Primary Pulmonary Hypertension

Transcription

1 PULMONARY DISEASE BOARD REVIEW MANUAL PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Bruce M. White EDITORIAL DIRECTOR Debra Dreger SENIOR EDITOR Becky Krumm, ELS ASSOCIATE EDITOR Lamont Williams ASSISTANT EDITOR Jennifer M. Vander Bush EDITORIAL ASSISTANT Nora H. Landon EXECUTIVE VICE PRESIDENT Barbara T. White, MBA PRODUCTION DIRECTOR Suzanne S. Banish PRODUCTION ASSOCIATES Tish Berchtold Klus Mary Beth Cunney PRODUCTION ASSISTANT Stacey Caiazzo ADVERTISING/PROJECT MANAGER Patricia Payne Castle MARKETING MANAGER Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Endorsed by the Association for Hospital Medical Education The Association for Hospital Medical Education endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in medical education as they affect residency programs and clinical hospital practice. Primary Pulmonary Hypertension Series Editor: Robert A. Balk, MD, FACP, FCCP, FCCM Professor of Internal Medicine, Rush Medical College; Director of Pulmonary and Critical Care Medicine, Rush-Presbyterian-St. Luke s Medical Center, Chicago, IL Contributor: Vallerie V. McLaughlin, MD Assistant Professor of Medicine and Associate Director, Center for Pulmonary Heart Disease, Rush-Presbyterian-St. Luke s Medical Center, Chicago, IL Table of Contents Introduction General Considerations Conventional Medical Therapy Epoprostenol Therapy Lung Transplantation Medications Under Investigation Summary Points Board Review Questions Answers References Cover Illustration by May Cheney Copyright 2002, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA , All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications, Inc. The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White Communications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the authors and do not necessarily reflect those of Turner White Communications, Inc. Pulmonary Disease Volume 9, Part 2 1

2 PULMONARY DISEASE BOARD REVIEW MANUAL Primary Pulmonary Hypertension Vallerie V. McLaughlin, MD INTRODUCTION Primary pulmonary hypertension (PPH), the idiopathic form of pulmonary arterial hypertension, is a disease that affects the pulmonary vascular bed. It is characterized by a sustained and substantial increase in pulmonary arterial pressure and pulmonary vascular resistance. The annual incidence of PPH has been estimated at 1 to 2 cases per million in the general population. The incidence of pulmonary arterial hypertension is increased among patients with portal hypertension or HIV infection and among those who use appetite suppressants. 1 Pulmonary arterial hypertension also occurs in association with collagen vascular diseases (eg, scleroderma, systemic lupus erythematous) and congenital systemic-to-pulmonary shunts. The diagnostic classification of the various forms of pulmonary hypertension was revised in 1998 at a symposium sponsored by The World Health Organization (Table 1). Over the years, clinical scientists have become aware that all forms of pulmonary arterial hypertension are similar to each other in terms of pathology, clinical manifestations, and response to therapy. This manual discusses characteristics of PPH and uses casebased discussions to delineate important steps in determining an appropriate treatment for a patient with the disease. The manual also discusses therapies for PPH that are currently under investigation. GENERAL CONSIDERATIONS PATHOPHYSIOLOGY The pathophysiology of PPH involves 3 key features: vasoconstriction, vascular-wall remodeling, and thrombosis in situ. Approximately 20% of patients with PPH have a particularly prominent component of vasoconstriction, which has implications for therapy. Altered function of the pulmonary vascular endothelium has been shown, with an imbalance in the ratio of metabolites of prostacyclin to those of thromboxane. Impaired synthesis of the endothelium-derived vasorelaxant nitric oxide and an enhanced production of the endothelium-derived vasoconstrictor endothelin-1 have also been shown in PPH. COMMON SYMPTOMS AND CLASSIFICATION The symptoms of PPH are nonspecific. The National Institutes of Health (NIH) registry for patients with PPH found dyspnea the most common initial presenting symptom, 2 and it was reported by nearly all patients at some point in the disease process. Fatigue was another common early symptom. The disease is also characterized by angina, syncope, and edema. PPH is usually classified according to the functional classification system developed by the New York Heart Association for heart failure. There are 4 categories (classes I, II, III, and IV). The following clinical vignette describes a patient manifesting typical symptoms of PPH and common physical examination findings related to this disorder. CASE 1 PRESENTATION A 38-year-old woman presents with a 2-year history of dyspnea. Initially, the dyspnea occurred only with substantial exertion. However, over the past 6 months, the dyspnea has worsened and has occurred with less and less exertion. Currently, the patient becomes dyspneic after approximately 1 block of walking or with having walked up less than 1 flight of stairs. She has also experienced light-headedness and near syncopal episodes with exertion. She reports atypical chest pain and mild lower extremity edema. She denies paroxysmal nocturnal dyspnea and orthopnea. She had 2 children without difficulty, 4 and 6 years ago. Her medical and surgical history is otherwise unremarkable, as is her family and social history. On physical examination, her blood pressure is 104/78 mm Hg; she has a heart rate of 94 bpm. Her lungs are clear to auscultation. Her jugular venous pressure is approximately 12 cm of water. Her carotid upstrokes are reduced. She has a prominent right ventricular impulse. On cardiac auscultation, she has a regular rate and rhythm with a normal S 1, a loud pulmonic component to her S 2, a right-sided S 4, and a grade II murmur of tricuspid regurgitation. Her abdomen is soft and nontender without hepatosplenomegaly. There is 1+ lower extremity edema. 2 Hospital Physician Board Review Manual

3 DIAGNOSTIC EVALUATION The diagnosis of PPH is sometimes very difficult to make; the major obstacle to the early diagnosis of PPH is the nonspecific nature of its symptoms. In the NIH registry of patients with PPH, the mean length of time from the onset of symptoms to diagnosis was approximately 2 years. 2 Pulmonary function tests, an electrocardiogram, chest radiograph, echocardiogram, and ventilationperfusion lung scan are important diagnostic tools when PPH is suspected. At times, more extensive testing, including high-resolution chest computed tomography (CT) and pulmonary angiography, is indicated. Pulmonary function tests are crucial to evaluate for lung disease. In patients with PPH, there is generally a mild restrictive pattern but no evidence of obstruction. The diffusing capacity of carbon monoxide may be reduced. Because exercise tolerance correlates well with the severity and prognosis of pulmonary hypertension, it is also important to have the patient perform a treadmill stress test or 6-minute walk test. The electrocardiogram may indicate right ventricular enlargement and may show a right ventricular strain pattern (Figure 1). Chest radiographs commonly show enlarged pulmonary arteries (Figure 2); right ventricular enlargement may be appreciated on the lateral view. An echocardiogram is vitally important to evaluate for left heart and valvular disease and congenital heart defects; it is also useful to estimate the severity of pulmonary hypertension and to evaluate the size of the right heart chambers (Figure 3). Ventilation-perfusion lung scans are important to rule out thromboembolic disease. In the setting of PPH, the ventilation-perfusion lung scan may be normal or may reveal a patchy distribution of tracer. Conversely, in the setting of thromboembolic disease, there are multiple large perfusion defects (Figure 4). If the ventilation-perfusion scan or spiral CT is inconclusive, pulmonary arteriography should be performed to evaluate for the possibility of chronic thromboembolic disease or multiple pulmonary emboli. Serologic studies are often performed to screen for connective tissue diseases. A positive antinuclear antibody test result is common in the setting of PPH, although higher titers and specific antibody patterns should raise the suspicion of collagen vascular diseases. HIV testing is also indicated. Cardiac catheterization is critical in the evaluation of all patients with suspected PPH, to confirm the diagnosis and determine the severity of disease. In addition to an elevated pulmonary arterial pressure, other altered hemodynamics may include an elevated right atrial pressure and a depressed cardiac output. In the NIH Table 1. Diagnostic Classification of Pulmonary Hypertension Pulmonary arterial hypertension Primary pulmonary (arterial) hypertension Sporadic Familial Pulmonary arterial hypertension related to Collagen vascular disease Congenital systemic-to-pulmonary shunts Portal hypertension HIV infection Anorexigens Persistent pulmonary hypertension of the newborn Pulmonary venous hypertension Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia Pulmonary hypertension caused by chronic thrombotic and/or embolic disease Pulmonary hypertension associated with miscellaneous diseases Adapted from the World Health Organization. World Symposium on Primary Pulmonary Hypertension;1998 Sept 6 10; Evian, France. registry, the mean right atrial pressure was 9.7 mm Hg; mean pulmonary arterial pressure, 60 mm Hg; cardiac index, 2.3 L/min/m 2 ; and pulmonary vascular resistance index, 26 Wood units m 2. 2 In the setting of PPH, the pulmonary capillary wedge pressure is normal. Acute vasodilator testing with short-acting vasodilators such as adenosine, nitric oxide, or epoprostenol is commonly performed in the cardiac catheterization laboratory and is critical in making treatment decisions. PATIENT PROGNOSIS Historically, the prognosis of a patient with PPH has been poor despite conventional medical intervention (eg, diuretic therapy). The NIH registry estimated a median survival of 2.8 years among the 194 patients enrolled. 2 The survival rates at 1, 3, and 5 years were 68%, 48%, and 34%, respectively. Mortality was closely associated with parameters of right ventricular hemodynamic function. The registry formulated the following equation, which was predictive of survival, by using 3 variables (ie, mean pulmonary arterial pressure [PAP], mean right atrial pressure [RAP], and cardiac index [CI]): P(t) = [H(t)] A(x,y,z) In this equation, A(x,y,z) = EXP( x y z). In the previous equation, x = PAP; y = RAP; Pulmonary Disease Volume 9, Part 2 3

4 Figure 1. Electrocardiogram of a patient with PPH, indicating right axis deviation, right ventricular enlargement, and right bundle branch block. Figure 2. Chest radiograph of a patient with PPH, showing enlarged pulmonary arteries and cardiomegaly. and z = CI. The NIH registry equation was later prospectively validated in a study of 61 patients. 3 In general, the most common causes of death are progressive right ventricular failure and sudden death. Pneumonia and pulmonary embolus are particularly life threatening in patients with pulmonary hypertension. Great advancements in the treatment of PPH have been made in the 2 decades since the NIH registry was established. New drugs, such as epoprostenol, have an important positive impact on patient prognosis. CONVENTIONAL MEDICAL THERAPY Conventional medical therapy for PPH has centered around the following agents: diuretics, digoxin, vasodilators, and anticoagulants. Diuretics are frequently used to reduce excessive edema in patients with PPH who have right-sided heart failure. They are also particularly useful when hepatic congestion and ascites are present. In refractory cases, more than 1 diuretic is required, and in some instances, patients must be treated with intravenous diuretics. Digoxin can increase cardiac output and reduce circulating neurohormones. However, its use for PPH is controversial. Although many drugs have been used for vasodilatation in the setting of PPH, calcium channel blockers have been the agents tested the most for this purpose and have appeared to produce a more consistent reduction in pulmonary arterial pressure and pulmonary vascular resistance than other vasodilators. Approximately 20% of patients with PPH will respond to calcium channel blockers. This favorable response is usually predicted by the response to a short-acting vasodilator such as adenosine, epoprostenol, or nitric oxide at the time of cardiac catheterization (see section, Vasodilator Testing, on page 5 in this manual). Anticoagulant therapy has been associated with improved survival in one prospective and one retrospective study. 1,4 In one study, 4 patients who did not respond to calcium channel blockers had a significant improvement in survival when treated with anticoagulants, with a survival of 91%, 62%, and 47% after 1, 2, and 3 years compared with 52%, 31%, and 31% among patients who did not receive anticoagulant therapy. Although the effectiveness of warfarin anticoagulation therapy in patients with PPH has never been tested in a prospective, randomized long-term trial, the use of low-dose warfarin, maintaining an international normalized ratio (INR) of 2.0 to 2.5 times control, is recommended. This recommendation is based on the known pathogenesis of PPH and the available data concerning treatment of PPH with warfarin. Patients with hypoxemia, either at rest or with exercise, should receive supplemental oxygen. CASE 2 PRESENTATION A 31-year-old woman presents with an 8-month history of increasing dyspnea with activity, as well as fatigue 4 Hospital Physician Board Review Manual

5 Figure 3. (A) Echocardiogram of a patient with PPH (short-axis view), showing right ventricular enlargement and flattening of the interventricular septum. (B) 4-Chamber view, showing marked right atrial and right ventricular enlargement. The left heart chambers are small. A B and palpitations. Her history, physical examination, and diagnostic evaluation are consistent with the diagnosis of PPH. She undergoes a right heart catheterization, during which the following hemodynamics are recorded: pulmonary arterial pressure, 75/40 mm Hg (with a mean of 50 mm Hg); right atrial pressure, 6 mm Hg; and pulmonary capillary wedge pressure, 6 mm Hg. Her cardiac output is 4.65 L/min, with a cardiac index of 2.31 L/min/m 2 ; this calculates to a pulmonary vascular resistance of 9.5 Wood units. She is administered adenosine by intravenous infusion to assess her vasodilator reserve; with the adenosine, her pulmonary arterial pressure declines dramatically to 35/19 mm Hg, with a right atrial pressure of 1 mm Hg and a pulmonary capillary wedge pressure of 10 mm Hg. Her cardiac output increases to 9.11 L/min with a cardiac index of 4.53 L/min/m 2 ; her pulmonary vascular resistance calculates to 1.1 Wood units. What is considered a positive response to an acute vasodilator, and how should a patient with a positive response be treated? VASODILATOR TESTING Therapy with calcium channel blockers is the most misunderstood concept with regard to the management of PPH. A substantial reduction in both pulmonary arterial pressure and pulmonary vascular resistance is required in order for this therapy to be successful. The mean pulmonary arterial pressure should return to the normal or a near-normal range. Of a group of 17 patients who responded to highdose calcium channel blockers, Rich and colleagues reported a 94% 5-year survival rate compared with a 36% survival rate among patients who did not respond to therapy. 4 Because of the dramatic effect that this therapy has had on patients who respond, most patients with PPH should be considered for acute vasodilator testing to determine if calcium channel blockers would be warranted. However, calcium channel blockers must A B Perf Perf Vent Vent Figure 4. A ventilation-perfusion scan of (A) a patient with primary pulmonary hypertension and (B) a patient with chronic thromboembolic disease. Note the large unmatched perfusion defects in panel B. Perf = perfusion; Vent = ventilation. be used with great caution. Some patients, such as those who are clinically unstable, should not be challenged. Calcium channel blockers should almost always be instituted with invasive hemodynamic guidance. An increase in right atrial pressure and/or decline in cardiac output warrants discontinuation of therapy. When used without the benefit of hemodynamic monitoring, calcium channel blockers may worsen right ventricular failure and potentially cause premature death. Patients who respond to calcium channel blockers should receive long-term treatment with the appropriate dose, and these individuals should be carefully followed to monitor both the safety and efficacy of the treatment. Patients who initially tolerate calcium channel blockers but whose condition subsequently deteriorates should have them discontinued. CONTINUED CLINICAL COURSE OF PATIENT 2 Patient 2 is managed in the intensive care unit and is administered 20 mg of short-acting nifedipine hourly. Pulmonary Disease Volume 9, Part 2 5

6 This results in a sustained decrease in mean pulmonary arterial pressure, with an increase in cardiac output. Notably, the right atrial pressure does not increase, nor does the systemic arterial pressure fall. The patient is treated as an outpatient with amlodipine 30 mg/day. She notes a sustained improvement in her exercise tolerance. After 1 year of therapy, a right heart catheterization is repeated, and the following hemodynamics are recorded: pulmonary arterial pressure, 34/18 mm Hg (with a mean of 22 mm Hg); right atrial pressure, 4 mm Hg; and pulmonary capillary wedge pressure, 8 mm Hg. Her cardiac output is 6.66 L/min, with a cardiac index of 3.45 L/min/m 2. The pulmonary vascular resistance calculates to 2.1 Wood units. EPOPROSTENOL THERAPY CASE 3 PRESENTATION A 23-year-old woman presents with a 1-year history of dyspnea on exertion. Initially, she thought this was simply a result of deconditioning. However, over the past month her dyspnea worsened. She reports fatigue, light-headedness, and near syncope. After a thorough evaluation, a diagnosis of PPH is made. A right heart catheterization shows the following hemodynamics: pulmonary arterial pressure, 74/48 mm Hg (with a mean of 53 mm Hg); right atrial pressure, 18 mm Hg; and pulmonary capillary wedge pressure, 12 mm Hg. Her cardiac output is 2.23 L/min, with a cardiac index of 1.22 L/min/m 2. This calculates to a pulmonary vascular resistance of 18.3 Wood units. She is administered adenosine by intravenous infusion to assess her vasodilator reserve. With the adenosine, her mean pulmonary arterial pressure declines to 45 mm Hg, and her cardiac output increases to 5.03 L/min. Her pulmonary vascular resistance calculates to 6.5 Wood units. How should patient 3 be treated? DISCUSSION Although a substantial reduction in pulmonary vascular resistance occurred in patient 3 with adenosine, a significant reduction in mean pulmonary arterial pressure did not occur. Also, the mean pulmonary arterial pressure did not return to the normal or a near-normal range. Additionally, this patient has evidence of right ventricular failure, considering that her right atrial pressure was 18 mm Hg. In such a patient, a trial of calcium channel blockers is contraindicated. The most appropriate therapy for this patient is epoprostenol. GENERAL CHARACTERISTICS OF EPOPROSTENOL Epoprostenol (Flolan) is a synthetic version of the naturally occurring chemical, prostacyclin. Prostacyclin is a metabolite of arachidonic acid that is produced primarily in the vascular endothelium. The major pharmacologic actions of prostacyclin include potent vasodilatation of the pulmonary and systemic arterial and venous beds and inhibition of platelet aggregation. Patients with PPH have a reduction in prostacyclin synthase; Flolan was the first drug treatment approved by the US Food and Drug Administration (FDA) for patients with PPH. The FDA approved Flolan for PPH functional classes III and IV. The initial enthusiasm for epoprostenol was based on demonstration of pulmonary vasodilator effects in experimental animals. These effects were later demonstrated in patients with PPH. Epoprostenol is currently commercially available; unfortunately, it is very expensive. In the United States the average cost of epoprostenol therapy is $60,000 per year. Prostacyclin analogues that are under investigation include the subcutaneous analogue treprostinil, the oral analogue beraprost, and the inhaled analogue iloprost (see section, Medications Under Investigation on page 8 in this manual). Epoprostenol is administered through a permanent intravenous catheter and delivered by an ambulatory infusion system. The delivery system is complex and requires patients to learn the techniques of sterile preparation, how to operate the ambulatory infusion pump, and how to care for the permanent intravenous catheter. CLINICAL STUDIES OF EPOPROSTENOL Based on the observation that epoprostenol reduces pulmonary vascular resistance and increases cardiac output and oxygen delivery when administered acutely to patients with PPH, Jones and colleagues studied the medication and first reported sustained beneficial symptomatic responses to epoprostenol in patients with PPH who received the drug by continuous intravenous infusion. 5 Subsequently, Rubin and colleagues reported the results of a prospective, randomized, parallel study of patients with PPH treated with continuous intravenous epoprostenol infusion or conventional therapy. 6 They studied 24 patients with PPH over an 8-week period. In the group treated with epoprostenol, there was a reduction in total pulmonary resistance (from a baseline of 21.6 units to 13.9 units), whereas there was no change in the group receiving conventional therapy. After the completion of the 8-week study, all patients were allowed to enter a compassionate use extension trial. In 1994, Barst and colleagues described the exercise tolerance, hemodynamics, and survival of 18 patients 6 Hospital Physician Board Review Manual

7 treated with epoprostenol. 7 With a 6-minute walk test, used to evaluate exercise capacity, patients could walk, on average, more than 100 meters farther after epoprostenol therapy was initiated. The mean walk distance for patients who received epoprostenol therapy was 264 ± 160 meters at baseline, 370 ± 119 meters at 6 months, and 408 ± 138 meters at 18 months. Hemodynamics were also favorably affected for the patients who received epoprostenol. The cardiac index increased by 27%, and total pulmonary resistance decreased by 32% at the end of 12 months time. Kaplan-Meier estimates of 1-, 2-, and 3-year survival rates for the patients treated with epoprostenol were 86.9%, 72.4%, and 63.3%, respectively, which compared favorably to that described in historical controls (77.4%, 51.6%, and 40.6%). In 1996, Barst and colleagues reported the results of a prospective randomized, multicenter trial comparing the effects of a continuous intravenous infusion of epoprostenol plus conventional therapy with that of conventional therapy alone in 81 patients with functional class III or IV PPH. 8 The primary end point of distance walked in 6 minutes improved in the 41 patients treated with epoprostenol plus conventional therapy (from 315 meters at baseline to 362 meters at 12 weeks), whereas it decreased in the 40 patients treated with conventional therapy alone (270 meters at baseline compared with 204 meters at 12 weeks). There were also improvements in hemodynamic parameters: mean changes in pulmonary vascular resistance in the epoprostenol and control groups were 21% and +9%, respectively (P > 0.001). There was also a significant difference in survival: of the 8 patients who died during the study, all had been randomly assigned to the conventional therapy group (P = 0.003). Shortly after the study by Barst and colleagues of 1996, Flolan was approved by the FDA for use in patients with functional class III or IV PPH. We subsequently reported the results of our long-term (16.7-month) study of epoprostenol therapy in 27 patients with PPH. 9 Twenty-six patients had improvement in symptoms and hemodynamic parameters. The mean pulmonary arterial pressure decreased by 20%, and the pulmonary vascular resistance decreased by 53% compared with baseline values. Moreover, in all but 1 patient, the longterm effects of epoprostenol exceeded the acute pulmonary vasodilator response achieved. Importantly, even patients with little or no response to acute vasodilator testing at the time of cardiac catheterization experienced a substantial reduction in pulmonary vascular resistance after long-term therapy with epoprostenol. Shapiro and colleagues demonstrated improved survival in patients treated with epoprostenol. 10 The 1-, 2-, and 3-year survival rates in their patients were 80%, 76%, and 49%, respectively, which were superior to those of historical control subjects and were comparable to the survival rates reported by Barst and colleagues in ADVERSE EFFECTS OF EPOPROSTENOL THERAPY Adverse effects related to epoprostenol therapy are common and include headache, flushing, nausea, diarrhea, and an unusual type of jaw discomfort, which occurs with the first or second bite of a meal. Other chronic adverse effects include thrombocytopenia, weight loss, foot pain, gastropathy, and ascites. In most patients, the symptoms are minimal and well tolerated. Other complications related to epoprostenol therapy include infection of the central venous catheter and subsequent interruptions of therapy. The expected local central line infection rate is in the range of 0.22 to 0.68 per patient per year and that of bacteremia is 0.39 per patient per year. 9 Even a brief interruption in therapy can result in rebound pulmonary hypertension and has been fatal in some instances. DOSING OF EPOPROSTENOL Dosing of epoprostenol is problematic. It was noted early that tolerance to the beneficial effects of epoprostenol seemed to occur in patients. This led to the practice of clinicians progressively increasing the dose in anticipation of symptoms. In 1999, we made the observation that patients treated with chronic epoprostenol therapy may suffer adverse effects related to high cardiac output states. 11 We studied 12 patients on chronic epoprostenol therapy with intolerable adverse effects and high cardiac output. All patients underwent successful reduction in the dose of epoprostenol (mean dose reduction, 39%) without a change in pulmonary arterial pressure. Although the cardiac output returned to the normal range, all patients retained their clinical benefit without a return of intolerance to the drug; importantly, patients had fewer adverse effects related to epoprostenol. CONTINUED CLINICAL COURSE OF PATIENT 3 Patient 3 is treated with epoprostenol in addition to diuretics, digoxin, and warfarin. Her condition improves substantially over several months, with a marked increase in her exercise tolerance. Over the initial 12 months, her epoprostenol is titrated up to 21 ng/kg body weight per min. A heart catheterization after 1 year of therapy documents the following hemodynamics: pulmonary arterial pressure 60/30 mm Hg (with a mean of 39 mm Hg); right atrial pressure, 2 mm Hg; and pulmonary capillary wedge pressure, 9 mm Hg. Her cardiac output is 5.88 L/min, Pulmonary Disease Volume 9, Part 2 7

8 with a cardiac index of 3.11 L/min/m 2. Her pulmonary vascular resistance calculates to 5.1 Wood units. LUNG TRANSPLANTATION CASE 4 PRESENTATION A 44-year-old woman with PPH has been treated with epoprostenol for 2 years. She was critically ill at the time of diagnosis, and epoprostenol was started emergently. Her baseline hemodynamics at the time of epoprostenol initiation were as follows: pulmonary arterial pressure, 72/48 mm Hg (with a mean of 65 mm Hg); right atrial pressure, 17 mm Hg; and pulmonary capillary wedge pressure, 13 mm Hg. Her cardiac output was 1.96 L/min, and her pulmonary vascular resistance calculated to 26.5 Wood units. Despite aggressive up-titration of her epoprostenol, she has remained in PPH functional class III for 2 years. Presently, she receives epoprostenol (48 ng/kg per min); her hemodynamics are as follows: pulmonary arterial pressure, 72/41 mm Hg (with a mean of 51 mm Hg); right atrial pressure, 18 mm Hg; and pulmonary capillary wedge pressure, 11 mm Hg. Her cardiac output is 2.21 L/min, and her pulmonary vascular resistance calculates to 8.1 Wood units. What is the appropriate course of action for a patient who does not improve substantially on epoprostenol? DISCUSSION Lung transplantation has been performed successfully in patients with PPH for more than a decade. Because these patients have severe right ventricular dysfunction, it was originally believed that heart-lung transplantation was the only transplantation option. More recently, bilateral lung transplantation and single lung transplantation have been performed successfully in patients with PPH. The immediate reduction in pulmonary arterial pressure and pulmonary vascular resistance is associated with an improvement in right ventricular function. Bilateral lung transplantation is preferred at most centers because there is greater pulmonary vascular reserve, should the patient sustain a rejection or infection. Single lung transplantation may be preferred in some situations because the operation is technically less challenging and the wait time is shorter. As with any type of organ transplantation, the major long-term morbidity and mortality rates are related to the high incidence of rejection and opportunistic infections. In addition, lung transplantation carries a high risk for the development of bronchiolitis obliterans. In the era of epoprostenol, lung transplantation should be considered a treatment of last resort for patients with PPH. However, because of the long wait time for a lung transplantation at most institutions, it is prudent to evaluate and list a patient for transplantation at the time of the diagnosis of PPH. If the patient responds well to medical therapy, he or she may go inactive on the transplantation list. MEDICATIONS UNDER INVESTIGATION TREPROSTINIL Because of the complexity associated with delivery of epoprostenol (ie, intravenously) and the potential for associated infections and other severe adverse events, an alternative mode of delivery is desirable. Clinical studies have suggested that subcutaneously delivered treprostinil (Remodulin), an analogue of prostacyclin, may also be efficacious in the treatment of PPH. One study was a small, double blind, randomized, placebocontrolled trial of treprostinil involving 26 patients with functional class III or IV PPH. 12 Over an 8-week period, there was an increase in cardiac index and a reduction in pulmonary vascular resistance in patients treated with treprostinil compared with those given placebo. There was also an improvement in exercise tolerance of 36 meters as determined by the 6-minute walk test. This trial demonstrated that treprostinil could be used safely in ambulatory patients by using a novel subcutaneous delivery pump system. Subsequently, a parallel placebo-controlled 12-week trial involving 470 patients with pulmonary arterial hypertension demonstrated improvements in 6-minute walk distance, symptoms, and hemodynamics in patients treated with treprostinil compared with those treated with placebo. 13 There was a significant improvement in the primary endpoint of 6-minute walk distance (17 meters). Importantly, improvements in 6-minute walk distance were related to the dose of treprostinil. The mean dose at week 12 was 9.1 ng/kg per min. The group in the highest quartile of dose (13.8 ng/kg per min) had a 35-meter improvement in 6-minute walk distance. There were also improvements in indices of dyspnea, such as the Borg Dyspnea scale and the Dyspneic Fatigue rating. Most patients experience pain and/or erythema at the site of the subcutaneous infusion. In some patients, this can be severe and can limit dose escalation. Numerous therapies have been used in an attempt to control this infusion-site reaction. However, no therapy has emerged 8 Hospital Physician Board Review Manual

9 as uniformly successful to treat this problem; current recommendations include local therapies such as warm and cold packs, and nonsteroidal anti-inflammatory agents. Narcotic opioids should not be used to control pain. The FDA has recently issued an approvable letter for treprostinil. BERAPROST Beraprost is an orally active prostacyclin analogue that has been used primarily in Japan for the treatment of pulmonary hypertension. A retrospective analysis compared survival of 24 patients treated with beraprost with survival of 34 patients treated with conventional therapy in Japan. 14 Kaplan-Meier survival curves demonstrated that the 1-, 2-, and 3-year survival rates for the beraprost group were 96%, 86%, and 76%, respectively as compared with 77%, 47%, and 44% for the group receiving conventional therapy (log-rank test, P < 0.05). Because of the small and retrospective nature of this study, further investigation with beraprost is warranted. A European trial evaluating beraprost has recently concluded and results should be available soon. In the United States enrollment has been completed in a multicenter, doubleblind, placebo-controlled, randomized trial evaluating beraprost in the treatment of PPH and pulmonary arterial hypertension related to scleroderma. The primary end point of this trial is maximal oxygen consumption as measured by cardiopulmonary exercise testing. These results should be available in mid ILOPROST Iloprost, an inhaled analogue of prostacyclin, has been studied in Europe. One uncontrolled long-term observational study demonstrated an improvement in cardiopulmonary hemodynamics and exercise capacity with aerosolized iloprost. 15 Six-minute walk distance improved from 278 ± 96 meters at baseline to 363 ± 135 meters after 12 months (P < 0.001) among 24 patients with PPH receiving iloprost for at least 1 year. Hemodynamic improvements included a 12% reduction in mean pulmonary arterial pressure, a 16% increase in cardiac output, and a 23% reduction in pulmonary vascular resistance. The cumbersome nature of this treatment, which requires inhalation approximately 9 times per day, may limit the practicality of its use. BOSENTAN Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen. It likely contributes to the increase in pulmonary vascular tone in patients with pulmonary hypertension. Plasma endothelin-1 levels are elevated in patients with PPH, and these levels correlate inversely with prognosis. Recently, endothelin antagonists have been investigated in the setting of pulmonary hypertension. The first placebo-controlled study with the dual endothelin receptor antagonist bosentan (Tracleer), involving 32 patients with PPH or pulmonary arterial hypertension related to scleroderma, demonstrated an improvement in exercise tolerance and hemodynamics with use of the drug. 16 The trial was a 2:1 randomized, double blind, placebo-controlled, 12-week trial. The difference among groups in terms of mean change at week 12 in 6-minute walk distance was 76 meters in favor of bosentan (P = 0.021). There were also significant improvements in cardiac index and pulmonary vascular resistance. The most concerning adverse effect associated with bosentan is an increased incidence of abnormal liver function tests results. Patients treated with this drug should undergo liver function monitoring regularly. Recommendations to either reduce the dose or discontinue the drug are based on the degree of aminotransferase level elevations. Hemoglobin level must also be monitored, because there is a small incidence of anemia associated with bosentan. Bosentan should not be used during pregnancy. Also, because of drug interactions, bosentan should not be used with cyclosporin A or glyburide. Bosentan should soon be commercially available in the United States. SUMMARY POINTS The major obstacle to the early diagnosis of PPH is the nonspecific nature of its symptoms. Increased awareness of this serious disease is important. The diagnostic evaluation should be thorough. Important studies include electrocardiography, chest radiography, pulmonary function tests, ventilationperfusion lung scanning, echocardiography, and exercise testing. Cardiac catheterization is required to make the diagnosis. In most instances, the patient should be challenged with a short-acting vasodilator. Diuretics are used to treat right-sided heart failure. Warfarin anticoagulation prolongs survival. Calcium channel blockers improve symptoms and survival in a select subset of patients with PPH. Calcium channel blockers should be used with caution in patients with PPH. Epoprostenol improves symptoms, exercise tolerance, hemodynamics, and survival in patients with PPH. Lung transplantation is an option for those with Pulmonary Disease Volume 9, Part 2 9

10 advanced disease who are refractory to epoprostenol therapy. Because of the complex nature of the disease and its treatments, early referral to a pulmonary hypertension center is appropriate. BOARD REVIEW QUESTIONS Choose the single best answer for each question. 1. With which of the following conditions is pulmonary arterial hypertension NOT associated? A) Atrial septal defects B) The CREST (calcinosis, Raynaud s disease, esophageal dysmotility, sclerodactyly telangiectasia) syndrome C) Mitral stenosis D) Portal hypertension 2. Which of the following is the most common symptom of PPH? A) Dyspnea C) Fatigue B) Chest pain D) Syncope 3. Which of the following patients might be a candidate for high-dose oral calcium channel blockers? A) A 27-year-old man with PPH whose pulmonary vascular resistance dropped from 14 Wood units to 9 Wood units after an acute challenge with prostacyclin, but who did not experience a reduction in pulmonary arterial pressure B) A 33-year-old woman with recently diagnosed PPH who has dyspnea at rest and 3+ lower extremity edema C) A 37-year-old woman with recently diagnosed PPH whose mean pulmonary arterial pressure dropped from 62 mm Hg to 50 mm Hg with inhaled nitric oxide D) A 41-year-old woman with PPH whose mean pulmonary arterial pressure fell from 45 mm Hg to 28 mm Hg with an adenosine challenge 4. A 39-year-old woman has shortness of breath with minimal activity and has marked lower extremity edema and ascites. A complete diagnostic evaluation establishes PPH as the cause of her illness. Which of the following medications is the most appropriate therapy for this patient? A) Calcium channel blockers, digoxin, and diuretics B) Epoprostenol, calcium channel blockers, and bosentan C) Epoprostenol, calcium channel blockers, and diuretics D) Epoprostenol, diuretics, and warfarin 5. Which of the following patients is the most appropriate candidate for lung transplantation? A) A 32-year-old woman with functional class II PPH who is receiving oral calcium channel blockers B) A 37-year-old man who has just been diagnosed with PPH and who does not have an acute response to vasodilators at the time of his right heart catheterization C) A 41-year-old woman with PPH who remains severely symptomatic despite appropriate epoprostenol dose titration D) A 46-year-old woman with PPH who has done well on calcium channel blockers for 5 years but who has recently experienced worsening dyspnea ANSWERS 1. C 2. A 3. D 4. D 5. C REFERENCES 1. Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984;70: Rich S, Dantzker RS, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107: Sandoval J, Baurele O, Palomar A, et al. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 1994;89: Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327: Jones K, Higenbottam T, Wallwork J. Pulmonary vasodilation with prostacyclin in primary and secondary pulmonary hypertension. Chest 1989;96: Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Ann Intern Med 1990;112: Hospital Physician Board Review Manual

11 7. Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121: Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334: McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with longterm epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338: Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol 1997;30: Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol 1999;34: McLaughlin VV, et al. Efficacy and safety of UT-15, a prostacyclin analog, for primary pulmonary hypertension. Eur J Cardiol 1999;20: Simonneau G, Barst RJ, Galie N, et al for the UT-15 Study Group. Continuous subcutaneous infusion of UT-15, a prostacyclin analogue in patients with pulmonary arterial hypertension. A double-blind randomized controlled trial. Am J Respir Crit Care Med 2002 (in press). 14. Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiology 1999;34: Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000; 342: Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358: Copyright 2002 by Turner White Communications Inc., Wayne, PA. All rights reserved. Pulmonary Disease Volume 9, Part 2 11