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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. ACTTR1387_Card_PulmInsert_Mv09 4/5/06 6:14 PM Page 1 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 ACTTR1387_Card_PulmInsert_Mv09 ACTTR1387_Card_PulmInsert_Mv09 4/5/06 6:14 PM Page 2 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 ACTTR1387_Card_PulmInsert_Mv09 ACTTR1387_Card_PulmInsert_Mv09 4/5/06 6:14 PM Page 3 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. ACTTR1387_Card_PulmInsert_Mv09 ACTTR1387_Card_PulmInsert_Mv09 4/5/06 6:14 PM Page 4 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 Flolan_Brief Summary_8.5x11 3/21/06 5:59 PM Page 1 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 RL-1139 FLL087R0_FCAD_Survival 3/21/06 6:04 PM Page 1 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 Advs in PH V5N1 4/14/06 12:15 PM Page 16 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 Advs in PH V5N1 4/14/06 12:15 PM Page 17 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 Advances in Pulmonary Hypertension 17 Advs in PH V5N1 4/14/06 12:15 PM Page 18 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. Advs in PH V5N1 4/14/06 12:15 PM Page 19 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. ■ References 1. Owan T, Redfield M. Epidemiology of diastolic heart failure. Prog Cardiovasc Dis. 2005;47:320-32. 2. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004;43:317-27. 3. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216-23. 4. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-7. 5. Sitbon O, McLaughlin VV, Badesch DB, Barst RJ, Black C, Galie N, Humbert M, Rainisio M, Rubin LJ, Simonneau G. 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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 Advs in PH V5N1 4/14/06 12:15 PM 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. ■ References 1. 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. 2. Baker BJ, Wilen MM, Boyd CM, et al. Relation of right ventricular ejection fraction to exercise capacity in chronic left ventricular failure. Am J Cardiol. 1984;54:596-599. 3. DiSalvo TG, Mathier M, Semigram MJ, Dec GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol. 1995;25:1143-1153. 4. Butler J, Chromsky DB, Wilson R. Pulmonary hypertension and exercise intolerance in patients with heart failure. J Am Coll Cardiol. 1999;34:1802-1806. 5. Ghio S, Gavazzi A, Capana C, et al. Independent and additive prognostic value of right ventricular function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2005;37:183188. 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 the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease ). J Am Coll Cardiol. 1998;32:1588. 8. Alexopoulos D, Lazzam C, Borrico S, Fiedler L, Ambrose JA. Isolated chronic mitral regurgitation with preserved systolic left ventricular function and severe pulmonary hypertension. J Am Coll Cardiol. 1989;14:319-322. 9. Pennington DG, Merjavy MT, Swartz MT, et al. 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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 Cardiol. 1972;30:820-826. 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 Advs in PH V5N1 4/14/06 12:15 PM Page 30 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 Advs in PH V5N1 4/14/06 12:15 PM Page 31 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 Advs in PH V5N1 4/14/06 12:15 PM 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. ■ References 1. Thom TJ, Kannel WB. Congestive heart failure: epidemiology and cost of illness. Dis Manage Health Outcomes. 1997; I: 75–83. 2. Barker WH, Mulloly JP, Getchell W. Changing Incidence and Survival for Heart Failure in a Well-Defined Older Population, 1970–1974 and 1990–1994 Circulation. 2006;113:799-805. 3. Hunt SA, Abraham WT, Chin MH, et al. 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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. 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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. 4848 Loop Central Drive Suite 700 Houston, Texas 77081 ©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. Non Profit US POSTAGE PAID Permit No. 999 Syracuse, NY
