathogen is susceptible), and to PO therapy after 10 days of IV therapy • Treat for 2 weeks after blood cultures are negative – New CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately. – Where do pharmacists come in? β -1,3 glucan synthase chitin Ergosterol Yeast • Appropriate dosing! Cornely OA et al. Clin Microbiol Infect. 2012; 18:19‐37. Andes DR et al. Clin Infect Dis. 2012;54:1110‐ 22. Eschenauer GA et al. J Antimicrob Chemother. 2013;68(4):922‐6. Echinocandin resistance relatively uncommon globally FKS mutations are associated with reduced echinocandin susceptibility AA Fks1p 0 F625 – P663 Hot spot 1 1900 AA Fks2p 0 D1340 – L3148 F658 – P667 Hot spot 1 Hot spot 2 • Susceptibility patterns of 3,107 Candida species from 34 countries • 38% cross‐resistance to fluconazole 1900 D1374 – L1381 Hot spot 2 Rates of resistance (varies by region) • Two regions (HS1 and HS2) of Fks1/2p are associated with echinocandin resistance • Prominent mutations typically confer cross‐ resistance to all echinocandins All Candida species Up to 1.7% Candida albicans Up to 0.6% Candida glabrata Up to 3.8% Pfaller MA et al. J Clin Microbiol. 2013; 51:390‐2. Will echinocandin resistance make us change to a more individualized dosing strategy? Emergence of echinocandin resistance in C. glabrata 35 35 30 30 25 20 15 10 20 Shields et al. (2011) (n = 39) Prior echinocandin therapy OR 10.65; 95% CI 2.51‐ 45.24 OR 19.65; 95% CI 7.19‐58.1 P=0.0001 Prior episode of candidemia OR 18.59; 95% CI 1.56 – 221.69 P = < 0.05 ‐‐‐ Prior echinocandin therapy OR 9.17; 95% CI 1.9 – 44.46 P = < 0.05 P = 0.008 Presence of an FKS mutation P = 0.033 P = 0.0391 OR 41.7; 95% CI 3.96‐ 445.7 15 10 5 0 0 Echinocandin Alexander et al. (2013) (n = 278) Risk factors for FKS mutant C. glabrata 25 5 Fluconazole Beyda et al. (2014) (n = 78) Texas Medical Center % Resistant % Resistant Duke University Hospital Risk factors for echinocandin treatment failure Fluconazole Caspofungin Alexander BD et al. Clin Infect Dis. 2013; 56:1724‐32. Beyda ND et al. Clin Infect Dis; 2014; 59:819‐25. Alexander BD et al. Clin Infect Dis. 2013; 56:1724‐32. Beyda ND et al. Clin Infect Dis; 2014; 59:819‐25. Shields RK et al. Antimicrob Agents Chemother. 2012;56:4862‐9. 132 CLASSIFICATION OF ASPERGILLOSIS The Fungal World FUNGI YEASTS Candida spp. MOULDS Cryptococcus Trichosporon beigelii Blastochizomyces capitus Zygomycetae Airway or nasal exposure to airborne Aspergillus Dimorphic Fungi Invasive aspergillosis Septate Fungi Chronic aspergillosis Rhizopus Aspergillus spp. (>3 months) Hyalohyphomycoses Fusarium sp. Pseudoallescheria boydii Scedosporium prolificans Paecilomyces spp Mucor Persistence without disease Allergic (colonization of the airways or nose/sinuses) Absidia • Acute (<1 month course) • Subacute /chronic necrotizing (1‐3 months) • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis • Maxillary sinus aspergilloma • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis • Asthma with fungal sensitization • Allergic Aspergillus sinusitis Timeframe of Fungal Infection post HSCT Patient case – diagnosis of aspergillosis Phase I Pre-engraftment (<30 days posttransplant) • AR is a 42‐year‐old male, post‐HSCT for AML, complicated by grade II GVHD, who presents with cough, dyspnea with pulmonary nodules 3 weeks post‐transplant. Phase II Post-engraftment (30-100 days posttransplant) Neutropenia, mucositis, and acute graft‐versus‐ host disease • Invasive pulmonary aspergillosis was diagnosed via: – chest CT (nodules with halo) Phase III Late post-engraftment (>100 days posttransplant) Impaired cellular Impaired cellular and immunity and acute and humoral immunity and chronic graft‐versus‐host chronic graft‐versus‐host disease disease All Candida spp. – positive galactomannan antigen tests (levels 3.2, 1.9) Aspergillus spp – a needle biopsy which grew A. fumigatus. Day 0 Image provided by Dr. Carver Factors relating to Underlying Condition Primary Host Factor • Hematological malignancy • Allogeneic hematopoietic stem cell transplantation • Solid organ transplantation • Solid tumor • Other immune disorder • Climate • Construction work • Place of residence • Tobacco or cannabis use • Contaminated food or spices • Pets, potted plants, gardening • Lack of HEPA filtration during hospitalization Environmental Factors Day 365 and beyond Difficulties in the Diagnosis of Invasive Aspergillosis Risk Factors for Invasive Aspergillosis Innate Immune Status Day 100 Day 15‐45 Tomblyn M et al. Biol Blood Marrow Transplant. 2009 Oct;15(10):1143‐238 Engraftment: absolute neutrophil count ≥500 cells/mm3 AML = acute myeloid leukemia; GVHD = graft‐versus‐host‐disease; HSCT=Hematopoietic Stem Cell Transplantation Polymorphisms of: • Toll‐like receptors • C‐type lectins • Mannose‐binding lectins • plasminogen • Others? Aspergillus spp. • Clinical/patient ‒ nonspecific symptoms • Neutropenia • Progressive cancer • Graft vs host disease • Chemotherapy • Corticosteroids • Anti‐T‐cell antibodies ‒ tissue biopsies difficult to obtain • Microbiological ‒ Tissue cultures often unavailable ‒ Difficult to differentiate • Diabetes • Iron overload • Trauma, burns • Renal impairment • Metabolic acidosis • Prior respiratory disease colonization vs. infection ‒ Blood cultures rarely positive Other Factors 30 Adapted from Herbrecht R et al. Ann N Y Acad Sci. 2012. 1272:23‐30. 133 The search for fungal biomarkers for invasive aspergillosis Radiological Difficulties in the Diagnosis of Invasive Aspergillosis CT Scan • “Halo sign” – – – – Halo very sensitive but non specific perimeter of ground‐glass opacity surrounding hemorrhagic nodular lesion small vessel angioinvasion thrombosis of small/medium sized vessels ischemic necrosis seen EARLY in disease; lasts <5 days • Galactomannan antigen – – – – ‒ (also Penicillium spp) – good negative predictive value, but low positive predictive value • test performs less well in solid organ transplant patients Cross‐reactivity with pip/tazo ‒ – crescent of gas above a soft tissue sequestrum within a nodular or cavitary lesion; due to tissue contraction Air not useful for early diagnosis crescent seen LATE in angioinvasive IA correlates with recovery of neutrophils – – Species specific Simple, sensitive but potential for contamination Novel methods under development ‒ monoclonal antibody JF5 Aspergillus nucleic acids siderophore detection MALDI‐TOF ‒ • β‐D‐glucan ‒ nonspecific for Candida ‘pan’ fungal except cryptococcus and zygomycetes ‒ Johnson G, et al. Biomark Med. 2014; 8:429‐51. Hornton CR. 2014. Exp Rev Clin Imm 10(6):771‐80. Images provided by Dr. Carver http://www.medscape.org/viewarticle/444470_4. Pinto PS. Radiology. 2004; 230: 109‐110. PCR Detects Aspergillus species – • “Air‐crescent” Sign • – Patient case – initial therapy of aspergillosis Activity of Common Systemic Antifungal Agents against non‐Candida Species Fungus • AR was initiated on voriconazole, but he experienced visual hallucinations, which responded to a dosage reduction, and then a severe rash. • Therapy was changed to Liposomal‐AmB (5 mg/kg/day IV). AmB Aspergillus spp. (not A. terreus) Fusarium occas R Scedosporium occas R Flucon Itra Vori Posa Echino X X X (breakthrus) occas R X X +/‐ X occas R Zygomycetes X X X X Cryptococcus X X = no in vitro activity; = in vitro activity; R = resistance AmB = amphotericin B; Flucon = fluconazole; Itra = itraconazole; Posa = posaconazole; Vori = voriconazole; Echino = echinocandins (caspofungin, micafungin, anidulafungin) Image provided by Dr. Carver First Line Therapy for Invasive Aspergillosis IDSA (USA)1 United Kingdom2 d‐AmB D D L‐AmB AI AI Antifungal agent Voriconazole vs. d-AmB for Aspergillosis ECIL DGHO (European guidelines)3 German guidelines4 Australia5 D EII Alternative BI AII Alternative 22% relative survival benefit P = 0.02 AMPHOTERICIN B BII ABCD D Voriconazole 80 % Surviving ABLC 100 AZOLES Itraconazole Voriconazole C AI AI AI AI CII AI Recommended Posaconazole 58% AmB/OLAT* 40 20 ECHINOCANDINS Caspofungin Median d‐AmB duration = 10 days; (n=107) Median voriconazole duration = 77 days 0 Micafungin COMBINATION Antifungal Therapy 71% 60 0 Not recommended Discouraged Discouraged CIII 14 28 42 56 70 84 # Days of Therapy ‘No supportive evidence’ OLAT (other licensed antifungal therapy) utilized: Lipid AmB 44%; itraconazole 36%; other or combo 21% d‐AmB= deoxycholate AmB 1Walsh TJ et al. Clin Infect Dis 2008; 46:32‐60; 2Prentice AG et al. http://www.bcshguidelines.com/documents/fungal_infection_bcsh_2008.pdf accessed 10/24/14; 3Maertens J et al. Bone Marrow Transpl 2011;46:709‐18; 4Bohme A et al. Ann Hematol 2009;88:97‐110; 5Thursky KA et al. Intern Med J 2008;38;496‐520. AmB = amphotericin B; d‐AmB= deoxycholate AmB; L‐AmB = liposomal AmB; ABLC = AmB lipid complex; ABCD = AmB colloid dispersion 134 Herbrecht R, et al. N Eng J Med. 2002; 347(6):408‐15. Herbrecht R, et al. Clin Infect Dis 2014. Epub 014/11/22. What if the patient doesn’t respond to Voriconazole? Mechanism of Action of Antifungals • Causes of antifungal therapy failure – – – – Echinocandins affect β-1,3 cross-linking Cell membrane and cell wall Fungal cell Host factors (severity of illness, immune suppression) Primary or acquired drug resistance Wrong diagnosis or mixed infection Pharmacokinetic factors Mannoproteins -(1,6)-glucan -(1,3)-glucan Cell wall Chitin • complex pharmacokinetics of antifungal agents • Drug‐drug or drug‐food interactions • adherence Cell Membrane (Phospholipid bilayer) • Treatment options ‐ salvage therapy of aspergillosis -(1,3)-glucan synthase Ergosterol – CONTINUE with the same agent, or another agent in the same class with a broader spectrum – CHANGE to a different antifungal class – COMBINE antifungal drugs Azoles inhibit enzymes involved in this pathway Nucci M. et al. Clin Infect Dis 2008;1426‐33. AmB binds to ergosterol Ergosterol Synthesis Pathway Squalene Slide adapted from R. Lewis, Pharm.D http://www.doctorfungus.org/thedrugs/antif_pharm.php Accessed 10/7/14. Combination Therapy for Invasive Aspergillosis Should we use Combination Antifungal Therapy ? The Case FOR Combination Therapy • Mortality rates are HIGH Study Design Main outcomes CASPOFUNGIN + L‐AmB Aliff 2003 • Retrospective study in leukemics (N=30) • Salvage therapy with L‐AmB + caspo The Case AGAINST Kontoy‐ iannis 2003 • Retrospective, heme patients, (N=48) • Salvage therapy of caspo addition after ≥7 d L‐AmB • Only 18% response to combo therapy Combination Therapy Caillot 2007 • Prospective, open label in heme patients (N=30) • L‐AmB 3 mg/kg/d + caspo vs L‐AmB 10 mg/kg/day • “Combistrat” study. More favorable responses (partial or complete) in combo tx group • Favorable response in 60% (18/30) CASPOFUNGIN or ANIDULAFUNGIN + VORICONAZOLE • • Enables ↑ spectrum of ac vity Lack of • • Marr 2004 • Vori (prior to 2001) vs vori + caspo (after 2001) after progression of disease on ≥7 d AmB • combo therapy pts had a significantly lower rate of mortality vs vori monotherapy • correlation between in vitro data, animal models, and clinical experience • Salvage therapy with caspo + another ‘mold‐active’ agent in Maertens patients refractory to or intolerant of standard antifungal therapy 2006 (N=53) • solid clinical data Singh 2006 • Prospective, randomized, MC, observational • Vori or caspo (N=40) 1o therapy vs historical control (N=47) of L‐AmB therapy in SOT • No difference in 90 day survival overall, although in pts with renal failure or A. fumigatus, combo therapy was associated with survival Upton 2007 • Retrospective in HSCT (N=405); Vori + caspo vs caspo alone • No difference in clinical outcomes of Vori + caspo as primary therapy vs vori monotherapy Marr 2012 • Prospective, randomized, MC study in heme ± HSCT (N=277 ) • Vori alone vs vori + anidula; 1o endpoint = 6 wk survival • trend toward 6 wk survival with combination of vori + anidula vs vori monotherapy. • More rapid killing • chances of developing resistance • No overlapping toxicities Regimen Possibility of antagonism ↑ risk of drug interactions and toxicities • Success = 55% & 49% (at end of combo therapy & Day 84, respectively). • Day 84 survival = 55%. Aliff. Cancer 2003;4:1025-32; Kontoyiannis. Cancer 2003;2:292-9. Caillot D. Cancer 2007; 110:2740. Marr et al. CID 2004;39:797-802.; Maertens et al. Cancer 2006;107:288897. Singh. Transplantation 2006; 81(3): 320-6; Upton. CID 2007;44:531. Marr K. Presented at: 22nd ECCMID, London, UK, 3/31/12-4/3/12. MC = multicenter; SOT = Solid organ transplant; HSCT = hematopoietic stem cell transplant; heme= hematological malignancy; L-AmB = liposomal amphotericin B; Vori = voriconazole; anidula = anidulafungin; caspo = caspofungin; mica=micafungin Therapeutic drug monitoring (TDM) of antifungals ? Drug Interactions with Azole Antifungals CYP enzymes • When is TDM needed? – An established relationship exists between plasma drug concentrations and: • efficacy • toxicity – Recommended for drugs with: • narrow therapeutic index • variable pharmacokinetics • questionable compliance, absorption, or drug‐drug interactions P‐glycoprotein Substrate Inhibitor Substrate Inhibitor Fluconazole 3A4 3A4 (++) 2C9, 2C19 (++) Yes No Itraconazole 3A4 3A4 (+++) Yes Yes Voriconazole 3A4 2C9, 2C19 (for N‐oxide metabolite) 3A4 (+) 2C9 (++) 2C19 (++) No No 3A4 (++) Yes Yes Posaconazole NOT a substrate of CYPs; metabolized via UGT pathway UGT = UDP‐glucuronidation; CYP = cytochrome P450; CYP interactions are classified as +++ = strong; ++ = moderate; + = weak. Saad AH, et al. 2006. Pharmacotherapy 26(12):1730‐44. 135 Side Effects of Systemic Antifungal Agents Adverse Effect AmB Flucon Itra Vori X X (possible with IV) (possible with IV) Posa Echino X X Nephrotoxicity X Abdominal Discomfort X X Hepatic Transaminases Rash, photosensitivity X Infusion‐related Reactions / Histamine Release X X X X CNS & Visual Disturbances X X X X X Cardiomyopathy (itra), QT (azoles), ? echinos X (vori ‐ malignancy) Plasma Concentration Monitoring of Antifungals Serum concentration monitoring necessary? Drug Itraconazole Voriconazole Posaconazole suspension & tablets Flucytosine ? Target concentrations for Treatment & Prophylaxis Timing of sample Trough after 7 days therapy Yes, to ensure absorption & efficacy Trough > 0.5 μg/mL Yes • Wide range of recs due to heterogeneous study designs. • Trough after 5 days • Troughs >1‐2 µg/mL; therapy? concs >2.05 µg/mL assoc with • Nonlinear metabolism, improved outcome; 2‐5.5 μg/mL so time to SS is probably best target unpredictable • Concs >5.5 μg/mL assoc with risk of visual & hepatic adverse events • variable metabolism due to nonlinear PK & genetic variability in CYP2C19 unpredictable dose‐ exposure relationship • low concs are assoc with poor outcome; high concs are assoc with adverse effects. • Random level at SS Maybe • Outcomes (but not adverse events) correlate with higher plasma concs in prophylaxis & possibly treatment Yes • high concs are assoc with toxicity • Treatment: not well studied concs >1.25 mg/L needed? • Prophylaxis: ≥700 ng/mL ? Peak conc < 100 μg/mL (>7 days therapy). • Long t1/2 ensures little fluctuation in peaks & troughs at SS. • 2 hours post‐dose peak Adapted from: Dodds‐Ashley ES et al. Clin Infect Dis. 2006;43 suppl 1:S28‐39. ; Smith J et al. Antimicrob Agents Chemother. 2006; 50:1570‐2. ; Jang SH et al. Clin Pharmacol Ther. 2010; 88:115‐9. ; Hussaini T et al. Pharmacotherapy 2011:31(2)214‐25. NA = not applicable or not known; concs = concentrations; SS=steady state Adapted from Lewis RE. Mayo Clin Proc. 2011;86(8):805‐817 Conclusions Long‐term adverse effects of antifungals • Pharmacists reacting to rapid diagnostic tests for systemic candidiasis could significantly improve patient care • Treatment of candidemia • Long‐term use of antifungals is common – Prophylaxis – Treatment of aspergillosis – Fluconazole: • ≥6 mg/kg (800 mg for all?) • Improved benefit (treatment success, mortality, and resistance) – Echinocandins: • Voriconazole • Fixed doses are great with low MICs • Did this fixed dosing strategy encourage resistance? • Individualized dosing strategy needs further study – Alopecia – Phototoxicity • Although aspergillosis is most often treated with voriconazole, amphotericin B, and echinocandins are often utilized in therapy, in particular as salvage therapy or as part of combination therapy • Adverse effects and drug interactions remain problematic with antifungals • The role of therapeutic drug monitoring of antifungals remains controversial; however, voriconazole (and perhaps posaconazole) should be monitored • skin cancer • photosensitivity – Periostitis/Fluoride toxicity 136 Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing Antifungal Therapy Self-assessment Questions 1. When do IDSA Guidelines recommend initial therapy with fluconazole? a. When the patient is severely ill b. When the patient has recent azole exposure c. When the patient only has IV access d. When the patient is less critically ill with no recent azole exposure 2. Long term therapy with antifungal agents: a. is more common in patients who are treated for aspergillosis b. is always well tolerated, if therapeutic drug monitoring (TDM) is employed c. is associated with the same toxicities as observed with short term therapy d. is rare, since most fungal infections require only short term (< 2 week) therapy 3. Long term therapy with voriconazole has been associated with: a. nephrotoxicity b. periostitis c. fluoride deficiency d. hirsutism Answers 1. d 2. a 3. b 137 Instructions for Processing CE Credit with Enrollment Code Pharmacists and Technicians: Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity. All ACPE accredited activities which are processed on the eLearning site will be reported directly to CPE Monitor. To claim pharmacy credit, you must have your NABP e-Profile ID, birth month, and birth day. If you do not have an NABP e-Profile ID, go to www.MyCPEMonitor.net for information and application. Please follow the instructions below to process your CPE credit for this activity. 1. The ASHP eLearning site allows participants to obtain statements of continuing education credit conveniently and immediately using any computer with an internet connection. Type the following link into your web browser to access the e-Learning site: http://elearning.ashp.org/my-activities 2. If you already have an account registered with ASHP, log in using your username and password. If you have not logged in to any of the ASHP sites before and/or are not a member of ASHP, you will need to set up an account. Click on the Register link and follow the registration instructions. 3. Once logged in to the site, enter the enrollment code for this activity in the field provided and click Redeem. Note: The Enrollment Code was announced at the end of the live activity. Please record the Enrollment Code in the grid below for your records. 4. The title of this activity should now appear in a pop-up box on your screen. Click on the Go button or the activity title. 5. Complete all required elements. A green You can now claim your credit. should appear as each required element is completed. 6. Available credit(s) will appear beneath the completed required activities. Look for your profession in the list of available credits and click the appropriate Claim button. You might have to click to see more credit options if you don’t see your profession listed. CPE Credit for Pharmacists and Technicians: To claim continuing pharmacy education (CPE) credit, you will need to enter your NABP e-Profile ID, birth month, and birth day. Once you have entered this information the first time, it will auto fill in the future. Please note: All CPE credit processed on the eLearning site will be reported directly to CPE Monitor. 7. Review the information for the credit you are claiming. If all information appears to be correct, check the box at the bottom and click Claim. You will see a message if there are any problems claiming your credit. 8. After successfully claiming credit, you may print your statement of credit by clicking on Print. If you require a reprint of a statement of credit, you can return here at any time to print a duplicate. Please note that for CPE credit, printed statements may not be necessary because your credit will be reported directly to CPE Monitor. Date of Activity 5/23/15 Activity Title Enrollment Code Management of Invasive Fungal Infections: Applying Evidencebased Strategies and Individualizing Antifungal Therapy NEED HELP? Contact [email protected]. 138 14 Credit Hours 1.0 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Saturday, May 23 9:00—11:00 a.m. Emerging Technologies to Decrease Opioid Abuse: An Update for Pharmacists/ Technicians Gregory L. Holmquist, PharmD, CPE Board of Advisors / Directors, American Society of Pain Educators, Montclair, NJ Consultant / Core team member, Chronic Pain Team, Group Health Seattle, Washington Consultant, Home Health and Hospice Services, Group Health Seattle, Washington Director and Owner, Palliative Care Strategies Everett, WA 0179-0000-15-009-L01-P / 0179-0000-15-009-L01-T 2.0 contact hours (0.2 CEUs) Knowledge based activity Pharmacist Objectives: Describe how the role for the use of opioids in acute, Technician Objectives: Describe how the role for the use of opioids in acute, chronic and cancer pain has changed in the past 20 years. Differentiate addiction, physical dependency, tolerance, pseudoaddiction, and hyperalgesia. Identify typical characteristics of patients who would be identified as "high risk" , "moderate risk" and "low risk" for opioid misuse and what is the current standard best practice model for properly monitoring these patients when they are receiving opioid therapy. State the best practice model for using opioids in a patient with a past and/or current history of abuse or diversion of opioids. Describe the key features of the REMS recommendations of the FDA for opioids. Describe the FDA current guidelines regarding the current and future labeling of opioids products in the category of those with “abuse-deterrent technology”. List examples of opioids products that have “abusedeterrent” technology and how these products could be utilized to improve patient care and community safety. chronic and cancer pain has changed in the past 20 years. Recognize the best practice model for using opioids in a patient with a past and/or current history of abuse or diversion of opioids. Describe how the FDA defines opioids that contain “abuse-deterrent technology”. List examples of opioids products that have “abusedeterrent” technology. 139 Speaker has disclosed that he has no relevant financial relationships. Emerging Technologies to Decrease Opioid Abuse Objectives Describe how the role for the use of opioids in chronic noncancer pain has changed in the past 20 years. Managing Risk Maximizing Benefit Differentiate addiction, physical dependency, tolerance, pseudoaddiction, and hyperalgesia. Identify typical characteristics of patients who would be Gregory L. Holmquist, PharmD, CPE identified as "high risk" , "moderate risk" and "low risk" for opioid misuse and what is the current standard best practice model for properly monitoring these patients when they are receiving opioid therapy. Certified Pain Educator Board Certified Oncology Pharmacist Pain Management / Palliative Care Pharmacist Specialist Hospice Consultant Chronic non-cancer Pain Team LTC Elderly Pain Consultant Private pain management consultant Pain Patient: Case example Objectives (continued) Describe the FDA current guidelines regarding the current and Patient History: 38-year-old female; 65”; 173 lbs Vital Signs: within normal limits Chronic case of “pain all over”; poor sleep; daytime drowsiness; future labeling of opioids products in the category of those with “abuse-deterrent technology”. fatigue; pain of shoulder, lower back, buttocks, knee and hip; myalgia; progressive weight gain; peripheral edema; memory issues Give examples of opioids products that have “abuse-deterrent” technology and how these products could be utilized to improve patient care and community safety. Medical History: Fibromyalgia, migraine w/aura, IBS, TMJ, GERD Social History: ~3 cigarettes/day on/off; social drinker; SRDU– marijuana 1-2x/week Married, mother of 2 children (16-yo twins) Vocation: real estate sales Avocation: cycling TMJ, temporomandibular joint; FMS, fibromyalgia syndrome; GERD, gastroesophageal reflux disease; SRDU, social-recreational drug user • Meet the Patient and Her Medications Clinical Considerations to Think About… When asked to rate her pain, the patient indicates 10/10 on the pain scale. What concerns do you have regarding the use of opioids for this patient? Clinical Abuse/misuse/diversion risk by the patient? By teenagers in the Prescriptions in home: sumatriptan 50mg PO (2x/month) home? topiramate 100mg QHS metoclopramide (PRN, 2x/mo) omeprazole 20mg QD dicyclomine 20mg Q6H methadone 20mg Q8H cyclobenzaprine 10mg Q8H pregabalin 150 mg Q12 oxycodone 5mg Q6H PRN tramadol 50mg 2 tabs Q6H PRN trazodone 100mg QHS carisoprodol 350mg PRN Does the cannabinoid use by the patient concern you? What would be the benefits/risks of using opioids with ADT for this patient? What type of follow-up would you want for this patient? Counseling tips for this patient? 140 Using Medication for Pain: “An outdated model of care” “New Model of Care” Acetaminophen / ibuprofen or hydrocodone-combination for Medications are not the only option for pain everyone. management. React (over-react) to pain – only prescribe medications PRN or prescribe (in the name of compassion) way more than needed “Everyone gets addicted” or “No one gets addicted” “My patients would never misuse their medications” “What is urine testing?” Heat / cold Physical therapy TENS Acupuncture Massage Distraction Relaxation If the patient continues to complain, “Vote them off the island!” “New Model of Care” “New Model of Care” There does not exist any one medication which will solve all For some patients medications relieve most / all of the pain, pain conditions. What are the patient’s expectations for pain medications? for other patients medications may only relieve part of the pain. Pain is unique to each person Reaction to medication is unique to each person Side effects may be worse than the reduction in pain “Feel better?” Improvement in their ability to function? Improve their sleep? Not have to suffer? “New Model of Care” Pain – Treatment Options… Manage your risk by managing your patient Non-pharmacological (heat, cold, distraction, massage, TENs, acupuncture, spinal cord stimulation) Patient agreements Urine testing Risk stratification Physical therapy – strengthening, rehabilitation Behavioral – relaxation, stress reduction Incorporate tools Simple analgesics Functional improvement assessment Abuse deterrent technology (ADT) Acetaminophen Salicylates NSAIDs Non-selective versus selective Oral versus topical Pharmacist is your friend Opioids often make better “cabooses than engines” Multimodality approaches 141 …Pain – Treatment Options …Pain – Treatment Options Opioids Adjuvants PRN administration of IM / IV / oral short-acting Patient-controlled analgesia Regular scheduled administration of long-acting (controlled- release / sustained release) opioids Unique routes (transdermal, transmucosal, spinal opioids) Local anesthetics Local instillation / infiltration Spinal (epidural / intrathecal) Topical Nerve blocks Antidepressants Anticonvulsants Antiarrhythmics / local anesthetics Alpha-2-adrenergic agents NMDA antagonists Topical products Muscle relaxants Sleeping agents Miscellaneous (cannabinoids, antihistamines, adenosine, antipsychotics, psychostimulants, anxiolytics) Opioids as a “Friend” of pain management Opioids: Friend or Foe of Pain Management?? No risk of GI bleeds, renal toxicity, hepatotoxicity Strongest of analgesics Quick onset No ceiling effect with many of the agents Ability to provide analgesia in a variety of pain syndromes American Academy of Pain Medicine and American Pain Society. The use of opioids for the treatment of chronic pain. Consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain. 1997;13:6-8. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv Ther. 2000;17:70-83. Opioids as a “Foe” of pain management The Opioid Pendulum Constipation Decreased functioning Risk of dependency, addiction Lack of anti-inflammatory effect Avoidance Even dying people at risk of addiction Tolerance, neuroadaptation, hyperalgesia Potential of misuse, abuse and diversion Chang G, Chen L and Mao J. Opioid tolerance and hyperalgesia. Med Clin N Am 2007;91:199-211. Angst MS and Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology 2006;104:570-587. Chou R et al. J Pain 2009;10:113-130 FDA. Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. 04/2013.FDA. Extended-Release (ER) and Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS). 04/3013. 142 Widespread Use Opiophobia must go Balance Risk stratification and principles of addiction medicine applied to opioid prescribing regardless of the pain problem at hand Ethical Principles of Pain Management The Four “A’s” of Pain Treatment Outcomes Analgesia (pain relief) Balancing act “Prevent harm”, “Remove harm”, “Do good” “Provide compassionate care” “Do no harm” “Patient rights” Activities of daily living (physical and psychosocial functioning) Adverse effects (side effects) Aberrant drug-taking concerning opioid use (addiction-related outcomes) Passik SD, Weinreb HJ. Adv Ther. 2000;17:70-80. Pain Relievers Obtained for Nonmedical Use Factors That Argue Against Abuse Lower amounts of opioids Advanced age Cancer pain Perioperative pain No history of alcohol or substance abuse *Source of drugs for the most recent nonmedical use of pain relievers reported by persons aged 12 or older in the United States 2010. Chou R, et al. J Pain. 2009;10:113-30. Gourlay DL, et al. Pain Med. 2009;10(S2):S115-23. SAMHSA. Results From the 2010 National Survey on Drug Use and Health. HHS Publication No. (SMA) 11-4658, 2011. More Predictive Less Predictive Previous drug abuse Aggressive complaining Alcoholism Drug hoarding during reduced Forging Stealing meds Unsanctioned dose escalation Recurrent lost Rx Goals for medication therapy 1. 2. 3. 4. time of need Requesting specific meds Unapproved uses Improve patient functionality Provide analgesia (comfort) Minimize side effects Eliminate misuse, abuse, diversion Sharing with relatives Younger age High dose Pain syndrome controversial Trescot AM, Boswell MV, Atluri SL et al. Opioid guidelines in the management of chronic noncancer pain. Pain Physician 20069:1-40. Portenoy RK. J Pain Symptom Manage 1996;11:203-217. Chou R, et al. J Pain. 2009;10:113-30. 143 Considerations for Implementing Chronic Opioid Therapy (> 90 days) Responsible and Ethical Prescribing of Opioids Pick the right patient Initiate on the basis of an explicit decision and Outcomes Reliability History Intensity Syndrome Duration of treatment Severity agreement between prescriber and patient Office measurements Gain informed consent – benefit and risks Pain diaries Screen for potential comorbidities and risk ADL functioning Diversion prevention factors Pain agreement adherence Depression, anxiety, current and past substance abuse Drug tests & pill counts Failure of other physical, behavioral, and non- Molecule risks opioid Rx Webster LR, Webster RM: Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool. Pain Med 6:432-442, 2005 Chou R, et al. J Pain. 2009;10:113-30. Trescot AM et al. Pain Physician. 2006;9:1-40. Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Chronic Pain – Pharmacological Interventions: “Ideal Model of Care” Multimodal Drug Therapy Descending Modulation -Opioids -Antidepressants (e.g. tricyclic and SNRI) -Alpha-2 agonists (e.g. clonidine) -Tapentadol and tramadol Interdisciplinary approach. Medications not to be considered as the sole strategy. Focus on functional improvement, not just pain reduction. Central Sensitization -Neuraxial local anesthetics -Alpha-2 agonists (e.g. clonidine) -NMDA-receptor antagonists (e.g. methadone) -Anticonvulsants (e.g. gabapentin, pregabalin, topiramate) -Antidepressants (e.g. tricyclic and SNRI) -Tapentadol and tramadol -Opioids -Acetaminophen Role of medications should be to complement, not supplant nonpharmacological approaches, physical therapy, life style changes, behavioral approaches, etc. Have a risk management strategy in place. Do not merely follow a “traditional approach” When possible, one prescriber, one pharmacy for medications Have a consistent documentation system Consider role of patient pain diaries, medication agreements / contracts. Peripheral Sensitization -Topical local anesthetics, opioids, capsaicin, and tricyclic antidepressants -Non-steroidal anti-inflammatory drugs Consistent urine testing Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Federation of State Medical Boards. Model Policy on the Use of Opioid Analgesics for the Treatment of Chronic Pain. 2013. Adapted from Gottschalk A, Smith DS. Am Fam Phys. 2001;63:1979-1986. Differentiating Types of Pain Nociceptive Pain Somatic Pain Location Localized Generalized Radiating or specific Patient Description Pinprick, stabbing, or sharp Ache, pressure, or sharp Burning, prickling, tingling, electric shocklike, or lancinating Mechanism of Pain A-delta fiber activity Located in the periphery C Fiber activity Involved deeper innervation Dermatomal (periphery), or non-dermatomal (central) •Periosteum, joints, muscles •Sickle cell •Superficial laceration •Superficial burns •Intramuscular injections, venous access •Otitis media •Stomatitis •Extensive abrasion •Colic pain •Appendicitis •Kidney stone •Chronic pancreatitis •IBS •Angina •Menstrual cramps •Trigeminal neuralgia •Avulsion neuralgia •Posttraumatic neuralgia •Peripheral neuropathy (diabetes, HIV) •Limb amputation •Herpetic neuralgia Clinical Examples Somatic Pain Neuropathic Pain Visceral Pain Medication therapy overview APAP/ NSAID based on symptoms Institute for Clinical Systems Improvement (ICSI). Assessment and Management of Acute Pain. Sixth Edition, March 2008. www.icsi.org. 144 + Opioid Visceral Pain Neuropathic Pain Medication therapy overview Medication therapy overview Anticholinergic + Opioid / NSAID Adjuvant + Opioid / NSAID “Let the adjuvant be the engine and the opioid the caboose” Pain Patients vs. Addicts Round 1 Pain Patients = Addict??? Pain Patients Addicts Able to control use of medications Out of control with any medications Medications improve the Medications cause quality of the patient’s life decrease in the quality of life Will want to decrease medication if side effects are present Continues or increases dose even with side effects Schnoll SH, Finch J. J Law Med Ethics. 1994;22:252-6. Pain Patients vs. Addicts Physical dependence vs. addiction Round 2 Pain Patients Addicts Continued concern about the cause of the pain Unaware or in denial of medical problems related to the pain Follows agreement for the use of meds Does not follow the agreement, escalates dosage Frequently has meds left over from the previous visit Has no medication left over, loses meds or scripts, and always has a “story” Physical dependence is a physiological phenomenon defined by the development of an abstinence syndrome following abrupt discontinuation of therapy, substantial dose reduction, or administration of an antagonist drug. American Society of Addiction Medicine. Public Policy Statement on definitions related to the use of opioids in pain treatment. J Addictive Dis. 1998;17:129-133. Schnoll SH, Finch J. J Law Med Ethics. 1994;22:252-6. 145 Addiction vs. Pseudo Addiction Physical dependence vs. addiction Physical dependence is an expected occurrence in all individuals in the presence of continuous use of opioids for therapeutic or non-therapeutic purposes. It does not, in and of itself imply addiction. Addiction Pseudo-Addiction Compulsive need for and use of a habit-forming substance characterized by tolerance and physiological symptoms upon withdrawal A drug-seeking behavior that simulates true addiction occurring in patients who are receiving inadequate pain medication Broadly: persistent compulsive use of a substance known by the user to be harmful American Society of Addiction Medicine. Public Policy Statement on definitions related to the use of opioids in pain treatment. J Addictive Dis. 1998;17:129-133. Pappagallo M. Pseudotolerance. J Pharm Care Pain Symptom Control. 1998;6:95-98 Addiction Does Not Reside Solely in Drugs Addiction: 5Cs Addiction is not merely a disorder of drug Chronic Compulsive use Control—impaired Craving Continued use despite harm use Addiction also involves the following realms Hemby SE. Curr Psychiatry Rep. 1999;1:159-65. Prescott CA, Kendler KS. Am J Psychiatry. 1999;156:34-40. Enoch MA, Goldman D. Curr Psychiatry Rep. 2001;3:144-51. Tsuang MT, et al. Arch Gen Psychiatry. 1998;55:967-72. Miller WR. Addiction. 1998;93:979-90. Hemby SE. Curr Psychiatry Rep. 1999;1:159-65. Prescott CA, Kendler KS. Am J Psychiatry. 1999;156:34-40. Enoch MA, Goldman D. Curr Psychiatry Rep. 2001;3:144-51. Tsuang MT, et al. Arch Gen Psychiatry. 1998;55:967-72. Miller WR. Addiction. 1998;93:979-90. Addiction: ….A Multi-factorial Disease State Psychology Environment Biology Innate Acquired * Universal Precautions Availability & Milieu Drug Genetic/familial Psychiatric Environment Social Spiritual Determine patient’s risk for opioid therapy or their outcome status regarding abuse Every patient on long-term opioid treatment should be *Manifestation of the disease of addiction monitored for abuse/addiction Patient treatment agreement, education Secure storage of medications Structured initial and follow-up assessments Urine toxicology, prescription monitoring data Reinforcement Figure courtesy of JD Haddox, DDS, MD. McLellan, et al. JAMA. 2000;284:1689-95. Hemby SE. Curr Psychiatry Rep. 1999;1:159-65. Kendler KS, et al. Arch Gen Psychiatry. 2000;57:261-9. Tsuang MT et al. Arch Gen Psychiatry. 1998;55:967-72. Gourlay DL et al. Pain Medicine 2005;6:107-112 146 Risk Screening Tools Opioid Risk Tool (ORT) Administration Opioid Risk Tool (ORT) – risk of opioid addiction On initial visit Prior to opioid therapy CAGE-AID – alcohol or drug problems PHQ-9 – depression severity Scoring Urine testing and pill counts 0-3: low risk (6%) 4-7: moderate risk (28%) >8: high risk (>90%) Function and pain assessment Webster LR, Webster RM. AAPM 2005;6:432-442. Brown RL, Rounds LA. Wisc Med J 1995;94:135-140. Couwenbergh C, Gaag RJVD, Koeter et al. Substand Use and MIsuse 2009;44:823-834. Leonardson GR, Kemper E, Ness FK et al. Psychological Reports 2005;97:161-166. Kroenke K, Spitzer R, Williams W. JGIM 2001;16:601-616. Webster LR, Webster RM. Pain Med 2005;6:432-442. Tools for Assessing Function & Pain Risk assessment for Opioid Use SF36 Health Survey High risk –need high intensity monitoring http://www.rand.org/health/surveys_tools/mos/mos_core_36item.html Brief Pain Inventory http://www.ohsu.edu/ahec/pain/paininventory.pdf Quality of Life Scale http://www.uic.edu/orgs/qli/questionaires/ questionnairehome.htm Taking > 120mg MED (morphine oral equivalent mg per day) Taking methadone Current alcohol and/or drug abuse 25 years old and younger Repeated problems following opioid management tx plan Frequent early refill requests Escalating dose without consultation with physician Getting opioids from multiple prescribers Oswestry Disability Index http://www.workcover.com/public/download.aspx?id=794&str=disability index oswestry Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Patient treatment agreements… Risk assessment for Opioid Use Acknowledgement that previous treatment strategies have been inadequate. Medium risk – need moderate intensity monitoring Extensive written explanations of the side effects and risks of opioid therapy. Taking between 40mg - 120mg MED (morphine oral equivalent mg per day) Personal or family history of alcohol and/or drug abuse or mental health issues Terms for routine, random substance testing Outlining conditions in which therapy will be conducted (refills, how often, etc.) Consequences for violating agreement Low risk – low intensity monitoring Taking < 40mg MED No personal or family history of alcohol and/or drug abuse or Procedures for discontinuing opioids should it become necessary. Emphasis on the importance of improved functionality in order for opioid mental health issues therapy to continue. Restrictions regarding single prescriber, single pharmacy Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Trescot AM et al. Pain Physician. 2006;9:1-40. Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov 147 UDS – Red Flag Results Tapering or discontinuing opioids Negative for opioid(s) prescribed Positive for amphetamine , methamphetamine, cocaine, benzodiazepines Positive for other opioids not prescribed Positive for alcohol Indication for tapering Taper method • Urine drug screen is consistent with substance abuse concerns • Behavior suggests that patient may be misusing or diverting1 Over 3-7 days or 15% / day2 • Medication side effects indicate risks greater than benefit 3 • Co-morbidities increase risk of consumption • Morphine equivalent exceeds recommended threshold 10% per week • Function and pain not improved • Long-term opioid prescription with tolerance • Co-morbidities increase risk of consumption 10% every 2-4 weeks 1. Behaviors may include: stealing/borrowing drugs, injecting oral/topical opioids, aggressive demands for opioids 2. Opioid withdrawal is unpleasant for the patient but is not dangerous 3. Side effects of opioids may include: depression, sleeping problems, worsening pain, sexual problems, fatigue, constipation, falling/breaking bones, itching, nausea or vomiting, breathing problems Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Commercially Available Oral / SL / Nasal Opioids Combination Teaching About Medication Storage and Sharing Hydrocodone / APAP: Sharing meds seen as safe by “self-treaters” (includes generic and branded Vicodin, Loratab, Zydone) 5/325; 7.5/325; Educate patients about medication storage Hydrocodone / Ibuprofen: (Vicoprofen) 5/200; 7.5/200 “Safe” or “lock box” Kadian specific: 10;20;30;40;50;60;80;100;200 Avinza specific: 30; 45; 60;75; 90; 120 Embeda (morphine+naltrexone): 20/0.8; 30/1.2; 50/2; 60/2.4; 80/3.2; 100/4 Oxycodone (generic) Oxycodone-LA 5; 10, 15; 30 IR (includes generic and Percocet, Roxicet) 2.5/325; 5/325; 7.5/325; 10/325; schedule programmed by the MD elixirs: 2mg/ml, 4mg/ml,20mg/ml “Long acting” (LA/ER) Morphine-LA 15; 30; 60; 100; 200; Tramadol:(generic and Ultram) 50 Tapentadol: (Nucynta) 50, 75, 100 elixirs: 1mg/ml, 20mg/ml Oxycodone / APAP: New devices being developed -- patient have access and on a Immediate Release Morphine 10; 15; 30 Hydromorphone(generic,/Dilaudid) tablets: 2; 4; 8 IR elixir: 1mg/ml OxyContin specific: 10, 15, 20, 30, 40, 60, 80 Targiniq (oxycodone+naloxone) 10/5; 20/10; 40/20 Oxymorphone-LA 5; 7.5; 10; 15; 20; 30; 40 Oxycodone / Ibuprofen: 5/400 Oxymorphone 5; 10 Fentanyl-TTS 12; 25; 50; 75;100(mcg/hr) Codeine/APAP Codeine 15; 30; 60 Hydrocodone ER 15/300;30/300;60/300 Hysingla specific: 20, 30, 40, 60, 80, 100, 120 Zohydro specific: 10, 15, 20, 30, 40, 50 Fentanyl tabs (buccal/ OTFC) Hydromorphone ER 8, 12, 16 Actiq, Fentora: 0.2;0.3;0.4 0.6;0.8;1.2; 1.6 Fentanyl SL Methadone 5; 10; elixir 1mg/ml Spray (Subsys): 0.1; 0.2; 0.4; 0.6; 0.8 Film (Onsolis): 0.2; 0.4; 0.6; 0.8; 1.2 Fentanyl nasal (Lazanda) 0.1, 0.4 LA/ER Oral Opioid Formulations Name Dosing Interval Dosage form Morphine MS Contin/generic Avinza Embeda Kadian Q 8 or 12 H Q 24 H Q 12 or 24 H Q 12 or 24 H Tablet Capsule Capsule Capsule No No Yes No Q 12 H Tablet Q 12 H Tablet Yes Yes Q 12 H Q 12 H Tablet Tablet Yes No Q 24 H Q 12 H Tablet Capsule Yes Yes with new formulation Targiniq Oxymorphone Opana Generic Hydrocodone Hysingla Zohydro Hydromorphone Exalgo Tapentadol Nucynta Q 24 h Tablet Yes Q 24 H Tablet Yes 50, 100, 150, 200, 250 Three Significant Risks of Using Opioids for Chronic Pain Tamper resistant Deterioration of functioning / increasing pain Misuse, abuse, diversion Inadvertent over-dosage Oxycodone OxyContin Tapentadol ER 148 Hyperalgesia Thought to involved NMDA receptor activation sensitization of pronociceptive pathways Hyperalgesia Characterized by patients who once responded to an Fact or fiction? opioid and in spite of being on a stable doses for a period of time now have increased pain sensitivity Chang G, Chen L and Mao J. Opioid tolerance and hyperalgesia. Med Clin N Am 2007;91:199-211. Angst MS and Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology 2006;104:570587. Differentiation of Opioid-induced Hyperalgesia (OIH) Opioid-induced Hyperalgesia (OIH) Two forms of OIH can be distinguished Need to distinguish from All can result in either: Increased sensitivity to pain; aggravation of preexisting pain; or, expression of novel pain symptoms. OIH1: Opioid maintenance therapy Involves up-regulation of pain facilitating neuronal pathways at multiple levels of the central and peripheral nervous system Stimulation of excitatory amino acid neurotransmitter system. OIH2: Very high and escalating doses of opioids Usually implicated with high doses of morphine or hydromorphone Severe allodynia, myoclonus noted Thought to be due to metabolites inhibiting glycineric inhibition at spinal cord tolerance progression of painful disease process increased activity increased stress clinical exacerbation of preexisting pain Typically produces diffuse pain, less defined in quality and often extending to other areas OIH can mimic opioid withdrawal level inducing a strychnine-like excitatory intoxication. OIH often worsened with increasing dosage Angst MS and Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology 2006;104:570-587. Davis MP, Shaiova LA, Angst. When opioids cause pain. J Clin Oncol 2007;25:4497-4498. Lee M, et al. Pain Physician 2011;14:145-161. Misuse, abuse and diversion Prevention Strategies for Opioid-Induced Hyperalgesia Misuse Using opioid for purposes other than intended Use of adjuvant therapies for “opioid sparing” effect Anticonvulsants Antidepressants Depression, sleep, anxiety, constipation pain Abuse Opioid rotation Manipulating the opioid delivery system, or using the opioid at a higher than prescribed dose to attempt to obtain a faster onset, or greater euphoria To take advantage of “incomplete cross tolerance” To avoid toxic metabolites FDA definition: “Intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect” Combination of opioid and low-dose mu receptor antagonist (e.g. buprenorphine and naltrexone) Blockade of the NMDA receptor (e.g., ketamine) Diversion Selling/giving/buying a portion of a prescription to/from another person Stealing medication from a friend/relative/stranger Silverman SM. Pain Physician. 2009;12(3):679-684. 149 Methods of abuse Abuse Deterrent Technology (ADT) FDA Guidance for Industry Crush/grind/grate Goals Mastication ADT intended to make manipulation more difficult or to make Intravenous injection abuse of manipulated product less attractive or rewarding Nasal insufflation Caveats Inhalation by vaporization “FDA approved technologies have not yet proven successful at deterring the most common form of abuse – swallowing a number of intact tablets or capsules to achieve a feeling of euphoria” “A product with ADT does not mean that there is no risk of abuse. It means rather that the risk of abuse is lower than it would be without those properties” Ethanol co-ingestion Multiple oral dose administration Heating/microwaving Freezing Solvent extraction FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. Abuse-Deterrent Technologies (ADT) Abuse-Deterrent Technologies (ADT) (continued) Aversion Physical/chemical barriers Substances added to product to produce an unpleasant effect if Prevent chewing, crushing, cutting, grating, grinding Resist extraction of opioid with common solvents These barriers can limit drug release or change the physical form manipulated or if a higher dose is used than directed E.g. nasal irritants Delivery system of the drug rendering it less amenable to abuse Drug-release designs can offer resistance to abuse Agonist/antagonist combinations E.g. depot injections, SQ implants Antagonist to interfere with, reduce or defeat the euphoria New molecular entities or prodrugs associated with abuse. Design so there is a need for enzymatic activation, different Antagonist can be sequestered and released only on receptor binding profiles, slower penetration into the CNS manipulation of the drug. FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. FDA Labeling for ADT(continued) FDA Labeling for ADT Types of studies: Need scientifically rigorous studies to evaluate In vitro manipulation/extraction studies Positive controls, comparator drugs, outcome measures, Test the ability of product to be crushed, cut, grated, etc with common household items statistical analysis (spoons, cutters, coffee grinders) and solvents (vinegar, alcohol, water, isopropanol, acetone) Will ADT be expected to have meaningful impact on the abuse If two ingredients in product (e.g. agonist-antagonist) can agonist be extracted without antagonist contamination? of that product E.g. short-acting opioids with nasal deterrents. Usual route of Vaporization (smoking) Nasal particle size Ability to liquefy and inject product (solvent, melting) abuse is ORAL not NASAL with short-acting opioids Pharmacokinetic studies Effects of food/alcohol Compare oral to nasal, injectable FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. Clinical abuse potential studies Drug-experienced, recreational drug user Pre-marketing trials to assess potential ADT under controlled settings FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. 150 FDA Categories of Abuse Deterrent Labeling FDA Labeling for ADT(continued) Types of studies: Category I: Post-marketing studies In vitro physical and chemical tablet manipulation studies To determine whether the marketing of a product with ADT results in demonstrate that the product resists crushing, breaking and dissolution using a variety of tools and solvents and retains some of the extended-release properties despite manipulation. In vitro data demonstrates product cannot be crushed and dissolved or extracted in a small volume of solution suitable for injection. These products would be labeled: “In vitro data demonstrate that the meaningful reductions in abuse, misuse and related adverse clinical outcomes including addiction, overdose and death. Comments: FDA will expect manufacturers to compare their formulations against approved ADT versions of the same opioid. product has physical and chemical properties that are expected to deter intravenous abuse. However the abuse of this product is still possible by the oral and nasal routes FDA is concerned that, with time, abusers may adapt to ADT and discover methods to defeat them. FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. FDA Categories of Abuse Deterrent Labeling FDA Categories of Abuse Deterrent Labeling Category I and II: Category II and III: In vitro data demonstrates from study of the oral and nasal routes Pharmacokinetic and clinical abuse potential studies demonstrate demonstrated that no changes occurred in the extended-release properties of the opioid after crushing or dissolution in a variety of solvents These products would be labeled: “In vitro data demonstrate that the the release of an antagonist following crushing or intravenous abuse of the oral product (in a combination agonist-antagonist product) and that the presence of the antagonist resulted in less drug liking compared to a similar amount of the opioid alone when given by oral or intranasal routes. These products would be labeled, “Pharmacokinetic studies, oral and product has physical and chemical properties that are expected to deter oral, nasal and intravenous abuse. However, abuse of the product is still possible by the oral route. intranasal studies demonstrate that the product has properties expected to deter abuse via the oral, intranasal and intravenous routes. However, abuse by these routes is still possible. FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015. Current ER Opioids with ADT (in order of date of FDA approval) Mythology of ADT Technology Opioid Product Description of technology Embeda® Addition of sequestered naltrexone – designed to release antagonist if crushed, and then snorted, or crushed, dissolved and then injected intravenously All ADT technology is the same OxyContin® Resistec polymer matrix – designed to be plastic-like, hard to break, becomes gel in water, thus difficult to use in a syringe ADT technology is fail-safe Opana® INTAC polyethylene oxide matrix – designed to render tablet highly resistant to crushing; when exposed to water forms a gel leading to difficulty drawing into a syringe. ADT technology has been proven to decrease addiction, Nucynta® Polyethylene oxide matrix – designed to render tablet highly resistant to crushing or extraction of active drug Exalgo® OROS technology - osmotically active bilayer core enclosed in a semipermeable tablet shell membrane – designed to minimize crushing and active drug extraction Targiniq® Addition of naloxone – designed to block the euphoric effect if its crushed and then snorted, or crushed, dissolved and then injected intravenously. Hysingla® Resistec polymer matrix – designed to be plastic-like, hard to break, becomes gel in water, thus difficult to use in a syringe Zohydro® BeadTek formulation – designed to make it hard to crush and snort. Prevents abuse/misuse/diversion abuse, over-dosages, misuse, diversion, etc. ADT technology alone will ensure that my patients will not misuse, abuse or divert their opioids ADT technology ensures the best pharmacokinetics of the opioid delivery system. 151 Precautions / wrong assumptions regarding ADT Opioids Precautions / wrong assumptions regarding ADT Opioids (continued) ADT do not prevent the most common form of abuse – taking Generic oxymorphone (Opana) does not have tamper resistant extra tablets/capsules properties. Some of the new formulations with ADT are contraindicated in Still need to account for FDA requirement that patients be mechanical bowel obstruction opioid tolerant prior to prescribing some of the higher dosage strengths. Some of the new formulations must be taken ONE tablet at a All of the ADT products can still be abused and misused time and not be wet or licked prior to swallowing Abusers may turn to other opioids: Reviewing post-marketing studies, the FDA concluded, “the data do not yet demonstrate a reduction in OxyContin abuse following the replacement of OxyContin with reformulated OxyContin in the marketplace”. Short-acting Transdermal fentanyl Buprenorphine Potential reasons for Inadvertent Overdosages with ER Opioids Tolerance “Needing increased doses to maintain level of pain control” Patient error Has not proven to be a limitation to short- or Misread dose or dosing instructions Chew, split, break or crush ER formulation for ease of swallowing Food / alcohol interactions long-term opioid use. Rapid escalation of drug doses in cancer pain usually due to disease progression. Patient not opioid tolerant Studies suggest that use of long-acting oral opioids Wrong conversions as maintenance therapy for primarily nociceptive pain does not lead to uncontrolled dose escalation. In appropriate use of Fentanyl products Methadone Savage S, Covington EC, Heit HA et al. (2001). Definitions related to the use of opiates for the treatment of pain: a consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. American Society of Addiction Medicine. http://www.asam.or/pain/definitions2.pdf. American Society of Addiction Medicine. Public Policy Statement on definitions related to the use of opioids in pain treatment. J Addictive Dis. 1998;17:129-133. Tolerance Tolerance To which effects does opioid tolerance occur? Innate tolerance Genetically determined, seen with first dose Analgesic effects? Acquired tolerance Pharmacokinetic (desensitization of receptors) Pharmacodynamic (reduced concentration of drug Dizziness? Euphoria / dysphoria feelings? Respiratory depression? at receptors) Learned (reinforcement of an effect of a drug) Sedation? Constipation? Nausea? Chang G, Chen L and Mao J. Opioid tolerance and hyperalgesia. Med Clin N Am 2007;91:199-211. Angst MS and Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology 2006;104:570-587. 152 FDA Tolerance definition for ER Opioids Opioid Tolerance - LA / ER Opioids Product FDA Indications: moderate to severe pain in opioid tolerant Morphine • MS Contin / generic • Avinza • Kadian • Embeda patients who require continuous around-the-clock opioid analgesia for an extended period of time Opioid tolerant definitions: (taking at least a week) Oxycodone oral 30 mg / 24 hours Fentanyl 25 mcg / hr patch Hydromorphone 8 mg oral / 24 hours Oxymorphone oral 25 mg / 24 hours FDA. Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. 04/2013.FDA. Extended-Release (ER) and Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS). 04/3013. Approximate Equianalgesic Dose Morphine (reference) 30 mg oral 10 mg intravenous / SQ Codeine 200 mg oral Fentanyl transdermal 12.5 mcg/hr transdermal Hydrocodone 30 mg oral Hydromorphone 7.5 mg oral 1.5 mg intravenous / SQ Methadone Chronic 4 mg – 7.5 mg* Oxycodone 20 mg oral Oxymorphone 10 mg oral Tapentadol 100 mg oral Tramadol N/A 100 and 200 mg size 90, 120 mg size 100, 130, 150 and 200 mg sizes 100 mg / 4 mg size • Targiniq • 60 and 80 mg size, or any single dose > 40 mg or total daily dose > 80 mg • Any single dose > 40/20 or total daily dose > 80/40 mg Hydrocodone • Hysingla • Zohydro • Any single dose > 80 mg • 50 mg size, or any single dose > 40, or any daily dose > 80 Exalgo (hydromorphone) All strengths 8, 12, 16 mg Duragesic (fentanyl TDS) All dosage strengths (12, 25, 50, 75, 100 mcg/hr) Nucynta (tapentadol) No FDA limitations Opana (oxymorphone) No FDA limitations Checklist for Appropriate Use of Transdermal Fentanyl Opioid Equivalent Doses Patient should not be cachectic or edematous or sweaty. **(remember fentanyl is lipophilic, doesn’t pass easily through aqueous media) AND Patient should not be running fevers or putting a heat source (pads, water beds, etc) directly on or near the transdermal patch **(remember heat dramatically speeds up transdermal delivery of drug) AND Patient’s pain should be relatively stable. **(remember fentanyl has a lag time of 16-24 hrs to absorb) AND Patient has pain described as “moderate” or “severe” and is not opioid naive. **(remember even the lowest size patch is “worth” > 30 mg oral morphine per day) AND Patient cannot tolerate oral therapies * Conversion highly variable based on dose, drug interactions, unique patient variables **(remember sustained-release oral morphine provides greater consistency in serum opioid levels) Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update. Available at: http://www.agencymeddirectors.wa.gov Short-Acting Fentanyl Products Fentanyl Products Indication: management of breakthrough pain in cancer patients 18 Actiq® (and generic equivalents) “Lollipop” formulation – 200, 400, 600, 800, 1200, 1600 mcg years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain Opioid tolerant definitions: (receiving for one week or longer) • • • • Oxycodone • OxyContin Morphine oral 60 mg / 24 hours Opioid Product sizes and dosages at which patient needs to be opioid tolerant prior to being prescribed the ER opioid Fentora® Buccal tablet – 100, 200, 300, 400, 600, 800 mcg Morphine oral 60 mg / 24 hours Oxycodone oral 30 mg / 24 hours Abstral® Sublingual tablet – 100, 200, 300, 400, 600, 800 mcg Fentanyl 25 mcg / hr patch Hydromorphone 8 mg oral / 24 hours Oxymorphone oral 25 mg / 24 hours Onsolis® Buccal soluble film – 200, 400, 600, 800, 1200 mcg Contraindications include: Acute pain, post-op pain, dental pain, migraines Subsys® Sublingual spray – 100, 200, 400, 600, 800, 1200, 1600 mcg May be dispensed only to patients enrolled in the transmucosal immediate release fentanyl (TIRF) REMS Access program @ www.TIRFREMSaccess.com Lazanda® Nasal spray – 100, 400 mcg 153 What makes the use of methadone more complex than other opioids? Fentanyl Products Do NOT interchange products without first starting over at the Methadone has unique pharmacokinetics leading to variations in serum levels, the amount of free drug available at receptor and drug accumulation. LOWEST dose available of the new product Differences exist in pharmacokinetics of TIRF medications TIRF medications are NOT equivalent to any other fentanyl product, Long, and variable half-life: mean 40 hours (range: 5 - 130 hours) Good, and variable bioavailability: mean 75% (range: 36 – 100%) Highly bound to plasma proteins: mean free fraction 13% including another TIRF medication, on a mcg for mcg basis. (4-fold interindividual variation) Limit use of TIRF medications to 4 or fewer doses per day. Methadone has numerous drug interactions. Unique and potentially dangerous side effects Titration and conversion to- and from- other opioids does not follow “textbook” standards Eap CB, Buclin T and Baumann P. Clin Pharmacokinet 2002;41:1153-1193. TIRF = transmucosal immediate release fentanyl Drug interactions with methadone… Methadone and Torsades Methadone, by itself, in low to moderate doses (< 100 Methadone is metabolized mainly through the CYT P450 3A4 and mg/day), most likely has little risk to cause torsades. 2D6 isoenzymes By itself, at higher doses (> 100 mg/day) or at low- to Common inhibitors of 3A4 and 2D6 moderate doses in conjunction with other drugs associated with QT prolongation, methadone can cause Torsades. ( METH serum levels opioid effects, sedation, risk resp. depression) 3A4: amitriptyline, ciprofloxacin, fluconazole, sertraline Drugs that prolong QT and/or induce Torsades 2D6: fluoxetine, paroxetine, sertraline Azithromycin, chlorpromazine, cisapride, clarithromycin, dolasetron, erythromycin, haloperidol, levofloxacin, lithium, methadone, ondansetron, quetiapine, risperidone, tizanidine, venlafaxine Common inducers of 3A4 ( METH serum levels opioid effects, risk withdrawal reaction) Amprenavir, efavirenz, nelfinavir, nevirapine, phenobarbital, phenytoin, rifampin, ritonavir, spironolactone Krantz MJ, Lewkowlez L, Hays H et al. Ann Intern Med. 2002;137:501-504 Piguet V et al. J Clin Psychopharm. 2994;24:446-8. Eap CB, Buclin T and Baumann P. Clin Pharmacokinet 2002;41:1153-1193. Methadone conversion recommendations TDD Oral Morphine EPERC Conversion (morphine : methadone)* % of morphine dose (FDA) < 100 mg 3:1 20 - 30% 101 – 300 mg 5:1 10 - 20% 301 – 600 mg 10 : 1 8 – 12% 601 – 800 mg 12 : 1 5 – 10% 801 – 1000 mg 15 : 1 5 – 10% > 1000 mg 20 : 1 < 5% Friedman method < 1000mg per day AND < 65 yo < 1000mg per day BUT > 65 yo > 1000mg per day BUT < 2000mg per day > 2000mg per day 10 : 1 20 : 1 20 : 1 Call pharmacist *Gazelle G and Fine P End-of-life Physician Education Resource Center, July 2006 Friedman LL, Rodgers PE Clinics in Family Practice 2004;6:371-393 154 Back to our patient, now what do you think… Pain –“Ideal Model of Care” Have a risk management strategy in place for chronic pain What concerns do you have regarding the use of opioids for this patients on maintenance opioid therapy patient? Clinical Abuse/misuse/diversion risk by the patient? By teenagers in the Do not merely follow a “traditional approach” One prescriber, one pharmacy for medications Have patient and prescriber sign opioid agreement Do not combine opioids with sedative-hypnotics, benzodiazepines or home? Does the cannabinoid use by the patient concern you? barbiturates unless benefits outweigh risks Routinely assess function, pain state and aberrant behaviors Have a consistent documentation system and urine testing Consider role of patient pain diaries Use ADT technology IN ADDITION TO all of the above Proactively manage side effects, especially CONSTIPATION What would be the benefits/risks of using opioids with ADT for this patient? What type of follow-up would you want for this patient? Counseling tips for this patient? Balancing Medication Use in Patients Pain control Comfort level Non-pharmacological strategies Improving overall function Minimizing side effects Medical / legal guidelines for opioid use Ethical issues 155 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Saturday, May 23 11:00 a.m.—12:00 p.m. Sterile Compounding: USP <797> Update Anne P LaVance, BS, CPhT Director - Pharmacy Technician Program Delgado Community College New Orleans, LA 0179-0000-15-007-L04-P / 0179-0000-15-007-L04-T 1.0 contact hour (0.1 CEU) Knowledge-based activity Pharmacist Objectives: Identify USP Chapter <797> Risk Levels Describe Primary and Secondary Engineering Controls Explain quality assurance and identify products and methods of ensuring proper aseptic technique Identify best practice standards for Pharmacists in USP Chapter <797> compliance Identify gaps in USP Chapter <797> compliance Technician Objectives: Identify the primary areas of focus for the health and safety management system for HDs Identify USP Chapter <797> Risk Levels Describe Primary and Secondary Engineering Controls Explain quality assurance and identify products and methods of ensuring proper aseptic technique Identify best practice standards for Pharmacy Technicians in USP Chapter <797> compliance Speaker has disclosed that she has no relevant financial relationships. 156 Learning Objectives: Pharmacist Sterile Compounding: USP Chapter <797> Anne P LaVance, BS, CPhT Pharmacy Technician Program Director – Delgado Community College ACPE Certified Trainer: Sterile Compounding and Aseptic Technique Identify USP Chapter <797> Risk Levels Describe Primary and Secondary Engineering Controls Identify USP Chapter <797> Risk Levels Explain quality assurance and identify products and methods of ensuring proper aseptic technique Describe Primary and Secondary Engineering Controls Explain quality assurance and identify products and methods of ensuring proper aseptic technique Identify best practice standards for Pharmacy Technicians in USP Chapter <797> Compliance Identify best practice standards for Pharmacists in USP Chapter <797> Compliance Identify gaps in USP <797> compliance Compounded Sterile Products (CSPs) USP General Chapter <797> The objective of this chapter is to describe conditions and practices to prevent harm, including death, to patients that could result from Any Compounded: Drug (1) Microbial contamination (nonsterility), Biologic (2) Excessive bacterial endotoxins, Nutrient (3) Variability in the intended strength of correct ingredients that exceeds either monograph limits for official articles Diagnostic (4) Unintended chemical and physical contaminants, and (5) Ingredients of inappropriate quality in compounded sterile preparations (CSPs). Radiopharmaceutical 3 Source: 2015 USP Compounding Compendium Chapter <979> Standards: Who and Where? Technicians Physicians Everywhere CSPs are prepared Hospitals Clinics Anywhere Aqueous bronchial or nasal inhalations Irrigation for wounds and body cavities Ophthalmic preparations Level Medium-Risk Level High-Risk Level Nurses Physician Injections Low-Risk Pharmacists Risk Levels Anyone who prepares CSPs Pharmacy Pharmacy Technician Practice CSPs are stored 157 Low-Risk Level CSP ISO Class 5 or better air quality Only sterile ingredients, products, components, and devices Low-Risk Level CSP Involves only transfer, measuring, and mixing not more than three commercially manufactured sterile products Not more than two entries into any one sterile container or package Single-volume transfers with a sterile syringe and needle 48 hours at controlled room temperature 14 days refrigerated 45 days in a solid frozen state (-25o to -10o) 12-Hour or Less BUD PEC not located in a ISO Class 7 or better area PEC MUST be ISO Class 5 Windows and doors must be sealed if connected to outdoors or high traffic Procedures for PPE must be followed; Sinks must not be located in immediate area of PEC device Follow specifications for Cleaning and Disinfecting the Sterile Compounding Areas, Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices and Cleaning/Disinfecting Procedure, and Viable and Nonviable Environmental Sampling Testing must be followed. Meets requirements of Low-Risk and has one or more of the following conditions: Multiple individual or small doses are combined to prepare a CSP that will administered in multiple doses Ampuls – contents passed through a sterile filter Bottles, Medium-Risk Level CSP Examples of Low-Risk CSPs Storage cannot exceed: Bags Complex aseptic manipulations other than a singe-volume transfer Vials Requires Simple aseptic measuring and transferring – not more than 3 manufactured sterile products unusually long compounding duration Admixtures Nutritional solutions Medium-Risk Level CSP At risk for contamination Nonsterile ingredients Exposed to air quality worse than ISO Class 5 for more than 1 hour Compounding personnel are improperly garbed and gloved Nonsterile water containing preparations are stored for more than 6 hours before being sterilized Unopened bulk ingredients: Chemical purity and content strength is assumed, not verified Storage cannot exceed: 30 9 hours at controlled room temperature days refrigerated 45 HIgh-Risk Level CSP days in a solid frozen state (-25o to -10o) Examples of Medium-Risk CSP TPN Filling reservoirs of injection and infusion devices with more than three sterile drug products Transfer of volumes from multiple ampuls or vials into one or more final sterile containers 158 High-Risk Level CSP Additional High-Risk CSP Requirments All nonsterile devices rinsed with sterle, pyrogen-free water If product will be subjected to terminal sterilization – prefilter with 1.2 micron filter or smaller 3 Sterilization by filtration shall be completed with a 0. or 0.22 micron filter; entire process must be completed in an ISO Class 5 or better environment days in a solid frozen state (-25o to -10o) Examples of High-Risk CSP Dissolving nonsterile bulk drug and nutrient powders to make a solution that will be terminally sterilized Exposing sterile ingredients/components to room air quality worse than ISO Class 5 for more than 1 hour Measuring and mixing sterile ingredients in nonsterile devices Engineering Controls Primary Engineering Controls (PECs) days refrigerated 45 Engineering Controls Storage cannot exceed: 24 hours at controlled room temperature ISO Class 5 LAFW Secondary Engineering Controls Area/Environment where PEC is located Controlled temperature Well lit Clean room / Buffer area Anteroom Characteristics BSC CAI CACI Located within a restricted access ISO Class 7 buffer area Quality Assurance Air quality Disinfection processes PPE Review of orders and packages Inspection of CSPs for absence of particulate matter and leaks Inspection of label for accuracy and completeness Media-fill testing Gloved finger-tip sampling Surface sampling Bacterial Endotoxin testing Temperature monitoring of all storage environments ISO Class 8 or better Impervious Free from cracks and crevices Smooth Non-Shedding Resistant to damage from disinfecting agents Quality Assurance Testing and evaluation ISO Class 7 or better 159 Characteristics of a QA Program: Formal and Written policy Descriptive oh specific activities for monitoring and evaluation and how results will be reported and evaluated Thresholds for evaluations and follow-up Effectively addresses risk management Chapter <797> QA Requirements Media Fill Tests Routine disinfection and air quality testing Visual confirmation of properly donned PPE Review orders and packages for correct identity and amounts Visual inspection of CSPs and labels Media fill test to verify aseptic process Best Practice Completed annually Completed without interruption Appropriate risk level environments under conditions that simulate the most challenging or stressful conditions Best Practice: Training USP Chapter <797> LABP regulations ASHP gap analysis tool Review /Revise P&P to match current standards TRAINING, Validation, and Documentation Training course involving written exams, technique demonstration, process validation, and media-fill testing Training and evaluation must occur before making CSPs for patient administration Recertified/Validated annually Maintain records of training hours, testing and validations Pharmacists Pharmacy Technicians Gap Analysis Identifies areas of compliance Identifies areas of non-compliance Are you here? Recommended minimum 40 hour course in sterile compounding and aseptic technique Identify Gaps Why is Gap analysis important? USP <797> Partial Compliance Recommended minimum 20 hour course in sterile compounding an aseptic technique USP <797> Compliant Standards in USP Chapter <797> Training Lack of formal Sterile compounding training Trainer not fully knowledgeable in USP <797> Lack of specialty expertise Or, are you here? 160 Resources Bridge the Gap Resources 2015 USP Compounding Compendium Gap Analysis Survey Compounding Sterile Preparations USP <797>; International Journal of Pharmaceutical Compounding ASHP ACPE LABP Buchanan, E. Clyde, M.S. FASHP and Cassano, Angela T., Pharm.D., BCPS (2007). The ASHP Discussion Guide on USP Chapter <797> for Compounding Sterile Preparations. Douglas, Kate, Kastango, Eric S., MBA, RPh, FASHP, and Cantor, Peter (2014). The 2014 USP Chapter <797> Compliance Survey. Pharmacy Purchasing & Products,Vol 11 No. 10: 6 http://www.pppmag.com/article/1589/October_2014_Cleanro oms_Compounding/The_2014_USP_Chapter_797_Compliance_S urvey/ Kastango, Eric S., MBA, RPh, FASHP (2009). The Top 10 Gaps in USP Chapter <797> Compliance. Pharmacy Purchasing & Products,Vol 6 No. 10: http://www.pppmag.com/article/617/October_2009_Cleanroo ms_Compounding/The_Top_10_Gaps_in_USP_Chapter_797_Co mpliance/ McCarney,Lisa, BAAS, CPhT, PhTR (2012). Sterile Compounding and Aseptic Techniques; St. Paul, MN: Paradigm Publishing Inc. Ochoa, Pamella S., and Vega, Jose’ A. (2015). Concepts in Sterile Preparations and Aseptic Technique. Burlington, MA: Jones & Bartlett Learning. The United States Pharmacopeial Convention (2015). 2015 USP Compounding Compendium; Update Feb 2015: <797> 43-87 Create a Culture of Excellence Patient safety is ALWAYS #1 Follow Best Practices Uses errors as opportunities for learning Do the right thing 161 Louisiana Society of Health System Pharmacists 2015 Annual Meeting Saturday, May 23 12:00—1:00 p.m. Trends in Pharmacy Law & Regulation Jeffery Evans, PharmD Assistant Professor University of Louisiana at Monroe Monroe, LA William Kirchain, PharmD, CDE Associate Professor of Clinical Sciences Xavier University of Louisiana College of Pharmacy New Orleans, LA 0179-0000-15-012-L03-P / 0179-0000-15-012-L03-T 1.0 contact hour (0.1 CEU) Knowledge-based activity Pharmacists Objectives: Outline the elements of the Changes in current Pharmacy Law or Health Policy that are either functioning or "in place” and a part of the current health care environment Translate to patients what issues, challenges and benefits may be available to them under the Changes in current Pharmacy Law or Health Policy List possible practice opportunities for pharmacist to exploit to their patient’s benefit brought about by the changes in current Pharmacy Law or Health Policy Create initial business plans to expand into collaborative care practices. Technician Objectives: Outline the elements of the Changes in current Pharmacy Law or Health Policy that are either functioning or "in place” and a part of the current health care environment Translate to patients what issues, challenges and benefits may be available to them under the Changes in current Pharmacy Law or Health Policy List possible practice opportunities for pharmacist to exploit to their patient’s benefit brought about by the changes in current Pharmacy Law or Health Policy Create initial business plans to expand into collaborative care practices. Speakers have disclosed that they have no relevant financial relationships. 162 Medical Marijuana (HB 6, HB 117) William R. Kirchain, PharmD, CDE Xavier University of Louisiana, College of Pharmacy Jeffrey D. Evans, PharmD, BCPS University of Louisiana Monroe, School of Pharmacy Physician… 1. Neurologist, oncologist, or ophthalmologist with valid DEA #. 2. With a LA # to prescribe cannabis sativa. 3. Doctrines of patient relationship and therapeutic choice are satisfied. Pharmacists… 1. BOP issued cannabis sativa dispensing permit. 2. Doctrine of corresponding responsibility is satisfied. 3. FDCA related issues are satisfied. Creates Therapeutic Marijuana Utilization Review Board. Creates “Grower” license. Creates regulatory fund. 163 Puts legalized marijuana on ballot for this fall. Exempts NP’s with MSN, DNP from Collaborative Practice Agreement… if in a medically underserved area or an area comprising at least 1 medically underserved population; as designated by the HRSA or DHH Suspends Louisiana Board of Pharmacy rule providing that computer generated electronic signatures on prescriptions are invalid. (Buford) Status: Status: adds to the LA Health Care Consumers‘ Right to Know law: (1) Healthcare quality information published by DHH that allows comparison of information across providers. (2) Data related to payments for services published by DHH in a format from which the user can generate reports. Prohibits the dispensing of an interchangeable biological product if the prescription requires the named product and requires notification to the prescriber when an interchangeable biological product is dispensed. Status Status: Changes the abilities of Physician Assistants in the State of Louisiana For LTC residents; prohibits limits on # of Rxs per day including… (1) DHH (2) DHH contractors (3) Managed or Coordinated Care Organizations (4) Status Establishes a formula for reimbursement Status: 164 Authorizes Rxs of opioid antagonists (naloxone) without individual assessment as long as… Establishes… Closed Pharmacy Formulary Oversight Panel Excludes coverage of… Narcotics, Compounded, Investigational Drugs Establishes… Maximum Nonemergent Out-of-Pocket = $750.00 (1) The person receiving the opioid antagonist has completed training (by DHH) for the safe administration during a drug overdose. (2) The opioid antagonist is approved by the FDA for intranasal administration. Status: Status: Protocol to Provide Naloxone Pharmacist obtains CPE: Opiate Overdose to provide to either Potential Recipient/Patient… i. Determine – Hx Opiate Use (overdose risk) ii. Determine - Appropriate product (SQ /Nasal) iii. Provide instruction: Prevention – Treatment iv. Referral to Addiction Treatment Providers v. FAQ Sheet on Naloxone/Opiate Overdose What are your legislative priorities for Louisiana? 1. Grassley [R-IA] Brown [D-OH] Capito [R-WV] Casey [D-PA] Cochran [R-MS] Gardner [R-CO] S–314: Provider Status HR–592: Provider Status S–776: Reduces MTM chronic disease threshold to 1 from the current 2 or more. 165 Gillibrand [D-NY] Heinrich [D-NM] Kirk [R-IL] Schumer [D-NY] Wicker [R-MS] Running count = 75 (34 D, 41 R) Including… Byrne (AL) Harper (MS) Palazzo (MS) O’Rouke (TX) What are your legislative priorities for the United States? Palazzo (TX) dot-pharmacy domain Drug Quality/Security Continuing competency Prescription Abuse Potentially Legitimate VIPP or Vet-VIP Certifiied Illegitimate Internet Drug Outlet Identification Program. Progress report for state and federal regulators. National Association of Boards of Pharmacy. October 2014 What are your regulatory priorities for the Board of Pharmacy? D.E.A. Initiatives 166 & Related State (Year) Required for Initial Rx… Exempted for… Penalties OH (2011) CII – CV > 12 weeks; then Annually upon Renewal If patient suspected of abusing/diverting drugs Hydrocodone then Q3M Hospice Patients Disciplinary Action Emergency Rx Post-surgery Rx Hospitals & LTC facilities Cancer & Hospice patients Single dose Rx for a procedure Hospice patients, Post-surgery - NR or ≤ 7 days Hospitals, Residential Care ED (≤5 d supply) Hospice patients, When it is not practicable to access PMP in a timely manner If PMP query will adversely affect the patient Disciplinary Action KY (2012) Additional Hydrocodone same patient TN (2013) Any CS Rx with refills Opioids & Benzos > 7 days Annually upon Renewal NY(2013) Initial Rx for C II-IV 12-42.5-402… (7) the board shall develop criteria for indicators of misuse, abuse, and diversion and based on those criteria, provide unsolicited reports of dispensed controlled substances to… pharmacies for Disciplinary Action purposes of education to prevent and reduce occurrences of controlled substance misuse, abuse, and diversion. $2000 fine + 1 year Prision + Disciplinary Action Haffajee RL, et a. Mandatory use of prescription drug monitoring programs. JAMA. doi:10. 1001/jama.2014.18514. http://jama.jamanet work.com/ accessed: on A.C.A. Witters D. Arkansas, Kentucky see most improvement in uninsured rates. Gallup Healthways Well Being Index. http://www. gallup. com/ poll/1 81664/arkansas-kentucky-improvementuninsured-rates.aspx. accessed 24 Feb 2015. Catastrophic BRONZE SILVER Gold Platinum USA 210 256 314 369 441 17.2% Louisian a 209 274 359 411 454 4.6% 11.4% Alabama 169 191 249 238 229 255 303 243 279 326 369 315 319 375 419 353 334 n/a 487 384 171 200 258 377 438 2013 2014 Louisiana 21.7% Massachusetts 4.9% 22.5% Arkansas Arkansas Florida Mississipp i Tennessee Witters D. Arkansas, Kentucky see most improvement in uninsured rates. Gallup Healthways Well Being Index. http://www. gallup. com/ poll/1 81664/arkansas-kentuckyimprovement-uninsured-rates.aspx. accessed 24 Feb 2015. Gabel JR, Whitmore H, Stromberg S, et al. Analysis finds no nationwide increase in health insurance marketplace premiums. The Commonwealth Fund. http://www.commonweal thfund.org/publications/blog/2014/dec/zero‐inflation‐nationwide‐for‐marketplace‐ premiums. 22 December 2014. accessed 22 January 2015. 167 Catastrophic BRONZE SILVER Gold Platinum $ 6,574 $ 5,203 $2,965 $1,215 $ 552 Louisian $ 6,435 a $4,848 $2,642 $1,071 $ 449 USA Alabama $ 6,560 $ 5,712 $ 3,142 $ 1,368 $ 602 Arkansas $ 6,600 $ 5,636 $ 2,458 $ 1,227 n/a Florida $ 6,600 $ 5,680 $ 4,048 $ 1,152 $ 710 Mississipp $ 6,600 $ 5,147 $ 3,000 $ 1,209 $ 472 i Gabel JR, Whitmore H, Stromberg S, Tennessee $ 6,600 $ et al. Analysis finds no nationwide increase in health 4,823 $ 3,011 $ 2,313 $1,000 insurance marketplace premiums. The Commonwealth Fund. http://www.commonweal thfund.org/publications/blog/2014/dec/zero‐inflation‐nationwide‐for‐marketplace‐prem iums. 22 December 2014. accessed 22 January 2015. Altman D. Why low growth in health care costs still sting. Washington Post – Washington Wire. http://blogs.wsj.com/washwire/2015/04/08/why-low-growthin-health-costs-still-stings. April 2015. For the budget period 2010-2019 $ 800 700 $ 600 500 $ 400 300 200 100 Social Safety & Support Systems Environment & Culture Maslow’s Hammer … "if all you have is a hammer, everything looks like a nail." (déformation professionnelle ) 0 2010 Estimate 2015 Estimate Congressional Budget Office. Congress of the United States. Updated budget projections 2015-2025. March 2015. http://www.cbo.gov/sites/default/ files/cbofiles/attachments/ 49973-Udated_Budget_Projections.pdf. accessed March 2015. By the end of 2016… 30% tied to Quality/Value-based Outcomes By the end of 2018 50% tied to Quality/Value-based Outcomes C.M.S. … Hospital Value Based Purchasing and Better, smarter, healthier: in historic announcement, HHS sets clear goals and timeline for shifting Medicare reimbursements from volume to value. Centers for Hospital Readmissions Reduction Programs Medicare & Medicaid Services. Dept Health & Human Services. Washington, DC. http://www.hhs. 168 Payments 1 % for fiscal year 2014 - Data Blocking Interoperability Barriers… 2015. Base on 3 categories of HAC… 1. 2. 3. inconsistent technical standards divergent privacy, security policies inefficient culture of data exchange Central-line associated infections (sepsis) Catheter-associated urinary tract infections, Serious Complications, (8 types of injuries) Report to Congress. Subcommittee on Labor, Health and Human Services, Education And Related Agencies, Committee on Appropriations, on health information blocking April 2015. The Office of the National Coordinator for Health Information Technology (ONC) Department of Health and Human Services. http://www.healthit.gov/sites/default/files Rau J. 721 hospitals penalized for patient safety. http://kaiserhealthnews.org/news/721-hospitals-penalized-for-patient-safety/ lh b Prescribers must be enrolled to Under Part B Allows Equip/Supplies @ Home Under Part D Facilitates IV Medication @ Home issue a valid Medicare Rx Enrollment deadline is June 1, 2015 Manufacturers are required to post the most up to date ePI on FDA.gov Pharmacists must access the e-PI through FDA.gov F.D.A. 169 In LA the patient MUST be… a danger to self or others OR unable to provide for basic needs AND unable to survive safely or guard against serious harm. Treatment Advocacy Center. Eliminating barriers to the treatment of mental illness. http://www.treatmentadvocacycenter.org/legal-resources/louisiana. … involuntary treatment is valid under “Donaldson” only if it is determined that such treatment is in the patient's best interest and that the patient lacks the capacity to decide to seek such treatment. SCOTUS. O’Connor v. Donaldson 1975 …“there is no constitutional basis to civilly commit a person if she is not dangerous to others and is capable of surviving safely in freedom.” Rudnick A. Depression and competence to refuse psychiatric treatment, J Med Ethics 2002;28:151-155 Elements of competent decisions… No legal basis for “punishment” Little legal basis outside of psych Coherence of preferences Expression … of thoughts … of understanding … of reasoning … of appreciation Rudnick A. Depression and competence to refuse psychiatric treatment, J Med Ethics 2002;28:151-155 170 Because of increasing concerns that AVMA has received from members… 1) Veterinary pharmacology education is encouraged; 2) Pharmacists are reminded consult the veterinarian if there are questions about patient care and/or use of over the counter drugs; 3) Veterinarians are reminded to deliver clear prescriptions in line with state rules, to help avoid medication errors. Must bear Veterinary Legend Labeled with Animal’s Species Labeled with the Animal’s/Client’s Name Should not be filled with drugs approved/labeled for human use. Disruptive engagement Reflections Personalized experiences Value-driven practice 171
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