1. health and fitness
2. disease

Advances in
Pulmonary
Hypertension
Spring 2006
Vol 5, No 1
Official Journal of the Pulmonary Hypertension Association
Pulmonary
Hypertension and
Left Heart Disease
• Diagnostic Dilemmas:
Cases and Comment
on Diastolic Heart Failure
and PH
• PH Out of Proportion to
Left Heart Disease
• Heart Failure and
Transplantation
• Roundtable Discussion:
Controversies and
Consensus
Table of Contents
Guest Editor for this issue:
Ronald Oudiz, MD
Associate Professor of Medicine
UCLA School of Medicine
Director, Liu Center for
Pulmonary Hypertension
Division of Cardiology
Harbor-UCLA Medical Center
Torrance, California
Editor’s Note: This issue focuses on the very
common but poorly understood problem of pulmonary hypertension due to left heart disease.
Dr Margaret Redfield and her colleagues present
typical cases and summarize the issues related
to left heart disease and PH, examining the
forces at play in detail. Drs Jose Tallaj and
Raymond Benza offer a practical approach to
PH out of proportion to left heart disease,
examining treatment options for PH and for the
left heart disease. Finally, Dr Srinivas Murali
describes his approach to assessing and treating
PH in a heart transplant candidate. These articles
are timely and offer insight into the complex
forces that challenge the clinician when dealing
with PH and left heart disease.
4
Profiles in Pulmonary
Hypertension: Jack Reeves, MD
13
Diagnostic Dilemmas: Diastolic
Heart Failure and PH
21
PH Out of Proportion to Left
Heart Disease
30
PH, Heart Failure, and
Transplantation
36
Pulmonary Hypertension
Roundtable Discussion:
Controversies and Consensus
Publisher
Pulmonary Hypertension Association
Jack Stibbs, Chair of the Board
Rino Aldrighetti, President
Justine Elliot, Director of Medical Services
Publishing Staff
Stu Chapman, Executive Editor
Susan Chapman, Managing Editor
Heidi Green, Associate Editor
Gloria Catalano, Production Director
Michael McClain, Design Director
PHA Office
Pulmonary Hypertension Association
801 Roeder Rd. Suite 400
Silver Spring, MD 20910-4496
301-565-3004, 301-565-3994 (fax)
www.phassociation.org
© 2006 by Pulmonary Hypertension Association. All rights
reserved. None of the contents may be reproduced in any
form whatsoever without the written permission of PHA.
Editorial Offices
Advances in Pulmonary Hypertension, DataMedica,
P.O. Box 1688, Westhampton Beach, NY 11978
Tel (631) 288-7733 Fax (631) 288-7744
E-mail: [email protected]
Advances in Pulmonary Hypertension is circulated to cardiologists, pulmonologists, rheumatologists and other selected
physicians by the Pulmonary Hypertension Association.
The contents are independently determined by the Editor
and the Editorial Advisory Board.
Cover image:
Diastolic assessment of the left and right ventricle using Doppler
echocardiography in a young woman with severe idiopathic pulmonary
arterial hypertension. Echocardiographic results are superimposed on
ECG tracings. (Images courtesy of Margaret M. Redfield, MD, Mayo
Clinic College of Medicine).
Printed on recycled paper.
Editor’s Memo
Chronicling the Evolution of a Journal:
We Welcome New Support to Meet
Growing Educational Needs of Physicians
“Ten years ago physicians treating pulmonary hypertension would have
been amazed at today’s options for managing a disease that had a dismal
prognosis. Progress has been swift, and we stand at the threshold of a
new era in treatment. As our treatment options for pulmonary hypertension
have expanded dramatically, so has our need for more information to keep
pace with major advances.”
With this statement, our previous Editor-in-Chief, Victor Tapson, MD,
kicked off the first issue of Advances in Pulmonary Hypertension in Spring 2002. With this
hefty, 48-page issue, we stand somewhat similarly on the threshold of a new era—this one in
providing essential information to our readers with a journal that continues to evolve as the
most comprehensive source of knowledge for clinicians whose primary focus is pulmonary
hypertension.
We are pleased to welcome a new cohort of commercial supporters to Advances in
Pulmonary Hypertension because it means the journal can (1) expand its coverage by
bringing readers more content on the most important topics relevant to the care of
patients, (2) present more information on translational research by investigators worldwide, and (3) help us to more firmly establish the journal as an authoritative source as
we eventually pursue a designation as an indexed journal on the MEDLINE database.
The support by additional sponsors suggests exactly how far we are moving into the
new era of treatment and the therapies represented here reflect the growing commitment
by the pharmaceutical industry to research and development of drugs that expand the
spectrum of therapy. While it is encouraging to see this support, we remain committed
to a journal that will present rigorously peer-reviewed, unbiased, scientifically valid and
balanced information, reflecting the highest standards of care by the medical community.
This community is well represented on our Editorial Advisory Board, our Editorial
Committee and the Scientific Leadership Council of the Pulmonary Hypertension
Association. All of the physicians listed on page 3 play an integral role in planning the
program of the Pulmonary Hypertension Association (PHA), including the Scientific
Sessions held every other year. Please see pages 24 and 25 for information on this year’s
dynamic International Conference in Minneapolis, Roadmap to a Cure, June 23 to 25.
Many of these physicians also take on leadership roles in developing content for our
conferences and guiding creation of manuscripts for our journal. Our Associate Editor for
this issue, Ronald J. Oudiz, MD, had the particularly daunting task of overseeing the
content development of this expanded issue and we greatly appreciate his contribution in
reviewing and editing the manuscripts. As Dr Oudiz points out in his introduction, this
issue focuses on the very common but poorly understood problem of pulmonary hypertension due to left heart disease, including reviews examining the relationship between
diastolic heart failure and pulmonary hypertension, another review on pulmonary
hypertension out of proportion to left heart disease, and heart failure patients with
pulmonary hypertension referred for cardiac transplantation.
In looking ahead, I recall another perspective from the first Editor’s Memo by
Dr Tapson who also noted, “As exciting as the last decade has been in expanding the
spectrum of therapy, the years ahead look even more promising as we gather more data
on the use of endothelin receptor antagonists and perhaps additional agents that will
address the proliferative mechanisms of the disease.” We look forward to continuing our
mission to put these trends in intelligent perspective and welcome your comments and
suggestions.
Vallerie V. McLaughlin, MD
Editor-in-Chief
Editorial Advisory Board
Editor-in-Chief
Vallerie V. McLaughlin, MD
Associate Professor of Medicine
Director, Pulmonary Hypertension
Program
University of Michigan Health
System
Ann Arbor, Michigan
Immediate Past Editor
Victor F. Tapson, MD
Professor of Medicine
Division of Pulmonary and Critical
Care Medicine
Duke University Medical Center
Durham, North Carolina
Associate Editors
Ramona Doyle, MD
Associate Professor of Medicine
Division of Pulmonary/Critical
Care Medicine
Co-Director, Vera M. Wall Center
for Pulmonary Vascular Disease
Stanford University Medical Center
Stanford, California
Karen A. Fagan, MD
Associate Professor of Medicine
University of Colorado Health
Sciences Center
Pulmonary Hypertension Center
Denver, Colorado
Robert Frantz, MD
Consultant in Cardiovascular
Diseases and Internal Medicine
Assistant Professor of Medicine
Mayo Clinic College of Medicine
Rochester, Minnesota
The Scientific Leadership
Council of the Pulmonary
Hypertension Association
The scientific program of the Pulmonary
Hypertension Association is guided by
the association’s Scientific Leadership
Council. The Council includes the
following health care professionals:
Robyn J. Barst, MD
SLC Chair
Columbia Presbyterian Medical
Center Babies Hospital
New York, New York
David B. Badesch, MD
SLC Vice-Chair
Chair, Nominations Committeee
University of Colorado
Health Sciences Center
Denver, Colorado
Srinivas Murali, MD, FACC
Professor of Medicine
Drexel University College of Medicine
Director, Division of
Cardiovascular Medicine
Medical Director, Gerald McGinnis
Cardiovascular Institute
Allegheny General Hospital
Pittsburgh, PA
Ronald J. Oudiz, MD
Associate Professor of Medicine
UCLA School of Medicine
Director, Liu Center for
Pulmonary Hypertension
Division of Cardiology
Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical
Center
Torrance, California
Olivier Sitbon, MD
Consultant
Center for Pulmonary Vascular
Diseases
Respiratory and Intensive
Care Unit
Antoine Beclere Hospital
Paris-Sud University
Clamart, France
Editorial Board
Gregory Ahearn, MD
Medical Director
Pulmonary Hypertensin Center
St. Joseph’s Medical Center
Phoenix, Arizona
Murali Chakinala, MD
Director, Pulmonary
Hypertension Clinic
Washington University School
of Medicine
St. Louis, Missouri
Jeffrey Edelman, MD
Associate Professor of Medicine
Division of Pulmonary and
Critical Care Medicine
Oregon Health and Sciences University
Portland, Oregon
Robert Schilz, DO, PhD
Medical Director of Lung
Transplantation and Pulmonary
Vascular Disease
University Hospital
of Cleveland
Case Western Reserve
University
Cleveland, Ohio
Roxana Sulica, MD
Assistant Professor of Medicine
Mount Sinai School of Medicine
Director, Mount Sinai Pulmonary
Hypertension Program
Mount Sinai Medical Center
New York, New York
Editorial Mission
Advances in Pulmonary Hypertension is committed to help physicians in their clinical decision making by informing them of important
trends affecting their practice. Analyzing the
impact of new findings and covering current
information in the peer-reviewed literature,
Advances in Pulmonary Hypertension is published four times a year. Advances in Pulmonary Hypertension is the official journal
of the Pulmonary Hypertension Association.
Each article in this journal has been reviewed
and approved by members of the Editorial
Advisory Board.
Vallerie V. McLaughlin, MD
University of Michigan
Health System
Ann Arbor, Michigan
Liaisons
Natalie Kitterman, RN, BSN
PH Resource Network Chair
Salt Lake City, Utah
Adaani Frost, MD
Baylor College of Medicine
Houston, Texas
John H. Newman, MD
Vanderbilt Medical School
Nashville, Tennessee
JoAnne Sperando Schmidt
Patient Liaison
Sean Gaine, MD, PhD
Mater Misericordiae Hospital
Dublin, Ireland
Ronald J. Oudiz, MD
Liu Center for Pulmonary Hypertension
Los Angeles Biomedical Research Instit.
Harbor-UCLA Medical Center
Torrance, California
Nazzareno Galiè, MD
Universita di Bologna
Bologna, Italy
Nicholas Hill, MD
Division of Pulmonary, Critical Care
and Sleep Medicine
Tufts-New England Medical Center
Boston, Massachusetts
Marc Humbert, MD
Hopital Antoine Beclere
Clamart, France
Todd Bull, MD
University of Colorado
Health Sciences Center
Denver, Colorado
Michael J. Krowka, MD
Mayo Clinic
Rochester, Minnesota
C. Gregory Elliott, MD
LDS Hospital
University of Utah
School of Medicine
Salt Lake City, Utah
Todd Bull, MD
Division of Pulmonary and
Critical Care Medicine
University of Colorado Health
Sciences Center
Denver, Colorado
James P. Maloney, MD
Associate Professor
Pulmonary and Critical
Care Medicine
University of Colorado Health Sciences
Center
Denver, Colorado
Karen Fagan, MD
University of Colorado
Health Sciences Center
Denver, Colorado
Dunbar Ivy, MD
University of Colorado
Denver, Colorado
Ramona Doyle, MD
Vera M. Wall Center for
Pulmonary Vascular Disease
Palo Alto, California
Erika Berman Rosenzweig, MD
Assistant Professor of Pediatrics
Department of Pediatrics
Columbia College of Physicians
and Surgeons
New York, New York
Jacques Benisty, MD, MPH
Children’s Hospital Boston
Harvard Medical School
Boston, Massachusetts
Raymond L. Benza, MD
University of Alabama
Birmingham, Alabama
Richard N. Channick, MD
UCSD Medical Center
San Diego, California
Raymond Benza, MD
Associate Professor of Medicine
Director, Pulmonary Vascular
Disease Program
Section of Advanced Heart Failure,
Transplant and Pulmonary
Vascular Diseases
University of Alabama
at Birmingham
Birmingham, Alabama
David Langleben, MD
Jewish General Hospital
Montreal, Quebec, Canada
James E. Loyd, MD
Vanderbilt University Medical Center
Nashville, Tennessee
Michael McGoon, MD
Pulmonary Hypertension Clinic/
Mayo Clinic
Rochester, Minnesota
Marlene Rabinovitch, MD
Stanford University
School of Medicine
Stanford, California
Carol E. Vreim, PhD
Division of Lung Diseases, NHBLi
Bethesda, Maryland
Emeritus Members
Bruce H. Brundage, MD
St. Charles Medical
Center-Bend
Bend, Oregon
Alfred P. Fishman, MD
University of Pennsylvania
Health System
Philadelphia, Pennsylvania
Ivan M. Robbins, MD
Chair, Consensus Committee
Vanderbilt University
Nashville, Tennessee
Lewis J. Rubin, MD
Chair, Research Committee
University of California at
San Diego
San Diego, California
The Mission of the Scientific Leadership
Council is to provide medical and scientific
guidance and support to the PHA by:
Julio Sandoval, MD
Cardiopulmonary Department
National Institute of
Cardiology of Mexico
Tlalpan, Mexico
• Developing and disseminating knowledge
for diagnosing and treating pulmonary
hypertension
• Advocating for patients with pulmonary
hypertension
• Increasing involvement of basic and clinical
researchers and practitioners
James Seibold, MD
University of Michigan
Health System
Ann Arbor, Michigan
Victor E. Tapson, MD
Division of Pulmonary and
Critical Care Medicine
Duke University Medical Center
Durham, North Carolina
Advances in Pulmonary Hypertension 3
Jack Reeves, MD, Remembered
as ‘Renaissance Ideal,” in Stellar
Career Spanning Diverse
Pulmonary Research
It is rare for a clinician to be described
as someone who came “as close as any
of us will see to the Renaissance ideal.”
Yet this is the praise earned by John
“Jack” Reeves, MD, who died last
September in a motor vehicle-bicycle
accident in Colorado where he earned a
reputation as a preeminent clinician and
Jack Reeves, MD
scholar..
The description of Dr Reeves came
in a tribute to him from Richard Krugman, MD, Dean of
the School of Medicine at the University of Colorado
Health Sciences Center, Denver. Dr Reeves made excep-
tional contributions in teaching, mentoring, research,
administration, and leadership to the Colorado Center for
Altitude Medicine and Physiology. “He was a scientist of
international stature. He made major advances at the
molecular, cellular, animal, and human level with regard
to the pulmonary circulation and adaptation to high altitude,” added Dr. Krugman.
For many years Dr Reeves was a senior member of the
Cardiovascular Pulmonary Laboratory of the School of
Medicine within the Department of Medicine and most
recently played a significant role in the establishment of
the Colorado Center for Altitude Medicine and Physiology
in the Department of Surgery. In recent years Dr Reeves
was an integral part of the pulmonary vascular biology
group in the Department of Pediatrics and, according to
Dr Krugman, was “a friend, counselor, mentor, scientific
advisor and inspiration to a generation of pediatric pulmonologists, critical care physicians, cardiologists, neonatologists, and their colleague PhD investigators.”
Returning to the theme of Dr Reeves as the embodiment of the Renaissance ideal, Dr Krugman called him an
internationally renowned investigator, a deeply compassionate physician, an athlete, an accomplished photographer, and a literary scholar.” Pursuing a strong interest in
the formation and guidance of medical education groups,
(continued on page 29)
ERRATA
Editor’s Note: In the Winter 2005 issue of Advances in
Pulmonary Hypertension the Figure on page 17 of Managing
Right Ventricular Failure in PAH and the Table on page 13
of Perioperative Management of PH should have contained
arrows as noted below. Several of these symbols were
incorrect because of a typesetting error.
Table 1. Hemodynamic Patterns of Four
Etiologies of Systemic Hypertension.
Symptomatic/declining phase
Rising RAP
Inadequate CO with exercise
Decompensated phase
↓ CO, RAP
A-VDO2
Hypoxia
Acidosis
Life-threatening dysrhythmias
↓
RV dilation:
Wall stress + heart rate
+ ↓ endomyocardial perfusion
Tricuspid regurgitation
RV ischemia
RV dilation (DVI):
Interventricular septal shift to left
Intrapericardial pressure
↓ Distending LV transmural pressure
↓ LV compliance
↓ LV preload
↓ CO
↓
↓
↓
4 Advances in Pulmonary Hypertension
↓
RV diastolic and systolic failure
CVP
PAP
PAOP
Decreased preload
Decreased contractility
Decreased SVR
Increased PVR
↓↓
↓
↓
→
↓
→
↓
Maladaptive RV hypertrophy, fibrosis
RV diastolic dysfunction
Etiology
↓
Compensated phase
Normal CO, RAP
↓
Neurohormonal and other
mediator activation
RV remodeling
Adaptive concentric RV hypertrophy
RV chamber size normal or ↓
Decreased wall stress
CO
↓
RV pressure overload
→ or ↓
↓
↓
Pulmonary hypertension
↓
↓
or →
↓
CO = cardiac output; CVP = central venous pressure; PAOP = pulmonary
artery occlusion pressure; PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance.
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In pulmonary arterial hypertension
WHO Class III or IV
Tracleer
Stands
Alone
*Clinical worsening defined as the combined
endpoint of death, hospitalization for treatment
related to PAH, discontinuation of therapy
due to worsening PAH, or initiation of
epoprostenol therapy.
Liver and pregnancy warnings
Requires attention to two significant concerns: Potential for
serious liver injury—Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.
High potential for major birth defects—Pregnancy must be excluded and prevented by two forms of birth control;
monthly pregnancy tests should be obtained Contraindicated for use with cyclosporine A and glyburide
I
I
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In pulmonary arterial hypertension (PAH) WHO Class III or IV
Only Tracleer Reduces
the Risk of Clinical Worsening
Time from randomization to clinical worsening (Kaplan-Meier estimates)
1
100
Event-free (%)
89%
Tracleer
p=0.0015
p=0.0038
63%
Control
50
0
4
8
12
16
Time (weeks)
20
24
Relative Risk
Reduction
28
BREATHE-1 All patients (n=144 in the Tracleer group and n=69 in the control group) participated in the first 16 weeks.
A subset of this population (n=35 in the Tracleer group and n=13 in the control group) continued for up to 28 weeks.
I
Treatment effect was notable because both the Tracleer groups and the control groups could have
received background therapy, which excluded IV epoprostenol but many have included vasodilators
(calcium channel blockers or ACE inhibitors), digoxin, anticoagulants, and/or diuretics2
Clinical worsening is defined in bosentan clinical
trials as the combined endpoint of 1:
I
Death
I
Hospitalization for treatment related to PAH
I
Discontinuation of therapy due to worsening PAH
I
Initiation of epoprostenol therapy
To learn more about Tracleer and
PAH, call 1-866-228-3546 or visit
www.TRACLEER.com.
A Cornerstone
of Oral Therapy
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Tracleer Provides
2-Year Follow-up Data
Kaplan-Meier estimates with 99.9% CI.
All bosentan-treated PAH patients.3
% of event-free patients
100
90
93%
80
84%
70
60
Still Alive
at 2 Years
50
40
30
20
10
0
235
6
225
12
219
18
206
24 Months
146 Patients at risk
93% and 84% of patients in the 2 Tracleer pivotal trials and their open-label extensions (N=235)
were still alive at 1 year and 2 years, respectively, after the start of treatment with Tracleer.2
I
Without a control group, these data must be interpreted cautiously2
I
These estimates may be influenced by the presence of epoprostenol treatment, which was
administered to 43 of the 235 patients2
I
Patients in the Tracleer trials may have also been receiving vasodilators (calcium channel
blockers or ACE inhibitors), digoxin, anticoagulants, and/or diuretics2
Liver and pregnancy warnings
I
Requires attention to two significant concerns: Potential for serious liver injury—
Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.
High potential for major birth defects—Pregnancy must be excluded and prevented by two
forms of birth control; monthly pregnancy tests should be obtained
I
Contraindicated for use with cyclosporine A and glyburide
Prescribed to over 30,000 patients
3
THE DUAL ENDOTHELIN
RECEPTOR ANTAGONIST
Tracleer can be prescribed only through the Tracleer Access Program at 1-866-228-3546.
Please see brief summary of prescribing information and full reference list on following page.
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62.5 mg and 125 mg
film-coated tablets
Brief Summary: Please see package insert for full prescribing information.
Use of TRACLEER® requires attention to two significant concerns: 1) potential for serious liver injury, and
2) potential damage to a fetus.
WARNING: Potential liver injury. TRACLEER® causes at least 3-fold (upper limit of normal; ULN) elevation of
liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small
number of cases. Because these changes are a marker for potential serious liver injury, serum aminotransferase
levels must be measured prior to initiation of treatment and then monthly (see WARNINGS: Potential Liver Injury
and DOSAGE AND ADMINISTRATION). In the post-marketing period, in the setting of close monitoring, rare
cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with TRACLEER®
in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure.
The contribution of TRACLEER® in these cases could not be excluded.
In at least one case the initial presentation (after > 20 months of treatment) included pronounced elevations in
aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly
over time after discontinuation of TRACLEER®. This case reinforces the importance of strict adherence to the
monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping TRACLEER® with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction.
(see DOSAGE AND ADMINISTRATION).
Elevations in aminotransferases require close attention (see DOSAGE AND ADMINISTRATION). TRACLEER®
should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical
symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or
fatigue) or increases in bilirubin ≥ 2 x ULN, treatment should be stopped. There is no experience with the
re-introduction of TRACLEER® in these circumstances.
CONTRAINDICATION: Pregnancy. TRACLEER® (bosentan) is very likely to produce major birth defects if used by
pregnant women, as this effect has been seen consistently when it is administered to animals (see
CONTRAINDICATIONS). Therefore, pregnancy must be excluded before the start of treatment with TRACLEER®
and prevented thereafter by the use of a reliable method of contraception. Hormonal contraceptives, including
oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving TRACLEER® (see Precautions: Drug
Interactions). Therefore, effective contraception through additional forms of contraception must be practiced.
Monthly pregnancy tests should be obtained.
Because of potential liver injury and in an effort to make the chance of fetal exposure to TRACLEER®
(bosentan) as small as possible, TRACLEER® may be prescribed only through TRACLEER® Access Program by
calling 1 866 228 3546. Adverse events can also be reported directly via this number.
INDICATIONS AND USAGE: TRACLEER® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in
patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.
CONTRAINDICATIONS: TRACLEER® is contraindicated in pregnancy, with concomitant use of cyclosporine A, with coadministration of glyburide, and in patients who are hypersensitive to bosentan or any component of the medication.
Pregnancy Category X. TRACLEER® is expected to cause fetal harm if administered to pregnant women. The similarity of
malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other
endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use
of TRACLEER® in pregnant women. TRACLEER® should be started only in patients known not to be pregnant. For female
patients of childbearing potential, a prescription for TRACLEER® should not be issued by the prescriber unless the patient
assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test
performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual
intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential
taking TRACLEER®. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect
pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician
and patient must discuss the risk to the pregnancy and to the fetus.
WARNINGS: Potential Liver Injury: Elevations in ALT or AST by more than 3 x ULN were observed in 11% of bosentan-treated
patients (N = 658) compared to 2% of placebo-treated patients (N = 280). The combination of hepatocellular injury (increases
in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 3 x ULN) is a marker for potential serious liver injury.
Elevations of AST and/or ALT associated with bosentan are dose-dependent, occur both early and late in treatment,
usually progress slowly, are typically asymptomatic, and to date have been reversible after treatment interruption or
cessation. These aminotransferase elevations may reverse spontaneously while continuing treatment with TRACLEER®.
Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated. If liver aminotransferase elevations are
accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual
lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment should be stopped. There is no experience with the
re-introduction of TRACLEER® in these circumstances. Pre-existing Liver Impairment: TRACLEER® should generally be
avoided in patients with moderate or severe liver impairment. In addition, TRACLEER® should generally be avoided in
patients with elevated aminotransferases (> 3 x ULN) because monitoring liver injury in these patients may be more difficult.
PRECAUTIONS: Hematologic Changes: Treatment with TRACLEER® caused a dose-related decrease in hemoglobin and
hematocrit. The overall mean decrease in hemoglobin concentration for bosentan-treated patients was 0.9 g/dl (change to
end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan
treatment and hemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all
uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values of < 11 g/dl) were
observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with pulmonary arterial
hypertension treated with doses of 125 and 250 mg b.i.d., marked decreases in hemoglobin occurred in 3% compared
to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 1 g/dl was observed in 57% of
bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of cases, the decrease occurred
during the first 6 weeks of bosentan treatment. During the course of treatment the hemoglobin concentration remained
within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation for the
change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific
treatment. Fluid retention: In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased
incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with TRACLEER®. In addition, there have been numerous post-marketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting TRACLEER®. Patients required intervention with a diuretic, fluid
management, or hospitalization for decompensating heart failure.
Information for Patients: Patients are advised to consult the TRACLEER® Medication Guide on the safe use of TRACLEER®.
The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases and
urine or serum pregnancy testing and of avoidance of pregnancy. The physician should discuss options for effective
contraception and measures to prevent pregnancy with their female patients. Input from a gynecologist or similar expert
on adequate contraception should be sought as needed.
Drug Interactions: Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes will likely increase the
plasma concentration of bosentan. Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently, plasma
concentrations of drugs metabolized by these two isoenzymes will be decreased when TRACLEER® is co-administered.
Contraceptives: Co-administration of bosentan and the oral hormonal contraceptive Ortho-Novum® produced decreases of
norethindrone and ethinyl estradiol levels by as much as 56% and 66%, respectively, in individual subjects. Therefore,
hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when
TRACLEER® is co-administered. Women should practice additional methods of contraception and not rely on hormonal
contraception alone when taking TRACLEER®. Cyclosporine A: During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. Steady-state bosentan plasma concentrations were
3- to 4-fold higher than in the absence of cyclosporine A (see CONTRAINDICATIONS). Tacrolimus: Co-administration of
tacrolimus and bosentan has not been studied in man. Co-administration of tacrolimus and bosentan resulted in markedly
increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used
together. Glyburide: An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant
therapy with glyburide (see CONTRAINDICATIONS). Alternative hypoglycemic agents should be considered. Bosentan is
also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by
CYP2C9 or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered. Ketoconazole:
Co-administration of bosentan 125 mg b.i.d. and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations
of bosentan by approximately 2-fold. No dose adjustment of bosentan is necessary, but increased effects of bosentan
should be considered. Simvastatin and Other Statins: Co-administration of bosentan decreased the plasma concentrations
of simvastatin (a CYP3A4 substrate), and its active ß-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other statins
that have significant metabolism by CYP3A4, eg, lovastatin and atorvastatin. The possibility of reduced statin efficacy
should be considered. Patients using CYP3A4 metabolized statins should have cholesterol levels monitored after TRACLEER®
is initiated to see whether the statin dose needs adjustment. Warfarin: Co-administration of bosentan 500 mg b.i.d. for
6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate)
by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients
with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose, and the need to
change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients. Digoxin, Nimodipine and Losartan: Bosentan has been shown to have no pharmacokinetic interactions with digoxin and nimodipine, and losartan has no effect on plasma levels of bosentan.
Sildenafil: In healthy subjects, co-administration of multiple doses of 125 mg b.i.d bosentan and 80 mg t.i.d. sildenafil resulted
in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. A dose
adjustment of neither drug is necessary. This recommendation holds true when sildenafil is used for the treatment of pulmonary arterial hypertension or erectile dysfunction.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Two years of dietary administration of bosentan to mice produced
an increased incidence of hepatocellular adenomas and carcinomas in males at doses about 8 times the maximum
recommended human dose [MRHD] of 125 mg b.i.d., on a mg/m2 basis. In the same study, doses greater than about 32 times
the MRHD were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary
administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at
doses about 16 times the MRHD. Impairment of Fertility/Testicular Function: Many endothelin receptor antagonists have
profound effects on the histology and function of the testes in animals. These drugs have been shown to induce atrophy of
the seminiferous tubules of the testes and to reduce sperm counts and male fertility in rats when administered for longer
than 10 weeks. Where studied, testicular tubular atrophy and decreases in male fertility observed with endothelin receptor
antagonists appear irreversible. In fertility studies in which male and female rats were treated with bosentan at oral doses
of up to 50 times the MRHD on a mg/m2 basis, no effects on sperm count, sperm motility, mating performance or fertility
were observed. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses
as low as about 4 times the MRHD for two years but not at doses as high as about 50 times the MRHD for 6 months. An
increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to about 75 times the
MRHD or in dogs treated up to 12 months at doses up to about 50 times the MRHD. There are no data on the effects of
bosentan or other endothelin receptor antagonists on testicular function in man.
Pregnancy, Teratogenic Effects: Category X
SPECIAL POPULATIONS: Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk, breastfeeding while taking TRACLEER® is not recommended. Pediatric Use: Safety and
efficacy in pediatric patients have not been established. Use in Elderly Patients: Clinical experience with TRACLEER® in
subjects aged 65 or older has not included a sufficient number of such subjects to identify a difference in response
between elderly and younger patients.
ADVERSE REACTIONS: Safety data on bosentan were obtained from 12 clinical studies (8 placebo-controlled and 4
open-label) in 777 patients with pulmonary arterial hypertension, and other diseases. Treatment discontinuations due to
adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary
arterial hypertension were more frequent on bosentan (5%; 8/165 patients) than on placebo (3%; 2/80 patients). In this
database the only cause of discontinuations > 1%, and occurring more often on bosentan was abnormal liver function. In
placebo-controlled studies of bosentan in pulmonary arterial hypertension and for other diseases (primarily chronic heart
failure), a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients
were treated with placebo. The duration of treatment ranged from 4 weeks to 6 months. For the adverse drug reactions that
occurred in ≥ 3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on placebo
(≥ 2% difference) were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg edema
(5% vs. 1%), and anemia (3% vs. 1%). Additional adverse reactions that occurred in > 3% of bosentan-treated
pulmonary arterial hypertension patients were: nasopharyngitis (11% vs. 8%), hypotension (7% vs. 4%), palpitations (5% vs.
1%), dyspepsia (4% vs. 0%), edema (4% vs. 3%), fatigue (4% vs. 1%), and pruritus (4% vs. 0%). Post-marketing experience:
hypersensitivity, rash, angiodema.
Special Considerations: Patients with Congestive Heart Failure (CHF): Based on the results of a pair of studies with 1613
subjects, bosentan is not effective in the treatment of CHF with left ventricular dysfunction.
OVERDOSAGE: Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for
2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to
moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given
concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe
headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart
rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above.
Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.
DOSAGE AND ADMINISTRATION: TRACLEER® treatment should be initiated at a dose of 62.5 mg b.i.d. for
4 weeks and then increased to the maintenance dose of 125 mg b.i.d. Doses above 125 mg b.i.d. did not appear to confer
additional benefit sufficient to offset the increased risk of liver injury. Tablets should be administered morning and evening
with or without food.
Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Abnormalities
ALT/AST levels
Treatment and monitoring recommendations
> 3 and ≤ 5 x ULN
Confirm by another aminotransferase test; if confirmed, reduce the daily dose or
interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the
aminotransferase levels return to pre-treatment values, continue or re-introduce the
treatment as appropriate (see below).
> 5 and ≤ 8 x ULN
Confirm by another aminotransferase test; if confirmed, stop treatment and monitor
aminotransferase levels at least every 2 weeks. Once the aminotransferase levels
return to pre-treatment values, consider re-introduction of the treatment (see below).
> 8 x ULN
Treatment should be stopped and reintroduction of TRACLEER® should not be considered.
There is no experience with re-introduction of TRACLEER® in these circumstances.
If TRACLEER is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days
and thereafter according to the recommendations above. If liver aminotransferase elevations are accompanied by clinical
symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or
increases in bilirubin ≥ 2 x ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER®
in these circumstances. Use in Women of Child-bearing Potential: See CONTRAINDICATIONS and Drug Interactions.
Dosage Adjustment in Renally Impaired Patients: The effect of renal impairment on the pharmacokinetics of bosentan is
small and does not require dosing adjustment. Dosage Adjustment in Geriatric Patients: Clinical studies of TRACLEER® did
not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger
subjects. In general, caution should be exercised in dose selection for elderly patients given the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group. Dosage
Adjustment in Hepatically Impaired Patients: The influence of liver impairment on the pharmacokinetics of TRACLEER® has
not been evaluated. Because there is in vivo and in vitro evidence that the main route of excretion of TRACLEER® is biliary,
liver impairment would be expected to increase exposure to bosentan. There are no specific data to guide dosing in hepatically impaired patients; caution should be exercised in patients with mildly impaired liver function. TRACLEER® should generally be avoided in patients with moderate or severe liver impairment. Dosage Adjustment in Children: Safety and efficacy in pediatric patients have not been established. Dosage Adjustment in Patients with Low Body Weight: In patients with
a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg
b.i.d. Discontinuation of Treatment: There is limited experience with abrupt discontinuation of TRACLEER®. No evidence for
acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction
(62.5 mg b.i.d. for 3 to 7 days) should be considered.
HOW SUPPLIED: 62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking “62,5”.
NDC 66215-101-06: Bottle containing 60 tablets. 125 mg film-coated, oval, biconvex, orange-white tablets, embossed with
identification marking “125”. NDC 66215-102-06: Bottle containing 60 tablets.
Rx only.
®
STORAGE: Store at 20°C – 25°C (68°F – 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP
Controlled Room Temperature].
References for previous pages: 1. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903. 2. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US,
Inc. 2005. 3. Data on file, Actelion Pharmaceuticals.
To learn more: Call 1-866-228-3546 or visit www.TRACLEER.com
Manufactured by:
Patheon Inc.
Mississauga, Ontario, CANADA
Marketed by:
Actelion Pharmaceuticals US, Inc.
South San Francisco, CA
© 2006 Actelion Pharmaceuticals US, Inc. All rights reserved. ACTU TRA JA 021 0406
ACTTR1387_Card_PulmInsert_Mv09
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BRIEF SUMMARY
FLOLAN® (epoprostenol sodium) for Injection
The following is a brief summary only; see full Prescribing Information for complete product information.
INDICATIONS AND USAGE:
FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.
CONTRAINDICATIONS:
A large study evaluating the effect of FLOLAN on survival in NYHA Class III and IV patients with congestive heart failure due
to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving FLOLAN plus conventional therapy than in those receiving conventional therapy alone. The chronic use of FLOLAN in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.
Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. FLOLAN should not be used chronically in patients who develop pulmonary
edema during dose initiation.
FLOLAN is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.
WARNINGS:
FLOLAN must be reconstituted only as directed using Sterile Diluent for FLOLAN. FLOLAN must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
Abrupt Withdrawal: Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of
FLOLAN may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and
asthenia. In clinical trials, one Class III PPH patient’s death was judged attributable to the interruption of FLOLAN. Abrupt
withdrawal should be avoided.
Sepsis: See ADVERSE REACTIONS: Adverse Events Attributable to the Drug Delivery System.
PRECAUTIONS:
General: FLOLAN should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension.
The diagnosis of PPH or PH/SSD should be carefully established.
FLOLAN is a potent pulmonary and systemic vasodilator. Dose initiation with FLOLAN must be performed in a setting with
adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation in controlled PPH clinical trials was performed during right heart catheterization. In uncontrolled PPH and controlled PH/SSD clinical trials, dose
initiation was performed without cardiac catheterization. The risk of cardiac catheterization in patients with pulmonary hypertension should be carefully weighed against the potential benefits. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, dose reduction should be
considered, but such an increase does not imply that chronic treatment is contraindicated.
During chronic use, FLOLAN is delivered continuously on an ambulatory basis through a permanent indwelling central
venous catheter. Unless contraindicated, anticoagulant therapy should be administered to PPH and PH/SSD patients receiving FLOLAN to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. In
order to reduce the risk of infection, aseptic technique must be used in the reconstitution and administration of FLOLAN as
well as in routine catheter care. Because FLOLAN is metabolized rapidly, even brief interruptions in the delivery of FLOLAN
may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. The
decision to initiate therapy with FLOLAN should be based upon the understanding that there is a high likelihood that intravenous therapy with FLOLAN will be needed for prolonged periods, possibly years, and the patient’s ability to accept and
care for a permanent intravenous catheter and infusion pump should be carefully considered.
Based on clinical trials, the acute hemodynamic response to FLOLAN did not correlate well with improvement in exercise
tolerance or survival during chronic use of FLOLAN. Dosage of FLOLAN during chronic use should be adjusted at the first
sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events
associated with FLOLAN (see DOSAGE AND ADMINISTRATION). Following dosage adjustments, standing and supine
blood pressure and heart rate should be monitored closely for several hours.
Information for Patients: Patients receiving FLOLAN should receive the following information. FLOLAN must be reconstituted only with Sterile Diluent for FLOLAN. FLOLAN is infused continuously through a permanent indwelling central
venous catheter via a small, portable infusion pump. Thus, therapy with FLOLAN requires commitment by the patient to drug
reconstitution, drug administration, and care of the permanent central venous catheter. Sterile technique must be adhered
to in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of FLOLAN may result in
rapid symptomatic deterioration. A patient’s decision to receive FLOLAN should be based upon the understanding that there
is a high likelihood that therapy with FLOLAN will be needed for prolonged periods, possibly years. The patient’s ability to
accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.
ADVERSE REACTIONS:
During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2)
adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.
Adverse Events During Dose Initiation and Escalation: During early clinical trials, FLOLAN was increased in 2-ng/kg/min
increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events
that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of FLOLAN.
The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal
pain, and tachycardia. Adverse events reported in ≥1% of patients receiving FLOLAN (n = 391) during dose initiation
and escalation in decreasing order of frequency are as follows: flushing 58%; headache 49%; nausea/vomiting 32%;
hypotension 16%; anxiety, nervousness, agitation 11%; chest pain 11%; dizziness 8%; bradycardia 5%; abdominal pain 5%;
musculoskeletal pain 3%; dyspnea 2%; back pain 2%; sweating 1%; dyspepsia 1%; hypesthesia/paresthesia 1%; and tachycardia 1%.
Adverse Events During Chronic Administration: Interpretation of adverse events is complicated by the clinical features
of PPH and PH/SSD, which are similar to some of the pharmacologic effects of FLOLAN (e.g., dizziness, syncope). Adverse
events probably related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to FLOLAN. These include headache,
jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness.
Adverse Events During Chronic Administration for PPH: In an effort to separate the adverse effects of the drug from the
adverse effects of the underlying disease, the following is a listing of adverse events that occurred at a rate at least 10% different in the 2 groups [FLOLAN (n = 52), conventional therapy (n = 54)] in controlled trials for PPH (events are listed by body
system with the incidence for FLOLAN followed by conventional therapy):
Occurrence More Common with FLOLAN: General: chills/fever/sepsis/flu-like symptoms (25%, 11%);
Cardiovascular: tachycardia (35%, 24%), flushing (42%, 2%); Gastrointestinal: diarrhea (37%, 6%), nausea/vomiting
(67%, 48%); Musculoskeletal: jaw pain (54%, 0%), myalgia (44%, 31%), nonspecific musculoskeletal pain (35%, 15%);
Neurological: anxiety/nervousness/tremor (21%, 9%), dizziness (83%, 70%), headache (83%, 33%), hypesthesia, hyperesthesia, paresthesia (12%, 2%).
Occurrence More Common With Standard Therapy: Cardiovascular: heart failure (31%, 52%), syncope (13%,
24%), shock (0%, 13%); Respiratory: hypoxia (25%, 37%).
Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving FLOLAN.
Additional adverse events that occurred at a rate with less than 10% difference reported in PPH patients receiving FLOLAN
plus conventional therapy (n = 52) compared to conventional therapy alone (n = 54) during controlled clinical trials are as
follows (events are listed by body system with incidence for FLOLAN followed by conventional therapy): General: asthenia
(87%, 81%); Cardiovascular: angina pectoris (19%, 20%), arrhythmia (27%, 20%), bradycardia (15%, 9%), supraventricular tachycardia (8%, 0%), pallor (21%, 30%), cyanosis (31%, 39%), palpitation (63%, 61%), cerebrovascular accident (4%,
0%), hemorrhage (19%, 11%), hypotension (27%, 31%), myocardial ischemia (2%, 6%); Gastrointestinal: abdominal pain
(27%, 31%), anorexia (25%, 30%), ascites (12%, 17%), constipation (6%, 2%); Metabolic: edema (60%, 63%), hypokalemia
(6%, 4%), weight reduction (27%, 24%), weight gain (6%, 4%); Musculoskeletal: arthralgia (6%, 0%), bone pain (0%, 4%),
chest pain (67%, 65%); Neurological: confusion (6%, 11%), convulsion (4%, 0%); depression (37%, 44%), insomnia (4%,
4%); Respiratory: cough increase (38%, 46%), dyspnea (90%, 85%), epistaxis (4%, 2%), pleural effusion (4%, 2%); Skin
and Appendages: pruritus (4%, 0%), rash (10%, 13%), sweating (15%, 20%); Special Senses: amblyopia (8%, 4%), vision
abnormality (4%, 0%).
Adverse Events During Chronic Administration for PH/SSD: In an effort to separate the adverse effects of the drug from
the adverse effects of the underlying disease, the following is a listing of adverse events that occurred at a rate at least 10%
different in the 2 groups [FLOLAN (n = 56) and conventional therapy (n = 55)] in the controlled trial for patients with PH/SSD
(events are listed by body system with the incidence for FLOLAN followed by conventional therapy):
Occurrence More Common With FLOLAN: Cardiovascular: flushing (23%, 0%), hypotension (13%, 0%);
Gastrointestinal: anorexia (66%, 47%), nausea/vomiting (41%, 16%), diarrhea (50%, 5%); Musculoskeletal: jaw pain
(75%, 0%), pain/neck pain/arthralgia (84%, 65%); Neurological: headache (46%, 5%); Skin and Appendages: skin ulcer
(39%, 24%), eczema/rash/urticaria (25%, 4%).
Occurrence More Common With Conventional Therapy: Cardiovascular: cyanosis (54%, 80%), pallor (32%,
53%), syncope (7%, 20%); Gastrointestinal: ascites (23%, 33%), esophageal reflux/gastritis (61%, 73%); Metabolic:
weight decrease (45%, 56%); Neurological: dizziness (59%, 76%); Respiratory: hypoxia (55%, 65%).
Additional adverse events that occurred at a rate with less than 10% difference reported in PH/SSD patients receiving
FLOLAN plus conventional therapy (n = 56) or conventional therapy alone (n = 55) during controlled clinical trials are as follows (adverse events occurred in at least 2 patients in either treatment group and are listed by body system with the incidence for FLOLAN followed by conventional therapy): General: asthenia (100%, 98%), hemorrhage/hemorrhage injection
site/hemorrhage rectal (11%, 2%), infection/rhinitis (21%, 20%), chills/fever/sepsis/flu-like symptoms (13%, 11%); Blood
and Lymphatic: thrombocytopenia (4%, 0%); Cardiovascular: heart failure/heart failure right (11%, 13%), myocardial
infarction (4%, 0%), palpitation (63%, 71%), shock (5%, 5%), tachycardia (43%, 42%), vascular disorder peripheral (96%,
100%), vascular disorder (95%, 89%); Gastrointestinal: abdominal enlargement (4%, 0%), abdominal pain (14%, 7%), constipation (4%, 2%), flatulence (5%, 4%); Metabolic: edema/edema peripheral/edema genital (79%, 87%), hypercalcemia
(48%, 51%), hyperkalemia (4%, 0%), thirst (0%, 4%); Musculoskeletal: arthritis (52%, 45%), back pain (13%, 5%), chest
pain (52%, 45%), cramps leg (5%, 7%); Respiratory: cough increase (82%, 82%), dyspnea (100%, 100%), epistaxis (9%,
7%), pharyngitis (5%, 2%), pleural effusion (7%, 0%), pneumonia (5%, 0%), pneumothorax (4%, 0%), pulmonary edema
(4%, 2%), respiratory disorder (7%, 4%), sinusitis (4%, 4%); Neurological: anxiety/hyperkinesia/nervousness/tremor (7%,
5%), depression/depression psychotic (13%, 4%), hyperesthesia/hypesthesia/paresthesia (5%, 0%), insomnia (9%, 0%),
somnolence (4%, 2%); Skin and Appendages: collagen disease (82%, 84%), pruritus (4%, 2%), sweat (41%, 36%);
Urogenital: hematuria (5%, 0%), urinary tract infection (7%, 0%).
Although the relationship to FLOLAN administration has not been established, pulmonary embolism has been reported in
several patients taking FLOLAN and there have been reports of hepatic failure.
Adverse Events Attributable to the Drug Delivery System: Chronic infusions of FLOLAN are delivered using a small,
portable infusion pump through an indwelling central venous catheter. During controlled PPH trials of up to 12 weeks’ duration, up to 21% of patients reported a local infection and up to 13% of patients reported pain at the injection site. During a
controlled PH/SSD trial of 12 weeks’ duration, 14% of patients reported a local infection and 9% of patients reported pain at
the injection site. During long-term follow-up in the clinical trial of PPH, sepsis was reported at least once in 14% of patients
and occurred at a rate of 0.32 infections/patient per year in patients treated with FLOLAN. This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in
oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in FLOLAN were associated with symptoms related to excess or insufficient FLOLAN, respectively (see ADVERSE
REACTIONS: Adverse Events During Chronic Administration).
Observed During Clinical Practice: In addition to adverse reactions reported from clinical trials, the following events have
been identified during post-approval use of FLOLAN. Because they are reported voluntarily from a population of unknown
size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their
seriousness, frequency of reporting, or potential causal connection to FLOLAN.
Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly.
Endocrine and Metabolic: Hyperthyroidism.
OVERDOSAGE:
Signs and symptoms of excessive doses of FLOLAN during clinical trials are the expected dose-limiting pharmacologic
effects of FLOLAN, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will
ordinarily require dose reduction of FLOLAN.
One patient with secondary pulmonary hypertension accidentally received 50 mL of an unspecified concentration of
FLOLAN. The patient vomited and became unconscious with an initially unrecordable blood pressure. FLOLAN was discontinued and the patient regained consciousness within seconds. In clinical practice, fatal occurrences of hypoxemia,
hypotension, and respiratory arrest have been reported following overdosage of FLOLAN.
Single intravenous doses of FLOLAN at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase human
dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity,
ataxia, loss of righting reflex, deep slow breathing, and hypothermia.
DOSAGE AND ADMINISTRATION:
Important Note: FLOLAN must be reconstituted only with STERILE DILUENT for FLOLAN. Reconstituted solutions of
FLOLAN must not be diluted or administered with other parenteral solutions or medications (see WARNINGS).
Dosage: Continuous chronic infusion of FLOLAN should be administered through a central venous catheter. Temporary
peripheral intravenous infusion may be used until central access is established. Chronic infusion of FLOLAN should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established and further increases in the infusion rate are not
clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then the infusion rate should be
decreased to an appropriate chronic infusion rate whereby the pharmacologic effects of FLOLAN are tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain,
or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is
not tolerated, a lower dose that is tolerated by the patient should be identified.
In the controlled 12-week trial in PH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min.
During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment.
At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3
weeks.
Dosage Adjustments: Changes in the chronic infusion rate should be based on persistence, recurrence, or worsening of
the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of
FLOLAN. In general, increases in dose from the initial chronic dose should be expected.
Increments in dose should be considered if symptoms of pulmonary hypertension persist or recur after improving. The infusion should be increased by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response;
these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to
48 hours or longer. Following establishment of a new chronic infusion rate, the patient should be observed, and standing
and supine blood pressure and heart rate monitored for several hours to ensure that the new dose is tolerated.
During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate,
but the adverse event may occasionally resolve without dosage adjustment. Dosage decreases should be made gradually
in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of FLOLAN
or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g., unconsciousness,
collapse, etc.), infusion rates of FLOLAN should be adjusted only under the direction of a physician.
Administration: FLOLAN is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, FLOLAN may be administered peripherally.
To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous
infusion sets. A multi-lumen catheter should be considered if other intravenous therapies are routinely administered.
To facilitate extended use at ambient temperatures exceeding 25°C (77°F), a cold pouch with frozen gel packs was used in
clinical trials. Any cold pouch used must be capable of maintaining the temperature of reconstituted FLOLAN between 2°
and 8°C for 12 hours.
Reconstitution: FLOLAN is stable only when reconstituted with STERILE DILUENT for FLOLAN. FLOLAN must not
be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
GlaxoSmithKline
Research Triangle Park, NC 27709
© 2006, GlaxoSmithKline. All rights reserved.
September 2002
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FLL087R0_FCAD_Survival
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6:04 PM
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What‘s More Important Than...
Survival?
In Idiopathic Pulmonary Arterial Hypertension,
FLOLAN Is Proven to Improve Survival*
FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension in
NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.
IMPORTANT SAFETY INFORMATION: Use of FLOLAN is contraindicated in patients with congestive
heart failure due to severe left ventricular systolic dysfunction. FLOLAN should not be used in patients
who develop pulmonary edema during dose initiation. FLOLAN is also contraindicated in patients with
known hypersensitivity to the drug or structurally-related compounds. Abrupt withdrawal or reductions
in delivery of FLOLAN, as well as overdoses, may result in hemodynamic instability, including rebound
pulmonary hypertension or fatal hypotension. FLOLAN should be used only by clinicians experienced in
the diagnosis and treatment of pulmonary hypertension.
* Results from a 12-week, prospective, multicenter, randomized, open trial study of NYHA Class III and Class IV
Idiopathic Pulmonary Arterial Hypertension (iPAH) patients
treated with FLOLAN and conventional therapy (n=41) or
conventional therapy alone (n=40) (which included anticoagulants, oral vasodilators, diuretics, digoxin, and supplemental oxygen), 100% vs 80% survival; respectively
(p=0.003).1
when survival counts think
Reference: 1. Barst RJ et al. N Engl J Med. 1996:334;296-301.
Please see important information on the next page.
©2006 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. FLL087R0 January 2006
S T A R T W I T H C O N F I D E N C E™
REVATIO: for patients with PAH as early as class II
Proven effective for patients with
Pulmonary Arterial Hypertension
(WHO Group I)
• Increased 6-minute walk distance as early as week 4
• Significantly reduced mean pulmonary arterial pressure
In a long-term, uncontrolled extension study
94% of patients were still alive at 1year
• Walk distance and functional class appeared stable
• Without a control group, these data must be
interpreted cautiously
The lowest-priced oral PAH therapy 1*
• REVATIO 20-mg tablets tid
REVATIO contains sildenafil citrate,
the same active ingredient
found in Viagra®
*Actual pharmacy or out-of-pocket costs may vary. Price comparisons do not imply comparable efficacy or safety. The clinical trial for REVATIO included patients who were
predominantly functional classes II and III, and the clinical trial for the other oral PAH treatment included patients who were predominantly functional class III.
REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability. The efficacy of
REVATIO has not been evaluated in patients currently on bosentan therapy.
The use of REVATIO and organic nitrates in any form, at any time, is contraindicated.
Co-administration of REVATIO with potent CYP3A4 inhibitors, eg, ketoconazole, itraconazole, and ritonavir, is not recommended as serum
concentrations of sildenafil substantially increase.
Before starting REVATIO, physicians should consider whether patients with underlying conditions could be adversely affected by the mild
and transient vasodilatory effects of REVATIO on blood pressure. Pulmonary vasodilators may significantly worsen the cardiovascular
status of patients with pulmonary veno-occlusive disease (PVOD) and administration of REVATIO to these patients is not recommended.
Should signs of pulmonary edema occur when sildenafil is administered, the possibility of associated PVOD should be considered.
Patients with the following characteristics did not participate in the preapproval clinical trial: patients who have suffered a myocardial
infarction, stroke, or life-threatening arrhythmia within the last 6 months, unstable angina, hypertension (BP>170/110), retinitis
pigmentosa, or patients on bosentan. The safety of REVATIO is unknown in patients with bleeding disorders and patients with active
peptic ulceration. In these patients, physicians should prescribe REVATIO with caution.
Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely post-marketing in temporal association with the use
of PDE5 inhibitors for the treatment of erectile dysfunction, including sildenafil. It is not possible to determine if these events are related
to PDE5 inhibitors or to other factors. Physicians should advise patients to seek immediate medical attention in the event of sudden loss
of vision while taking PDE5 inhibitors, including REVATIO.
The most common side effects of REVATIO (placebo-subtracted) were
epistaxis (8%), headache (7%), dyspepsia (6%), flushing (6%), and
insomnia (6%). Adverse events were generally transient and
mild to moderate.
Please see brief summary of prescribing information on adjacent page.
Reference: 1. Based on wholesale acquisition cost: First DataBank Inc, 2005.
Brief summary of prescribing information
In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were
administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these
study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and
8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg,
and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic
postural hypotension. These reports included dizziness and light-headedness, but not syncope (see PRECAUTIONS:General).
Concomitant administration of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg) did not affect the
pharmacoknetics of sildenafil.
Concomitant administration of a single 100 mg dose of sildenafil with 10 mg of atorvastatin did not alter the
pharmacokinetics of either sildenafil or atorvastatin.
INDICATIONS AND USAGE
REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy.
Effects of REVATIO on Other Drugs
CONTRAINDICATIONS
Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), sildenafil was shown
to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either
regularly and/or intermittently, in any form is therefore contraindicated.
REVATIO is contraindicated in patients with a known hypersensitivity to any component of the tablet.
WARNINGS
The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases
serum concentrations of sildenafil, therefore co-administration with REVATIO is not recommended (see Drug Interactions and
DOSAGE AND ADMINISTRATION).
REVATIO has vasodilator properties, resulting in mild and transient decreases in blood pressure (see
PRECAUTIONS). Prior to prescribing REVATIO, physicians should carefully consider whether their patients with
certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting
hypotension (BP <90/50), or with fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction.
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary
veno-occlusive disease (PVOD). Since there are no clinical data on administration of REVATIO to patients with veno-occlusive
disease, administration of REVATIO to such patients is not recommended. Should signs of pulmonary edema occur when
sildenafil is administered, the possibility of associated PVOD should be considered.
There is no controlled clinical data on the safety or efficacy of REVATIO in the following groups; if prescribed, this should be
done with caution:
• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
• Patients with coronary artery disease causing unstable angina;
• Patients with hypertension (BP >170/110);
• Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases);
• Patients currently on bosentan therapy.
PRECAUTIONS
General
Before prescribing REVATIO, it is important to note the following:
• Caution is advised when phosphodiesterase type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5
inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering
effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some
patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic
hypotension. In the sildenafil interaction studies with alpha-blockers (see Drug Interactions), cases of symptomatic
hypotension consisting of dizziness and lightheadedness were reported. No cases of syncope or fainting werereported
during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors
and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of
anti-hypertensive drugs.
• REVATIO should be used with caution in patients with anatomical deformation of the penis (such as angulation,
cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (such
as sickle cell anemia, multiple myeloma or leukemia).
• In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets
indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). The
combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this
interaction has not been studied in humans.
• The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH
patients (sildenafil 3%, placebo 2%). The incidence of epistaxis was also higher in sildenafil-treated patients with
concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).
• The safety of REVATIO is unknown in patients with bleeding disorders and patients with active peptic ulceration.
Information for Patients
Physicians should discuss with patients the contraindication of REVATIO with regular and/or intermittent use of
organic nitrates.
Sildenafil is also marketed as VIAGRA® for male erectile dysfunction.
Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely post-marketing in temporal association
with the use of PDE5 inhibitors when used in the treatment of male-erectile dysfunction, including sildenafil. It is not
possible to determine if these events are related to PDE5 inhibitors or to other factors. Physicians should advise patients to
seek immediate medical attention in the event of sudden loss of vision while taking PDE5 inhibitors, including REVATIO.
Drug Interactions
In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted in a greater incidence of reports of
bleeding (primarily epistaxis) versus placebo.
Effects of Other Drugs on REVATIO
In vitro studies: Sildenafil metabolism is principally mediated by the CYP3A4 (major route) and CYP2C9 (minor route)
cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these
isoenzymes may increase sildenafil clearance.
In vivo studies: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil
clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the
combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on
sildenafil pharmacokinetics.
Population data from patients in clinical trials indicated a reduction in sildenafil clearance when it was
co-administered with CYP3A4 inhibitors. Sildenafil exposure without concomitant medication is shown to be
5-fold higher at a dose of 80 mg t.i.d. compared to its exposure at a dose of 20 mg t.i.d. This concentration range covers the
same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A4 inhibitors (except
for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). Cimetidine (800 mg), a nonspecific CYP inhibitor,
caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy
volunteers. When a single 100 mg dose of sildenafil was co-administered with erythromycin, a CYP3A4 inhibitor, at steady
state (500 mg twice daily [b.i.d.] for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In a study
performed in healthy volunteers, co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state
(1200 mg t.i.d.) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in
sildenafil AUC. Stronger CYP3A4 inhibitors will have still greater effects on plasma levels of sildenafil
(see DOSAGE AND ADMINISTRATION).
In another study in healthy volunteers, co-administration with the HIV protease inhibitor ritonavir, a potent CYP3A4 inhibitor,
at steady state (500 mg b.i.d.) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and
a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately
200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked
effects on a broad range of P450 substrates (see WARNINGS and cDOSAGE AND ADMINISTRATION). Although the interaction
between other protease inhibitors and REVATIO has not been studied, their concomitant use is expected to increase
sildenafil levels.
In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.), with the endothelin
receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state
(125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. The combination of both
drugs did not lead to clinically significant changes in blood pressure (supine or standing). Concomitant administration of
potent CYP3A4 inducers is expected to cause greater decreases in plasma levels of sildenafil.
In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4
(IC50 >150 µM).
In vivo studies: When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to
hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and
7 mmHg diastolic.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized
by CYP2C9.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood
alcohol levels of 0.08%.
Sildenafil at steady state (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in Cmax of bosentan
(125 mg b.i.d.).
In a study of healthy volunteers, sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease
inhibitors saquinavir and ritonavir, both of which are CYP3A4 substrates.
Sildenafil had no impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose
resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and
female rats, respectively, the human exposure at the Recommended Human Dose (RHD) of 20 mg t.i.d. Sildenafil was not
carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a
maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m2 basis.
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human
lymphocyte and in vitro mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose
producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite 19 and 38 times, for males and
females, respectively, the human exposure at the RHD of 20 mg t.i.d.
Pregnancy
Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in pregnant rats or
rabbits, dosed with 200 mg sildenafil/kg/day during organogenesis, a level that is, on a mg/m2 basis,
32- and 68-times, respectively, the RHD of 20 mg t.i.d. In a rat pre- and postnatal development study, the
no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). There are no
adequate and well-controlled studies of sildenafil in pregnant women.
Nursing Mothers
It is not known if sildenafil citrate and/or metabolites are excreted in human breast milk. Since many drugs are excreted in
human milk, caution should be used when REVATIO is administered to nursing women.
Pediatric Use
Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients has not been established.
Geriatric Use
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, but studies did not include sufficient
numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension
patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Safety data were obtained from the pivotal study and an open-label extension study in 277 treated patients with pulmonary
arterial hypertension. Doses up to 80 mg t.i.d. were studied.
The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg t.i.d. was low (3%)
and the same as placebo (3%). In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug
reactions that were reported by at least 3% of REVATIO patients treated at the recommended dosage (20 mg t.i.d.) and were
more frequent in REVATIO patients than placebo patients, are shown in Table 2. Adverse events were generally transient and
mild to moderate in nature.
TABLE 2. Sildenafil Adverse Events in ⱖ3% of Patients and More Frequent Than Placebo
ADVERSE EVENT %
Epistaxis
Headache
Dyspepsia
Flushing
Insomnia
Erythema
Dyspnea exacerbated
Rhinitis nos
Diarrhea nos
Myalgia
Pyrexia
Gastritis nos
Sinusitis
Paresthesia
Placebo (n=70)
1
39
7
4
1
1
3
0
6
4
3
0
0
0
Sildenafil 20 mg t.i.d. (n=69) Placebo Subtracted
9
8
46
7
13
6
10
6
7
6
6
5
7
4
4
4
9
3
7
3
6
3
3
3
3
3
3
3
At doses higher than the recommended 20 mg t.i.d. there was a greater incidence of some adverse events including
flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were
predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.
In the pivotal study, the incidence of retinal hemorrhage at the recommended sildenafil 20 mg t.i.d. dose was 1.4% versus
0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both the
recommended dose and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing
these events had risk factors for hemorrhage including concurrent anticoagulant therapy.
In post-marketing experience with sildenafil citrate at doses indicated for male erectile dysfunction, serious
cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death,
ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary
hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of
the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were
reported to occur during or short ly after sexual activity, and a few were reported to occur shortly after the use of sildenafil
without sexual activity. Others were reported to have occurred hours to days after use concurent with sexual activity. It is
not possible to determine whether these events are related directly to sildenafil citrate, to sexual activity, to the patient’s
underlying cardiovascular disease, or to a combination of these or other factors.
Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely post-marketing in temporal association
with the use of PDE5 inhibitors when used in the treatment of male-erectile dysfunction, including sildenafil. It is not
possible to determine if these events are related to PDE5 inhibitors or to other factors. Physicians should advise patients to
seek immediate medical attention in the event of sudden loss of vision while taking PDE5 inhibitors, including REVATIO.
OVERDOSAGE
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses
but rates were increased.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to
accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
August 2005
RV268198B
© 2006 Pfizer Inc.
All rights reserved.
Printed in USA/January 2006
U.S. Pharmaceuticals
Diagnostic Dilemmas: Diastolic Heart Failure
Causing Pulmonary Hypertension and Pulmonary
Hypertension Causing Diastolic Dysfunction
Brian P. Shapiro, MD
Rick A. Nishimura, MD
Michael D. McGoon, MD
Margaret M. Redfield, MD
Mayo Clinic College of Medicine
Rochester, Minnesota
Brian P.
Shapiro, MD
Rick A.
Nishimura, MD
Michael D.
McGoon, MD
Margaret M.
Redfield, MD
Left heart disease can cause pulmonary hypertension via multiple mechanisms. In the past, a normal ejection fraction and the
absence of left-sided valve disease or congenital heart disease
provided reassurance that pulmonary hypertension was not
related to left-sided heart disease. However, it is now recognized that patients with clinical heart failure commonly have a
normal ejection fraction, a syndrome referred to as diastolic
heart failure or heart failure with normal ejection fraction.1,2 As
reviewed below, the pathophysiologic mechanisms present in
patients with diastolic heart failure may be heterogeneous.
Although pulmonary hypertension has been reported in patients
with diastolic heart failure, its prevalence and severity remain
poorly defined.
Idiopathic pulmonary arterial hypertension (IPAH) has been
characterized as a disease of children and young adults,3,4 yet
increasingly the diagnosis is made in elderly persons.5,6 This
raises concern that some patients with dyspnea, unexplained
pulmonary hypertension, and a normal ejection fraction could
have diastolic heart failure with secondary pulmonary hypertension related to chronic pulmonary venous hypertension.
However, as reviewed below, chronic right ventricular pressure
overload can cause left ventricular diastolic dysfunction. Thus,
a diagnostic dilemma arises in elderly dyspneic patients with
otherwise unexplained pulmonary hypertension and a normal
ejection fraction or when patients with a presumptive diagnosis
of IPAH undergo right heart catheterization and are found to
have an elevated pulmonary capillary wedge pressure (PCWP).
Do these patients have diastolic heart failure with secondary
pulmonary hypertension or is it IPAH causing left ventricular
diastolic dysfunction and elevated PCWP?
In this review, illustrative cases of both scenarios outlined
above are presented, followed by a discussion of diastolic heart
failure, novel concepts relevant to diastolic dysfunction and
secondary pulmonary hypertension, and the phenomenon of left
ventricular diastolic dysfunction related to chronic right ventricular pressure overload. Lastly, potential diagnostic strategies
and implications for therapy are discussed.
CASE 1: A 79-year-old woman presented with acutely decompensated heart failure after starting bosentan for pulmonary
hypertension. She had a history of paroxysmal atrial fibrillation
that began in 1986 and underwent a surgical MAZE procedure
in 1996 because of worsening tachypalpitations. Atrial fibrillation recurred and an atrioventricular node ablation with pacemaker implantation was performed later that year. In 1998 the
patient developed symptoms of dyspnea and peripheral edema
and was found to have pulmonary vascular congestion on chest
radiography. Echocardiography revealed Doppler evidence of
severe diastolic dysfunction, no mitral regurgitation and a normal ejection fraction. A diagnosis of diastolic heart failure was
made and she was treated with diuretics. In 2000 she had
worsening dyspnea and peripheral edema and a repeat echocardiogram demonstrated a normal ejection fraction, severe diastolic dysfunction, and a right ventricular systolic pressure of 56
mmHg. The following year, her condition once again clinically
deteriorated. Repeat echocardiography was unchanged with the
exception of the right ventricular systolic pressure, which had
increased to 75 mmHg. She then underwent a work-up for other
secondary causes of pulmonary hypertension, but none were
identified and she was referred to the pulmonary hypertension
clinic. A right heart catheterization was performed that revealed
a pulmonary artery pressure of 73/25 mmHg and a PCWP of 26
mmHg (Figure 1) with very prominent V waves in the PCWP
wave form. Treatment was started with bosentan, an endothelin
receptor antagonist, but she experienced a rapid increase in
edema and dyspnea and had pulmonary edema on examination
and chest radiography.
The question arises whether or not this patient had lateonset IPAH with concomitant or secondary diastolic dysfunction
or diastolic heart failure with secondary pulmonary hypertension. Atrial fibrillation is extremely common among patients
with diastolic dysfunction7 and more common among patients
with left heart disease than right heart disease. Demographic,
clinical, and echocardiographic information seemed to favor a
diagnosis of longstanding diastolic heart failure and would suggest that her pulmonary hypertension is likely related to “reactive” pulmonary hypertension and/or congestive pulmonary vasculopathy as addressed below. However, she was treated with
bosentan on the basis of her worsening pulmonary hypertension. In the absence of significant mitral regurgitation, the presence of a large V wave indicates poor atrial compliance, and as
outlined below, reduction in atrial compliance may be an impor-
Advances in Pulmonary Hypertension 13
Figure 1. Case 1. Hemodynamic catheterization in an elderly woman
with dyspnea and pulmonary hypertension. Electrocardiographic
(ECG), aortic, pulmonary capillary wedge pressure (PCWP), and right
atrial pressure tracings showing elevated PCWP and a large (50
mmHg) V wave during systole in the PCWP tracing.
tant mediator of secondary pulmonary hypertension in mitral
stenosis or in patients with heart failure regardless of ejection
fraction. Indeed, large atrial V waves in the absence of mitral
regurgitation can occur in patients with several types of cardiac
disease.8,9 This case also underscores the potential for development of worsening pulmonary edema after the initiation of
pulmonary vasodilators. This may be related to the preferential
vasodilatory effect on the pulmonary vasculature with increased
blood flow to a noncompliant left ventricle as has been
described with inhaled nitric oxide.10-13 Alternatively, this may
be related to volume retention associated with endothelin
receptor antagonism.14
CASE 2: A 72-year-old man with a history of long-standing
hypertension, atrial fibrillation, diabetes mellitus, and previous
aortic valve replacement for aortic stenosis and mitral valve
repair for mitral regurgitation presents with progressive dyspnea. Echocardiography demonstrated a normal ejection fraction, a normally functioning aortic prosthesis, diastolic dysfunction, and biatrial enlargement. There was no mitral stenosis and only mild mitral regurgitation. The right ventricular systolic pressure was estimated at 51 mmHg. A right and left heart
catheterization using a transseptal approach was performed
and revealed systemic arterial hypertension with a central aortic pressure of 170/63 mmHg. Contrast ventriculography
revealed only mild mitral regurgitation despite the systemic
hypertension. Transseptal left atrial and left ventricular pressures revealed the absence of any significant transmitral gradient. Left atrial pressure tracings demonstrated a large V wave
of over 50 mmHg with a mean left atrial pressure of 28 mmHg
(Figure 2). The pulmonary arterial systolic pressure was 48
mmHg. Nitroglycerin administration reduced the systemic pressure to 121/51 mmHg and the V wave in the left atrium fell to
22 mmHg with a mean left atrial pressure of 15 mmHg.
The hemodynamic profile of this patient is one of diastolic
heart failure related to hypertensive heart disease with moder14 Advances in Pulmonary Hypertension
Figure 2. Case 2. Hemodynamic catheterization in an elderly man
with dyspnea and pulmonary hypertension. At baseline, aortic, left
ventricular (LV), and left atrial (LA) pressures (transseptal approach)
were measured. The patient was hypertensive with elevated mean LA
pressures where the V wave exceeded 50 mmHg. Nitroglycerin
reduced the systemic pressure to 121/51 mmHg. With that the mean
LA pressure fell to 15 mmHg and the V wave dropped to 22 mmHg.
ate secondary pulmonary hypertension that was largely due to
the passive effects of pulmonary venous hypertension and still
reversible with normalization of the PCWP. Again, the presence
of large atrial V waves suggests decreased atrial compliance.
CASE 3: An otherwise healthy 30-year-old woman presents with
a 12-month history of progressive dyspnea, fatigue, and peripheral edema. Physical examination revealed a markedly elevated
jugular venous pressure, loud S2P, parasternal lift, and peripheral edema. Echocardiography showed normal left ventricular
size and function, systolic flattening of the interventricular septum (D-shaped left ventricle), severe right ventricular and right
atrial enlargement, a small pericardial effusion (Figure 3), mild
tricuspid regurgitation, and severe pulmonary hypertension.
The estimated right ventricular systolic pressure calculated
from the tricuspid regurgitant velocity was 97 mmHg (107% of
systemic systolic blood pressure). Left ventricular diastolic
assessment with transmitral inflow pulsed-wave Doppler
revealed a reduced early-to-late (E/A) filling velocity ratio and a
prolonged deceleration time (Figure 4A), reduced pulmonary
venous diastolic flow velocity (Figure 4B), and reduced tissue
Doppler early diastolic septal annulus velocity (Figure 4C), all
suggesting the presence of impaired left ventricular relaxation
(grade I diastolic dysfunction). Right heart catheterization confirmed severe pulmonary hypertension and elevated right ventricular diastolic and right atrial pressures in the presence of a
normal PCWP.
Although this patient has diastolic dysfunction (impaired
relaxation) related to her chronic right ventricular pressure
overload, it is not the type of diastolic dysfunction that will be
associated with increased filling pressures, at least at rest (see
discussion of echo assessment of diastolic function and Figure
5 below). No formal assessment of left ventricular compliance
was performed. However, even if reduced compliance was present, it was not associated with elevated filling pressures in this
case. However, her transtricuspid inflow pattern showed a high
E/A ratio and a short deceleration time (Figure 4D) and her
hepatic vein Doppler flow pattern showed reduced systolic for-
Figure 3. Case 3. Doppler echocardiographic findings in a young
woman with severe idiopathic pulmonary arterial hypertension. A.
Short-axis view of the right (RV) and left (LV) ventricles in diastole at
the mid-LV level. The RV is markedly enlarged while the LV is normal
in size. There is a small pericardial effusion (PE). B. Short-axis view
of the RV and LV in systole. The intraventricular septum is flattened,
producing a D-shaped LV. The PE is more apparent in systole. C.
Apical four-chamber view demonstrating the marked RV and right
atrial (RA) enlargement.
ward flow and increased atrial reversal velocities (Figure 4E); all
suggestive of severe right ventricular diastolic dysfunction with
reduced right ventricular compliance (grade III-IV diastolic dysfunction). This is consistent with the elevated right atrial pressure demonstrated at her catheterization.
The echocardiogram from this patient illustrates the effect
of severe right ventricular pressure overload on right and left
ventricular diastolic function. There is evidence of impaired
relaxation but no Doppler evidence of decreased left ventricular
compliance or elevated filling pressures. This is the type of
diastolic dysfunction most frequently observed in patients with
IPAH. The concept of ventricular interdependence and its effect
on left ventricular diastolic function is discussed in detail
below.
Diastolic Heart Failure
Epidemiologic studies have established that 50% of patients
with a clinical diagnosis of heart failure have preserved ejection
fraction and this entity has been referred to as diastolic heart
failure.1,2 Patients with diastolic heart failure are generally elderly but a significant subset are somewhat younger. Although
there is a predominance among women, the syndrome also frequently affects men. More recently, the term “heart failure with
normal ejection fraction” has been suggested because of concerns that diastolic dysfunction may not be present in all
patients.15,16
Risk factors for diastolic heart failure beyond advanced age
and female sex include hypertension, coronary artery disease,
and risk factors for coronary artery disease, including diabetes.1
Although classically described in patients with left ventricular
hypertrophy, echocardiographic evidence of left ventricular
hypertrophy is not uniformly present. Indeed, fewer than 50%
of patients have left ventricular hypertrophy in several series of
patients with diastolic heart failure.17,18
Although the diagnosis of diastolic heart failure is predicated on the presence of clinical heart failure, a normal ejection
fraction, and the absence of significant left-sided valve disease,
the proper methods to confirm the presence of diastolic dysfunction remain controversial. To characterize left ventricular
diastolic function, invasive assessment of the two primary components of diastolic function, left ventricular relaxation and
compliance, is needed.
Figure 4. Case 3. Diastolic assessment of the left (LV) and right ventricle (RV) using Doppler echocardiography in the young woman with
severe idiopathic pulmonary arterial hypertension shown in Figure 3.
LV diastolic assessment (left panels): A. Transmitral pulsed-wave
Doppler flow velocity profile. The early diastolic velocity (E) is
reduced and the late diastolic velocity (A) is increased. The deceleration time of the E velocity is also increased. B. The pulmonary
venous inflow velocity profiles show reduced diastolic forward flow
(D) with most flow occurring during ventricular systole (S). C. The
mitral annular tissue Doppler profile measured at the septal aspect of
the mitral annulus. The early diastolic velocity (e’) is low (0.08
m/sec) for a young woman where the e’ velocity usually exceeds 0.10
m/sec and usually exceeds the late diastolic velocity (a’). The patterns in A-C are consistent with impaired relaxation in the LV (grade I
diastolic dysfunction; see Figure 5). In contrast, diastolic assessment
of the RV (right panels) shows that the transtricuspid early diastolic
velocity (E) is increased with a shortened deceleration time and there
is very little filling in late diastole (A) (panel D). Doppler evaluation of
the hepatic veins (E) shows blunted systolic forward flow (S) and
marked increase in atrial reversal flow (AR). These findings are consistent with reduced RV compliance and would indicate grade III or
IV RV diastolic dysfunction (see Figure 5 for complementary LV pattern).
The degree of impairment in left ventricular relaxation can
be quantified by calculating the time constant of isovolumic
relaxation (tau) from a high fidelity left ventricular pressure
tracing. Impairment in relaxation likely contributes to symptoms of dyspnea with exercise where brisk relaxation is needed
to enhance early diastolic filling without increased left atrial
pressures. Patients with significantly impaired relaxation are
dependent on left ventricular filling during atrial contraction
(atrial kick) to maintain filling without increased atrial pressure
and thus are prone to develop acute diastolic heart failure associated with the onset of atrial fibrillation. As the speed and
extent of left ventricular relaxation are very dependent on afterload, relaxation may become severely impaired with hypertensive episodes19 and contribute to elevation in mean left atrial
pressures, as is likely the case in patients with a normal ejection fraction (hypertensive pulmonary edema).20
Assessment of alterations in left ventricular compliance
depends on demonstration of an upward and leftward shift of
the end diastolic pressure volume relationship (LV-EDPVR) such
that the left atrial pressure required to fill the left ventricle to a
normal volume is markedly elevated. Marked reduction in left
Advances in Pulmonary Hypertension 15
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shown to correlate with worsventricular compliance is
ening prognosis, suggesting
clearly present in patients
that the elevated filling preswith rare diseases such as
sures reflected in the Doppler
infiltrative cardiomyopathy
measurements are the result
due to amyloidosis, in those
of progressive ventricular
with primary restrictive carremodeling and diastolic dysdiomyopathies, and in some
function rather than transient
patients with hypertrophic
volume overload. Unfortucardiomyopathy. In these
nately, this may not be the
patients, blood pressure is
case in every patient. Further,
low, left ventricular volumes
diastolic assessment is someare normal to reduced, and
what difficult to perform,
left atrial pressures are
requires informed interpretachronically elevated. Attion, and is limited by atrial
tempts to lower atrial presfibrillation, tachycardia, consures with diuretic therapy
duction defects, and atrial
often result in hypotension as
systolic dysfunction. Left atrileft ventricular filling is
al enlargement may also be a
dependent on markedly elegood indicator of chronic atrivated filling pressures.
al pressure overload and comWhether the more typical
plements the Doppler assesspatients with diastolic heart Figure 5. Doppler echocardiographic assessment of diastolic function.
ment. Unfortunately, no other
failure (who are often hyper- E, peak early filling velocity; A, velocity at atrial contraction; DT, decelenoninvasive assessment of
tensive) have reduced left ration time; Adur, A duration; ARdur, AR duration; S, systolic forward
ventricular compliance re- flow; D, diastolic forward flow; AR, pulmonary venous atrial reversal flow; diastolic function exists.
Although less frequently
mains somewhat controver- e’, velocity of mitral annulus early diastolic motion; a’, velocity of mitral
annulus motion with atrial systole; DT, mitral E velocity deceleration time.
performed in clinical pracsial.21 Demonstration of From Redfield et al.25
tice, similar Doppler interroreduced compliance mangation of the tricuspid inflow and hepatic vein inflow can be
dates the need for the instantaneous assessment of left venperformed to gain insight into right ventricular diastolic functricular pressure and volume over a range of pressures and voltion, as illustrated in Case 3.
umes produced by increasing or decreasing preload. Highly
Given the difficulty in accurately characterizing diastolic
accurate instantaneous assessment of left ventricular volume
function underscored above, few studies have assessed diasand pressure is very difficult to obtain. In humans, use of the
tolic function in patients with diastolic heart failure. Invasive
conductance catheter is really the only means of reliably obtainassessment of impaired ventricular relaxation and reduced vening such data; although some studies have used echocardiogtricular compliance has been demonstrated in a landmark study
raphy and left ventricular pressure tracings. Further, even once
of patients with heart failure and normal ejection fraction.17
armed with the data defining the LV-EDPVR, the curvilinear
nature of the relationship, which is rarely perfectly monoexpoAnother small but elegant invasive study did not demonstrate a
nential, makes it difficult to derive a single parameter that
significant alteration in either relaxation or compliance as comreflects the steepness and position of the relationship, and
pared to elderly hypertensive patients without heart failure
advanced analyses are needed.22
despite the presence of elevated left ventricular diastolic presComprehensive Doppler echocardiography can be very usesures in heart failure patients.19 However, in these patients
ful in gaining information regarding diastolic function and fillblood pressure and left ventricular diastolic pressure increased
ing pressures. Doppler patterns (Figure 5) consistent with
dramatically in association with marked impairment in relaximpaired relaxation with normal filling pressure (grade I diasation with exercise. In such patients, arterial stiffening, which
tolic dysfunction), impaired relaxation with moderate elevation
promotes labile hypertension and load-dependent diastolic dysof filling pressures (grade II diastolic dysfunction), impaired
function, may be an important mechanism contributing to diasrelaxation with severe elevation of filling pressures that can be
tolic heart failure even if resting diastolic function is not
reversed with preload-reducing maneuvers (grade III diastolic
markedly aberrant. Another study that did not characterize diasdysfunction), or impaired relaxation with severe elevation of filltolic function invasively but used Doppler assessment of left
ing pressures that can not be reversed with preload reducing
ventricular filling pressures and 3-D echocardiography to assess
maneuvers (grade IV diastolic dysfunction) have been described
volume suggested that volume expansion with normal systolic
and validated against invasive assessment of left ventricular
and diastolic function may produce the clinical syndrome in
relaxation and filling pressures.23-25 Equating these Doppler
some patients.21 It is quite likely that heart failure with normal
patterns with the severity of diastolic dysfunction makes severejection fraction is a heterogeneous condition with multiple
al assumptions and paramount among these is that the elevamechanisms contributing to chronic pulmonary venous hypertion of filling pressures detected by these parameters is meditension.18
ated by a reduction of left ventricular compliance. Supportive
of this assumption is the fact that this grading system has been
16 Advances in Pulmonary Hypertension
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Diastolic Dysfunction Causing
Pulmonary Hypertension
That left-sided heart failure is the most common cause of pulmonary hypertension has long been recognized.26 The passive
effect of pulmonary venous hypertension elevates pulmonary
artery pressure. However, patients also develop “reactive” pulmonary hypertension with increases in the transpulmonary gradient. This component of pulmonary hypertension may be related to humoral factors and endothelial dysfunction in chronic
heart failure associated with severe systolic dysfunction or
mitral stenosis.27 Finally, chronic pulmonary venous hypertension may lead to congestive pulmonary vasculopathy characterized by pulmonary arteriolar remodeling with medial hyperplasia and intimal fibrosis.28 Pulmonary hypertension related to
reactive pulmonary hypertension and/or congestive pulmonary
vasculopathy result in pulmonary hypertension beyond that
associated with the passive effects of pulmonary venous hypertension and may not be reversible with acute reduction in pulmonary venous pressures or acute pulmonary vasodilator infusion. Similarly, if medications have normalized resting PCWP or
if PCWP primarily becomes elevated with exertion or when
blood pressure fluctuates, it may be possible for patients with
diastolic heart failure to have elevated pulmonary arterial pressures but a normal PCWP at rest at catheterization and provocative measures may be needed to demonstrate the pulmonary
venous hypertension.
Although common in patients with left heart disease, the
development of pulmonary hypertension is highly variable. The
factors that predispose to development of significant pulmonary
hypertension in the presence of chronic pulmonary venous
hypertension are not fully understood. As noted above, the presence of humoral activation and endothelial dysfunction likely
play a role. Although early case reports described severe pulmonary hypertension in patients with diastolic heart failure, the
frequency with which patients with diastolic heart failure develop pulmonary hypertension and its severity remain poorly
defined.29,30 Klapholz et al described the presence of pulmonary hypertension in patients with diastolic heart failure in a
larger series of patients with diastolic heart failure and found
that the average right ventricular systolic pressure in patients
hospitalized with diastolic heart failure was 47 mmHg using
Doppler echocardiography.31 In patients with aortic stenosis,
most of whom had a normal ejection fraction, the severity of
diastolic dysfunction rather than the severity of aortic stenosis
correlated best with the severity of pulmonary hypertension and
a significant number of patients developed severe pulmonary
hypertension.32 Similarly, in patients with heart failure and a
reduced ejection fraction (systolic heart failure), it was the
severity of concomitant diastolic dysfunction rather than ejection fraction or cardiac output that correlated best with the
severity of pulmonary hypertension.33 Thus, diastolic dysfunction associated with valvular disease, reduced ejection fraction,
or in isolation is the common mediator that results in chronic
pulmonary venous hypertension and secondary pulmonary
hypertension. It is therefore not unexpected that patients with
diastolic heart failure will develop pulmonary hypertension.
It seems reasonable to expect that elderly persons would be
more susceptible to the development of pulmonary hypertension as age related systemic vascular stiffening has been con-
sistently reported34-37 and age-related pulmonary artery stiffening may well occur. Interestingly, age-related increases in
arterial stiffening are worse in women than in men.34,37-40 Thus,
the elderly women patients who develop diastolic heart failure
may also be more prone to developing pulmonary hypertension
in response to chronic pulmonary venous hypertension associated with diastolic heart failure. Alternatively, some patients
may have a primary pulmonary arteriopathy of late onset and
have concomitant (but unrelated) diastolic dysfunction related
to their age.
Atrial compliance is a little studied factor that may contribute to the pathophysiology of diastolic heart failure and predispose to pulmonary hypertension as well. Insight into the role
of atrial compliance comes from early hemodynamic studies
where large left atrial V waves were described in patients with
various cardiac diseases in the absence of mitral regurgitation.8,9 The large V wave represents large increases in left atrial pressure in response to the atrial filling that occurs during
ventricular systole (closed mitral valve), and thus reflects
reduced atrial compliance. Although much focus is placed on
left ventricular diastolic pressures in mediating chronic pulmonary venous hypertension, it is mean left atrial pressure that
reflects the degree of pulmonary vascular congestion41 and high
left atrial pressure during ventricular systole contributes to elevated mean left atrial pressure. Indeed, in patients with mitral
stenosis, two recent studies demonstrate that in the absence of
mitral regurgitation, the presence of reduced atrial compliance
as reflected by large atrial V waves was a potent independent
predictor of the severity of pulmonary hypertension in mitral
stenosis.42,43
Left Ventricular Diastolic Dysfunction in
Chronic Right Ventricular Pressure Overload
Chronic right ventricular pressure overload can affect left ventricular diastolic function in several ways. Changes in left ventricular relaxation as well as in compliance (characterized by
the LV-EDPVR) have been described.
Left ventricular relaxation is under the triple control of load,
myocardial properties, and the uniformity of load in space and
time.44 In chronic right ventricular pressure overload, the load
on the intraventricular septum is dramatically increased and as
it hypertrophies, the myocardial properties of the septum are
altered. The motion of the intraventricular septum in systole
and diastole is asynchronous. All these factors could contribute
to impairment in global left ventricular relaxation. In Doppler
echocardiographic studies of IPAH, impaired relaxation with
decreased E/A ratio and increased isovolumic relaxation time
and deceleration time have been consistently reported.45-50 An
“impaired relaxation” pattern (grade I diastolic dysfunction) is
usually associated with normal left ventricular filling pressures
and indeed, patients with severe IPAH entered into clinical trials must have normal PCWP. Thus, based on Doppler echocardiographic studies, the effect of chronic right ventricular pressure overload on relaxation appears unassociated with increases in left ventricular filling pressure.
While patients must have normal PCWP to be diagnosed
with IPAH, there is considerable evidence that chronic right
ventricular pressure overload can cause reduced left ventricular
compliance. The external forces affecting the LV-EDPVR
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include right ventricular pressure and pericardial pressure.51,52
The effect of right ventricular pressures on the LV-EDPVR is
termed “ventricular interdependence” and is accentuated in
the presence of an intact pericardium. Visner et al. used both
acute and chronic canine pulmonary banding models and
showed that the LV-EDPVR was shifted leftward (decreased
compliance) by acute or chronic right ventricular pressure overload.53,54 The shift in the LV-EDPVR with acute right ventricular pressure overload was related to ventricular interdependence
with decreases in left ventricular volume related to leftward
shift of the intraventricular septum as right ventricular pressures increased. These effects were also apparent in chronic
right ventricular pressure overload, but a decrease in myocardial compliance (as assessed by the stress-strain relationship)
was also seen. This effect, not seen in acute right ventricular
pressure overload, suggests that chronic right ventricular pressure overload alters intrinsic left ventricular myocardial properties. Whether this effect is wholly mediated by the altered intraventricular system or whether the left ventricular free wall
myocardium also becomes abnormal is unclear. However, Little
et al showed that the effect of right ventricular pressures on the
LV-EDPVR was attenuated in the presence of chronic right ventricular pressure overload produced by pulmonary artery banding in the dog.52 Consistent with concepts introduced by
Sunagawa et al, Little’s study showed that when the stiffness of
the septum was greater than the stiffness of the left ventricular
free wall, right ventricular pressures had less effect on the LVEDPVR. Although this study was performed in the absence of
the pericardium, Blanchard et al showed that the pericardium
remodels in chronic right ventricular pressure overload and that
pericardiotomy did not alter right or left ventricular filling pressures or cardiac output.55
Although these animal studies and limited studies in the
human56,57 confirm adverse effects of right ventricular pressure
overload on left ventricular diastolic function, the clinical significance of left ventricular diastolic dysfunction associated
with chronic right ventricular pressure overload is difficult to
appreciate. In the studies of Little and Visner, dogs with acute
and chronic right ventricular pressure overload had left ventricular diastolic pressures that were not different from those of
control dogs. Although the compliance of the left ventricle was
reduced, it was not reduced enough to result in elevated left
ventricular filling pressures. Similarly, in humans with chronic
pulmonary hypertension related to thromboembolic disease,
indices of left ventricular diastolic compliance were reduced
and improved after thrombectomy, but PCWP was normal both
before and after surgery.57 Lastly, patients entered into IPAH
trials have severe pulmonary hypertension, often with severe
right ventricular remodeling and dysfunction and yet have normal PCWP. These studies would suggest that while left ventricular diastolic function is altered in IPAH, it is not perturbed
enough to result in elevated PCWP. However, as most studies
describing hemodynamics in IPAH were performed in the context of a drug trial (where patients with elevated PCWP are
excluded), the frequency of left ventricular diastolic dysfunction severe enough to result in elevated filling pressures in
patients with IPAH may be underrecognized.
18 Advances in Pulmonary Hypertension
Strategies for Diagnosing Diastolic Heart Failure
in the Setting of Pulmonary Hypertension
It is likely that diastolic heart failure is an underrecognized
cause of pulmonary hypertension and that otherwise unexplained dyspnea and pulmonary hypertension in elderly patients
with a normal ejection fraction and normal valves should
prompt consideration of diastolic heart failure as well as IPAH.
Yet, distinguishing between diastolic heart failure with secondary pulmonary hypertension and IPAH with secondary diastolic
dysfunction can be quite challenging.
Echocardiography may be helpful and evidence of left ventricular hypertrophy, left atrial enlargement, and Doppler evidence of advanced diastolic dysfunction (grades II–IV) may
favor the diagnosis of diastolic heart failure. However, not all
patients with diastolic heart failure have echocardiographic evidence of left ventricular hypertrophy and not all echocardiographic laboratories perform a comprehensive diastolic assessment nor measure left atrial volume.
All patients with significant pulmonary hypertension should
undergo right heart catheterization and if the PCWP is elevated
(ⱖ15 mmHg), a diagnosis of isolated pulmonary arteriopathy
cannot be made even if there is a significant transpulmonary
gradient.58 In patients with an elevated PCWP, one should look
for evidence of systemic hypertension and if present, use of a
systemic vasodilator to lower arterial pressures should be considered. Prompt reduction in PCWP with normalization of blood
pressure supports the diagnosis of diastolic heart failure.
Provocative testing with exercise in elderly patients with pulmonary hypertension in whom diastolic heart failure is suspected may be useful. Marked elevation in PCWP and blood pressure with exercise would support the diagnosis of diastolic heart
failure that could be causing the patients’ symptoms and their
pulmonary hypertension. Patients with severe IPAH should not
experience increases in PCWP during exercise59. Additionally,
one should look for evidence of reduced atrial compliance (large
V waves in the PCWP tracing). Exercise testing may also be
helpful and if associated with marked increases in PCWP, a
diagnosis of diastolic heart failure would be supported.59
Finally, if diastolic heart failure is strongly suspected, care
should be taken with use of vasodilators that are very selective
for the pulmonary vasculature (such as inhaled nitric oxide) as
increases in right heart output in the presence of a noncompliant left ventricle may result in further increases in left atrial
pressure and pulmonary edema, as outlined above.10-13
Therapeutic Implications
To date, patients with pulmonary hypertension and a PCWP of
15 mmHg or greater have been excluded from pulmonary arterial hypertension drug trials. It remains unclear how often
patients with suspected pulmonary arterial hypertension and an
elevated PCWP are treated with new therapies and whether they
experience benefit. Similarly, whether patients with diastolic
heart failure and pulmonary hypertension would benefit from
specific treatment of the pulmonary hypertension is unclear.
Although use of epoprostenol was associated with increased
mortality in patients with systolic heart failure,60 the mechanism responsible for the increased mortality is unclear and the
outcome in diastolic heart failure, or with alternate agents, may
be different and deserves consideration.
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Back to the Patients
Case 1. This patient demonstrates the progressive development
of pulmonary hypertension on a background of longstanding
and fairly well documented diastolic heart failure. We would
speculate that she has secondary pulmonary hypertension and
not IPAH of late onset. While her pulmonary hypertension may
be characterized by some as “out of proportion to her left heart
disease,” without knowledge of severity of her chronic pulmonary venous hypertension, one can not conclude that is the
case. Certainly, chronic pulmonary venous hypertension related
to mitral stenosis (the ultimate diastolic dysfunction) can result
in severe pulmonary hypertension that is accompanied by
increased transpulmonary gradient and that can take months to
years to resolve after treatment of mitral stenosis.
Treatment for diastolic heart failure is supportive as no therapy has been documented to improve outcomes in this condition. Thus, consideration of specific therapy for pulmonary
hypertension in such patients is not unreasonable. As the use of
agents for IPAH have been expanded to patients with pulmonary
hypertension related to connective tissue disease, expansion to
use in patients with diastolic heart failure and secondary pulmonary hypertension would be a reasonable avenue for investigation. However, the potential for worsening pulmonary congestion must be recognized, as was observed in this patient.
Case 2. This patient demonstrates a milder form of pulmonary hypertension secondary to diastolic heart failure. In this
case, the pulmonary hypertension is largely related to the passive effect of the pulmonary venous hypertension and is acutely reversible. The diagnosis of diastolic heart failure with secondary pulmonary hypertension is much easier to make in this
instance.
Case 3. This patient has IPAH and has diastolic dysfunction
but does not have elevated PCWP. The impairment in left ventricular relaxation mediated by the abnormal septum and septal motion causes characteristic changes in the left ventricular
diastolic parameters that are generally associated with normal
filling pressures at rest. Although decreases in left ventricular
compliance related to ventricular interdependence have been
described in animal models, and could lead to elevated left ventricular filling pressures, elevated left ventricular filling pressures are not commonly seen in patients with IPAH. However,
as formal assessment of left ventricular compliance with pressure volume analysis over a range of preloads was not performed in this patient, we can not exclude the presence of
decreased compliance with normal PCWP related to decreased
filling as a result of her severe pulmonary hypertension and
right ventricular dysfunction. In contrast, she has severe right
ventricular systolic and diastolic dysfunction with elevated right
ventricular diastolic pressure. ■
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Lakatta LE, Yin FCP, Lakatta EG. Effects of age and aerobic capacity
on arterial stiffness in healthy adults. Circulation. 1993;88:1456-62.
36. Kelly R, Hayward C, Avolio A, O’Rourke M. Noninvasive determination of age-related changes in the human arterial pulse. Circulation.
1989;80:1652-9.
37. Redfield MM, Jacobsen SJ, Bourlaug BA, Rodeheffer RJ, Kass DA.
Age- and gender-related ventricular-vascular stiffening: a community
based study. Circulation. 2005;112(15):2254-62.
38. Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME.
Comparative effects of aging in men and women on the properties of
the arterial tree. J Am Coll Cardiol. 2001;37:1374-80.
39. Hayward CS, Kelly RP. Gender-related differences in the central
arterial pressure waveform. J Am Coll Cardiol. 1997;30:1863-71.
40. Gatzka CD, Kingwell BA, Cameron JD, Berry KL, Liang YL, Dewar
EM, Reid CM, Jennings GL, Dart AM. Gender differences in the timing
of arterial wave reflection beyond differences in body height. J
Hypertens. 2001;19:2197-203.
41. Braunwald E, Frahm CJ. Studies on Starlin’s law of the heart (IV.
Observations on the hemodynamic functions of the left atrium in man).
Circulation. 1961;24:633-642.
42. Schwammenthal E, Vered Z, Agranat O, Kaplinsky E, Rabinowitz
B, Feinberg MS. Impact of atrioventricular compliance on pulmonary
artery pressure in mitral stenosis: an exercise echocardiographic study.
Circulation. 2000;102:2378-84.
43. Ha JW, Chung N, Jang Y, Kang WC, Kang SM, Rim SJ, Shim WH,
20 Advances in Pulmonary Hypertension
Cho SY, Kim SS. Is the left atrial v. wave the determinant of peak pulmonary artery pressure in patients with pure mitral stenosis? Am J
Cardiol. 2000;85:986-91.
44. Brutsaert DL, Rademakers FE, Sys SU. Triple control of relaxation:
implications in cardiac disease. Circulation. 1984;69:190-196.
45. Louie EK, Rich S, Brundage BH. Doppler echocardiographic
assessment of impaired left ventricular filling in patients with right ventricular pressure overload due to primary pulmonary hypertension. J Am
Coll Cardiol. 1986;8:1298-306.
46. Tutar E, Kaya A, Gulec S, Ertas F, Erol C, Ozdemir O, Oral D.
Echocardiographic evaluation of left ventricular diastolic function in
chronic cor pulmonale. Am J Cardiol. 1999;83:1414-7, A9.
47. Xie GY, Lin CS, Preston HM, Taylor CG, Kearney K, Sapin PM,
Smith MD. Assessment of left ventricular diastolic function after single
lung transplantation in patients with severe pulmonary hypertension.
Chest. 1998;114:477-81.
48. Galie N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido
T, Espinola-Zavaleta N, Rocchi G, Manes A, Frantz R, Kurzyna M,
Nagueh SF, Barst R, Channick R, Dujardin K, Kronenberg A, Leconte
I, Rainisio M, Rubin L. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients
with pulmonary arterial hypertension. J Am Coll Cardiol.
2003;41:1380-6.
49. Stojnic BB, Brecker SJ, Xiao HB, Helmy SM, Mbaissouroum M,
Gibson DG. Left ventricular filling characteristics in pulmonary hypertension: a new mode of ventricular interaction. Br Heart J.
1992;68:16-20.
50. Moustapha A, Kaushik V, Diaz S, Kang SH, Barasch E.
Echocardiographic evaluation of left-ventricular diastolic function in
patients with chronic pulmonary hypertension. Cardiology.
2001;95:96-100.
51. Dauterman K, Pak PH, Maughan WL, Mussbacher M, Arie S, Liu
C-P, Kass DA. Contribution of external forces to left ventricular diastolic
pressure. Ann Intern Med. 1995;122:737-742.
52. Little WC, Badke FR, O’Rourke RA. Effect of right ventricular pressure on the end-diastolic left ventricular pressure-volume relationship
before and after chronic right ventricular pressure overload in dogs
without pericardia. Circ Res. 1984;54:719-30.
53. Visner MC, Arentzen CE, O’Connor MJ, Larson EV, Anderson RW.
Alterations in left ventricular three-dimensional dynamic geometry and
systolic function during acute right ventricular hypertension in the conscious dog. Circulation. 1983;67:353-65.
54. Visner MS, Arentzen CE, Crumbley AJ 3rd, Larson EV, O’Connor
MJ, Anderson RW. The effects of pressure-induced right ventricular
hypertrophy on left ventricular diastolic properties and dynamic geometry in the conscious dog. Circulation. 1986;74:410-9.
55. Blanchard DG, Dittrich HC. Pericardial adaptation in severe chronic pulmonary hypertension. An intraoperative transesophageal echocardiographic study. Circulation. 1992;85:1414-22.
56. Krayenbuehl HP, Turina J, Hess O. Left ventricular function in
chronic pulmonary hypertension. Am J Cardiol. 1978;41:1150-8.
57. Dittrich HC, Chow LC, Nicod PH. Early improvement in left ventricular diastolic function after relief of chronic right ventricular pressure overload. Circulation. 1989;80:823-30.
58. McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA,
Loyd JE. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
Chest. 2004;126:14S-34S.
59. Nootens M, Wolfkiel CJ, Chomka EV, Rich S. Understanding right
and left ventricular systolic function and interactions at rest and with
exercise in primary pulmonary hypertension. Am J Cardiol.
1995;75:374-7.
60. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF,
McNulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E,
Harrell FE Jr, Wheeler W, Soler-Soler J, Swedberg K. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure:
The Flolan International Randomized Survival Trial (FIRST). Am Heart
J. 1997;134:44-54.
Pulmonary Hypertension Out of Proportion
to Left Heart Disease
José A. Tallaj, MD
Department of Medicine
Birmingham VA Medical Center
Division of Cardiology
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Raymond L. Benza, MD
Division of Cardiology
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Raymond L. Benza, MD
Classically, the term pulmonary hypertension (PH) refers to
a resting mean pulmonary pressure greater than 25 mmHg.
There are many different etiologies of PH, but by and large,
the most common cause is pulmonary venous hypertension
(PVH). This particular form of PH occurs in the setting of
elevated left sided filling pressure. The main causes of PVH
are listed in Table 1. Typically, in this form of PH, the degree
of elevation in pulmonary artery pressure is concordant with
the degree of elevation in left atrial pressure. Identification
of this form of PH is important because treatment with
selective pulmonary vasodilators typically reserved for use in
pulmonary arterial hypertension (PAH) may be potentially
harmful. However, some patients have a severely elevated
PA pressure with only modestly elevated left-sided filling
pressure. This class of patient often causes much confusion
for treating physicians because of the uncertainty of whether
or not these patients would benefit or be harmed by PAHselective therapy. It is the aim of this paper to provide an
insightful and helpful review of PH related to left heart disease, with specific emphasis on the patient with pulmonary
hypertension “out-of-proportion” to the degree of elevation
in left-sided pressure.
The differentiation of PAH from PVH can be quite difficult. Some conditions predisposing to this form of PH are
quite obvious, such as mitral valve disease or left ventricular (LV) systolic dysfunction. However, other causes like diastolic dysfunction or early restrictive cardiomyopathy are
more difficult to diagnose noninvasively. PAH requires a high
index of suspicion and the appropriate diagnostic tests.
Physical examination can be nonspecific and even normal in
some of these patients. Echocardiography can be misleading, as only the right ventricular systolic pressure is routinely estimated. More importantly, echocardiography can not
measure left-sided filling pressure, but only comment on
abnormal left ventricle filling patterns, which can be
markedly abnormal even in the face of normal filling pressure in advanced PH.1 It is for these reasons, that it is
imperative for patients suspected to have pulmonary hypertension to undergo invasive measurement of the PA and
wedge pressures.
The results obtained from right heart catheterization
alone is usually enough to confirm the diagnosis of PAH.
José A. Tallaj, MD
Table 1. Main Causes of Pulmonary
Venous Hypertension.
Heart failure
• Systolic dysfunction
• Diastolic dysfunction, including restrictive cardiomyopathy
Mitral valve disease
• Mitral stenosis
• Mitral regurgitation
Aortic valve disease
• Aortic stenosis
• Aortic regurgitation
Cor triatriatum
Occasionally, however, it is quite difficult to obtain accurate
pulmonary capillary wedge pressure (PCWP) in patients with
severe PH, due to the significant dilatation of the proximal
pulmonary arteries, rapid pruning of distal branches, tricuspid insufficiency and dilatation of the right heart chambers.
Figure 1 shows how the PCWP was erroneously measured
twice (panel A and B) before a correct PCWP (panel C) was
obtained in a patient with PAH. If there are any doubts
regarding the accuracy of the pressure obtained, then a correct positioning could be verify by measuring the oxygen saturation in blood obtained in the “wedge position.” However,
even this method could be inaccurate in cases of “overwedging”, like example A of Figure 1. If the right heart
catheterization is nondiagnostic, then a left heart catheterization should be done to accurately measure the left ventricular end-diastolic pressure (LVEDP). We strongly believe
that an accurate LVEDP can only be measured with a multihole pigtail catheter placed in the body of the left ventricle,
as a single end-hole catheter only measures the pressure in
one direction and not the sum of all intraventricular pressures.
Significance of Pulmonary Hypertension
in Patients With Left-heart Disease
The presence of significant PH in patients with left heart disease is associated with a poor prognosis in light of its effects on
Advances in Pulmonary Hypertension 21
B
A
Figure 1. Correct wedge measurement in a
patient with PH. Panel A shows the classic
“overwedging”. Panel B shows incomplete
wedge pressure, with a resultant “elevated”
wedge. Panel C shows the correct wedge
pressure.
C
the right ventricular (RV) function. Irregardless of the etiology
of left heart disease, a reduced LVEF is a powerful predictor of
death in patients with heart failure; however, its prognostic
value loses strength when applied to patients with advanced
heart failure.1 A number of studies have provided evidence that
the RVEF, either directly measured (by radionuclide angiography or rapid response thermodilution) or indirectly estimated
(by echocardiography), is an independent prognostic factor in
patients with moderate to severe heart failure.2-6 Pulmonary
hypertension frequently complicates heart failure and is generally considered “per se” an indicator of poor prognosis.7, 8
The RV is a low pressure, high volume pump, allowing
blood to flow into a highly compliant pulmonary circulation.
The RV is able to accommodate large changes in volume
with minimal pressure changes. As the pulmonary pressure
rises, the RV dilates and its hemodynamics, contraction and
pressure-volume loops are similar to that of the LV. This
depends heavily on interventricular interactions which
allows the RV to expand and accommodate the additional
preload. As the RV loses the capacity to overcome the high
vascular resistance, it becomes more dependant on afterload, and the cardiac output declines precipitously. It is this
impaired RV function that portends a poor prognosis in
patients with PH of any etiology.
Heart Failure
Elevated PA pressure and abnormal RV function are important determinants of both prognosis and exercise capacity in
patients with LV dysfunction. Several studies have shown
that exercise capacity, as measured by peak VO2, is more
closely associated with RV ejection fraction (EF) than with
LVEF.2, 3 Moreover, the presence of PH in patients with LV
dysfunction further impairs exercise performance in patients
22 Advances in Pulmonary Hypertension
with heart failure (HF), as the increased PVR results in further reduction of the cardiac output.4 In addition, RV dysfunction is also an independent predictor of survival, in
patients with LV failure3 especially when PH is present.5
Ghio points out in his study that patients with a combined
high PAP on right heart catheterization and a low RVEF have
the worst prognosis and survival among patients with
advanced left sided heart failure. In fact these patients have
a seven times higher risk of death than those patients with
a normal PAP and preserved RVEF, a 4.3 times higher risk
than patients with a high PAP/preserved RVEF and 3.3 times
higher risk than that of the patients in the normal PAP/low
RVEF5. Historically, heart transplantation has been contraindicated in patients with fixed PH due to the very high
rate of perioperative mortality.6 In addition, in a small percentage of patients undergoing placement of a LV assist
device, the RV fails acutely, due to the elevated PA pressure
and pulmonary vascular resistance (PVR), requiring the concomitant placement of a RV assist device.9,10 As the surgical techniques and aggressive medical management
improves, it may be possible to reverse what has been called
“fixed” pulmonary hypertension, allowing these patients to
be eligible for transplantation11, 12.
Pulmonary venous hypertension can occur in the setting
of LV diastolic dysfunction, or diastolic heart failure.13,14
However, the incidence of significant of PH in the setting of
diastolic dysfunction has not been well characterized or
studied. As clinicians, we often struggle to differentiate
those patients with true PAH from those who may have some
form of diastolic dysfunction with reactive pulmonary hypertension. It has been postulated that in some patients, the
pulmonary vasculature undergoes reactive changes due to
the chronic elevation of the left ventricular filling pressure,
resulting in severe pulmonary hypertension. As the pulmonary vascular disease progresses the cardiac output is
reduced due to RV dysfunction, decreasing the venous
return to the left heart and, eventually, normalizing the LV
filling pressure. At the time of presentation and evaluation,
these patients may have normal or only mildly elevated left
heart filling pressure with significantly elevated pulmonary
pressure, being misdiagnosed as PAH.
Mitral Valve Diseases
Mitral stenosis (MS) is an important cause of pulmonary
hypertension. In this particular condition, the elevated leftsided filling pressure is at the atrial level, with normal
LVEDP. The elevated pulmonary pressure and PVR results in
increased RV end-diastolic volume and pressure, as well as
secondary tricuspid regurgitation, which may lead to right
heart failure and systemic venous congestion. The presence
of PH, either at rest or with exercise is an indication for percutaneous or open commisurotomy or replacement of the
stenotic mitral valve.7
Pulmonary hypertension can also occur in patients with
mitral regurgitation (MR). It is not only related to the LV dysfunction that complicates advanced stages of mitral regurgitation, but it is also seen in patients with chronic, isolated
mitral regurgitation with normal LV function.8 The presence
of PH in patients with MR is associated with substantial
decreases in cardiac output and possibly a poor outcome. As
in patients with MS, the presence of PH in patients with MR,
either at rest or with exercise, is an indication for mitral
valve surgery.8
Aortic Valve Diseases
The incidence of PH in the setting of aortic valve stenosis
and/or regurgitation is not as common as with mitral valve
diseases. It has been described in up to 4-29% of patients
with significant aortic stenosis,15,16 mainly as a result of elevated LVEDP and marked diastolic dysfunction. The perioperative mortality rate of patients with severe aortic stenosis
and PH may be as high as 40%.12 However, without therapy, the prognosis is even worse, with almost all patients
dying after 1.5 years.
The incidence of PH in patients with isolated aortic valve
regurgitation is rare, occurring mainly when the LVEDP is
already elevated, as a result of the chronic volume overload17 and it may portend a poor prognosis, even though the
data available is rather small and largely anecdotal.18
What Is Pulmonary Hypertension
Out of Proportion to Elevated Left-sided Pressure?
The primary goal in the initial evaluation of patients with PH
is to differentiate PAH from other causes, especially PVH. By
definition, patients with PAH should have a low or normal
left-sided filling pressure, as measured by the PCWP or
LVEDP. A left-sided filling pressure of <15 mmHg has been
accepted as the criteria for patients with pulmonary arterial
hypertension.19 As clinicians, we struggle every day with
patients who have severely elevated pulmonary pressure with
only modest elevation of the left-sided filling pressure.
Several different measurements have been used clinically in
an attempt to differentiate those patients with some component of pulmonary arterial hypertension in addition to their
left sided disease and PVH. Most of the studies are derived
from the heart transplant literature, especially the use of the
transpulmonary gradient (TPG).
The TPG is calculated as the difference between the mean
PA pressure and PCWP measured in mmHg. It is assumed that
a TPG of ⱕ15 mmHg is acceptable for transplantation, as the
elevated PA pressure is in direct proportion with the elevated
left-sided filling pressure. An elevated TPG is associated with a
very high incidence of post-operative right ventricular failure
and death.20 Many studies have shown that a high PVR is also
a risk factor for graft failure due to right heart failure early after
cardiac transplantation.9,21 However, the PVR, by using the cardiac output in its equation may be unreliable because of inherent inaccuracies in the measurement of cardiac output by thermodilution, particularly at low cardiac outputs. The TPG, it is
argued, is flow-independent and thus may better reflect resistance to flow across the pulmonary bed. In patients being considered for heart transplantation, the acute reactivity of the pulmonary bed is tested in the catheterization laboratory with
nitroprusside or nitroglycerin or chronically with aggressive
medical management, including the used of inotropic agents
and diuretics.22,23
Using the TPG and PVR to define a patient with PH outof-proportion to the left-sided filling pressure works best in
patients with only moderately elevated PA pressure. Most of
the patients with PVH seen in clinical practice fall into this
group. However, there is subgroup of patients (probable 1020% by our observation) with enough reactive pulmonary
vasoconstriction that develop severe PH with only modest
increases in the left-sided filling pressure. Interestingly,
even in this subgroup, the PA pressure normalizes with normalization of the elevated left-sided filling pressure. It has
been shown in multiple studies that in patients with mitral
stenosis, for example, when the PCWP is between 20-25
mmHg, the TPG is in excess of 15-20 mmHg, decompression of the left atrium, either surgically or percutaneously,
with a concomitant rapid decrease in the LA and PCWP
results in a marked decrease in PA pressure, lower TPG and
eventually leads to normalization of the pulmonary pressure.24,25 We have observed similar results in our practice,
especially in patients being considered for heart transplantation, after the administration of long-acting nitrates.
Interestingly, in some patients with mitral stenosis, the
improvement in the pulmonary hemodynamics does not
occur immediately, and further therapy is required, at least
acutely.26 In our institution, we considered PH out-of-proportion to left heart disease when the PA pressure is severely elevated (mean PA ⱖ35-40 mmHg) with only modest elevation in the left heart disease (PCWP or LVEDP ⱕ22
mmHg) and a TPG ⱖ18-20 mmHg. It is still unknown why
some patients develop severe and/or fixed PH with the same
degree of elevated left-sided filling pressure. Hopefully, further studies in the future will be able to answer this question, as it is likely that genetic predisposition may play an
important role.
Advances in Pulmonary Hypertension 23
Roadmap
To A
Cure
The Pulmonary Hypertension Association’s
SEVENTH INTERNATIONAL
PULMONARY HYPERTENSION CONFERENCE
AND SCIENTIFIC SESSIONS
June 23 to 25, 2006 • Hilton Minneapolis Hotel • Minneapolis, Minnesota
PHA’s biennial Scientific Sessions and International Conference is unique
in serving the pulmonary hypertension patient and medical communities. Over
900 attended in 2004.
Medical Professionals and Researchers,
Begin with the Scientific Sessions: June 23
A full day devoted to presentations from nationally and internationally renowned
PH experts, accompanied by poster sessions with
presentations of abstracts.
Presentations include:
• MR Imaging in Pulmonary Arterial Hypertension
Valentin Fuster, M.D., Ph.D., Zena and Michael A. Wiener
Cardiovascular Institute, Marie-Josée and Henry R. Kravis
Center for Cardiovascular Health, Mount Sinai Medical Center
• Current Experiences with Stress Echocardiography in
Pulmonary Arterial Hypertension
Ekkehard Grünig, M.D., University of Heidelberg
• Information Needed for Approval of PAH Drugs
Salma Lemtouni, Food and Drug Administration
• Genetics of Pulmonary Arterial Hypertension
John Newman, M.D., Vanderbilt Medical School
• Inflammation in Systemic Vascular Disease: What can we learn?
Paul M. Ridker, M.D., M.P.H., F.A.C.C., Harvard Medical School,
Brigham & Women’s Hospital
• Inflammation in Pulmonary Arterial Hypertension
Olivier Sitbon, M.D., Center for Pulmonary and Vascular Diseases,
Antoine Beclere Hospital
“Up to 8.0 hours of CME and nursing CEU credits are in the
process of being approved. Go to www.phassociation.org/conference
for more information.”
Attendees of the 2004 Conference have said…
e
“The PHA conferences have been uniqu
since their inception. The exceptional
blend of patients, clinicians and
researchers all working towards a cure
gives the meetings such a marvelous
tone. They are the most emotionally
stirring and satisfying meetings I have
ever attended.”
David Langleben, MD
Jewish General Hospital
Montreal, Quebec
Canada
rather
ences have been
“The PHA confer
abled
en
ve
ha
that that they
in
e
m
r
fo
ue
iq
un
have
th patients who
direct contact wi
m
fro
ed
fit
ne
be
undergone and
pressive
s indeed been im
m
treat ent. It ha
nces in
va
ad
markable
to witness the re
at until
th
e
as
se
t of a di
the managemen
read
tegorized as a “d
recently was ca
with
e
bl
now managea
disease” but is
life
of
ity
al
for the qu
bright prospects
.”
ity
and longev
an, MD
Alfred P. Fishm
th System
nnsylvania Heal
University of Pe
PA
a,
Philadelphi
“Two year
alone a
experience
to come
place th
intellectu
I found it
deeper un
opportunity
truly unders
want my da
kids with P
a chance
differen
For more information and registration, visit: www.phassociation.org/Conference or call 301-565-3004.
Ch
P
Patients, Caregivers and Medical Professionals,
Experience the International Conference:
June 23 – 25
Medically-led and patient-led sessions for the pulmonary hypertension
community of patients, family members, caregivers and medical professionals. Featuring over 50 medical and patient sessions (including several
sessions in Spanish), an exhibits area, a variety of patient and caregiver
support groups, special sessions for international attendees and more…
Don’t forget to encourage your patients and their families to attend.
d…
Over 50 presentations that include:
• The Latest in PH Therapies for Children (including
secondary PH)
• Associated Conditions: Liver Disease, Sleep Disorders, ILD,
COPD, Thyroid Disease,
• Emergency Situations
• Scleroderma, Connective Tissue Diseases & PH: the problems
and how to diagnose them
• Investigational Agents (Ambrisentan, Cialis, Statins, Pulmolar)
• Anti-coagulation, Drug-Drug Interactions, New studies
• Surgical and Interventional Options and Future Trends in the
Treatment of Pulmonary Hypertension
• Thromboembolic Disease: Diagnosis and Treatment
• Epoprostenol/Flolan: New Concepts in Dosing, Prevention &
Management of Catheter-Related Infections
• Prostanoids (Flolan, Remodulin, Iloprost)
• PDE-5 Inhibitors (Viagra) and the Nitric Oxide Pathway
• Changing to Different PH Medications: Important Things for
Patients to Know Before, During and After The Switch
• An Overview of Medical Therapies for PAH (Spanish)
• Understanding Pulmonary Hypertension: The Basics
• Lung Transplantation (UNOS) and Other Surgical Treatments
• Familial/Genetic PAH (Including Screening)
• Pregnancy and PH
• Working and Disability/Insurance Issues, New Medicare Program,
Living Wills, Power of Attorney
• And much more!
o years ago I attende
d Conference
one and it was such
a wonderful
rience that I want the
whole family
come this time. Confe
rence is a
ace that provides you
with both
llectual and emotional
renewal.
nd it to provide me wit
h hope, a
er understanding of PH
, and the
rtunity to meet other
people who
nderstand your strug
gles. I really
my daughter, Katy, to
meet other
with PH and on Flolan
, giving her
hance to feel less iso
lated and
ferent. We are really
looking
forward to it!”
4.
Christina Doak, UT
Parent Caregiver
Four easy ways to register
for Conference
For credit cards:
(1) www.phassociation.org/conference
(2) Call 301.565.3004
(3) Fax 301.565.3994
(4) Mail checks with registration to:
PHA
801 Roeder Road., Ste 400;
Silver Spring, MD 20910
Meet some of the brightest
minds in the field of PH!
These are just some of the
medical professionals scheduled
to present at Conference:
Serge Adnot, MD
Chris Archer-Chicko, RN
Stephen Archer, MD
Dave Badesch, MD
Robyn Barst, MD
Bob Bourge, MD, FACC
Daniela Brady, RN
Todd Bull, MD
Michelle Calderbank
Maureen Cavanagh, RN
Murali Chakinala, MD
Rich Channick, MD
Lori Claussen
Monica Colvin-Adams, MD
Paul Corris, MD
Natalie Doughty, RN
Ramona Doyle, MD
Louise Durst, RN
Raed Dweik, MD
Greg Elliott, MD
Karen Fagan, MD
Ray Foley, DO
Bob Frantz, MD
Adaani Frost, MD
Ann Gihl, RN, BSN
Reda Girgis, MD
Mardi Gomberg, MD
Rhonda Groebner, RN, MSN, ANP
Brian Hanna
Stephanie Harris, RN, BSN
Nick Hill, MD
Wendy Hill, NP
Monica Horn, RN, CCTC
Traci Housten-Harris, RN, MS
Steve Kawut, MD
Natalie Kitterman, RN, BSN
Mike Krowka, MD
Dave Langleben, MD
Lian Latham, RN
Juliana Liu, RN
Jim Loyd, MD
Thomas Mahrer, MD
Michael Mathier, MD
Deb McCollister, RN, BSN
Mike McGoon, MD
Val McLaughlin, MD
Sanjay Mehta, MD
Peggy Menzel, RD, LD
Omar Minai, MBBS
Jane Morse, MD
Kamal Mubarak, MD
Srinivas Murali, MD
John Newman, MD
Ronald Oudiz, MD
Michelle Ouellette, RN
Harold Palevsky, MD
Myung Park, MD
Janet Pinson, NP
Ioana Preston
Tomas Pulido, MD
David Ralph, MD
Janette Reyes, RN
Julio Sandoval, MD
Bob Schilz, MD
Arlene Schiro, NP
Marilyn Schmidt, RN
Cathy Severson, RN, BSN
Shelley Shapiro, MD, PhD
Roxana Sulica, MD
Thor Sundt, MD
Jacqueline Szmuszkovicz, MD
Vic Tapson, MD
Cynthia Toher, MD
Sue Tointon, RN
Fernando Torres, MD
Richard Trembath, MD
Lisa Wheeler, MT
Table 2. Major Trials With Pulmonary Vasodilators in Patients With Heart Failure
Study Ref
Agent
Condition
N patients
randomized
Clinical
Improvement
Hemodynamic
improvement
Effect on
Mortality
FIRST 29
Epoprostenol
Advanced HF
471
Yes
Yes
Worsen
RITZ-5 36
Tezosentan
Pulmonary edema
84
Yes
N/a
N/a
37
Tezosentan
ADHF
1300
Similar to placebo
+/-
None
REACH-1 39
Bosentan
Severe HF
377
Worse than placebo,
then similar
N/a
None
ENABLE 40
Bosentan
Severe HF
1613
Probable worse
than placebo
N/a
None
VERITAS
ADHF: Acute decompensated heart failure; HF: heart failure.
Therapy of Pulmonary Hypertension Out of
Proportion to Left Heart Disease
There has been a remarkable growth in the therapy for PAH
over the last decade. There are now five approved drugs in
the United States with several other awaiting FDA approval,
for a disease with a grim prognosis, once considered universally fatal in a short period of time. The increased awareness
for PAH has resulted in an augmented interest in PH secondary to left-heart disease. This interest has been followed
by the use of pulmonary vasodilators for patients with secondary PH. As patients with left heart disease and PH have
a worse prognosis than those without, it has been assumed
that improving the PA pressure should translate into an
improved prognosis and survival. As we will discuss below,
there is no correlation in the hemodynamic improvement
and overall survival.
The main concern in treating patients with elevated leftsided pressure and PH with pulmonary vasodilators is that
by decreasing the PVR, there is an associated increased in
the cardiac output and venous return to the left ventricle. If
the LV has either significant systolic or diastolic dysfunction,
it would not be able to handle this increased venous return.
This would trigger further failure by increasing an already
elevated left heart filling pressure and result in pulmonary
edema, a dread complication in these severely ill patients
with a very high mortality rate. This effect is probably worse
in patients with a noncompliant LV and significant diastolic
dysfunction than in dilated LV with normal filling pressure.
Most of the studies done to evaluate the response of pulmonary vasodilators in patients with left heart disease and
PH are in patients with advanced HF and systolic dysfunction with secondary PH. There are no studies with the use of
pulmonary vasodilators in patients with heart failure due to
diastolic dysfunction.
Maximize Therapy for Primary Condition
Before even considering the administration of pulmonary
vasodilators to patients with left heart disease, the therapy
for the specific condition should be maximized. Mitral valve
surgery or valvuloplasty results in a normalization of the pulmonary HTN in some patients with mitral stenosis.
Unfortunately, despite the normalization of their left atrial
pressures, a proportion of these patients are still left with
significant pulmonary hypertension. Whether specific pul-
26 Advances in Pulmonary Hypertension
monary arterial vasoremodeling therapy is beneficial in these
patients at this point is unknown. The use of PAH drugs in
patients with HF has failed to show any improvement in
symptoms, or survival (Table 2). Maximizing the therapy for
HF with approved drugs or assist devices may also result in
a normalization of the PA pressure in patients with secondary PH (Table 3). Several already approved therapies are
effective in these instances, like nitrates and chronic
inotropic use.
Prostacyclin Analogues
The acute administration of epoprostenol in patients with
HF and secondary PH results in significant reductions in
mean PA, PCWP and marked increase cardiac output with a
resultant decrement in the SVR and, more importantly, the
PVR27. These beneficial hemodynamics effects persist with
long-term infusions.28 In contrast to the improved survival
seen in patients with PAH, the chronic use of epoprostenol
in patients with HF and PH was not associated with a survival benefit. The large-scale Flolan International
Randomized Survival Trial (FIRST)29 randomized 471
patients to epoprostenol infusion or standard care. The trial
was terminated early because of strong trend (P = .055)
toward a decreased survival in patients treated with
epoprostenol. There is still debate regarding the potential
explanation for the discouraging results seen in FIRST. It
may be due to a direct stimulation of prostacyclin on certain
neurohormones, like renin30 and the sympathetic nervous
system.31 Moreover, therapeutic doses of prostacyclins exert
a positive inotropic effect in patients with heart failure,
which may explain the increased mortality observed in
FIRST28. Finally another possible explanation is that a subgroup of patients respond “too well” to the prostacyclin analogues, with marked decrease in the PCWP, which may lead
to negative pathophysiologic effects, not measured by the
usual hemodynamic parameters32. Ilopost is another prostacyclin analog that has been used in patients with HF. It is
administered by inhalation, therefore, exerting most of its
effect in the pulmonary vasculature and decreasing the
potential detrimental systemic effects. However, this effect
is probable no different than that observed with nitroglycerin, nitroprusside or nitric oxide.33 Given these results, we
believe that there is a very limited role for the use of
epoprostenol or other prostacyclin agonists in the therapy of
Table 3. Recommended Approach to Patients
With Pulmonary Hypertension Out of Proportion
to Left Heart Disease
Maximize medical management for primary condition
• Surgery for valvular heart disease
• ACE inhibitors, ␤-blocker, spironolactone, digoxin for
systolic heart failure
• Diuretics to optimize volume status
Test reactivity with nitrates, nitroprusside, nitric oxide
(transplant candidates)
Empiric treatment with oral nitrates and/or CCB
Reassess response frequently
Consider placement of LV assist device in patients with systolic
dysfunction to chronically unload the LV and decrease the pulmonary venous hypertension
Use of sildenafil or an endothelin antagonist should be avoided
until further studies are available
patients with PH secondary to left heart disease; however,
this has not been proven.
Endothelin Antagonists
Endothelin-1 levels are elevated in patients with HF and correlated with clinical and hemodynamic measures of severity,
as well as with a poor prognosis. Several studies of selective
(ETA) or nonselective (ETA/ETB) receptor antagonists in
patients with acute and chronic HF have now been completed, all with similar disappointing results.
The short-term administration of tezosentan, a dual
endothelin-receptor blocker results in a rapid, dose-dependant improvements in the PA, PCW pressure and cardiac
index34 in patients with advanced HF and class III to IV
symptoms. This beneficial hemodynamic effect was again
seen in patients hospitalized for acute decompensated HF35.
Further studies have failed to demonstrate any significant
clinical benefit from the use of tezosentan in patients with
pulmonary edema36 over usual therapy, including VERITAS,37 a large randomized trial that was stopped early due
to a lack of effect in the treatment arm.
A small pilot study using oral bosentan, a non-selective
endothelin antagonist in patients with HF, demonstrated
similar beneficial hemodynamic effects than intravenous
agents.38 A larger pilot study, REACH-1,39 randomized 377
patients with HF and NYHA class III-IV to receive oral
bosentan to goal doses of 500 mg twice daily or placebo
(four times the recommended dose for PAH). Bosentan
exerted no apparent benefit when all patients were analyzed,
but in the subgroup of patients that were treated for at least
26 weeks, there was a significant beneficial treatment effect
in favor of bosentan. The results of the large, randomized
trial ENABLE,40 powered to detect mortality differences
between bosentan-treated patients and placebo, was similarly disappointing with a lack of survival benefit, and an
early risk of worsening HF and hospitalization, as a consequence of fluid retention. The overall interest in the possible beneficial effect of endothelin antagonist in HF has
declined significantly lately, and there is the possibility that
we may not have any additional trials with these class of
agents, at least in patients with systolic HF.
Phosphodiesterase Inhibitors
Sildenafil is a selective phosphodiesterase-5 inhibitor that
has been used extensively for the treatment of male erectile
dysfunction. It has been recently approved for the use in
patients with PAH, given its beneficial hemodynamic and
clinical effects and safety profile. A single oral dose of sildenafil in patients with HF and PH results in significant reductions in the mean PA, PCWP, PVR and an increase in the cardiac index, and may even potentiate the effect of nitric
oxide.41 Moreover, sildenafil has been used to test pulmonary reactivity in patients with HF and PH being evaluated for heart transplantation.42 Sildenafil also appears to
improve the exercise capacity in this population.43 There are
also anecdotal reports of improvement in PH in patients with
HF awaiting transplantation, including one of our patients
with severe LV dysfunction, with a LV assist device and
markedly elevated PA pressure and PVR, despite adequate
unloading of the LV by the assist device to a PCWP of <12.
After 3 months of therapy the PA pressure normalized and
the patient was successfully transplanted. Whether the normalization of the PA pressure in this particular case was the
effect of the chronic unloading of the LV and therefore resolution of the pulmonary venous pressure, or a direct effect of
sildenafil is unknown. However, despite these anecdotal
reports, and until further studies are available, the long-term
use of sildenafil in patients with PH associated with left
heart disease should be discouraged.
Treatment of PH and Diastolic Dysfunction
The presence of diastolic heart failure has been known for
years. Epidemiologic studies have shown a very high prevalence of up to 50% of all patients diagnosed with heart failure, especially in the elderly population.44 However, only one
randomized trial has been done in patients with diastolic
dysfunction, the pre-specified subgroup of the CHARM trial
with preserved LVEF.45 The additional recommendations are
based on understanding the physiologic changes that occur
in a stiff, noncompliant left ventricle, like control of the
heart rate and reduction in the LV volume and pressure with
the adequate use of diuretics and nitrates. It is in this population where we worry the most that the inappropriate use
with pulmonary vasodilators may decrease the PVR, increasing the cardiac output and therefore the venous return to an
already non-compliant LV, increasing even further the pulmonary venous pressure resulting in pulmonary edema. In
order to answer this concern, a trial looking at the effect of
sitaxsentan, a specific endothelin type A receptor antagonist, in patients with diastolic dysfunction will start later this
year. Until the results of the study are available, we should
avoid the use of pulmonary vasodilators in patients with documented left heart disease, based on a PCWP or LVEDP
ⱖ16 mmHg.
Conclusions
The most common etiology for elevated pulmonary artery
Advances in Pulmonary Hypertension 27
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Page 28
pressure is pulmonary venous hypertension. This is most
commonly due to LV failure, either systolic or diastolic, but
also occurs in the setting of mitral and/or aortic valve disease. The concomitant presence of PH and left heart disease
carries a poor prognosis. In some patients, the elevated pulmonary pressure appears to be out-of-proportion to the elevated left-sided filling pressure. The exact reason why some
patients have severely a elevated PA pressure in the setting
of only modestly elevated left-sided filling pressure is
unknown. Pulmonary vasodilators have been tested in
patients with elevated left-sided filling pressure, mainly
prostacyclin agonists and endothelin antagonists in chronic
systolic HF. These trials have failed due to an increase in
mortality or worsening HF and hospitalization, possibly due
to fluid retention. Despite anecdotal reports of patients
improving after the addition of pulmonary vasodilators to
their HF regimen, especially with the use of sildenafil in
patients waiting for heart transplantation due to severe LV
systolic dysfunction, the routine use of these agents should
be discouraged. Further studies, using specific endothelin
anagonists in diastolic dysfunction are planned, and may be
able to answer these concerns. Until then, we recommend
maximizing the therapy for the primary condition (HF) as a
way of decreasing the elevated PA pressure in patients with
left heart disease. ■
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Am J Cardiol. 1984;54:596-599.
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6. Kirklin JK, Naftel DC, Kirklin JW, Blackstone EH, White-Williams C,
Bourge R. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant. 1988;7:331-336.
7. Bonow RO, Carabello B, de Leon AC Jr, et al. ACC/AHA guidelines
for the management of patients with valvular heart disease: a report of
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10. Kavanara MN, Pessin-Minsley MS, Urtecho J, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg. 2002;73:745-750.
11. Macdonald PS, Keogh A, Mundy J, et al. Adjunctive use of inhaled
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28 Advances in Pulmonary Hypertension
12. Martin J, Siegenthaler MP, Friesewinkel O, et al. Implantable left
ventricular assist device for the treatment of pulmonary hypertension in
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13. Willens HJ, Kessler KM. Severe pulmonary hypertension associated with diastolic left ventricular dysfunction. Chest. 1993;103:18771883.
14. Kessler KM, Willens HJ, Mallon SM. Diastolic left ventricular dysfunction leading to severe reversible pulmonary hypertension. Am
Heart J. 1993;126:234-235.
15. Silver K, Aurigemma G, Krendel S, Barry N, Ockene I, Alpert J.
Pulmonary artery hypertension in severe aortic stenosis: incidence and
mechanism. Am Heart J. 1993;125:146-150.
16. Malouf JF, Enriquez-Sarano M, Pellikka PA, et al. Severe pulmonary hypertension in patients with severe aortic valve stenosis: clinical
profile and prognostic implications. J Am Coll Cardiol. 2002;40:789795.
17. Naidoo DP, Mitha AS, Vythilingum S, Chetty S. Pulmonary hypertension in aortic regurgitation: early surgical outcome. Quarterly
Journal of Medicine. 1991;80:589-595.
18. Adamson RM, Dembitsky WP, Jaski BE, et al. Left ventricular
assist device support of medically unresponsive pulmonary hypertension and aortic insufficiency. ASAIO Journal. 1997;43:365-369.
19. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987;107:216223.
20. Erickson KW, Costanzo-Nordin MR, O’Sullivan EJ, et al. Influence
of preoperative transpulmonary gradient on late mortality after orthotopic heart transplantation. J Heart Transplant. 1990;9:537.
21. Bourge R, Kirklin J, Naftel D, White-Williams C, Mason DA, Epstein AE. Analysis and predictors of pulmonary vascular resistance after
cardiac transplantation. J Thorac Cardiovasc Surg. 1991;101: 432445.
22. Levine TB, Levine AB, Goldberg D, Narins G, Goldstein S, Lesch
M. Impact of medical therapy on pulmonary hypertension in patients
with congestive heart failure awaiting cardiac transplantation. Am J
Cardiol. 1996;78:440-443.
23. Pamboukian SV, Carere RG, Webb JG, et al. The use of milrione in
pre-transplant assessment of patients with congestive heart failure and
pulmonary hypertension. J Heart Lung Transplant. 1999;18:371.
24. Zener JD, Hancock EW, Shumway NE, Harrison DC. Regression of
extreme pulmonary hypertension after mitral valve surgery. Am J
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25. Fawzy ME, Minish K, Sivanandam, et al. Immediate and long-term
effect of mitral balloon valvotomy on severe pulmonary hypertension in
patients with mitral stenosis. Am Heart J. 1996;131:89-93.
26. Fattouch K, Sbraga F, Bianco G, et al. Inhaled prostacyclin, nitric
oxide and nitroprusside in pulmonary hypertension after mitral valve
replacement. J Card Surg. 2005;20:171-176.
27. Sueta CA, Gheorghiade M, Adams K, et al. Safety and efficacy of
epoprostenol in patients with severe congestive heart failure. Am J
Cardiol. 1995;75:34A-43A.
28. Montalescot G, Drobinski G, Meurin P, et al. Effects of prostacyclin
on the pulmonary vascular tone and cardiac contractility of patients
with pulmonary hypertension secondary to end-stage heart failure. Am
J Cardiol. 1998;82:749-755.
29. Califf RM, Adams KA, McKenna WJ, et al. A randomized controlled
trial of epoprostenol therapy for severe congestive heart failure: The
Flolan International Randomized Survival Trial (FIRST). Am Heart J.
1997;134:44-54.
30. Patrono C, Pugliese F, Ciabattoni G, et al. Evidence for a direct
stimulatory effect of prostacyclin on renin release in man. J Clin Invest.
1982;69:231-239.
31. Elsner D, Kromer EP, Riegger GA. Hemodynamic, hormonal and
renal effects of the prostacyclin analog iloprost in conscious dogs with
and without heart failure. J Cardiovasc Pharmacol. 1990;16:601-608.
32. Shah M, Stinnett SS, McNulty SE, et al. Hemodynamics as surrogate end points for survival in advanced heart failure: an analysis from
FIRST. Am Heart J. 2001;141:908-914.
33. Radovancevic G, Vrtovec B, Thomas CD. Nitric oxide versus prostacyclin E1 for the reduction of pulmonary hypertension in heart transplant. J Heart Lung Transplant. 2005;24:690-695.
34. Torre-Amione G, Young JB, Durand J-B, et al. Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure. Circulation.
2001;103:973-980.
35. Torre-Amione G, Young JB, Colucci WS, et al. Hemodynamic and
clinical effects of tezosentan, an intaravenous dual endothelin receptor
antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2003;42:140-147.
36. Kaluspi E, Kobrin I, Zimlichman R, et al. RITZ-5: randomized
intravenous tezosentan (an endothelin-A-B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind,
placebo-controlled study. J Am Coll Cardiol. 2003;41:204-214.
37. McMurray JJV. Value of endothelin receptor inhibition with tezosentan in acute heart failure studies (VERITAS): Two multicenter, double blind, placebo-group trials assessing the efficacy, safety and tolerability of tezosentan in acute heart failure. Presented at the American
College of Cariology Meeting, March 2005.
38. Sutsch G, Kiowski W YX-W, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation. 1998;98:2262-2268.
39. Packer M, McMurray J, Massie B, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic
heart failure: results of a pilot study. J Cardiac Failure. 2005;11:12-20.
Profile - Jack Reeves, MD
(continued from page 4)
Dr Reeves served on the board of directors for the Hypoxia
Symposium and for the Pulmonary Circulation Foundation.
He also served as the Research Director of the former
Colorado Altitude Research Institute in 1992.
An accomplished researcher, Dr Reeve authored 11
books and nearly 400 papers or journal articles pertaining
to high altitude medicine, pulmonary circulation, pulmonary hypertension, and pulmonary edema.
In another tribute, Benjamin Honigman, MD, Director
of the Colorado Center for Altitude Medicine and
Physiology, added: “Jack was a brilliant scientist and an
40. Packer M. Effects of the endothelin antagoinist bosentan on the
morbidity and mortality in patients with chronic heart failure. Results
of the ENABLE 1 and 2 trial program. Presented at the College of
Cardiology Meeting, March 2002.
41. Lepore JJ, Maroo A, Bigatello LM, et al. Hemodynamic effects of
sildenafil in patients with congestive heart failure and pulmonary
hypertension. Chest. 2005;127:1647-1653.
42. Alaeddini J, Uber PA, Park MH, Scott RL, Ventura HO, Mehra MR.
Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am J Cardiol. 2004;94:1475-1477.
43. Bocchi EA, Guimaraes G, Mocelin A, Becal F, Bellotti G, Ramires
JF. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebocontrolled, randomized study followed by a prospective treatment for
erectile dysfunction. Circulation. 2002;106:1097-1103.
44. Zile M, Brutsaert DL. New concepts in diastolic dysfunction: Part
I-diagnosis, prognosis and measurements of diastolic function.
Circulation. 2002;105:1387-1393.
45. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesatan in
patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet. 2003;362:777-781.
exceptional human being. He had the ability to explain
complex thoughts in simple terms and get to the heart of
an issue with candor, an unassuming manner, and a wonderful sense of humor. He was the inspiration for the
development of the altitude center at CU-Health Sciences
Center and will be missed in so many ways.”
On a personal level, Dr Reeves was generous with his
time and talent in helping those in poor countries. He
sought out and supported students and young faculty,
especially in the former Soviet Union and Asia. He
received numerous teaching awards and was the recipient
of the Thomas Jefferson Award at the University of
Colorado along with countless personal expressions of
thanks and appreciation. ■
Advances in Pulmonary Hypertension 29
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Pulmonary Hypertension in Heart Failure Patients
Who Are Referred for Cardiac Transplantation
Srinivas Murali, MD, FACC
Professor of Medicine
Drexel University College of Medicine
Director, Division of Cardiovascular Medicine
Medical Director, McGinnis Cardiovascular Institute
Allegheny General Hospital
Pittsburgh, PA
Epidemiology
Left-sided heart failure is an important and common cause
of pulmonary hypertension (PH). In the United States, >5
million people are affected by heart failure, and approximately 550,000 new cases are diagnosed annually.1,2 It
affects 10% of the population over 65 years of age, and is
the leading cause of hospitalization among adults.
Approximately two-thirds of heart failure is secondary to
diminished left ventricular contractility or systolic dysfunction, and the remaining are due to impaired left ventricular
filling / diastolic dysfunction. Coronary artery disease and
primary cardiomyopathy are the most common causes of
systolic left ventricular failure, while hypertension is the
leading cause of diastolic heart failure (Table 1).
Advanced heart failure accounts for at least 10% of all
heart failure (approximately 500,000 patients), and its
prevalence is increasing, particularly because of increased
emphasis upon evidence-based medical therapies, and
because of reduction in sudden cardiac death due to prophylactic defibrillator implantation. Severe heart failure is
frequently associated with PH, perhaps in 25-50% of
patients, but unfortunately there is little epidemiologic information available on its prevalence. Pulmonary hypertension
in association with left-sided heart failure may be either
mild or moderate, though it can be severe in up to a third of
patients. The speculation is that significant PH may be present in up to 250,000 heart failure patients in the United
States, which is far greater than the reported prevalence of
PH associated with other conditions. It is therefore critical
that every heart failure patient with advanced symptoms
undergo a thorough evaluation to ascertain the presence and
severity of PH.3 The focus of this discussion will be PH that
is associated with systolic heart failure.
Hemodynamic Characterization
The human pulmonary circulation, unlike the systemic circulation, is a low resistance vascular bed.4 According to the
hydrodynamic equation which draws an analogy from Ohm’s
30 Advances in Pulmonary Hypertension
Table 1. Leading Causes of Systolic and Diastolic
Heart Failure in the US
Systolic
Diastolic
• Coronary artery disease
• Hypertension
• Primary cardiomyopathy
• Coronary artery disease
• Hypertension
• Aging
• Valvular heart disease
• Restrictive heart disease
• Myocarditis
• Hypertrophic cardiomyopathy
• Drug-induced
• Valvular heart disease
• Toxin-induced
law, the resistance to flow (R) varies directly with the pressure drop (⌬P) and inversely with the rate of flow(Q) across
the pulmonary vascular bed such that R= ⌬P/Q. The pressure drop in the pulmonary vascular bed is also known as the
trans-pulmonary pressure gradient (TPG), which is the difference between the measured mean pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP).
Pulmonary vascular resistance (PVR) is calculated by dividing TPG by flow or cardiac output. It is important to remember that TPG is a measured variable, whereas PVR is calculated. PH in heart failure patients is usually “post-capillary,”
characterized by an elevated PCWP (>15 mm Hg) and PVR.
Initially, in PH associated with left-sided heart failure, the
TPG is normal, though over time it increases (>10 mm Hg).
The hemodynamic progression of PH is typically characterized by a progressive rise in TPG and PVR over time (Table
2). In the later stages, pulmonary artery pressures and cardiac output fall as right ventricular failure sets in, with
marked elevations in right atrial pressure. Occasionally, the
pulmonary artery pressure and TPG may be very high. Many
clinicians consider this to be a form of PH “out of proportion” to left-sided heart failure. Whether or not this is an
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Table 3. Hemodynamic Classification of PH
in Left Heart Failure
Table 2. Hemodynamic Progression of PH in
Left Heart Failure
Vasoreactive
Normal
Early
Stage
Mid
Stage
Nonvasoreactive
Late
Stage
End
Stage
Mean pulmonary
artery pressure
(mmHg)
TPG (mm Hg)
PVR
(Wood units)
Mild
25-34
10-12
2.5-3.4
3.5-4.9
PCWP
N
⇑
⇑⇑⇑
⇑⇑
⇑
Moderate
35-44
13-15
PA
N
⇑⇑
⇑⇑⇑
⇑⇑⇑
⇑⇑
Severe
>45
>15
TPG
N
N
⇑
⇑⇑
⇑⇑⇑
CO
N
N
N or ⇓
⇓
⇓⇓
PVR
N
N
⇑⇑
⇑⇑⇑
⇑⇑⇑⇑
RAP
N
N
N or ⇑
⇑⇑
⇑⇑⇑
Increased morbidity and mortality
extreme manifestation of PH in the spectrum of left-sided
heart failure or a combination of heart failure and intrinsic
pulmonary vascular disease is unknown. This topic is
addressed in the 2 separate articles elsewhere in this issue.
PH can be hemodynamically classified as mild, moderate or severe, based upon measured values of mean pulmonary artery pressures, TPG and calculated PVR (Table 3).
Initially, PH in heart failure is “reactive” and readily
reversed acutely with vasodilator challenge. Over time, PH
becomes “non-vasoreactive” or “fixed,” with reduced or no
responsiveness to pharmacologic treatments.5 Histologically,
PH associated with left-sided heart failure is characterized
by intimal thickening and fibrosis, medial hypertrophy and
adventitial fibrosis of the pulmonary vasculature. Hemodynamic progression from “reactive” to “fixed” disease is
accompanied by progressive structural pulmonary vascular
remodeling. Plexiform lesions, which are the histologic signature of idiopathic PH, are not typically seen in heart failure patients with PH.6,7
Pathogenesis
Left ventricular injury leading to structural remodeling and
dysfunction is the seminal event in the progression of heart
failure (Figure 1). The translation of injury to remodeling is
dependent on the up-regulation and down-regulation of several neuro-hormone and cytokine pathways that results in
neurohormonal imbalance. The renin-angiotensin-aldosterone system, the sympathetic nervous system and
endothelin are the vasoconstrictor systems that are activated whereas endogenous vasodilator systems, such as nitric
oxide and kinins are deactivated. All of these systems extensively interact with each other resulting in pulmonary vascular endothelial cell dysfunction. This triggers pulmonary
vasoconstriction and vascular remodeling through multiple
mechanisms, leading to the development of pulmonary
hypertension. The translation from endothelial cell dysfunction to intimal thickening and medial hypertrophy is not well
understood, but involves endothelin-1 and nitric oxide, both
of which play a critical role in the maintenance of vascular
tone in health.8 Left ventricular remodeling also results in
>5
mitral regurgitation which causes left atrial hypertension
and further triggers pulmonary vascular endothelial dysfunction.9
Plasma endothelin-1 levels vary directly with pulmonary
artery pressure and PVR, and vary inversely with stroke volume in heart failure patients with PH.10 Plasma endothelin1 level is a direct correlate of mortality in heart failure
patients.11-13 The increased pulmonary artery pressure and
vascular resistance increases the afterload of the right ventricle leading to right ventricular dysfunction, remodeling
and failure. Thus, left ventricular dysfunction always results
in right ventricular failure by way of pulmonary hypertension.
However, when the initial insult affects both ventricles
simultaneously, such as in acute myocarditis or myocardial
infarction involving the right and left ventricles, pulmonary
hypertension rarely develops as the failing right ventricle is
unable to generate high pulmonary pressures to overcome
the downstream resistance to flow.
Diagnosis
Every patient with PH associated with left-sided heart failure must have a detailed diagnostic work-up to help characterize the etiology of the heart failure and to identify if the
heart failure is from systolic or diastolic left ventricular dysfunction14 (Figure 2). A transthoracic echocardiogram can
frequently recognize the presence of PH and right ventricular dysfunction, in addition to providing evaluation of the left
ventricle and the valves. Pulmonary artery pressure can be
estimated from the Doppler measurement of the regurgitation velocity across the tricuspid valve. Right heart catheterization must however be performed to accurately measure
pulmonary artery pressures, PCWP, TPG and cardiac output.
Other potential causes or contributors to PH should be considered and appropriate testing done as indicated. In particular, thromboembolic pulmonary disease, coexistent pulmonary parenchymal disease such as chronic obstructive
pulmonary disease, and sleep apnea should be ruled out.
If the TPG and PVR are elevated, acute vasoreactivity
testing should be done at the time of right heart catheterization, particularly if the patient is to be considered for cardiac transplantation.15-19 Intravenous sodium nitroprusside,
milrinone, prostacyclin or inhaled nitric oxide are generally
used to assess acute vasoreactivity in PH associated with
left-sided heart failure (Table 4). Though there is no standard definition to identify a responder, the goal is to see if
the TPG and PVR can be decreased appreciably, without
Advances in Pulmonary Hypertension 31
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Page 32
Left ventricular injury
Left ventricular remodeling
LVEDP, Neurohormones, Cytokines, MR
Pulmonary EC dysfunction
ET, NO
Pulmonary vasoconstriction
Pulmonary vascular remodeling
Pulmonary hypertension
RV remodeling
PH present on
echocardiogram
Confirm by RHC
Rule out shunt
Acute vasoreactivity
testing
V/Q or CT scan
to rule out CTEPH
PFT with ABG
to rule out COPD
Sleep study
for sleep apnea
Figure 2—Proposed diagnostic work-up if PH is detected in a patient
with left heart failure. Once the diagnosis is suspected by echocardiography and confirmed by catheterization, other contributing
factors such as pulmonary emboli, parenchymal lung disease and
sleep apnea has to be ruled out. RHC=right heart catheterization,
V/Q scan=ventilation-perfusion scan, CT=computed tomography,
CTEPH=chronic thrombo-embolic PH, PFT=pulmonary function test,
ABG=arterial blood gases, COPD=chronic obstructive
pulmonary disease.
Morbidity and mortality
Figure 1—Proposed mechanism of pathogenesis of PH in left heart
failure. LVEDP=left ventricular end-diastolic pressure, EC=endothelial
cell, MR=mitral regurgitation, ET=endothelin-1, NO=nitric oxide.
Adapted from Moraes et al. Circulation. 2000; 102:1718-23.
raising PCWP or lowering cardiac output or causing systemic
hypotension. Patients who are acutely vasoreactive and listed for transplantation will require serial testing every 6-8
weeks to ensure that they remain vasoresponsive.
Clinical Course and Prognosis
When PH complicates heart failure, both morbidity and mortality are increased.20 Patients complain of worsening
fatigue and dyspnea, and declining exercise tolerance. The
peak exercise oxygen consumption (peak VO2) inversely correlates with mean pulmonary pressure and PVR, and correlates directly with resting right ventricular ejection fraction.21,22 Atrial arrhythmias are more frequent, which further
compromises cardiac output. As right ventricular failure sets
in, cardio-renal syndrome with progressive renal insufficiency, hyponatremia, and diuretic resistance develop. In the
advanced stages, patients have anasarca, severe tricuspid
regurgitation secondary to annular dilatation, and chronic
hepatic congestion that can lead to cardiac cirrhosis. Rarely,
patients develop hypoxemia either at rest or with activity
because of a right to left shunt through a patent foramen
ovale. Heart failure patients with PH have increased frequency of hospitalizations, increased risk of cardiovascular
events, and a higher mortality, compared to patients without
PH. The risk of death is directly proportional to the pulmonary vascular resistance.23
PH in Transplant Candidates
In heart failure patients, the presence of significant PH is a
contraindication to orthotopic cardiac transplantation.24,25
32 Advances in Pulmonary Hypertension
Table 4. Vasoreactivity Testing in PH
Associated With Left Heart Failure
Drugs used to assess vasoreactivity
1. IV Nitroprusside 250-750 mcg/kg/min q 10 min
2. IV Epoprostenol 2-10 ng/kg/min q min
3. Inhaled nitric oxide 10-40 ppm q 2 min
4. IV Milrinone 25-50 mcg/kg bolus over 5 mins
5. IV Neseritide 2mcg/kg bolus, 0.01 mcg/kg/min over 30 mins
Definition of “response”
No “standard” definition
• Fall in TPG to ⱕ12 mmHg, OR
• Fall in PVR to ⱕ3 Wood units, OR
• Fall in PVR by 20%, AND
• Unchanged or increased CO from baseline, AND
• No increase in PCWP from baseline, AND
• Systolic arterial pressure >80 mmHg
The donor right ventricle will fail acutely, resulting in allograft failure and death if it is required to pump into a high
resistance pulmonary circulation. A normal right ventricle
cannot acutely generate a pressure in excess of 50 mm Hg.
The risk posed by PH in transplant candidates is a continuous risk that is directly proportional to both PVR and TPG;
in other words, the greater the TPG and PVR, the higher the
risk of acute right ventricular failure following transplantation.26-28
Nonetheless, for clinical reasons, thresholds have been
defined for PVR and TPG beyond which the risk is considered excessive, and orthotopic transplantation contraindicated.29 These thresholds vary among transplant programs,
4/14/06
12:15 PM
Page 33
PH in left HF
Not transplant eligible
Transplant eligible
Acute vasoreactivity
testing
Vasoreactive
Not vasoreactive
Treat with IV Milrinone
or Neseritide LVAD
PH resolves or
becomes vasoreactive
Transplant
Drug
PAH
PH associated with LHF
Nitrates (oral or intravenous or sublingual)
No
Acute hemodynamic;
chronic symptomatic
benefit
Calcium channel blockers
Chronic benefit (in vasoreactive patients only)
No (except amlodipine
that causes chronic
symptomatic benefit)
Endothelin receptor antag- Acute hemodynamic and
chronic clinical benefit*
onists (Bosentan)
Acute hemodynamic; but
no chronic clinical benefit
Prostanoids (Epoprostenol) Acute hemodynamic and
chronic clinical benefit*
Acute hemodynamic; but
no chronic clinical benefit
PDE-III inhibitors
(Milrinone)
No
Acute hemodynamic
benefit; mortality during
chronic therapy
PDE-V inhibitors
(Sildenafil)
Acute hemodynamic and
chronic clinical benefit*
Acute hemodynamic;
chronic benefit unknown
Digoxin
No
Chronic clinical benefit*
ACE inhibitors
No
Chronic clinical benefit*
β-blockers (Carvedilol,
Metoprolol succinate)
No
Chronic clinical benefit*
Aldosterone antagonists
No
Chronic clinical benefit*
Hydralazine + Isosorbide
Dinitrate
No
Chronic clinical benefit*
VAD
No
Acute hemodynamic;
chronic clinical benefit*
Persistent PH
Continue HF therapy
Figure 3—Proposed algorithm for management of PH in left heart
failure. In patients who are acutely vasoreactive, the testing should
be repeated every 6-8 weeks as they await transplantation.
and are higher in experienced, high volume transplant centers. Heart failure patients with a TPG ⬍12mm Hg or PVR
⬍3 Wood Units are considered suitable with an acceptable
risk in most transplant centers, whereas patients with a TPG
ⱖ15 mm Hg or PVR ⱖ5 Wood Units, despite acute vasoreactive testing, are clearly not appropriate candidates. The
early post-transplant mortality is 3-fold higher in the latter
high risk group, and even higher if the gender is female.3034
In these patients, heterotopic transplantation, where a
donor heart is implanted without explantation of the recipient heart or heart-lung transplantation may be considered.
Long-term outcomes with heterotopic heart transplantation
are inferior to orthotopic transplantation, and therefore not
performed in most transplant centers.35 Heart-lung transplantation is limited by the lack of availability of donors. A
Domino procedure where the cardiac allograft from a donor
with idiopathic pulmonary hypertension who is to receive a
heart-lung transplantation is used has been advocated for
severe PH patients. The remodeled, hypertrophied right ventricle in these allografts can adequately sustain function in
the early post-operative period.36 Data from the International
Society for Heart and Lung Transplantation (ISHLT) registry
demonstrate that pre-transplantation PH is an independent
risk factor for poor outcome following transplantation.37 This
risk exists even with oversizing the donor allograft.
Left-sided heart failure patients with PH who undergo
transplantation will have gradual, complete resolution of
their PH during the first 6-12 months.38-40 However, even
those with only a mild to moderate degree of PH pre-transplantation have residual PH during the first few months.41
The greater the severity of PH prior to surgery, the longer the
time to resolution. In some patients with severe PH, there is
incomplete resolution, with residual elevations in pulmonary
pressures and PVR. Even those patients who undergo heterotopic heart transplantation have some resolution of PH
over time.35 Remodeling of the allograft right ventricle and
development of tricuspid insufficiency accompany the resolution of PH after transplantation.
↓
Advs in PH V5N1
Figure 4—The list of treatments available for pulmonary arterial
hypertension (PAH) and PH associated with left heart failure (LHF).
*FDA approved, PDE=phosphodiesterase, ACE=angiotensin converting
enzyme, VAD=ventricular assist device
Management
The managment paradigm for PH associated with left-sided
heart failure is outlined in Figure 3. All left-sided heart failure patients whether they have associated PH or not, should
be treated with evidence-based therapies which include
digoxin, diuretics, angiotensin converting inhibitors, ␤-adrenergic blockers and aldosterone antagonists.42 Any contributing condition should also be treated appropriately. If
PH is present and acutely vasoreactive, the patient may be
considered for transplantation, provided there are no other
contraindications. Every effort must be made to prevent the
progression of PH until transplantation and frequent monitoring (every 6-8 weeks) with right heart catheterization may
be necessary. If PH is not acutely vasoreactive, then chronic infusions of intravenous Neseritide (48-72 hrs) or intravenous milrinone (up to 2 weeks) or aerosolized inhalation of
milrinone should be considered in order to decrease pulmonary pressures, TPG and PVR.43-46 Chronic left ventricular unloading with a left ventricular assist device (either continuous flow or pulsatile) may also be considered in select
patients to reverse PH.47,48 If there is significant improvement in pulmonary hemodynamics with any of these strategies, cardiac transplantation may be feasible.
None of the therapies that are approved for the treatment
of pulmonary arterial hypertension have shown benefit in
chronic heart failure patients49 (Figure 4). Except for
amlodipine, calcium channel blockers worsen outcomes in
patients with left heart failure due to systolic dysfunction.
Though acute administration of endothelin antagonists
induces pulmonary vasodilation in left-sided heart failure
patients, chronic therapy has no proven survival benefit in
randomized, controlled trials.50,51 Likewise, intravenous
Advances in Pulmonary Hypertension 33
Advs in PH V5N1
4/14/06
12:15 PM
Page 34
epoprostenol infusions failed to show survival benefit in
patients with chronic heart failure.52 Incidently, several
patients in this study experienced reductions in pulmonary
pressures, PCWP and PVR.53 Unfortunately, none of the
aforementioned clinical trials carefully evaluated the longterm clinical and survival benefits in patients with PH associated with chronic left heart failure. Oral sildenafil, a phosphodiesrterase-5 inhibitor, which is approved for the treatment of pulmonary arterial hypertension, has been shown to
decrease pulmonary pressures and PVR in PH associated
with heart failure.54 This hemodynamic effect is augmented
when the drug is co-administered with inhaled nitric
oxide.55, 56 Whether chronic treatment with sildenafil can
cause sustained benefit in PH associated with heart failure
is unknown at this time.
Summary
Left heart failure is an important, and perhaps common
cause of PH. The morbidity and mortality in left heart failure is independently determined by the presence of associated PH which also directly contributes to the progressive
decline in symptoms and functional status in these patients.
Though, advances in medical and surgical therapy have significantly improved the outlook of chronic left heart failure
patients, to date, there is no FDA approved therapy for PH
associated with left heart failure. Cardiac transplantation is
risky in general, but can be offered for vasoreactive patients,
who have no other contraindications. Parenteral continuous
therapy with neseritide or milrinone and chronic left ventricular unloading with a left ventricular assist device may
improve pulmonary hemodynamics and allow successful
transplantation in certain select patients, who are not
responsive to acute vasoreactivity challenge. Clearly, further
research to identify targeted therapy for PH associated with
left heart failure is sorely needed. ■
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Advances in Pulmonary Hypertension 35
Pulmonary Hypertension Roundtable
Controversies and Consensus in PH
With Left Heart Disease: Dosing Issues,
Transplant Considerations, Wedge Pressure
Targets, Postop Drug Selection, and More
James P. Maloney, MD
James B. Young, MD
Michael A. Mathier, MD
Robert P. Frantz, MD
This discussion was moderated by James P. Maloney,
MD, Associate Professor, Division of Pulmonary
Science and Critical Care Medicine, University of
Colorado, Denver, Colorado. The participants included Robert P. Frantz, MD, Assistant Professor of
Medicine, Division of Cardiovascular Diseases, Mayo
Clinic College of Medicine, Rochester, Minnesota;
Michael A. Mathier, MD, Assistant Professor of
Medicine, Director, Pulmonary Hypertension Program, and Associate Director, Cardiovascular Fellowship Program, University of Pittsburgh, Pittsburgh,
Pennsylvania; and James B. Young, MD, Professor
and Chairman, Division of Medicine, and George and
Linda Kaufman Chair, Cleveland Clinic Foundation,
Cleveland, Ohio.
Dr Maloney: How big a problem is pulmonary
hypertension associated with left heart disease,
particularly pulmonary hypertension out of proportion to left heart failure?
Dr Young: I can speak as a heart failure clinician
and also as someone interested in sorting out
those patients with heart failure and pulmonary
hypertension who might benefit from heart transplantation. It’s a huge problem for us and not one
that’s been very carefully studied. We see several
scenarios in our advanced heart failure patients.
One, patients with terribly disturbed left ventricular systolic function and very high pulmonary artery
pressures noted in conjunction with a high wedge
pressure that responds to dropping the wedge
pressure with different tools that cause the pulmonary hypertension to improve, but leaves the
patient still walking around with pulmonary artery
systolic pressures in the 50 to 60 mmHg range.
This is still disturbing. Then you see the patient
with ejection fractions in the 35% to 40% or
maybe 50% (low normal) range, with severely
hypertrophied ventricles and so-called “diastolic
dysfunction” and pulmonary hypertension that is
surprisingly out of proportion to where one would
think those pressures should be. Finally, you can
see a third type of patient who clearly has two dis-
36 Advances in Pulmonary Hypertension
tinct physiologic problems and will have pulmonary hypertension with clear-cut gradient across
the lungs that is significant and a pulmonary artery
diastolic pressure to wedge pressure gradient that
points toward two different processes. Now, how
does one sort out those three scenarios without
catheterization and simply with noninvasive studies? What we do with brain natriuretic peptide
measurements, and even more important, how do
we treat them with the medicines we have available, is a contentious subject.
Dr Maloney: That sounds like that’s particularly a
problem with patients who are being evaluated for
heart transplants in that now they have these
chronically elevated wedge pressures and you
know that once you get them a new heart that pulmonary vascular remodeling is not going to go
away. How do you approach those patients pretransplant, and then also posttransplant when you
are left with a well-functioning left ventricle but
you have someone who’s had pulmonary vascular
remodeling from years of heart failure? How do you
evaluate those patients beforehand for such problems, and how do you approach them after the
transplant?
Dr Mathier: During pretransplant evaluation we
largely screen out patients who are eventually
going to end up in that category, so if we see, as
Jim pointed out, a high transpulmonary gradient
during the transplant evaluation process, we
actively look to see if we can bring that gradient
down into a normal or perhaps just mildly elevated
range. If we’re successful at doing that, we generally feel comfortable going on with an orthotopic
heart transplant, and in my experience, in general,
those patients don’t tend to go on to have very high
pulmonary pressures following transplant.
Occasionally, one will sneak through so that you
are left with significant pulmonary hypertension
even with normal or near normal left-sided filling
pressures and normal cardiac function. If that’s
the case, then that person in my mind falls into
that nebulous category of pulmonary hypertension
Dr Young: I’m old enough that I participated in some of
those “ancient” trials. The FIRST was pretty disappointing,
with observations indicating that Flolan, though effective in
some individual patients with high pulmonary artery pressures, produced problems more often than not. You could
turn some patients awfully blue pretty quickly as you preDr Frantz: For patients with left heart failure who are undercipitated intrapulmonic shunting if you weren’t terribly caregoing heart transplant evaluation and are found to have pulful. Indeed, it remains a bit of a mystery why some vasodilamonary hypertension that raises concern about risk of donor
tors have been associated with less than robust and benefiright ventricular failure, we administer nitroprusside in the
cial outcomes, including the endothelin antagonists. If you
catheterization laboratory in an effort to document reversibilthink about it, in congestive heart failure, endothelin antagity of the pulmonary hypertension. The goal here is to mimic
onists should have worked great, and in some of the initial
the posttransplant state, ie, what would the pulmonary artery
dose findings studies, data raised great hope based on pulpressures be if left-sided hemodynamics were normal? If
monary pressure lowering as well as improvement in flow
the pulmonary capillary wedge pressure normalizes but pulthrough the lungs. In the end, it just didn’t quite pan out.
monary artery pressures stay high, eg, with a transpulmonary
That suggests maybe it’s the wrong dose we’re
gradient of 14 or greater, then transplant will
using. Maybe there are other subtle issues
be risky or impossible. Sometimes ability to
For patients with prerelated to right heart and left heart function
administer nitroprusside is limited by systemic
served systolic function
that we haven’t quite cleared up, but interesthypotension, and it may not be possible to
but documented diastolic
ingly enough, I’m not ready to completely
bring down the pulmonary capillary wedge presheart failure, it is critithrow out those drugs in the patient with terrisure because of advanced cardiac failure. If the
cally important first to
ble pulmonary hypertension. I just think we
pulmonary capillary wedge pressure cannot be
achieve excellent blood
need to do some smarter studies to, perhaps,
corrected because of advanced congestive heart
pressure and heart rate
figure out the nuances of dosing these drugs.
failure, and the pulmonary artery pressures stay
control. This includes
high, then other maneuvers such as short-term
documentation of good
Dr Mathier: If I might add, the studies we
administration of inotropes to increase cardiac
blood pressure control
have available were performed in patients with
output may be helpful in demonstrating
during exercise, since
heart failure, but not specifically with pulreversibility. Occasionally we add inhaled nitric
high systemic and left
monary hypertension complicating it.
oxide to intravenous nipride in an effort to maxventricular pressures
imize pulmonary vasodilation while still trying to
during exercise often
Dr Maloney: Very good point.
lower pulmonary capillary wedge pressure. In
drive the symptomatoladdition, sometimes administration of inotropes
ogy. Many patients with
Dr Mathier: And secondly, with the endothelin
such as milrinone continuously for several
longstanding systemic
antagonist trials, the REACH-1 (Research on
weeks as an outpatient (if the patient has a
hypertension, especially
Endothelin Antagonism in Chronic Heart faildefibrillator to protect against risk of sudden
the elderly, develop subure) is the only one for which we have detailed
death) has been successful in our experience in
stantial diastolic heart
data. The doses were clearly inappropriate
lowering pulmonary artery pressures into a
failure that may be
compared to those we use for pulmonary artetransplantable range. This may reflect a more
improved just with really
rial hypertension today. So I think Jim may be
sustained unloading of the pulmonary vasculagood conventional antiexactly right that there are dosing issues that
ture. Occasionally this phenomenon occurs folhypertensive therapy.
were just not well worked out at the time those
lowing left ventricular assist device placement
studies were performed.
as well, thereby making the patient a more suitable heart transplant candidate.
Dr Frantz: I agree that we may have missed an opportunity
with endothelin antagonists in left heart failure by virtue of
Dr Maloney: What are the lessons you feel we can draw from
having the dosing wrong, but we have to acknowledge that is
trials such as the epoprostenol in chronic heart failure trial,
conjecture. In addition, we are wiser now about the issues of
which was called FIRST, the Flolan International Randomfluid retention sometimes accompanying use of endothelin
ized Survival Trial? As new drugs come on board for pulantagonists, and might have dealt with that better with
monary arterial hypertension, the pharmaceutical companies
diuretic adjustment. I draw an analogy to the lessons of
look to expand indications to more common disease, such as
beta-blocker use in congestive heart failure, where we need
congestive heart failure. It seems that just about every time
to be very cautious initially in order to reap the longer term
that’s been done, the drugs that work for pulmonary hyperbenefits as the heart remodels.
tension don’t work for congestive heart failure, such as
endothelin receptor antagonists. Still, some people were
Dr Maloney: The FIRST results were interesting in that the
tempted to use these drugs in patients who had a compodose of epoprostenol was quite low compared to what is
nent of pulmonary hypertension related to left heart disease.
used for pulmonary arterial hypertension, yet those congesWhat’s your experience in interpreting these studies and
tive heart failure patients hemodynamically improved. But
your advice to clinicians?
they had increased mortality. I guess it gets to the bigger
out of proportion to left heart disease and I would consider
specific pulmonary hypertension therapy in that setting.
Fortunately, this is not a terribly common patient in our
experience.
Advances in Pulmonary Hypertension 37
issue in that very commonly patients are referred to a pulmonary hypertension center because an echocardiogram
shows a pulmonary systolic pressure of 50 mmHg and a left
ventricle with diastolic dysfunction. We do a heart catheterization and find out they have a wedge pressure of 30
mmHg. Yet their main pulmonary arterial and pulmonary
diastolic pressures may seem elevated out of proportion to
that. At what point, even if you pushed treatment to such
patients for their diastolic dysfunction, do you become nervous on the level of wedge pressure? Where do you like to see
that wedge before using drugs that we typically would
reserve for pulmonary arterial hypertension? Is there a wedge
pressure cutoff that either of you have that you just simply
won’t treat someone with a pulmonary hypertension drug?
Dr Mathier: I don’t think there is any hard and fast number
in my mind. If a patient presents, and we see this quite a
bit, especially with so-called diastolic heart failure, where
they may have a wedge pressure of 30 mmHg, then obviously we try to optimize their heart failure care and drive
their wedge pressure down to what we think is the optimal
level for that patient. I like to see a wedge pressure under
20 mmHg with a persistently elevated transpulmonary gradient before I would consider a specific pulmonary arterial
hypertension therapy in a patient who appears to have heart
failure with complicating pulmonary hypertension.
Dr Young: Yes, I would agree with that number too. That’s
exactly the target I would endorse. I usually tell the fellows
who are watching the patients in the unit, 16 to 20 mmHg.
The magic number of 20 or 16 mmHg isn’t necessary, but
somewhere in that range, I agree completely. The problem is
if that wedge drops too low, and you start giving these
agents, and that left ventricle underfills, you can get into a
lot of systemic problems with hypotension and renal dysfunction.
Dr Frantz: I agree that the probability of causing more harm
than good is very real when using selective pulmonary
vasodilators in patients with a wedge of 18 mmHg or above.
For patients with preserved systolic function but documented diastolic heart failure, it is critically important first to
achieve excellent blood pressure and heart rate control. This
includes documentation of good blood pressure control during exercise, since high systemic and left ventricular pressures during exercise often drive the symptomatology. Many
patients with longstanding systemic hypertension, especially the elderly, develop substantial diastolic heart failure that
may be improved just with really good conventional antihypertensive therapy.
Dr Maloney: What percentage of your patients in that range
of wedge pressures you gave us would you estimate you
actually have on additional therapies, such as sildenafil,
endothelial receptor antagonists, and prostenoids?
Dr Young: Well, it’s not very many, and the reason it’s not is
because there still is some concern about a) which patient
might benefit from this off-label use of these drugs, and b)
38 Advances in Pulmonary Hypertension
how to dose the drugs and maybe even how to choose the
drugs that are available. There is some reluctance to turn to
these agents, which I think actually could be very helpful
based on data from small clinical trials. Usually what happens is they’ll get admitted to the hospital and pounded with
phosphodiesterase inhibitors like milrinone or maybe a trial
of nitric oxide inhalation will be attempted. It’s rather paradoxical, because if you think about it, there aren’t any more
data with phosphodiesterase inhibitors than with these other
newer concepts. If you look at the number of patients who
would be eligible for these tactics, I would say as many as 1
in 10 of the real serious patients who get evaluated for heart
transplant are. I’d be curious to hear other estimates.
Dr Mathier: I agree that 10% is a reasonable number.
Another reason for the reluctance to use these agents offlabel is that patients must meet every one of a set of criteria: They must have a degree of pulmonary hypertension that
is judged to be “out of proportion” to their left heart dysfunction; they must be able to attain a low enough wedge
pressure to give an adequate safety margin with which to
work before we begin a specific pulmonary arterial hypertension therapy; they must be persistently symptomatic
despite having a reasonable wedge pressure so as to warrant
a trial of a specific pulmonary arterial hypertension therapy;
and lastly, they must have some evidence of a clinical
response for me to want to continue to use that agent. It’s a
relatively small percentage, I think, that meets all of those
criteria.
Dr Frantz: I agree it is a small number of patients. Most of
these patients with left ventricular systolic failure and pulmonary hypertension benefit most from optimization of conventional heart failure therapies.
Dr Maloney: In those patients who get a heart transplant, a
small subset develops symptomatic pulmonary arterial
hypertension afterward. It’s challenging to choose what
would be the drugs to treat those patients. Sildenafil might
be chosen, but could interfere with antifungal drugs; we like
to avoid epoprostenol because of line infection risk;
endothelial receptor blockers might seem a good choice as
long as fluid retention isn’t an issue. Is there any particular
go-to drug you might tend to use in that postoperative setting?
Dr Mathier: In the immediate postoperative setting, we tend
to look for a quicker acting agent with direct delivery, so it’s
not unusual for us to use inhaled nitric oxide immediately
post-op. I don’t think that’s terribly controversial. I believe
most centers that do a reasonable volume of transplants are
using that sort of approach. The question gets a little trickier when you start to think about medium and longer term
therapies, and as you point out, each of these drugs—just as
they do in the nontransplant setting—has pros and cons
associated with them. I think that if somebody has really significant pulmonary hypertension and I feel that a prostanoid
would be of value, then I’m increasingly comfortable using
inhaled iloprost in that setting, specifically to avoid catheter-
related complications, as you mentioned. If I think an oral
drug will be valuable, I tend to use an endothelin antagonist,
but with a careful eye on hepatic function, especially since
we like to employ statin therapy simultaneously in the posttransplant patient.
and pulmonary hypertension. I’d be curious to hear what
others think about that.
Dr Mathier: I would add one other thing to the mix, and that
is what we do to a patient’s tricuspid apparatus with repeated endomyocardial biopsies. I’m not sure that any of us have
a good way to really reliably assess right ventricular structure
Dr Frantz: It is important to point out that there is a serious
and function and their interrelationship with tricuspid valve
pharmacokinetic interaction between bosentan and
function. One thing I would like to add to this discussion is
cyclosporine, and concomitant use is not recommended.
a plea, an ongoing plea, from a cardiologist to other cardiologists in the pulmonary hypertension community to recogDr Young: I think that’s a great summary and it points to the
nize the absolute importance of right heart catheterization.
fact that there are really separate periods where pulmonary
Too often, as you pointed out, Jim, we see patients with a
hypertension after heart transplantation can get you into
suggestion of elevated pulmonary pressure on echo, with
trouble. One is the immediate postoperative period, includperhaps normal left ventricular systolic function, with or
ing challenges and troubles weaning off of cardio pulmonary
without ancillary evidence for a diastolic abnormality, who
bypass. Generally, if there are any issues in the operating
are just started down a pathway of pulmonary
room or early on in the intensive care unit,
hypertension therapy without a formal hemoinhaled nitric oxide is what we turn to. Actually
One thing I would like to
dynamic study to determine whether there are,
in the operating room, we have a low threshold
add to this discussion is a
in fact, elevated left heart pressures. These
for putting in a right heart mechanical bypass
plea, an ongoing plea,
patients, in my opinion, absolutely must
system. The second group represents a probfrom a cardiologist to
undergo a hemodynamic study so that we can
lem where you come out of the operating room
other cardiologists in the
know exactly which disease it is we’re dealing
with pulmonary hypertension, but it doesn’t
pulmonary hypertension
with.
cause cardiogenic shock or an early disastrous
community to recognize
problem, but then at day 10, 12, 14, three
the absolute importance of
Dr Maloney: That’s an absolutely key point. I
weeks, the patient is swollen with terrible triright heart catheterization.
think we all in the pulmonary hypertension
cuspid insufficiency and right heart failure due
Too often we see patients
community have tried to convince people that
pulmonary hypertension. In these patients I’ll
with a suggestion of elepulmonary arterial hypertension cannot just be
move toward a phosphodiesterase inhibitor earvated pulmonary pressure
diagnosed on an echocardiogram, but dictates
lier, and lots of diuretics to try to dry them out,
on echo, with perhaps
hemodynamic evaluation with right heart
as much as their kidneys will let us, in hopes
normal left ventricular
catheterization and very often, left heart
that we will see a turnaround. If they don’t, you
systolic function, with or
catheterization. Let’s say a patient undergoes
have to turn to some of the other agents that
without ancillary evidence
right heart catheterization and is found have a
were mentioned. The third type of patient is
for a diastolic abnormalimean pulmonary artery pressure of 30 mmHg
the one who’s out long term, and to me that’s
ty, who are just started
but suspiciously has a wedge pressure that is
the biggest problem because these patients
down a pathway of pul18 to 19 mmHg, long-standing systemic
usually have renal insufficiency. Their livers
monary hypertension therhypertension, and a prior suggestion of diasaren’t in the greatest shape either. They’ve had
apy without a formal
tolic dysfunction on the echocardiogram. Many
pulmonary hypertension ever since transplant
hemodynamic study to
people, myself included, would work with a
and the right heart is now really failing. This is
determine whether there
cardiologist, do an exercise study with this
a miserable patient and a terrible outcome is
are, in fact, elevated left
patient in the catheterization lab, and follow
usually guaranteed.
heart pressures.
the wedge pressure and LVEDP to see if this is
a patient who has exertion-related pulmonary
Dr Maloney: Are there other issues you would
hypertension due to diastolic dysfunction. There is a fair
like to bring up?
spread on how people evaluate that in these cases of mild
pulmonary hypertension. What are your experiences and
Dr Young: I have two issues I’d like to see addressed and,
biases?
really, it’s a plea for better studies. Perhaps we could do
multicenter studies focused on how best to handle these
Dr Mathier: I’m still uncertain about what role measurement
patients in the early postoperative phase when we see a lot
of pulmonary pressures during exercise is going to have in
of tricuspid insufficiency and pulmonary hypertension that
the long run. In the situation you described, where there is
can’t really be sorted out; how much is fixed and how much
a relatively modest transpulmonary gradient and elevation of
is going to turn around over time. The second issue relates
the wedge pressure with evidence of what we would call
to tricuspid insufficiency itself and to determining how
diastolic dysfunction, I generally would stop there in terms
much might be due to the mechanical implantation of the
of evaluation and focus my efforts on optimizing the care of
allograft versus right heart failure due to pulmonary hyperthe underlying diastolic abnormality, and then follow the
tension. It’s always been challenging to sort through these
patient to see if there is clinical improvement. If, however,
difficulties related to the way the heart was sutured into
there is evidence of a wider transpulmonary gradient, but
place versus a variety of combinations of right heart failure
Advances in Pulmonary Hypertension 39
the mean pulmonary pressure is still not through the roof,
then I might move toward an exercise study to see if there is
more of an exaggerated rise than I would expect with exercise.
Dr Young: After having been involved with doing a lot of
these studies, I virtually gave up because of the inability to
really predict outcomes in patients, but even more, the hassles of trying to do one of these studies. They’re extraordinarily bad in reproducibility of information and are just trouble. So I agree completely with that response.
Dr Frantz: In my experience, occasionally exercise hemodynamics in the catheterization laboratory can be helpful in
the differential diagnosis of dyspnea. Just today I performed
a right heart catheterization for a patient with a history of
systemic hypertension that had been variably controlled, but
who was still having complaints of exertional dyspnea. Her
resting hemodynamics were normal, but her wedge and right
atrial pressures rose to around 20 mmHg after 6 minutes of
exercise. I think that helped explain her dyspnea.
Dr Maloney: Patients with mitral regurgitation can often be
difficult because that can be worse with exercise. There’s a
subset of patients who have mitral regurgitation who with
exercise get pulmonary hypertension from the regurgitation.
It’s difficult to figure out the best way to evaluate those
patients. Some centers have a protocol for exercise such as
echocardiography with a recumbent bicycle; some people
prefer to do it in the catheterization lab. What do you do?
Dr Young: Again, in the past, I’ve run into the same problems with getting good reproducible measurements. Getting
good pressure tracings you can evaluate is a problem.
Personally, I’m not sure what intracardiac pressures mean
when obtained lying on your back pedaling a bicycle. If your
wedge goes up really high, or your pulmonary artery pres-
40 Advances in Pulmonary Hypertension
sures shoot up, I think it’s a bit of problem from a physiologic standpoint, but how do you relate that to someone who
is upright walking about? So, rather than doing a lot of exercise, in my experience, if you’re trying to flush out the severity of mitral regurgitation, simple things like hand grip,
where you’re increasing SVR arguably tell you as much as
anything. Even more important is careful measurement of
the regurgative wave in this situation, and that’s a lot different from trying to look at pulmonary artery pressures. I’d be
curious to hear what others think.
Dr Mathier: We are primarily doing stress echocardiographic
assessment in these patients, with the specific stress
employed determined more often by sonographer preference
and patient ability than by any programmatic decision.
We’ve done recumbent bicycle, treadmill, and dobutamine
protocols. We have, however, shared Jim’s observation that
trying to do exercise hemodynamic studies is just logistically so difficult that we only rarely do it unless the referring
doctor feels that it is the only way to get at the question at
hand.
Dr Frantz: We do exercise echo assessments, but also sometimes do supine bike exercise in the catheterization laboratory. I have also had occasional patients with functional
mitral regurgitation in the setting of an element of systemic
hypertension, where pulmonary artery pressures and wedge
pressures come down like a rocket with nipride in the cath
lab. In those patients it is a further incentive to aggressively manage their systemic hypertension. Aggressive blood
pressure control can be recommended without such hemodynamic assessment, but when patients are referred
because of their pulmonary hypertension, the ability to drastically improve it acutely makes the case for the proper medical approach, if mitral surgery is not advisable or appropriate. ■
Breathe Easier
As measured by improvements in Borg Dyspnea Score, Dyspnea
Fatigue Rating and PAH Symptoms associated with exercise,
for PAH Patients with NYHA Class II-IV symptoms.
®
Remodulin (treprostinil sodium) Injection, a prostacyclin analogue is approved:
• For the treatment of pulmonary arterial hypertension (PAH) in patients with New York Heart
Association (NYHA) Class II, III or IV symptoms
• Only as a continuous subcutaneous (SC) infusion or intravenous (IV) infusion (for those not able to
tolerate subcutaneous infusion)
• To diminish symptoms (including shortness of breath) associated with exercise
• As a new indication to diminish the rate of clinical deterioration in patients requiring transition
from Flolan®; the risks and benefits of each drug should be carefully considered prior to
transition
Remodulin also offers you and your patients:
•
•
•
•
Room-temperature stability
A delivery system as small as the size of a pager
Dosing flexibility provided by four vial concentrations
A 4-hour half-life
Clinical Effects:
The effect of Remodulin on 6-minute walk, the
primary end point of the studies, was small and
did not achieve conventional levels of statistical
significance. The median change from baseline on
Remodulin was 10 meters and the median
change from baseline on placebo was 0 meters.
Although it was not the primary endpoint of the
study, the Borg dyspnea score was significantly
improved by Remodulin during the 6-minute walk,
and Remodulin also had a significant effect,
compared with placebo, on an assessment that
combined walking distance with the Borg dyspnea
score. Remodulin also consistently improved
indices of dyspnea, fatigue and signs and
symptoms of pulmonary hypertension, but these
indices were difficult to interpret in the context of
incomplete blinding to treatment assignment
resulting from infusion site symptoms.
Contraindications:
• Hypersensitivity to Remodulin, its
ingredients, or to similar drugs
Precautions:
• Remodulin should be used only by physicians
experienced in the treatment of PAH.
• Remodulin therapy must be started in a
setting with equipment and personnel for
emergency care.
• Remodulin is a potent pulmonary and
systemic vasodilator.
• Blood pressure is lowered by Remodulin and
may be lowered further by other drugs that
also reduce blood pressure.
• Remodulin inhibits platelet aggregation and,
therefore, may increase the risk of bleeding,
particularly in patients on anticoagulants.
• Abrupt withdrawal or sudden large
reductions in dosage of Remodulin may
result in worsening of PAH symptoms and
should be avoided.
• Caution should be used in patients with
hepatic or renal problems.
The Most Common Side Effects:
• Side Effects Related To The Method of
Infusion (Subcutaneous or Intravenous)
Subcutaneous — Infusion site pain and
infusion site reaction (redness and swelling)
occur in the majority of patients on SC
Remodulin. These symptoms were often
severe and could lead to treatment with
narcotics or discontinuation of Remodulin.
Please see brief summary of prescribing information on the adjacent page.
United Therapeutics Corporation. Focused on Effective Therapies for PAH patients.
Learn more at www.remodulin.com.
Intravenous (results from an uncontrolled,
open-label study) — Line infections, sepsis,
arm swelling, tingling sensations, bruising
and pain.
• General (>5% more than placebo)
Diarrhea, jaw pain, vasodilatation and edema.
REMODULIN® (treprostinil sodium) Injection
BRIEF SUMMARY
The following is a brief summary of the full prescribing information on Remodulin
(treprostinil sodium) Injection. Please review the full prescribing information prior
to prescribing Remodulin.
INDICATIONS AND USAGE
®
Remodulin is indicated as a continuous subcutaneous infusion or intravenous
infusion (for those not able to tolerate a subcutaneous infusion) for the treatment
of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to
diminish symptoms associated with exercise.
Remodulin is indicated to diminish the rate of clinical deterioration in patients
®
requiring transition from Flolan ; the risks and benefits of each drug should be
carefully considered prior to transition.
DESCRIPTION
®
Remodulin (treprostinil sodium) Injection is a sterile sodium salt supplied in 20 mL
vials in four strengths, containing 1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL of
treprostinil. Each mL also contains 5.3 mg sodium chloride (except for the 10
mg/mL strength which contains 4.0 mg sodium chloride), 3.0 mg metacresol, 6.3
mg sodium citrate, and water for injection.
CONTRAINDICATIONS
Remodulin is contraindicated in patients with known hypersensitivity to the drug or
to structurally related compounds.
WARNINGS
Remodulin is indicated for subcutaneous or intravenous use only.
PRECAUTIONS
General
Remodulin should be used only by clinicians experienced in the diagnosis and
treatment of PAH. Remodulin is a potent pulmonary and systemic vasodilator.
Initiation of Remodulin must be performed in a setting with adequate personnel
and equipment for physiological monitoring and emergency care. Therapy with
Remodulin may be used for prolonged periods, and the patient’s ability to
administer Remodulin and care for an infusion system should be carefully
considered. Dose should be increased for lack of improvement in, or worsening of,
symptoms and it should be decreased for excessive pharmacologic effects or for
unacceptable infusion site symptoms. Abrupt withdrawal or sudden large
reductions in dosage of Remodulin may result in worsening of PAH symptoms and
should be avoided.
fatigue, chest pain, right ventricular heart failure, and pallor). During clinical trials
with subcutaneous infusion of Remodulin, infusion site pain and reaction were the
most common adverse events among those treated with Remodulin. Infusion site
reaction was defined as any local adverse event other than pain or
bleeding/bruising at the infusion site and included symptoms such as erythema,
induration or rash. Infusion site reactions were sometimes severe and could lead
to discontinuation of treatment. In addition, generalized rashes, sometimes
macular or papular in nature, and cellulitis have been infrequently reported in
postmarketing experience.
Percentages of subjects reporting subcutaneous infusion site adverse
events:
Reaction
Pain
Placebo
Remodulin
Placebo
1
38
2
39
NA**
NA**
1
32
Severe
Requiring
narcotics*
Leading to
discontinuation
0
3
0
7
Adverse Events in Controlled 12-Week Studies of Patients with PAH,
Occurring with at Least 3% Incidence and More Common on
Subcutaneous Remodulin than on Placebo.
Adverse Event
Remodulin
(N=236)
Percent of
Patients
Placebo
(N=233)
Percent of Patients
27
Drug Interactions
Reduction in blood pressure caused by Remodulin may be exacerbated by drugs
that by themselves alter blood pressure, such as diuretics, antihypertensive
agents, or vasodilators. Since Remodulin inhibits platelet aggregation, there is
also a potential for increased risk of bleeding, particularly among patients
maintained on anticoagulants. During clinical trials, Remodulin was used
concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel
blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids,
corticosteroids, and other medications. Remodulin has not been studied in
®
conjunction with Flolan or Tracleer (bosentan).
Headache
27
23
Diarrhea
25
16
Nausea
22
18
Rash
14
11
Jaw Pain
13
5
Vasodilatation
11
5
Dizziness
9
8
Edema
9
3
Pruritus
8
6
Hypotension
4
2
Effect of Other Drugs on Remodulin
In vivo studies: Acetaminophen - Analgesic doses of acetaminophen, 1000 mg
every 6 hours for seven doses, did not affect the pharmacokinetics of Remodulin,
at a subcutaneous infusion rate of 15 ng/kg/min.
Reported adverse events (at least 3%) are included except those too general to be
informative, and those not plausibly attributable to the use of the drug, because
they were associated with the condition being treated or are very common in the
treated population.
Effect of Remodulin on Other Drugs
In vitro studies: Remodulin did not significantly affect the plasma protein binding of
normally observed concentrations of digoxin or warfarin.
In vivo studies: Warfarin - Remodulin does not affect the pharmacokinetics or
pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and
the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected
by continuous subcutaneous Remodulin at an infusion rate of 10 ng/kg/min.
Adverse Events Attributable to the Drug Delivery System
Geriatric use
Clinical studies of Remodulin did not include sufficient numbers of patients aged
65 and over to determine whether they respond differently from younger patients.
In general, dose selection for an elderly patient should be cautious, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
Patients receiving Remodulin as a subcutaneous infusion reported a wide range of
adverse events, many potentially related to the underlying disease (dyspnea,
0.00006*
Remodulin Vial Strength
(mg/mL)
Remodulin must be diluted with either Sterile Water for Injection or 0.9%
Sodium Chloride Injection and is administered intravenously by continuous
infusion, via a surgically placed indwelling central venous catheter, using an
infusion pump designed for intravenous drug delivery. To avoid potential
interruptions in drug delivery, the patient must have immediate access to a backup
infusion pump and infusion sets. The ambulatory infusion pump used to
administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no
delivery, low battery, programming error and motor malfunction alarms, (3) have
delivery accuracy of ±6% or better of the hourly dose, and (4) be positive pressure
driven. The reservoir should be made of polyvinyl chloride, polypropylene or
glass. Diluted Remodulin has been shown to be stable at ambient temperature for
up to 48 hours at concentrations as low as 0.004 mg/mL (4,000 ng/mL). When
using an appropriate infusion pump and reservoir, a predetermined intravenous
infusion rate should first be selected to allow for a desired infusion period length of
up to 48 hours between system changeovers. Typical intravenous infusion system
reservoirs have volumes of 50 or 100 mL. With this selected Intravenous Infusion
Rate (mL/hr) and the patient’s Dose (ng/kg/min) and Weight (kg), the Diluted
Intravenous Remodulin Concentration (mg/mL) can be calculated using the
following formula:
The following table lists adverse events that occurred at a rate of at least 3% and
were more frequent in patients treated with subcutaneous Remodulin than with
placebo in controlled trials in PAH.
27
Pediatric use
Safety and effectiveness in pediatric patients have not been established. Clinical
studies of Remodulin did not include sufficient numbers of patients aged <16 years
to determine whether they respond differently from older patients. In general,
dose selection should be cautious.
x
=
Adverse Events During Chronic Dosing:
85
Nursing mothers
It is not known whether treprostinil is excreted in human milk or absorbed
systemically after ingestion. Because many drugs are excreted in human milk,
caution should be exercised when Remodulin is administered to nursing women.
Weight
(kg)
*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
83
Labor and delivery
No treprostinil sodium treatment-related effects on labor and delivery were seen in
animal studies. The effect of treprostinil sodium on labor and delivery in humans is
unknown.
x
Other adverse events included diarrhea, jaw pain, edema, vasodilatation and
nausea, and these are generally considered to be related to the pharmacologic
effects of Remodulin, whether administered subcutaneously or intravenously.
Infusion Site Reaction
Pregnancy
Pregnancy Category B - In pregnant rats, continuous subcutaneous infusions of
treprostinil sodium during organogenesis and late gestational development, at
rates as high as 900 ng treprostinil/kg/min (about 117 times the starting human
2
rate of infusion, on a ng/m basis and about 16 times the average rate achieved in
clinical trials), resulted in no evidence of harm to the fetus. In pregnant rabbits,
effects of continuous subcutaneous infusions of treprostinil during organogenesis
were limited to an increased incidence of fetal skeletal variations (bilateral full rib
or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in
body weight and food consumption) at an infusion rate of 150 ng
2
treprostinil/kg/min (about 41 times the starting human rate of infusion, on a ng/m
basis, and 5 times the average rate used in clinical trials). In rats, continuous
subcutaneous infusion of treprostinil from implantation to the end of lactation, at
rates of up to 450 ng treprostinil/kg/min, did not affect the growth and development
of offspring. Because animal reproduction studies are not always predictive of
human response, Remodulin should be used during pregnancy only if clearly
needed.
Dose
(ng/kg/min)
Subcutaneous
Infusion Rate
(mL/hr)
* based on prescriptions for narcotics, not actual use
**medications used to treat infusion site pain were not distinguished from those used to treat
site reactions
Infusion Site Pain
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies have not been performed to evaluate the carcinogenic potential
of treprostinil. In vitro and in vivo genetic toxicology studies did not demonstrate
any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not
affect fertility or mating performance of male or female rats given continuous
subcutaneous infusions at rates of up to 450 ng treprostinil/kg/min [about 59 times
the recommended starting human rate of infusion (1.25 ng/kg/min) and about 8
times the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m2
basis]. In this study, males were dosed from 10 weeks prior to mating and through
the 2-week mating period. Females were dosed from 2 weeks prior to mating until
gestational day 6.
For subcutaneous infusion, Remodulin is delivered without further dilution at a
calculated Subcutaneous Infusion Rate (mL/hr) based on a patient’s Dose
(ng/kg/min), Weight (kg), and the Vial Strength (mg/mL) of Remodulin being used.
During use, a single reservoir (syringe) of undiluted Remodulin can be
administered up to 72 hours at 37GC. The Subcutaneous Infusion rate is
calculated using the following formula:
Remodulin
Information for Patients
Patients receiving Remodulin should be given the following information:
Remodulin is infused continuously through a subcutaneous or surgically placed
indwelling central venous catheter, via an infusion pump. Therapy with Remodulin
will be needed for prolonged periods, possibly years, and the patient's ability to
accept and care for a catheter and to use an infusion pump should be carefully
considered. In order to reduce the risk of infection, aseptic technique must be
used in the preparation and administration of Remodulin. Additionally, patients
should be aware that subsequent disease management may require the initiation
®
of an alternative intravenous prostacyclin therapy, Flolan (epoprostenol sodium).
Hepatic and Renal Impairment
Caution should be used in patients with hepatic or renal impairment.
patient must have immediate access to a backup infusion pump and
subcutaneous infusion sets. The ambulatory infusion pump used to administer
Remodulin should: (1) be small and lightweight, (2) be adjustable to approximately
0.002 mL/hr, (3) have occlusion/no delivery, low battery, programming error and
motor malfunction alarms, (4) have delivery accuracy of ±6% or better and (5) be
positive pressure driven. The reservoir should be made of polyvinyl chloride,
polypropylene or glass.
In controlled studies of Remodulin administered subcutaneously, there were no
reports of infection related to the drug delivery system. There were 187 infusion
system complications reported in 28% of patients (23% Remodulin, 33% placebo);
173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of
these patients (4 Remodulin, 4 Placebo) reported non-serious adverse events
resulting from infusion system complications. Adverse events resulting from
problems with the delivery systems were typically related to either symptoms of
excess Remodulin (e.g., nausea) or return of PAH symptoms (e.g., dyspnea).
These events were generally resolved by correcting the delivery system pump or
infusion set problem such as replacing the syringe or battery, reprogramming the
pump, or straightening a crimped infusion line. Adverse events resulting from
problems with the delivery system did not lead to clinical instability or rapid
deterioration. here are no controlled clinical studies with Remodulin administered
intravenously. Among the subjects (n=38) treated for 12-weeks in an open-label
study, 2 patients had either line infections or sepsis. Other events potentially
related to the mode of infusion include arm swelling, paresthesias, hematoma and
pain.
OVERDOSAGE
Signs and symptoms of overdose with Remodulin during clinical trials are
extensions of its dose-limiting pharmacologic effects and include flushing,
headache, hypotension, nausea, vomiting, and diarrhea. Most events were selflimiting and resolved with reduction or withholding of Remodulin.
In controlled clinical trials, seven patients received some level of overdose and in
open-label follow-on treatment seven additional patients received an overdose;
these occurrences resulted from accidental bolus administration of Remodulin,
errors in pump programmed rate of administration, and prescription of an incorrect
dose. In only two cases did excess delivery of Remodulin produce an event of
substantial hemodynamic concern (hypotension, near-syncope). One pediatric
patient was accidentally administered 7.5 mg of Remodulin via a central venous
catheter. Symptoms included flushing, headache, nausea, vomiting, hypotension
and seizure-like activity with loss of consciousness lasting several minutes. The
patient subsequently recovered.
Intravenous Infusion
The Amount of Remodulin Injection needed to make the required Diluted
Intravenous Remodulin Concentration for the given reservoir size can then be
calculated using the following formula:
Step 1
Diluted
Intravenous
Remodulin
Concentration
(mg/mL)
Dose
(ng/kg/min)
x
Weight
(kg)
x
0.00006
=
Intravenous Infusion Rate
(mL/hr)
Step 2
Amount of
Remodulin
Injection
(mL)
Diluted
Intravenous
Remodulin
Concentration
(mg/mL)
=
Remodulin Vial
Strength
(mg/mL)
x
Total Volume of
Diluted Remodulin
Solution in
Reservoir
(mL)
The calculated amount of Remodulin Injection is then added to the reservoir along
with the sufficient volume of diluent (Sterile Water for Injection or 0.9% Sodium
Chloride Injection) to achieve the desired total volume in the reservoir.
In patients requiring transition from Flolan:
Transition from Flolan to Remodulin is accomplished by initiating the infusion of
Remodulin and increasing it, while simultaneously reducing the dose of
intravenous Flolan. The transition to Remodulin should take place in a hospital
with constant observation of response (e.g., walk distance and signs and
symptoms of disease progression). During the transition, Remodulin is initiated at
a recommended dose of 10% of the current Flolan dose, and then escalated as
the Flolan dose is decreased (see table below for recommended dose titrations).
Patients are individually titrated to a dose that allows transition from Flolan therapy
to Remodulin while balancing prostacyclin-limiting adverse events. Increases in
the patient’s symptoms of PAH should be first treated with increases in the dose of
Remodulin. Side effects normally associated with prostacyclin and prostacyclin
analogs are to be first treated by decreasing the dose of Flolan.
Recommended Transition Dose Changes
Step
Flolan Dose
Remodulin Dose
1
Unchanged
10% Starting Flolan Dose
2
80% Starting Flolan Dose
30% Starting Flolan Dose
3
60% Starting Flolan Dose
50% Starting Flolan Dose
4
40% Starting Flolan Dose
70% Starting Flolan Dose
5
20% Starting Flolan Dose
90% Starting Flolan Dose
6
5% Starting Flolan Dose
110% Starting Flolan Dose
7
0
110% Starting Flolan Dose +
additional 5-10% increments as
needed
DOSAGE AND ADMINISTRATION
®
Remodulin is supplied in 20 mL vials in concentrations of 1 mg/mL, 2.5 mg/mL,
5 mg/mL and 10 mg/mL. Remodulin can be administered as supplied or diluted for
intravenous infusion with Sterile Water for Injection or 0.9% Sodium Chloride
Injection prior to administration.
Initial Dose for Patients New to Prostacyclin Infusion Therapy
Remodulin is administered by continuous infusion. Remodulin is preferably
infused subcutaneously, but can be administered by a central intravenous line if
the subcutaneous route is not tolerated, because of severe site pain or reaction.
The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be
tolerated because of systemic effects, the infusion rate should be reduced to 0.625
ng/kg/min.
Dosage Adjustments
The goal of chronic dosage adjustments is to establish a dose at which PAH
symptoms are improved, while minimizing excessive pharmacologic effects of
Remodulin (headache, nausea, emesis, restlessness, anxiety and infusion site
pain or reaction). The infusion rate should be increased in increments of no more
than 1.25 ng/kg/min per week for the first four weeks and then no more than
2.5 ng/kg/min per week for the remaining duration of infusion, depending on
clinical response. There is little experience with doses >40 ng/kg/min. Abrupt
cessation of infusion should be avoided (see PRECAUTIONS).
Administration
Subcutaneous Infusion
Remodulin is administered subcutaneously by continuous infusion, via a selfinserted subcutaneous catheter, using an infusion pump designed for
subcutaneous drug delivery. To avoid potential interruptions in drug delivery, the
HOW SUPPLIED
®
Remodulin is supplied in 20 mL multi-use vials at concentrations of 1 mg/mL, 2.5
mg/mL, 5 mg/mL, and 10 mg/mL treprostinil, as sterile solutions in water for
injection, individually packaged in a carton. Unopened vials of Remodulin are
o
o
stable until the date indicated when stored at 15 to 25 C (59 to 77 F). Store at
o
o
o
o
25 C (77 F), with excursions permitted to 15-30 C (59-86 F) [see USP Controlled
Room Temperature].
During use, a single reservoir (syringe) of undiluted Remodulin can be
o
administered up to 72 hours at 37 C. Diluted Remodulin Solution can be
o
administered up to 48 hours at 37 C when diluted to concentrations as low as
0.004 mg/mL in Sterile Water for Injection or 0.9% Sodium Chloride Injection. A
single vial of Remodulin should be used for no more than 30 days after the initial
introduction into the vial.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. If
either particulate matter or discoloration is noted, Remodulin should not be
administered.
United Therapeutics Corp., Research Triangle Park, NC 27709
©Copyright 2006 United Therapeutics Corp. All rights reserved.
Rx only
March 2006
Refer to Full Package Insert for Complete Information
&ORôTHEôTREATMENTôOFôPULMONARYôARTERIALôHYPERTENSIONô7(/ô'ROUPô)ô
INôPATIENTSôWITHô.9(!ô#LASSô)))ôORô)6ôSYMPTOMS
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HYPERTENSION IT MAY BE TIME TO REEXAMINE YOUR
OPTIONS 7HATlS CHANGED 6ENTAVISqA POTENT
PROSTACYCLIN ANALOGUE DELIVERED THROUGH THE
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TREATMENTS ALMOST ANYWHERE
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HYPOTENSION INSOMNIA AND SYNCOPE OTHER SERIOUS ADVERSE EVENTS REPORTED WITH THE USE OF 6ENTAVIS
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FAILUREô6ITALôSIGNSôSHOULDôBEôMONITOREDôWHILEôINITIATINGô6ENTAVISô$OSEôADJUSTMENTSôORôAôCHANGEôINôTHERAPYôSHOULDôBEô
CONSIDEREDôIFôEXERTIONALôSYNCOPEôOCCURSô6ENTAVISôSHOULDôNOTôBEôINITIATEDôINôPATIENTSôWITHôSYSTOLICôBLOODôPRESSUREôLOWERô
THAN MM (G 3TOP 6ENTAVIS IMMEDIATELY IF SIGNS OF PULMONARY EDEMA OCCUR 4HIS MAY BE A SIGN OF PULMONARY VENOUS
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A Breakthrough in
Medical Education
New Complimentary
CD-ROM Available
Pulmonary Hypertension: An Interactive Guide to Diagnosis
This companion piece to the Fall issue of Advances
in Pulmonary Hypertension assists with diagnosis of
pulmonary hypertension and is an invaluable resource
for medical professionals in pulmonology, cardiology,
rheumatology and primary care.
Featuring comprehensive diagnostic
information on:
Physical examination
Introduction on jugular venous pulse
Please go to
www.phassociation.org/medical/cd.asp
to request your complimentary copy or
check the box on the reply card found at
the front of the journal.
The production of this CD-ROM was supported by Grant
Number Purchase Request (PR)# HCL33-2005-23060 and
Contract Award # 254-2005-M-13200 and Purchase
Request (PR)# HCL33-2004-09925 and Contract Award
# 200-2004-M-10076 from the Centers for Disease Control
and Prevention. Its contents are solely the responsibility of
the Pulmonary Hypertension Association and do not necessarily represent the official views of the Centers
for Disease Control and Prevention.
The distribution of this CD-ROM is being made possible by
an unrestricted educational grant from Myogen, Inc.
7 cases providing comprehensive diagnostic
information on:
• Valvular pulmonic stenosis
• Patent ductus arteriosus with pulmonary hypertension
(Eisenmenger syndrome)
• Restrictive ventricular septal defect (VSD)
• Non-restrictive VSD with pulmonary hypertension
(Eisenmenger)
• Hypertensive heart disease, atrial fibrillation, PH,
and tricuspid regurgitation
• Pulmonary arterial hypertension with tricuspid
regurgitation
• Pulmonary arterial hypertension with tricuspid and
pulmonic regurgitation
Initial Diagnostic Testing
Includes comprehensive and interactive information on:
• Echocardiography
• ECG
• Computed tomography
• Chest x-ray
• Right heart catheterization
• V/Q scan
• MRI
I N PA H , TA K E A I M AT E T-1
T H R O U G H E TA S E L E C T I V I T Y
Circulating levels of ET-1, the most potent subtype of ET, have been associated
with disease severity in PAH.1 The deleterious effects of elevated ET-1 include cellular
proliferation, vasoconstriction, and vascular remodeling.2-4
In pulmonary arterial hypertension (PAH), endothelin (ET-1)
exerts its cardiovascular effects through 2 receptors: ETA
and ETB. When ET-1 activates the ETA receptor on the
vascular smooth muscle, it leads to vasoconstriction and
vascular remodeling.4,5 Endothelial ETB receptors mediate
the release of vasodilating nitric oxide (NO) and prostacyclin
(PGI2), while inhibiting and clearing ET-1 from circulation.5,6
Blockade of ETB receptors may significantly impair the
balance of endothelium-derived vasodilating substances.4,7
Endothelial dysfunction has been shown to improve with
selective ETA blockade.8 Hence, preemptive targeting of
ET-1 through selective ETA receptor antagonism can slow
the progression of PAH, and may even provide better overall
outcomes.2-4,8
Figure 1: ETA receptor pathway
TARGETED ET-1 TREATMENTS MAY
PROVIDE BETTER OUTCOMES
Imbalances in the key endothelial cell–derived mediators
NO, PGI2, and specifically ET-1 are thought to be central
to the pathogenesis of PAH.9 NO and PGI are potent
vasodilators with antiproliferative activity.10 ET-1 is a potent
vasoconstrictor with proliferative activity.5 Chronically
elevated levels of ET-1 are associated with pulmonary
vascular resistance, excessive scar formation and cardiac
remodeling, cellular proliferation, and cardiac hypertrophy.1,11-13
A reduction of excess ET-1 levels may result in positive
outcomes for patients with PAH. It has been shown that in
patients with congestive heart failure, elevated ET-1 plasma
Figure 2: ETB receptor pathway
ET-1
ETB
ET-1
➔➔➔
VASOCONSTRICTION
PROLIFERATION
CELL MIGRATION
HYPERTROPHY
INHIBITS ET-1 PRODUCTION
CLEARS ET-1
NO AND PGI2 PRODUCTION
➔ ➔
➔➔➔➔
ETA
VASODILATION
ANTIPROLIFERATION
levels are at least partly associated with impaired ETB
receptor–mediated clearance.13 Furthermore, the longterm administration of a selective ETB receptor antagonist
was found to have unfavorable effects on vascular
remodeling.4 This is in sharp contrast to the benefits of
selective ETA antagonism.14
THE DIFFERENCE LIES IN E TA SELECTIVITY
Vasoconstriction, cellular proliferation, and vascular
remodeling are the hallmarks of PAH.12 Studies have
demonstrated that selective ETA antagonists play a pivotal
role in the regulation of ET-1 levels in PAH and have been
beneficial for vascular remodeling.4, 7,13
Selectivity to the ETA receptor15,17*
BOSENTAN
BQ-123†
1:1
1000:1
2000:1
3000:1
4000:1
5000:1
6000:1
7000:1
ETA SELECTIVITY RATIO
*Based on in vitro studies.
†
BQ-123 is a peptide probe used to measure ETA selectivity of agents.
Figure 3
Effect of ETA receptor selectivity on ET-1 levels 8,15,16
ET-1 AND RECEPTOR-MEDIATED ACTIVITIES
Highly selective ETA blockade maintains ET-1 clearance,
NO and PGI2 levels, and reduces or maintains circulating
ET-1 levels, resulting in vasodilation, increased blood
flow, and repair of remodeled vasculature compared to
less selective agents.5-7,14 (See Figures 1,2 )
HOW SELECTIVE TO E TA SHOULD
TREATMENT BE?
The more selective, the better. One should always be
aware of the varying degrees of selectivity, as they
equate to differences in blockade of the ETA and ETB
receptors and resulting levels of ET-1.8,15,16 Figure 3 illustrates
the difference between a less selective agent and highly
selective agents. These in vitro selectivity ratios demonstrate
the stark differences in ETA selectivity. Figure 4 depicts
how agents with low selectivity of the ETA receptor
(<2400) increase ET-1 levels whereas highly selective ETA
receptor (>2400) antagonists have been shown to
ET-1 LEVELS
INCREASED
Less selective agents
BQ-123†
1:1
1000:1
2000:1
ETA SELECTIVITY RATIO
3000:1
4000:1
5000:1
6000:1
7000:1
ET-1 LEVELS
DECREASED OR UNCHANGED
Highly selective agents
Note: Studies in patients with cardiovascular disease and healthy volunteers.
BQ-123 is a peptide probe used to measure ETA selectivity of agents.
†
Figure 4
decrease ET-1 levels or leave them unchanged.6,8,15
The benefits of ETA selectivity are being recognized.
TOWARD BETTER OUTCOMES IN PAH
Currently, there are no highly selective ETA antagonists
available for the treatment of PAH. In vivo studies have
shown that highly selective ETA antagonism may lead to
better overall outcomes.7,8,12
References: 1. Rubens C, Ewert R, Halank M, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest. 2001;120:1562-1569. 2. Lüscher TF,
Yang Z, Tschudi M, et al. Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins. Circ Res. 1990;66:1088-1094. 3. Yanagisawa M, Kurihara H,
Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. 4. Murakoshi N, Miyauchi T, Kakinuma Y, et al. Vascular endothelin-B receptor
system in vivo plays a favorable inhibitory role in vascular remodeling after injury revealed by endothelin-B receptor–knockout mice. Circulation. 2002;106:1991-1998. 5. Peacock AJ, Rubin LJ, eds. Pulmonary
Circulation: Diseases and Their Treatment. 2nd ed. London: Arnold; 2004. 6. Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats.
Biochem Biophys Res Commun. 1994;199:1461-1465. 7. Verhaar MC, Strachan FE, Newby DE, et al. Endothelin-A receptor antagonist–mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and
by endothelin-B receptor blockade. Circulation. 1998;97:752-756. 8. Halcox JPJ, Nour KRA, Zalos G, Quyyumi AA. Coronary vasodilation and improvement in endothelial dysfunction with endothelin ETA receptor
blockade. Circ Res. 2001;89:969-976. 9. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739. 10. Hankins
SR, Horn EM. Current management of patients with pulmonary hypertension and right ventricular insufficiency. Curr Cardiol Rep. 2000;2:244-251. 11. Spieker LE, Noll G, Ruschitzka FT, Lüscher TF. Endothelin receptor
antagonists in congestive heart failure: a new therapeutic principle for the future? J Am Coll Cardiol. 2001;37:1493-1505. 12. Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeutic
intervention in pulmonary hypertension. Pharmacol Ther. 2001;92:1-20. 13. Lüscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs.
Circulation. 2000;102:2434-2440. 14. Chen SJ, Chen YF, Opgenorth TJ, et al. The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary
hypertension and pulmonary vascular remodeling in Sprague-Dawley rats. J Cardiovasc Pharmacol. 1997;29:713-725. 15. Ihara M, Noguchi K, Saeki T, et al. Biological profiles of highly potent novel endothelin
antagonists selective for the ETA receptor. Life Sci. 1992;50:247-255. 16. Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with pulmonary
hypertension. Circulation. 2000;102:411-418. 17. Clozel M, Breu V, Gray GA, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol
Exp Ther. 1994;270:228-235.
Encysive Pharmaceuticals Inc.
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Suite 700
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©2006 Encysive Pharmaceuticals Inc. All rights reserved. Printed in USA. PAD05042 January 2006
www.encysive.com
Program Announcement:
Submission Deadlines: June 1, 2006 October 1, 2006 February 1, 2007
Pulmonary Hypertension
Association (PHA)
National Heart, Lung, and
Blood Institute (NHLBI)
Jointly Sponsored
Mentored Clinical Scientist Development Award (K08) &
Mentored Patient-Oriented Research Career Development Award (K23)
PURPOSE: K08
• To support the development of outstanding clinician research
scientists in the area of pulmonary hypertension.
• To provide specialized study for clinically trained professionals
who are committed to a career in research in pulmonary
hypertension and have the potential to develop into independent investigators.
• To support a 3 to 5 year period of supervised research experience that integrates didactic studies with laboratory or clinically
based research.
• To support research that has both intrinsic research importance
and merit as a vehicle for learning the methodology, theories,
and conceptualizations necessary for a well-trained independent researcher.
MECHANISM:
Awards in response to the program announcement will use the
National Institutes of Health (NIH) K08 or the K23 mechanism.
FUNDING:*
The award will be funded by PHA and NHLBI and the KO8
and/or the K23 will be awarded in 2006.
PURPOSE: K23
• To support career development of investigators who have
made a commitment to focus their research endeavors on
patient-oriented research.
• To support a 3 to 5 year period of supervised study and
research for clinically trained professionals who have the
potential to develop into productive, clinical investigators focusing on patient-oriented research in pulmonary hypertension.
• To support patient-oriented research, which is defined as
research conducted with human subjects (or on material of
human origin, such as tissues, specimens, and cognitive
phenomena) for which an investigator directly interacts with
human subjects.
• To support areas of research that include: 1) mechanisms of
human disease; 2) therapeutic interventions; 3) clinical trials;
and 4) development of new technologies.
Congratulations to the 2005 awardee
Roberta L. Keller, MD
University of California, San Francisco
Chronic Sildenafil for Severe
Diaphragmatic Hernia
FOR MORE INFORMATION:
Visit: www.phassociation.org/support/mentored.asp
* Restrictions apply. Please see complete announcement
at the Web site listed above.
Advances in
Pulmonary Hypertension
Pulmonary Hypertension Association
PO Box 8277
Silver Spring, MD 20907-8277
To order additional copies, call or contact PHA at 1-866-474-4742 or www.phassociation.org.
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PAID
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