Activase (alteplase): tPA clinical profile Every minute counts for acute ischemic stroke patients Damage to the brain during an acute ischemic stroke is a rapid and progressive process Penumbra Area of infarct Image is for illustrative purposes only. t Cells of the ischemic penumbra are metabolically active and potentially salvageable with timely assessment and management1,2 t The infarction expands in the penumbra over time, increasing the area of irreversible brain damage2 t Restoration of blood ﬂow to the affected area may interrupt this process3 Impact of acute ischemic stroke Without medical management, a typical large-vessel acute ischemic stroke may result in the following4: Time frame Neurons lost Ages the brain by Every second 32,000 8.7 hours Every minute 1.9 million 3.1 weeks Every hour 120 million 3.6 years 10 hours* 1.2 billion 36 years *The duration of a typical, unmanaged acute ischemic stroke.4 Calculations are based on a linear growth function, which does not reflect the actual rate of growth at particular points of time, but yields the average rate of infarct growth over the entire duration of infarct maturation for all possible growth function shapes.4 The equation used in this study was calculated as follows: brain elements lost per unit time = [(IV/VB) x TNE]/T, where IV indicates infarct volume; VB, volume of brain; TNE, total number of elements, which includes neurons, synapses, etc; and T, time.4 In this study, 22 billion neurons were included in the calculations, as this is the estimated number of neurons in the forebrain—the area where the majority of acute ischemic stroke events occur. Based on stereologic measurements of brains during the human lifespan, it is estimated that 531 million neurons are lost per year. The volume of infarct was estimated to be 54 mL, which was derived from actual measurements of infarct volume divided over 7 days as well as 3 months.4 Saver (Stroke, 2006) does not suggest that Activase® (alteplase) will help reverse the process of acute ischemic stroke. Activase (alteplase) is the standard of care for treating eligible acute ischemic stroke patients within 3 hours5 Evidence-based recommendations from national organizations support IV rtPA use for acute ischemic stroke AHA/ASA have reinforced their recommendations for IV rtPA use t Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke (Class 1; Level of Evidence A, 2013 AHA/ASA Guidelines)5 t In patients eligible for intravenous rtPA, beneﬁt of therapy is time dependent, and treatment should be initiated as quickly as possible. The door-to-needle time (time of bolus administration) should be within 60 minutes from hospital arrival (Class 1; Level of Evidence A, 2013 AHA/ASA Guidelines)5 ACEP and AAN have issued a joint recommendation for IV tPA t In order to improve functional outcomes, IV tPA should be offered to acute ischemic stroke patients who meet NINDS inclusion/ exclusion criteria and can be treated within 3 hours after symptom onset (Level A Recommendation, 2013 ACEP/AAN Joint Clinical Policy)6* — Once the decision is made to administer IV tPA, the patient should be treated as rapidly as possible *The effectiveness of tPA has been less well established in institutions without the systems in place to safely administer the medication. AAN has recommended the use of IV rtPA for over 15 years t Intravenous rtPA (0.9 mg/kg; maximum of 90 mg), with 10% of the dose given as a bolus, followed by an infusion lasting 60 minutes, is recommended treatment within three hours of onset of ischemic stroke (1996 AAN Practice Advisory, reafﬁrmed in 2003)7,8 Over 317,000 acute ischemic stroke patients have been treated with Activase since its approval in 1996.9 IV=intravenous; rtPA=recombinant tissue plasminogen activator; AHA=American Heart Association; ASA=American Stroke Association; ACEP=American College of Emergency Physicians; AAN=American Academy of Neurology; NINDS=National Institute of Neurological Disorders and Stroke. t Effective January 1, 2013, hospitals participating in the CMS Hospital IQR Program are required to report 8 stroke quality measures to CMS, including STK-4: Thrombolytic therapy for acute ischemic stroke patients t Hospitals must report all IQR measures to avoid a ﬁnancial penalty in the ensuing ﬁscal year Stroke Quality Measures Included in IQR10 STK-1: Venous thromboembolism (VTE) prophylaxis for patients with ischemic or hemorrhagic stroke STK-2: Ischemic stroke patients discharged on antithrombotic therapy STK-3: Anticoagulation therapy for atrial fibrillation/flutter STK-4: Thrombolytic therapy for acute ischemic stroke patients STK-5: Antithrombotic therapy by the end of hospital day two STK-6: Discharged on statin medication STK-8: Stroke education STK-10: Assessed for rehabilitation services CMS=Centers for Medicare & Medicaid Services; IQR=Inpatient Quality Reporting. Please see accompanying full Prescribing Information for additional Important Safety Information. Support for rtPA use CMS also recognizes the use of thrombolytic therapy for acute ischemic stroke as part of their Hospital IQR Program10,11 NINDS study design Two-part randomized trial of Activase (alteplase) vs placebo12,13 t Part 1 assessed changes in neurologic deﬁcits 24 hours after the onset of stroke t Part 2 assessed clinical outcomes at 3 months Part 1 primary outcome measure: Part 2 primary outcome measure: ≥4-point improvement on NIHSS or complete resolution of neurologic deficit (NIHSS score of 0) at 24 hours Global test statistic for favorable outcome defined as minimal or no disability as measured by 4 stroke scales* at 3 months Exclusion criteria Inclusion criteria Part 1 randomization Part 2 randomization n=291: Activase (n=144) placebo (n=147) n=333: Activase (n=168) placebo (n=165) *Based on a global test derived from 4 stroke scales: National Institutes of Health Stroke Scale (NIHSS), Barthel Index, modified Rankin Scale (mRS), and Glasgow Outcome Scale.12 Important Safety Information Activase therapy in patients with AIS is contraindicated in certain situations (eg, suspicion of subarachnoid hemorrhage on pretreatment evaluation), recent (within 3 months) intracranial or intraspinal surgery, history of intracranial hemorrhage, uncontrolled hypertension at time of treatment, active internal bleeding, known bleeding diathesis (eg, current use of oral anticoagulants, administration of heparin within 48 hours of onset of stroke, platelet count <100,000/mm3) (see CONTRAINDICATIONS for full list). The most common complication during Activase therapy is bleeding. Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase therapy should be discontinued immediately. Activase efﬁcacy proﬁle within 3 hours of symptom onset Activase showed statistically signiﬁcant improvement on all 4 stroke scales used in Part 2 of the NINDS trial Favorable outcomes at 90 days13† 33% 60 relative increase 40 relative increase 48% Placebo (n=165) Activase (n=168) P =0.02 relative increase 55% relative increase 30 20 10 20.0 31.0 37.6 50.0 26.1 38.7 31.5 44.0 0 NIHSS (≤1) Barthel Index (≥95) modiﬁed Rankin Scale (≤1) Glasgow Outcome Scale (=1) † Relative increase was calculated based on the numbers shown in the above chart. CI=confidence interval. Part 1 of the trial demonstrated no significant difference between the Activase and placebo groups based on the primary outcome measure (NIHSS) at 24 hours after treatment.13 Activase is proven to reduce disability in patients treated within 3 hours of symptom onset tActivase patients with acute ischemic stroke were at least 33% more likely to achieve minimal or no disability at 90 days vs those given placebo† – Global odds ratio for favorable outcome: 1.7 (95% CI, 1.2-2.6; P = 0.008)12 Important Safety Information Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes. Please see accompanying full Prescribing Information for additional Important Safety Information. Study design and efﬁcacy Patients (%) 50 40% Activase (alteplase) safety proﬁle within 3 hours of symptom onset sICH* occurred more commonly in Activase patients; 90-day mortality rates were not signiﬁcantly different between the Activase and placebo groups 25 sICH* incidence 13 25 P<0.01 Patients (%) Patients (%) P=0.36 20 20 15 10 5 0 Mortality 13 0.6 6.4 10 5 0 sICH at 36 hours Placebo (n=312) 15 Activase (n=312) 20.5 17.3 Mortality at 90 days Placebo (n=312) Activase (n=312) tThere was no increase in the t Of the 6.4% of Activase patients who experienced incidence of 90-day mortality sICH within 36 hours12 in Activase-treated patients — 45% experienced fatal sICH compared to placebo13 (9 of 20) vs 50% (1 of 2) of patients treated with placebo — 55% experienced nonfatal sICH (11 of 20) vs 50% (1 of 2) of patients treated with placebo *A hemorrhage was considered symptomatic if it was not seen on a previous computerized cranial tomography (CT) scan and there had subsequently been either a suspicion of hemorrhage or any decline in neurologic status.12 Important Safety Information The risks of Activase therapy may be increased and should be weighed against the anticipated beneﬁts in certain conditions. [See WARNINGS in full prescribing information.] tPatients with severe neurological deﬁcit (eg, NIHSS >22) at presentation. There is an increased risk of intracranial hemorrhage in these patients. Postmarketing studies support the results of the NINDS trial Multiple postmarketing studies investigated the safety of Activase in clinical practice STARS, CASES, and SITS-MOST were large, postmarketing, multicenter, open-label registry studies initiated to assess safety and efﬁcacy endpoints of Activase in helping achieve a favorable outcome in acute ischemic stroke patients when administered within 3 hours of symptom onset.14-16 Postmarketing study results: safety and efﬁcacy endpoints Clinical study N sICH Mortality rate STARS (US)14 389 3.3% (within 3 days) 13.4% (at 30 days†) 34.6% of patients achieved a favorable outcome (mRS score ≤1 at 30 days†) CASES (CANADA)15 1135 4.6% Efficacy 22.3% (at 90 days) 31.8% of patients achieved a favorable outcome (mRS score ≤1 at 90 days) † Data at 30 days available for 382 patients.14 The SITS-MOST definition of sICH was local or remote parenchymal hemorrhage type 2 on the 22- to 36-hour posttreatment imaging scan, combined with a neurologic deterioration of *4 points on the NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 hours, or leading to death.16 ‡ sICH=symptomatic intracranial hemorrhage; STARS=Standard Treatment with Alteplase to Reverse Stroke; CASES=Canadian Alteplase for Stroke Effectiveness Study; SITS-MOST=Safe Implementation of Thrombolysis in Stroke-Monitoring Study. Important Safety Information t Patients with major early infarct signs on a computerized cranial tomography (CT) scan (eg, substantial edema, mass effect, or midline shift). Treatment of patients with minor neurological deﬁcit or with rapidly improving symptoms is not recommended. Please see accompanying full Prescribing Information for additional Important Safety Information. Safety/Postmarketing studies SITS-MOST (EU)16 6483 1.7% (SITS-MOST criteria‡) 11.3% (at 90 days) 54.8% of patients achieved 7.3% (NINDS criteria*) functional independence (mRS score ≤2 at 90 days) Identify eligible Activase (alteplase) patients with conﬁdence Identify potentially eligible patients13 Eligibility criteria Ensure all apply An adult (≥18 years of age) Exclusion of intracranial hemorrhage by an imaging technique sensitive for the presence of hemorrhage Arrives at ED in time to be treated within 3 hours of symptom onset ED=emergency department. Ensure patients are not contraindicated13 Contraindications Evidence of intracranial hemorrhage on pretreatment evaluation Suspicion of subarachnoid hemorrhage on pretreatment evaluation Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or previous stroke History of intracranial hemorrhage Uncontrolled hypertension at time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic) Seizure at the onset of stroke Active internal bleeding Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis, including but not limited to: 4/,,!)./-!*"*,').%*#/').-!#1,",%)-* %/(*,) international normalized ratio (INR) >1.7 or a prothrombin time (PT) >15 seconds 4 (%)%-.,.%*)*"$!+,%)1%.$%)48 hours preceding the onset of stroke and an elevated activated partial thromboplastin time (aPTT) at presentation 4'.!'!.*/).100,000/mm3 Ensure none apply Identify eligible Activase patients— additional warnings and dosing Review additional warnings13 Additional warnings In addition to the contraindications, the risks of Activase therapy may be increased in the following conditions and should be weighed against the anticipated benefits: /,($+(%"%"*NI >22 at presentation) / %((".$(*)$).$#$*$'+)+)*antial edema, mass effect, or midline shift) Due to the increased risk for misdiagnosis of acute ischemic stroke, special diligence is required in making this diagnosis in patients whose blood glucose values are <50 mg/dL or >400 mg/dL. The safety and efficacy of treatment with Activase in patients with minor neurological deficit or with rapidly improving symptoms prior to the start of Activase administration has not been evaluated. Therefore, treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended. Treat eligible patients with Activase13 Dosing The recommended dose of Activase is 0.9 mg/kg (not to exceed 90-mg total dose) infused over 60 minutes with 10% of the total dose administered as an initial intravenous bolus over 1 minute. For information on reconstitution of 50- and 100-mg vials of Activase, please see full Prescribing Information. Please see accompanying full Prescribing Information for additional Important Safety Information. Patient eligibility Hospitals should ensure that Activase is readily available in the ED or in the CT scanner area (if CT scanner not located in the ED).17 —TARGET: STROKE Best Practice Strategies In acute ischemic stroke, time is brain The “Golden Hour” of acute ischemic stroke treatment Rapid intervention is crucial in the management of acute ischemic stroke t Door to treatment in )60 minutes is the standard of care recognized by professional medical associations involved in the treatment of acute ischemic stroke18 Door to treatment in 60 min19 LAB RESULTS 0 min Suspected stroke patient arrives at ED ≤10 min Initiate MD evaluation, including patient history and time last known well/symptom onset Initiate labwork Assess using NIHSS19 ≤15 min Notify stroke team (including neurologic expertise)20 ≤25 min Initiate CT scan19,20 ≤45 min Interpret CT scan and labs Review patient eligibility for Activase (alteplase)19,20 ≤60 min Give Activase bolus and initiate infusion in eligible patients19* *Activase must be administered within 3 hours of symptom onset. Adapted from: http://www.ninds.nih.gov/news_and_events/proceedings/stroke_proceedings/ recs-emerg.htm#emergency. Jauch EC. 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18)(suppl 3):S818-S828. “For patients experiencing acute ischemic stroke, and for the physicians and allied health personnel treating them, every second counts.” 4 –Saver JL, Stroke Important Safety Information Orolingual angioedema has been observed in postmarketing experience in patients treated with Activase for AIS. Patients should be monitored during and for several hours after infusion for signs of orolingual angioedema. Time-saving recommendations tEducate volunteers and admitting staff on stroke signs and symptoms tKeep “stroke toolkit” containing order sets, NIHSS information, 0 min and other stroke-related materials on hand17 tKeep Activase stocked in the ED or CT scanner area17 tPlace digital stopwatches above ED beds and start when a stroke patient arrives17 tObtain advance hospital notiﬁcation from EMS17 tTrain nursing staff to administer the NIHSS or other stroke assessment scale ≤10 min tPre-mix Activase so treatment can begin as soon as patient is deemed eligible17 tHave the stroke team (ie, the stroke coordinator, house supervisor, ≤15 min technician for the CT scanner, laboratory technician for the ED) carry pagers so they can be immediately alerted via a single-call activation system9,17 tComplete all diagnostics and have them ready for interpretation by the time the neurologist arrives at the patient’s bedside tInclude CT techs on stroke team pages and provide “Time Is Brain” ≤25 min training to instill the urgency of scanning stroke patients tLocate CT scanners in close proximity to the ED to reduce transit time tUtilize an acute stroke tracking tool to capture all times, including time ≤45 min all diagnostics are completed, to help ensure prompt data monitoring and feedback17 tRoutinely train nursing staff on Activase reconstitution ≤60 min EMS=emergency medical services. Please see accompanying full Prescribing Information for additional Important Safety Information. Golden Hour and administration tReport door-to-treatment times and patient outcomes to ED staff to foster best practices17 References 1. Fisher M. Characterizing the target of acute stroke therapy. Stroke. 1997;28(4):866-872. 2. Heiss W-D. Ischemic penumbra: evidence from functional imaging in man. J Cereb Blood Flow Metab. 2000;20(9):1276-1293. 3. Heiss WD. Flow thresholds of functional and morphological damage of brain tissue. Stroke. 1983;14(3):329-331. 4. Saver JL. Time is brain—quantiﬁed. Stroke. 2006;37(1):263-266. 5. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947. 6. Edlow JA, Smith EE, Stead LG, et al. Clinical policy: use of intravenous tPA for the management of acute ischemic stroke in the emergency department. American College of Emergency Physicians and American Academy of Neurology. Ann Emerg Med. 2013;61(2):225-243. 7. American Academy of Neurology. Practice advisory: thrombolytic therapy for acute ischemic stroke (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1996;47(3):835-839. 8. American Academy of Neurology Web site. Guideline search. http://aan.com/practice/guideline/index.cfm?fuseaction=home.welcome&Topics=20 &keywords=&Submit=Search+Guidelines. Accessed March 8, 2013. 9. Data on ﬁle. Genentech USA, Inc. 10. US Department of Health and Human Services. Centers for Medicare & Medicaid Services. Medicare Program; Hospital Inpatient Prospective Payment Systems for Acute Care Hospitals and the Long-Term Care Hospital Prospective Payment System and FY 2012 Rates; Hospitals’ FTE Resident Caps for Graduate Medical Education Payment. CMS-1518-F; CMS-1430-F. Kentucky Cabinet for Health and Family Services Web site. http://chfs.ky.gov/NR/rdonlyres/AB543C25-7C75-46B0-98453A520E7E1BFA/0/IPPSFinalRuleAug2011.pdf. Accessed March 8, 2013. 11. Centers for Medicare & Medicaid Services Web site. Hospital Inpatient Quality Reporting Program. http://cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ HospitalQualityInits/HospitalRHQDAPU.html. Accessed March 8, 2013. 12. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. 13. Activase Prescribing Information. Genentech USA, Inc. April 2011. 14. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000;283(9):1145-1150. 15. Hill MD, Buchan AM; the Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. 2005;172(10):1307-1312. 16. Wahlgren N, Ahmed N, Dávalos A, et al; the SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369(9558):275-282. 17. Heart.org Web site. TARGET: STROKE Best Practice Strategies. www.strokeassociation.org/idc/groups/heart-public/@wcm/@private/ @hcm/@gwtg/documents/downloadable/ucm_310253.pdf. Accessed March 8, 2013. 18. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation. 2011;123(7):750-758. 19. Jauch EC, Cucchiara B, Adeoye O, et al. Part 11: adult stroke: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18)(suppl 3):S818-S828. 20. Jauch EC. The “golden hour” of acute ischemic stroke. Internet Stroke Center Web site. http://www.strokecenter.org/ wp-content/uploads/2011/08/The-Golden-Hour-of-Acute-Ischemic-Stroke.pdf. Accessed March 8, 2013. Indication and Important Safety Information Indication Activase (Alteplase) is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage (see CONTRAINDICATIONS in the full prescribing information). Important Safety Information Activase therapy in patients with AIS is contraindicated in certain situations (eg, suspicion of subarachnoid hemorrhage on pretreatment evaluation), recent (within 3 months) intracranial or intraspinal surgery, history of intracranial hemorrhage, uncontrolled hypertension at time of treatment, active internal bleeding, known bleeding diathesis (eg, current use of oral anticoagulants, administration of heparin within 48 hours of onset of stroke, platelet count <100,000/mm3) (see CONTRAINDICATIONS for full list). The most common complication during Activase therapy is bleeding. Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase therapy should be discontinued immediately. Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes. The risks of Activase therapy may be increased and should be weighed against the anticipated beneﬁts in certain conditions. [See WARNINGS in full prescribing information.] t1BUJFOUTXJUITFWFSFOFVSPMPHJDBMEFmDJUFH/*)44 BUQSFTFOUBUJPO There is an increased risk of intracranial hemorrhage in these patients. t1BUJFOUTXJUINBKPSFBSMZJOGBSDUTJHOTPOBDPNQVUFSJ[FEDSBOJBMUPNPHSBQIZ (CT) scan (eg, substantial edema, mass effect, or midline shift). Treatment of patients with minor neurological deﬁcit or with rapidly improving symptoms is not recommended. Orolingual angioedema has been observed in postmarketing experience in patients treated with Activase for AIS. Patients should be monitored during and for several hours after infusion for signs of orolingual angioedema. Please see accompanying full Prescribing Information for additional Important Safety Information. Activase (alteplase) is proven to reduce disability in patients treated within 3 hours of symptom onset13 • Activase is the standard of care for treating eligible acute ischemic stroke patients within 3 hours5 • Activase patients were at least 33% more likely to achieve minimal or no disability* vs placebo at 90 days when treated within 3 hours of symptom onset13 • The rate of sICH for patients treated with Activase within 3 hours of symptom onset was 6.4% (vs 0.6% for placebo)13† • There was no increase in the incidence of 90-day mortality in Activase-treated patients compared to placebo13 In the treatment of acute ischemic stroke, every minute counts. Rapid action is crucial to help minimize permanent neurologic damage. *Based on a global test derived from 4 stroke scales: NIHSS, Barthel Index, mRS, and Glasgow Outcome Scale.13 † A hemorrhage was considered symptomatic if it was not seen on a previous CT scan and there had subsequently been either a suspicion of hemorrhage or any decline in neurologic status.12 Indication Activase (Alteplase) is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage (see CONTRAINDICATIONS in the full prescribing information). Important Safety Information All thrombolytic agents increase the risk of bleeding, including intracranial bleeding, and should be used only in appropriate patients. Not all patients with acute ischemic stroke will be eligible for Activase therapy, including patients with evidence of recent or active bleeding; recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or previous stroke; uncontrolled high blood pressure; or impaired blood clotting. Please see accompanying full Prescribing Information for additional Important Safety Information. © 2013 Genentech USA, Inc. All rights reserved. ACI0001436701 Printed in USA.