Case Study Investigation (CSI) Diagnosis and Management of Pulmonary Arterial Hypertension Case Review Monograph. editor

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1 PAH Case Study Investigation (CSI) Diagnosis and Management of Pulmonary Arterial Hypertension Case Review Monograph editor Harrison W. Farber, MD Professor of Medicine Director, Pulmonary Hypertension Center Boston University School of Medicine Boston, MA healthmatterscme A CONTINUING MEDICAL EDUCATION COMPANY This activity is supported by an independent educational grant from Gilead Sciences Medical Affairs. This activity is jointly sponsored by the University of Kentucky College of Medicine and HealthmattersCME.

2 CME INFORMATION CME Credit How to Obtain CME Credit 1. Complete monograph in its entirety 2. Upon completion go to 3. Enter activity code MEN Login or register for a free account 5. Complete posttest and evaluation 6. Get credit. A printable certificate will be issued Faculty Harrison W. Farber, MD Professor of Medicine Director, Pulmonary Hypertension Center Boston University School of Medicine Boston Medical Center Activity Overview CSI: PAH is an interactive case review in which the participants make choices at various decision points affecting the diagnosis and management of pulmonary arterial hypertension (PAH). This activity will enable clinicians who treat patients with PAH to learn about evidence-based, state-of-the-art strategies for the diagnosis of PAH, the value of current diagnostic tests, the implementation of early screening programs, currently available therapies, as well as a review of the 4th World Symposium on Pulmonary Hypertension treatment algorithm. Target Audience Cardiologists Pulmonologists Rheumatologists Accreditation Statement Medicine This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Kentucky College of Medicine and HealthmattersCME. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky College of Medicine designates this educational activity for a maximum of 1.75 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine. The content of the publication is provided solely by faculty who have been selected because of recognized expertise in their field. All faculty members participating in continuing medical education programs sponsored by the University of Kentucky College of Medicine are expected to disclose any real or perceived conflict of interest related to the content of the publication. Faculty disclosures are listed below. Financial Disclosures Harrison W. Farber, MD Consultant: Actelion Pharmaceuticals, Gilead Sciences, United Therapeutics Speakers Bureau: Actelion Pharmaceuticals, Gilead Sciences Educational Objectives After completing this activity, participants will be better able to: Identify patients with PAH by screening high-risk individuals Explore the most recent data regarding the pathogenesis of PAH and how this knowledge may affect choice of treatment Compare and contrast available treatments in terms of their benefits for patients Develop and implement appropriate treatment strategies for individual patients healthmatterscme A CONTINUING MEDICAL EDUCATION COMPANY This activity is jointly sponsored by the University of Kentucky College of Medicine and HealthmattersCME

3 PAH Case Study Investigation (CSI) Diagnosis and Management of Pulmonary Arterial Hypertension Case Review Monograph A CME/CE-Certified Enduring Material Release Date: September 1, 2009 Expiration Date: September 1, 2010 Estimated time to complete this activity: 1.75 hours editor Harrison W. Farber, MD Professor of Medicine Director, Pulmonary Hypertension Center Boston University School of Medicine Boston, MA This program is supported by an independent educational grant from Gilead Sciences Medical Affairs. hea lthmatt e r scme A CONTINUING MEDICAL EDUCATION COMPANY This activity is jointly sponsored by the University of Kentucky College of Medicine and HealthmattersCME.

4 2 CSI:PAH Harrison W. Farber, MD Professor of Medicine Director, Pulmonary Hypertension Center Boston University School of Medicine Boston, MA Table of Contents Dear Health Care Professional: Pulmonary arterial hypertension (PAH) is a disease with severe symptoms. It often goes undetected until the affected individual is seriously ill and experiences significant functional impairment. Many PAH patients are in the prime years of their lives; as such, the disease can have a devastating effect on their ability to participate fully in both work and family activities. Furthermore, PAH is rapidly fatal when left untreated, and even with adequate treatment, late diagnosis is associated with increased risk of death. However, the benefits of years of basic and clinical research are coming to fruition and have given us reason to be more optimistic about diagnosis and treatment. During the past several years, our knowledge and understanding of the epidemiology and pathophysiology of PAH have expanded greatly, and improved screening and diagnostic approaches have followed suit. Until recently, therapy options for PAH patients were limited to invasive and complex treatments, but now clinicians have a much broader range of therapies that not only improve symptoms but, in some cases, also prolong survival. As you will learn in this monograph, although PAH is a rare disease, it does affect particular subgroups at a higher rate, such as those with connective tissue disease, with certain genetic mutations, with human immunodeficiency virus (HIV) infection, and with other defined conditions. Recent evidence also suggests that the use of stimulants, such as methamphetamine, may be an important risk factor. However, PAH often presents on its own, without any identifiable associated condition; this form of the disease is termed idiopathic PAH. Therefore, all clinicians must maintain a high index of suspicion for PAH in any patient presenting with shortness of breath. The diagnostic approach to PAH involves excluding other possible causes of the patient s symptoms and eliminating any other forms of pulmonary hypertension. Because all suspected cases of PAH must be confirmed by right-heart catheterization, the recommended diagnostic path proceeds from noninvasive to invasive testing. Although noninvasive therapies, such as oral and inhaled medications are now available for treatment of PAH, this treatment is complex and requires a team of health care professionals. For this reason, clinicians are encouraged to refer their patients to pulmonary hypertension specialty centers for optimal treatment. Introduction... 4 Pulmonary Arterial Hypertension Overview... 4 Clinical Classification and Functional Class Staging... 5 Pathology... 8 Pathophysiology of PAH... 9 Diagnosis of PAH...12 PAH Treatment Modalities...19 PAH Treatment Strategies...21 Conclusions...25 References...25 This CME activity will benefit clinicians by alerting them to the signs of PAH in their patients. It will also give them a fundamental understanding of the differential diagnosis necessary to exclude or confirm suspected PAH. In turn, this CME activity will benefit PAH patients by increasing awareness of this condition among clinicians, encouraging earlier recognition and diagnosis, and optimizing treatment by promoting referral of patients to pulmonary hypertension specialty centers. I hope that you will find this Case Study Investigation monograph to be a useful part of your continuing education about this challenging and multifaceted disease. Sincerely, Harrison W. Farber, MD Editor

5 4 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 5 INTRODUCTION This monograph will describe the state of knowledge concerning the pathophysiology of pulmonary arterial hypertension (PAH), review strategies and technologies available for its screening and diagnosis, and discuss currently available and emerging therapies, as well as recommendations from expert panels for evaluating patients and selecting treatment. At different points throughout the program, a patient case study will be presented in order to highlight important decisions affecting the diagnosis and management of PAH. Learning Objectives Upon completion of this program, participants will be better able to: 1. Identify patients with PAH by screening high-risk individuals 2. Explore the most recent data regarding the pathogenesis of PAH and how this knowledge may affect choice of treatment 3. Compare and contrast available treatments in terms of their benefits for patients 4. Develop and implement appropriate treatment strategies for individual patients PULMONARY ARTERIAL HYPERTENSION OVERVIEW Description and Definition PAH is a rare but serious progressive disorder associated with vascular remodeling. Ultimately, it results in right ventricular dysfunction and impairment of functional abilities, leading to rightheart failure and death. 1,2 PAH is generally defined as a mean pulmonary artery pressure 25 mm Hg with a mean pulmonary capillary wedge pressure (or left ventricular end-diastolic pressure) 15 mm Hg, and a pulmonary vascular resistance of 240 dyn.sec.cm 5 or 2 or 3 Woods units. 3 Patients often present late in the course of the disease, years after symptoms first appear, and with marked functional impairment. 4 PAH is rare in the general population in the United States, with estimates ranging from 15 to 50 cases per million persons. 4,5 However, prevalence is higher in persons with certain conditions, particularly those with connective tissue disease. Among individuals with scleroderma, PAH occurs most often in those who have limited disease or the calcinosis, Raynaud s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome. Prevalence estimates range from 7% to 29% of patients, but when confirmed by right-heart catheterization, prevalence is approximately 12% in patients with both diffuse and limited forms of sclerosis. 4,6 Patients infected with the human immunodeficiency virus (HIV) are at elevated risk for PAH, including those taking highly active antiretroviral therapy (HAART). In this population, PAH prevalence is estimated to be 0.5%. 7 PAH is also more common among patients with certain hemolytic disorders, such as sickle cell anemia or thalassemia. 8 Prevalence estimates range from 5% to 30% depending on the population s age, severity of symptoms, and assessment methods used. 6,9 Approximately two thirds to three quarters of all PAH patients are female. 4,10 Although PAH can occur at any age, the median age of patients enrolled in a recently established patient registry in the United States is 53 years. 11 While most patients are diagnosed as adults between 20 and 50 years of age, 12 some data suggest that the age of newly diagnosed patients is increasing. 13 For example, a recent analysis of data from a national PAH registry in France found that 9% of patients were 70 years of age or older at initial diagnosis. 4 More specific studies on the epidemiology of PAH in the United States are lacking. The most valid and useful survival data were collected by the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension more than 2 decades ago, during the 1980s. 14 Other registries have been established in France, China, and Switzerland. 14 However, none of these registries fulfill the need for comprehensive data on PAH patients, treatments, and outcomes. In order to address the need for current and detailed data on PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) was established in March REVEAL Registry The REVEAL study was designed to provide updated and specific information about Group 1 PAH (described below under Clinical Classification), including patient demographics, clinical features, and effects of therapy. 14 The main objectives of REVEAL are listed in Table 1. REVEAL is a multicenter, observational registry based in the United States designed to run from 2006 through December As of September 30, 2007, a total of 2977 PAH patients had been enrolled, and the participation of an additional 500 newly diagnosed patients was pending. 14 All patients will be followed up for a minimum of 5 years. An important feature of REVEAL is its unique definition of PAH, which has broader hemodynamic parameters than traditional criteria. REVEAL allows the enrollment of patients who have a mean pulmonary capillary wedge pressure (or left ventricular end-diastolic pressure) >15 mm Hg (the usual cutoff point) but 18 mm Hg, as well as patients who were diagnosed with PAH based on clinical judgment rather than on strictly defined parameters. 14 The broader PAH definition should help refine PAH diagnostic criteria and identify the timing and selection of treatments that will benefit individual patients the most. Table 1: Main objectives of the REVEAL Study in patients with WHO Group 1 PAH. REVEAL objectives n Characterize patient demographics and clinical course of disease n Evaluate differences in outcomes among Group 1 subgroups n Compare outcomes between patients who do and do not meet traditional hemodynamic criteria for PAH diagnosis n Identify predictors of short-term and long-term outcomes n Assess the effect of monotherapy and combination therapy on patient outcomes n Report current trends in therapy and outcomes for recently diagnosed patients n Collect current and relevant data that will meet the needs of the PAH research community REVEAL, Registry to Evaluate Early and Long-term PAH Disease Management. Source: From Table 1. McGoon MD, Krichman A, Farber HW, et al. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc. 2008;83:924. CLINICAL CLASSIFICATION AND FUNCTIONAL CLASS STAGING Pulmonary hypertension (PH) is any elevation of arterial pressure in the lungs that may or may not be associated with vascular resistance. 12 In comparison, PAH is a disease of the pulmonary arterioles that results in an elevation in arterial pressure and is accompanied by vascular resistance. 12 During the past several decades, the different forms of pulmonary hypertension have been more specifically defined as knowledge of the underlying pathophysiology has grown and epidemiological data accumulated. 15 Classification schemes for pulmonary hypertension have been developed and periodically revised by international expert panels in Geneva, Switzerland, in 1973; in Evian, France, in 1998; in Venice, Italy, in 2003; and most recently in Dana Point, California, in 2008, at the 4th World Symposium on Pulmonary Hypertension. 8,15,16 The 4th World Symposium on Pulmonary Hypertension Clinical Classification The most recent classification system divides PH into 5 categories, or groups, based on mechanisms or pathology rather than on associated conditions, which was the case with previous classification systems. 16,17 This classification system retains the change made in Venice in 2003, which replaced the term primary pulmonary hypertension with idiopathic pulmonary arterial hypertension (IPAH) to describe PAH without a known underlying cause. 8,17 Table 2 lists the subgroups of Group 1 PAH, which is the focus of this monograph. Group 1 PAH comprises 6 subcategories: idiopathic PAH, heritable (formerly called familial) PAH, PAH associated with drug and toxin exposure, PAH associated with certain defined disorders, PAH in the newborn, and PAH associated with veno-occlusive disease and/or pulmonary capillary hemangiomatosis. All the Group 1 subgroups exhibit similar histological changes in the lung tissue. Table 3 classifies other types of pulmonary hypertension that mainly occur secondary to other medical conditions, such as left-heart disease, lung disease, and chronic pulmonary thrombotic embolism. Groups 2-5 are discussed in this monograph only in the context of the differential diagnosis of PAH. Idiopathic PAH Idiopathic PAH occurs in the absence of any known cause. 12 As discussed below, although diagnosis of idiopathic PAH requires one to exclude other causes of PH, idiopathic PAH is a distinct clinical entity. Evidence from a French registry study showed that, within the category of Group 1 PAH, idiopathic PAH is the most common form. 4 As displayed in Table 4, page 6, findings from the French registry study and the REVEAL registry indicated that, at the time of diagnosis, 40% to 50% of all patients with PAH had the idiopathic form. 4,11 Heritable PAH Heritable PAH has an underlying genetic component and has been identified in families worldwide. 12 Approximately 6% to 10% of all patients with idiopathic PAH have a family history of PH. 18 However, the penetrance of the mutations responsible for PH is low (20%), and many individuals who inherit the gene never develop the disease. 12 Heritable PAH is associated with so-called genetic anticipation, wherein the members of successive generations who develop PAH tend to have an earlier age Table 2: 2008 clinical classification of pulmonary hypertension group 1. Group Type of pulmonary hypertension 1 Pulmonary arterial hypertension (PAH) 1.1 Idiopathic (IPAH) 1.2 Heritable 1.2.1: BMPR : ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) 1.2.3: Unknown 1.3 Drug- and toxin-induced 1.4 Associated with (APAH): 1.4.1: Connective tissue disease 1.4.2: Human immunodeficiency virus (HIV) infection 1.4.3: Portal hypertension 1.4.4: Congenital heart disease 1.4.5: Schistosomiasis 1.4.6: Chronic hemolytic anemia 1.5 Persistent pulmonary hypertension of the newborn 1 Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) Source: Adapted with permission from Table 2. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S45. Table 3: 2008 clinical classification of pulmonary hypertension groups 2-5. Group Type of pulmonary hypertension 2 Pulmonary hypertension owing to left-heart disease 2.1: Systolic dysfunction 2.2: Diastolic dysfunction 2.3: Valvular disease 3 Pulmonary hypertension owing to lung diseases and/or hypoxia 3.1: Chronic obstructive pulmonary disease 3.2: Interstitial lung disease 3.3: Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4: Sleep-disordered breathing 3.5: Alveolar hypoventilation disorders 3.6: Chronic exposure to high altitude 3.7: Developmental abnormalities 4 Chronic thromboembolic pulmonary hypertension (CTEPH) 5 Pulmonary hypertension with unclear multifactorial mechanisms 5.1: Hematologic disorders: myeloproliferative disorders, splenectomy 5.2: Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis; lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3: Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4: Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Source: Adapted with permission from Table 2. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S45. of onset and more severe and rapidly progressive disease. 13 Possible mutations associated with heritable PAH are discussed below, under Pathophysiology. Drug- and toxin-induced PAH PAH can result from exposure to certain drugs and toxins. Use of anorexigens (appetite suppressants), particularly those derived from fenfluramine, is associated with an increased risk

6 6 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 7 Table 4: Breakdown of group 1 PAH by subgroup. French registry Group 1 PAH subgroup at time of diagnosis n Percentage* Idiopathic Connective tissue disease Congenital heart disease Portal hypertension Anorexigens HIV infection Heritable Two coexisting risk factors REVEAL registry Group 1 PAH subgroup at time of enrollment (n=1226) Percentage Idiopathic 46 Associated Collagen vascular disease Congenital heart disease Other Other 4 *Numbers do not add to 100% due to rounding. Sources: Adapted with permission from Table 1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1024. Adapted from Badesch. 11 of PAH. 16,19 An epidemic of PAH occurred in Europe in the 1960s following the introduction of the appetite suppressant aminorex fumarate, and similar increases in PAH prevalence were associated in both Europe and North America with the widespread use of fenfluramine derivatives. 6 Exposure to other drugs (including amphetamines and cocaine) and toxins (such as rapeseed oil) is also associated with an increased risk of PAH. 20 Emerging evidence suggests that methamphetamine use may be associated with PAH. 21 A retrospective study conducted at a large pulmonary hypertension referral center in California found that approximately 28% (n=97) of all patients with idiopathic PAH reported a history of stimulant use, of which methamphetamine was the most frequent. 21 Considering that 5% of all individuals 12 years old report using methamphetamine at some time during their lives, 22 these preliminary findings may have significant implications for the future incidence and prevalence of PAH. 13 PAH associated with specific conditions Connective tissue disease. As mentioned above, patients with limited systemic sclerosis, particularly the CREST variant, are at increased risk for PAH. In the French national registry study, 76% of patients with PAH associated with connective tissue disease had scleroderma. 4 Other connective tissue diseases may be associated with an increased risk of PAH, including systemic lupus erythematosus, mixed connective-tissue disease, and rheumatoid arthritis. 16 The presence of Raynaud s phenomenon is a common feature in patients with connective tissue disease and PAH. HIV infection. The prevalence of PAH is 6 to 12 times higher in patients infected with HIV than in the general population. 7,16 The mechanism underlying the association between HIV and PAH is unknown, but it appears to be unrelated to CD4 cell count. 16 PAH can occur at any stage of HIV infection, including when viral load is undetectable Portopulmonary hypertension. Pulmonary abnormalities, including PAH, are relatively common in patients with liver disease. 12 The prevalence rate of PAH in patients with portal hypertension is estimated at 1% to 6%. 3 Risk factors for portopulmonary hypertension include cirrhosis, female sex, and autoimmune hepatitis. 12,24 Patients with PAH associated with portal hypertension have clinical impairment similar to that of patients with idiopathic PAH, but they may have smaller increases in pulmonary vascular resistance or decreases in cardiac output. 6,12 PAH can also occur with portal hypertension in the absence of manifest liver disease. More severe disease and poor cardiac function are associated with poor prognosis. 25 Congenital heart disease. Congenital heart disease, particularly left-to-right intracardiac shunts, is a well-established risk factor for PAH. 8 There are 4 recognized phenotypes of PAH associated with congenital heart disease: Eisenmenger syndrome, PAH associated with systemic-to-pulmonary shunts, PAH with small defects, and PAH after corrective cardiac surgery. 8 The risk of PAH increases in proportion to the size of the defect; however, PAH can develop even among patients with small atrial or ventricular septal defects. 8,23 Schistosomiasis. The parasitic disease schistosomiasis is associated with an increased risk of PAH. 26,27 The underlying mechanism most likely involves more than one factor, such as inflammation caused by impacted schistosoma eggs, and portopulmonary hypertension, which is a frequent complication of schistosomiasis. 8 Schistosomiasis affects 200 million people worldwide; one recent screening study from Brazil using right-heart catheterization reported a 4.6% prevalence of PAH in patients with hepatosplenic schistosomiasis. 27 Chronic hemolytic anemia. PAH is now recognized as a complication of several chronic hereditary and acquired hemolytic anemias, including thalassemia, sickle cell disease, and hereditary spherocytosis. 8 PAH associated with sickle cell disease has been the most studied; however, accurate prevalence data are still lacking. Prospective studies are ongoing to estimate the prevalence of PAH in sickle cell disease. 8 Persistent pulmonary hypertension of the newborn. Persistent pulmonary hypertension of the newborn varies in severity, but most patients have severe hypoxemia and require mechanical ventilation. 12 Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH). PVOD and PCH are both very rare forms of PAH. 12 Both conditions are severe and often require lung transplantation. 12 Because PAH associated with PVOD and/or PCH shares characteristics with idiopathic PAH but still has some distinct differences, the 2008 classification system designated this form of PAH as 1. 8 Function Class Staging The staging of PAH is patterned after the system developed for heart disease by the New York State Heart Association. The functional classes allow clinicians to categorize patients according to disease severity. As shown in Table 5, there are 4 functional classes (FCs), I through IV. 13 The degree to which symptoms impair physical functioning increases along with functional class number, beginning at FC I, in which PAH symptoms do not limit Table 5: World Health Organization (WHO) functional classification of PAH. Functional class Class I Class II Class III Class IV Description Patients with pulmonary hypertension that causes no limitations on physical activities. Routine physical activity does not cause increased dyspnea, chest pain, fatigue, or presyncope. Patients with pulmonary hypertension that causes mild limitations on physical activities. Patients are comfortable at rest but routine physical activity results in increased dyspnea, chest pain, fatigue, or syncope. Patients with pulmonary hypertension that causes marked limitations on physical activities. Patients are comfortable at rest, but less than routine physical activity results in dyspnea, chest pain, fatigue, or syncope. Patients with pulmonary hypertension that results in the inability to perform any physical activities without symptoms. These patients may have signs of right-heart failure. Dyspnea with or without fatigue may be present at rest, and symptoms are increased by any physical activity. Source: Table 3. McLaughlin V V, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1424. World Health Organization. the routine physical activities of patients, and progressing to FC IV, in which symptoms limit patients from engaging in any physical activity. The functional class system is also frequently used as an end point in clinical trials of PAH treatments. 2 However, the functional class system is subjective, and categorization can vary by clinician. 28 Survival Survival times tend to vary according to severity of symptoms and PAH subgroup. In the NIH registry, the median survival time of Group 1 PAH patients was 2.8 years. 29 As expected, survival decreased with time: 68% of patients survived 1 year, 48% survived 3 years, and 34% survived 5 years. Survival also declined with higher functional class. Patients in FC I or II had a median survival time of approximately 59 months as compared with 32 months for patients in FC III and only 6 months for patients in FC IV. 29 In addition, right ventricular hemodynamic parameters correlated with survival. As shown in Figure 1, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, and decreased cardiac index were associated with shorter survival. 29 It is important to note that the NIH registry was compiled before the advent of more effective therapies. The effect that current PAH treatments have on length of survival is discussed below in the section on PAH Treatment Modalities. Survival also varies according to Group 1 PAH subgroup. 30 Available studies suggest that patients with PAH associated with congenital heart disease tend to have better survival rates than those with idiopathic PAH, or PAH associated with other conditions, as shown in Figure 2. (Data on survival rates for subgroups of PAH associated with other conditions are limited.) Patients with collagen vascular disease generally have the worst prognosis, with fewer than half surviving more than 2 years. 30 Those with PAH associated with HIV infection have somewhat lower rates of survival as compared with idiopathic PAH. Data on survival in patients with PAH associated with portal hypertension are very limited but may be similar to those for idiopathic PAH. 30 Factors that appear to have no effect on survival include family history of PAH, gender, history of oral contraceptive use, and smoking history. 29 Figure 1: Median survival times in months by hemodynamic parameter for patients with primary pulmonary hypertension. Median survival (months) <55 mmhg 85 mmhg Mean pulmonary artery pressure <10 mmhg 20 mmhg Mean right atrial pressure 4L/min/m 2 <2L/min/m 2 Mean cardiac index Source: Figure 2. D Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115:346. Reprinted with permission. Figure 2: Survival times by etiology. Survival (%) CHD IPAH CVD HIV Years Portopulmonary hypertension Abbreviations: CHD, congenital heart disease; CVD, collagen vascular disease; HIV, human immunodeficiency virus; IPAH, idiopathic pulmonary arterial hypertension. Source: Figure 1. McLaughlin V V, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension. Chest. 2004;126:80S. Reprinted with permission.

7 8 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 9 Key Learnings CLINICAL CLASSIFICATION AND FUNCTIONAL CLASS STAGING n PAH is typically defined as mean pulmonary artery pressure 25 mm Hg with a mean pulmonary capillary wedge pressure (or left ventricular end-diastolic pressure) 15 mm Hg, and a pulmonary vascular resistance of 240 dyn sec cm 5 or 2 or 3 Woods units n PAH is a rare disease, affecting an estimated 15 to 50 individuals per million in the US population. The prevalence of PAH is higher in patients with connective tissue disease, HIV infection, schistosomiasis, portopulmonary hypertension, congenital heart disease, and chronic hemolytic anemia n Approximately two thirds to three fourths of all PAH patients are female. Most patients are diagnosed as adults between ages 20 and 50 years, although the age at diagnosis appears to be increasing n The WHO 2008 classification system divides pulmonary hypertension into 5 groups based on mechanisms or pathology. Group 1 PAH includes idiopathic PAH (also known as IPAH), heritable PAH, PAH associated with specific disorders, PAH associated with significant venous or capillary involvement, and PAH in the newborn. All the Group 1 subgroups exhibit similar histological changes in the lung tissue Figure 3: Schematic diagram of plexiform lesions. SMC EC i Pulmonary circulation Muscularization of peripheral arteries ii Internal elastic lamina External elastic lamina Medial hypertrophy of muscular arteries iii Loss of small precapillary arteries Interrupted internal elastic lamina PATHOPHYSIOLOGY OF PAH The exact cause of PAH remains to be determined. However, its pathogenesis most likely involves a multiple-hit process wherein the disease arises from the interaction of several internal and external stimuli. 16 A combination of 2 or more stimuli (eg, a genetic disposition and an environmental exposure) can combine to activate and promote the vascular changes that lead to PAH. This process is analogous to those theorized for how some cancers develop, in which multiple factors interact with a genetic predisposition to initiate neoplastic growth. The molecular mechanisms of PAH are not completely clear, but research has identified a number of contributing causes (discussed next) that can be categorized as vasoactive mediators, environmental factors, and genetic predispositions. However, it is important to remember that these factors influence each other and most likely do not act in isolation to cause PAH. Vasoactive Mediators The vascular changes associated with PAH appear to be promoted by alterations in the normal balance between several factors: (1) vasoconstrictors and vasodilators, (2) growth inhibitors and mitogenic substances, and (3) antithrombotic and prothrombotic determinants. 16 Endothelial cell dysfunction or injury (eg, hypoxia, inflammation, shear stress, or toxins) most likely is the event that initiates these imbalances, which eventually lead to vascular remodeling. Vascular remodeling pathways There are 3 main pathways involved in the remodeling of pulmonary arteries: the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway. 2 Figure 4 illustrates a tranverse section of a small pulmonary artery and shows 3 pathways leading to vasoconstriction and cell proliferation. Dysfunctional endothelial cells produce greater amounts of endothelin-1 and reduced amounts of nitric oxide and prostacyclin. These 3 pathways contribute to the intimal proliferation and clinical hypertrophy seen in affected pulmonary arteries. These pathways also represent current and potential targets for PAH therapies (these are discussed in the section PAH Treatment Modalities, below). Key mediators of vasoactivity There are many mediators of pulmonary vascular responses in PAH. Those that play the most significant roles are endothelin-1, prostacyclin and thromboxane A 2, nitric oxide, serotonin, adrenomedullin, vasoactive intestinal peptide, and vascular endothelial growth factor (VEGF). The effects of these key vascular mediators on pulmonary arteries are summarized in Table 6, page 10, and described below. 16 Endothelin-1. Endothelin-1 is a peptide formed by the cleavage of its precursors by endothelin-converting enzymes. 33 It is a paracrine factor that is produced primarily by endothelial cells and acts locally. Endothelin-1 is a potent and longacting vasoconstrictor; it also stimulates smooth muscle cell n The staging of PAH by functional class allows clinicians to categorize patients according to disease severity. There are 4 functional classes: I-IV. The extent to which symptoms impair physical functioning increases with higher functional class number Lung Figure 4: Major pathways involved in vascular remodeling associated with PAH. PATHOLOGY In a healthy individual, the pulmonary vasculature is a high-flow, low-pressure, and low-resistance system. Normal pulmonary arteries are thin-walled and compliant, with few muscle fibers. In pulmonary hypertension, by contrast, pulmonary arteries exhibit a range of pathological changes, including smooth muscle cell hypertrophy, intimal hyperplasia, thrombosis, and eventually, plexiform lesions. 31 The frequency of these changes varies from patient to patient and can occur unevenly in the lung tissue regions of individual patients. 12 Plexiform lesions are characteristic of PAH but not diagnostic because they can occur in other forms of pulmonary hypertension. These arterial lesions are formed by complex dilations of an arterial branch distal to an obstructed larger artery. Such lesions are composed of a disorganized web of microchannels lined with endothelial cells, as well as smooth muscle cells, myofibroblasts, and macrophages. 12 Figure 3 shows the progressive pathological changes in the artery that lead to the formation of plexiform lesions. 32 First, the peripheral pulmonary arteries become muscularized as a result of smooth muscle cell growth and proliferation. Second, medial hypertrophy develops in large muscular arteries, which progressively thicken. Third, small precapillary arteries are lost. Fourth, neointimal formation occurs, which can become occlusive. Fifth, as disease advances, plexiform lesions develop as endothelial cells proliferate abnormally and microchannels form. v Plexiform lesion formation iv Neointima formation Pathobiology of PH. Schema illustrating the different vascular abnormalities compared with normal pulmonary circulation, associated with PH. This schema depicts the abnormalities throughout the pulmonary circulation, including (i) abnormal muscularization of distal precapillary arteries, (ii) medial hypertrophy (thickening) of large pulmonary muscular arteries, (iii) loss of precapillary arteries, (iv) neointimal formation that is particularly occlusive in vessels μm, and (v) formation of plexiform lesions in these vessels. Abbreviations: EC; endothelial cells; SMC, smooth muscle cells. Source: Figure 1. Rabinovich M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2008;118:2373. Reprinted with permission. Pre-proendothelin Endothelin receptor A Endothelinreceptor antagonists Smooth-muscle cells Endothelin pathway Proendothelin Endothelin-1 Vasoconstriction and proliferation Endothelial cells Endothelin receptor B L-arginine Phosphodiesterase type 5 Nitric oxide pathway Nitric oxide cgmp L-citrulline Vasodilatation and antiproliferation Phosphodiesterase type 5 inhibitor Exogenous nitric oxide Arachidonic acid Prostacyclin derivatives The 3 major pathways responsible for vascular remodeling are shown and the sequences targeted by some PAH therapeutic classes: endothelin-receptor antagonists, phosphodiesterase type 5 (PDE5) inhibitors, exogenous nitric oxide, and prostacyclin derivatives. +, increase in the intracellular concentration;, decrease in the intracellular concentration, receptor blockade, enzyme inhibition; cgmp, cyclic guanosine monophosphate. Source: Figure 1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1427. Reprinted with permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. Vessel lumen Prostacyclin (prostaglandin I 2 ) camp Prostacyclin pathway Vasodilatation and antiproliferation Prostaglandin I 2

8 10 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 11 proliferation. 16,34 Endothelin-1 levels are increased in PAH and are associated with deterioration of hemodynamic parameters. 13,34 Endothelin-1 acts through 2 receptor subtypes: ET A and ET B. 34 ET A receptors are located primarily on smooth muscle cells and fibroblasts, whereas ET B receptors are found mainly on endothelial cells and, to a lesser extent, on smooth muscle cells, macrophages, and fibroblasts. 34 The actions of ET A and ET B tend to oppose one another. 34 Stimulation of ET A receptors facilitates vasoconstriction, proliferation, and migration of smooth muscle cells, hypertrophy, and fibrosis, whereas stimulation of ET B receptors facilitates vasodilation and inhibits cell proliferation by triggering the release of nitric oxide and prostacyclin. In addition, ET B activation mediates endothelin clearance from kidney, liver, and lung tissue and inhibits endothelin-converting enzyme. Prostacyclin and thromboxane A 2. Prostacyclin and thromboxane A 2 derive from arachidonic acid in vascular cells and generally have opposing effects. 13,16 Prostacyclin acts as a potent vasodilator and inhibitor of platelet activation and cell proliferation, whereas thromboxane A 2 acts as a potent vasoconstrictor and promoter of platelet activity. In PAH, there is an imbalance between these 2 molecules activity that favors thromboxane A 2. The activity of prostacyclin synthase, a key enzyme in the formation of prostacyclin, is reduced, as are prostacyclin levels. In addition, levels of thromboxane A 2 increase. This imbalance creates an environment in which more negative effects of thromboxane A 2 can occur (eg, vasoconstriction and platelet activation) unopposed by the more protective effects of prostacyclin, such as vasodilation and inhibition of cell proliferation. Nitric oxide. Nitric oxide is formed from arginine by nitric oxide synthase (NOS) in endothelial cells. Nitric oxide has potent vasodilatory effects and inhibits platelet activation and vascular smooth muscle cell proliferation. Nitric oxide exerts its effects through a complex pathway involving the production of the second messenger cyclic guanosine monophosphate (cgmp) in vascular smooth muscle cells. 13 The production of cgmp leads to the opening of the potassium channels in the cell membrane, which results in membrane depolarization and calcium-channel inhibition. The resultant reduced entry of calcium into the cell, and the decreased release of calcium from sarcoplasmic stores, in turn inhibit the contractile response and lead to vasodilation. 13 Because NOS expression is reduced in patients with PAH, vasoconstriction and cell proliferation are promoted. 13,16 Serotonin. Serotonin is a hormone that acts as both a neurotransmitter and a vasoconstrictor. It may also promote pulmonary smooth muscle cell proliferation. 35 Normally, the vascular bed in the lungs is not exposed to high levels of serotonin because the serotonin is stored in platelets. 35 However, evidence suggests that in PAH, serotonin plasma levels may be elevated and serotonin platelet levels decreased. 13 As an example, the appetite suppressant dexfenfluramine, which is associated with an increased risk of PAH, inhibits the reuptake of serotonin and increases its release from platelets. 16,19 However, serotonin itself may not be the cause of the pathological changes in PAH; rather, the changes may result from alterations in one or more of the serotonin receptors or transporters. 13,16 More research is needed to define the precise role of serotonin in vascular remodeling. Adrenomedullin. Adrenomedullin is a peptide synthesized by a variety of cell populations in healthy lung tissue, as well as in Table 6: Vascular mediators and their effects on pulmonary vasculature. Vasoconstriction Cell proliferation Thrombosis + TxA 2 + VEGF + TxA 2 PGI 2 PGI 2 PGI 2 NO NO NO + ET-1 + ET HT + 5-HT + 5-HT VIP VIP VIP +, increased;, decreased; 5-HT, 5-hydroxytryptamine (serotonin); ET-1, endothelin-1; NO, nitric oxide; PGI 2, prostaglandin I 2 (prostacyclin); TxA 2, thromboxane A2; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide. Source: Adapted with permission from Figure 1. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351:1657. Copyright 2004 Massachusetts Medical Society. All rights reserved. blood vessels and the heart. 16,36 Adrenomedullin has vasodilatory, anti-inflammatory, and antioxidant effects. Adrenomedullin levels are increased in PAH and are correlated with increased mean right atrial pressure, pulmonary vascular resistance, and mean pulmonary vascular resistance. 16 However, evidence suggests that adrenomedullin is most likely a marker for pulmonary hypertension and not an underlying causal factor. 16 Vasoactive intestinal peptide. Vasoactive intestinal peptide (VIP) acts primarily as a neurotransmitter but also functions as a vasodilator in both the systemic and pulmonary circulation. 36 VIP also inhibits platelet activation and smooth muscle cell proliferation. 16 Levels of VIP appear to be decreased in the blood and lung tissue of patients with idiopathic PAH. 16,36 Vascular endothelial growth factor. VEGF is a polypeptide that stimulates angiogenesis and endothelial cell proliferation. In the lung, hypoxia induces increases in VEGF and its receptors. In PAH, the formation of plexiform lesions appears to be associated with disordered angiogenesis and elevated levels of VEGF, its receptors, and the presence of other, related signaling molecules. 16 Environmental Factors As mentioned above, multiple factors most likely act in concert to trigger the development of PAH. Several environmental factors are known to contribute to an increased risk of PAH and most likely are involved in the mechanisms that set in motion the associated pathogenic vascular changes. These include hypoxia, anorexigens, central nervous system stimulants, and other external triggers. Hypoxia Although hypoxia is not central to the development of PAH, it may contribute to the associated vascular remodeling. The response to acute hypoxia differs within the systemic and pulmonary vasculature. In the systemic circulation, acute hypoxia induces vasodilation, whereas in the pulmonary circulation, it induces vasoconstriction. 37 In response to hypoxia in pulmonary arteries, endothelial-cell-derived endothelin and serotonin mediate vasoconstriction. 16 In addition, acute hypoxia inhibits the normal functioning of potassium ion channels, leading to membrane depolarization, an increase in cytoplasmic calcium, and vasoconstriction. 37 The vasoconstriction caused by acute hypoxia is reversible; however, chronic hypoxia results in permanent and pathological changes to the pulmonary vasculature. These changes lead, in turn, to persistently elevated pulmonary vascular resistance, pulmonary hypertension, right ventricular failure, and possibly death. 37 Anorexigens As discussed above, appetite suppressants (especially fenfluramine derivatives) increase the risk of PAH. 16 Whereas most patients exposed to these drugs who develop PAH do so after an average of 3 months of use, PAH can appear in patients after as little as a few weeks of exposure. 35,38 Central nervous system stimulants As mentioned previously, use of central nervous system (CNS) stimulants, particularly amphetamines and cocaine, is associated with an increased risk of PAH. 21 These CNS stimulants have multiple pharmacological effects, including blockade of the release and reuptake of catecholamines, serotonin, and dopamine. 39 However, how these effects increase the risk of PAH is unknown. Previous theories suggested that contaminants or foreign bodies in the stimulants were causal factors; however, pathological changes in pulmonary arteries have been observed in patients who used cocaine free of contaminants. 39 Furthermore, fenfluramine derivatives and aminorex are CNS stimulants that do not contain contaminants or foreign bodies and yet increase the risk of PAH. Other external stimuli PAH can also be caused by other environmental factors. Examples include contaminated rapeseed oil, L-tryptophan, and possibly chemotherapeutic agents and antidepressants. 6 In addition, schistosomiasis has emerged as a significant condition associated with PAH. 26 It is likely that as awareness and recognition of PAH increases, other factors will be identified. n In pulmonary hypertension, pulmonary arteries exhibit a range of pathological changes, including smooth muscle cell hypertrophy, intimal hyperplasia, thrombosis, and eventually, plexiform lesions n The exact cause of PAH is unknown but most likely involves a multiple-hit process wherein the disease arises from a combination of 2 or more stimuli, such as a genetic predisposition and environmental exposure n The 3 main pathways involved in the pathogenesis of PAH are the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway. Dysfunctional endothelial cells produce greater amounts of endothelin-1 and reduced amounts of nitric oxide and prostacyclin n Endothelin-1 is a potent and long-acting vasoconstrictor; it also stimulates smooth muscle cell proliferation. Endothelin-1 acts through 2 subtypes of receptors: ET A and ET B. Stimulation of ET A receptors facilitates vasoconstriction, proliferation, and migration of smooth muscle cells, hypertrophy, and fibrosis, whereas stimulation of ET B receptors facilitates vasodilation and inhibits cell proliferation by triggering the release of nitric oxide and prostacyclin Key Learnings PATHOLOGY AND PATHOPHYSIOLOGY OF PAH Predisposing Genetic Conditions Several genotypes have been associated with an increased risk of PAH. These include mutations in bone morphogenetic protein (BMP ) receptor type II (BMPR2), activin-like kinase type 1 (ACVRL1), and possibly variants in the serotonin transporter (5-HTT ) gene promoter. Presence of these genotypes may predispose individuals to development of PAH if they are exposed to environmental factors such as use of anorexigens or hypoxia. Bone morphogenetic protein receptor type II BMPR2 is part of the transforming growth factor beta (TGF-b) receptor family. 40 TGF-b cytokines and receptors help regulate cell and tissue growth, stimulate inflammatory responses and wound healing, and initiate neoplastic transformation. 10 Mutations in BMPR2 interfere with normal signal transduction during the process of pulmonary vascular smooth muscle cell apoptosis (programmed cell death), leading to cell proliferation. 40 Although only a small percentage of patients with PAH have a family history of the disease, 65% of families with inherited PAH have a mutation in the BMPR2 gene; mutations in BMPR2 are also present in 10% of sporadic PAH cases. 40 However, because penetrance is low ( 20%), 80% of individuals with a BMPR2 mutation will never develop symptoms of PAH, and only 10% of the offspring of individuals with a mutation will develop the disease. Activin-like kinase type 1 Activin-like kinase type 1, found on endothelial cells, is a receptor that is also part of the TGF-b family and is encoded by the ACVRL1 gene. 40 Mutations in ACVRL1 are identified more rarely than BMPR2 mutations in patients with PAH, and are predominantly found in PAH associated with hereditary hemorrhagic telangiectasia. 8,10 n Prostacyclin acts as a potent vasodilator and inhibitor of platelet activation and cell proliferation. In PAH, there is an imbalance between prostacyclin and thromboxane A 2 that leads to excessive vasoconstriction and platelet activation n Nitric oxide has potent vasodilatory effects and inhibits platelet activation and vascular smooth muscle cell proliferation. Because NOS expression is reduced in patients with PAH, vasoconstriction and cell proliferation are promoted n Several environmental factors are known to contribute to an increased risk of PAH, including hypoxia, anorexigens (eg, fenfluramine derivatives), CNS stimulants (eg, amphetamines and cocaine), and other external triggers (schistosomiasis, toxic rapeseed oil, L-tryptophan) n Several genotypes have been associated with an increased risk of PAH. These include mutations in BMPR2, ACVRL1, and possibly variants in the 5-HTT gene promoter. The presence of these genotypes may predispose individuals to develop PAH if they are exposed to other factors, such as use of anorexigens or hypoxia

9 12 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 13 Serotonin transporter alleles Preliminary evidence suggests that variants in the promoter for the serotonin transporter 5-HTT gene polymorphisms may be associated with pulmonary artery smooth muscle cell proliferation. 13,41 However, further investigation is needed to determine the role that serotonin transporter alleles play in the pathogenesis of PAH. Role of Inflammation Dysfunctional inflammatory responses have been implicated in the pathogenesis of PAH. 42 Patients with systemic inflammatory diseases (eg, lupus) are at higher risk for developing PAH, and plexiform lesions in patients with idiopathic PAH show infiltration by macrophages, lymphocytes, and dendritic cells, as well as expression of chemokines. 42 DIAGNOSIS OF PAH Most PAH patients are diagnosed in the late stages of disease, when it has already progressed to severe functional impairment. 4 Analysis of data from a national PAH registry in France showed that 75% of patients were diagnosed at stage FC III and IV approximately 2 years after the initial onset of symptoms. 4 In addition, stage at diagnosis did not vary with PAH subgroup, even among patients with comorbid conditions that typically require PAH screening with echocardiography, such as congenital heart disease, portal hypertension, or systemic sclerosis. 4 Because length of survival decreases as functional status declines, improvements in screening and earlier diagnosis are needed. Screening Screening for PAH can be difficult due to a lack of diseasespecific symptoms and the fact that many patients are asymptomatic in earlier stages of this condition. 42 As PAH is a rare disease, screening the general population would not be useful 13 but may be appropriate in certain subgroups of patients who are at high risk. Evidence suggests that patients with congenital heart disease, connective tissue disease, HIV infection, or sickle cell disease benefit from screening for PAH with Doppler echocardiography, followed by right-heart catheterization to confirm the diagnosis. 13,40,42 Screening is also appropriate for patients who have multiple family members with PAH or carry a known genetic mutation that is associated with PAH. In addition, patients with symptoms of dyspnea on exertion, angina pectoris, or syncope that cannot be attributed to another cause should be screened for PAH. 40 Diagnosis Where there is a clinical suspicion of PAH, it is essential to confirm the diagnosis by right-heart catheterization. 3,43 However, first it is necessary to eliminate any other possible causes of the patient s symptoms through careful patient interview and stepwise use of noninvasive (Doppler echocardiography) or minimally invasive laboratory and diagnostic tests. Clinical history Diagnosis of PAH begins by taking a complete clinical history. Presenting symptoms that are suggestive of PAH are listed in Table 7 and reflect the impaired oxygen transport and reduced cardiac output associated with the disease. 44,45 Table 7: Symptoms of PAH. n Exertional dyspnea n Fatigue n Weakness n Angina n Syncope n Abdominal distension n Peripheral edema Common presenting symptoms Source: Barst R, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):S40. Dyspnea is considered the hallmark symptom of PAH. It affects 95% of patients and is the presenting symptom in 60% of all cases. 23 Initially, dyspnea may occur on exertion, but as the disease progresses may also be present at rest. 45 Early in the course of the disease, patients may attribute dyspnea to aging or not being physically fit. Complaints of fatigue and weakness are also commonly reported. Some patients report angina-type chest pain on exertion. Syncope may also occur and portends a negative prognosis, automatically placing a patient in FC IV. 40 Syncope may initially occur on exertion, but in later stages of PAH it occurs when the patient is at rest. In more advanced PAH, abdominal distension and peripheral edema signal right ventricular failure. 23 Patient and family history When taking a patient s history, all comorbid conditions, such as left-heart disease, and conditions associated with PAH, such as connective tissue disease, should be noted. 45 In addition, patients should be asked about any family members who have had similar symptoms, a diagnosis of PAH, or connective tissue disease. Patients also should be asked whether they have been exposed to any drugs or toxins associated with increased risk of PAH. 45 Physical examination Although the signs of pulmonary hypertension are subtle and easily overlooked, certain findings have been identified that are suggestive of PAH. These include the following 45 : Accentuated pulmonary component of the second heart sound, audible at the apex, which reflects the increased force of the pulmonary valve closure owing to increased pulmonary arterial pressure Early systolic ejection click caused by the sudden interruption of the pulmonary valve opening Midsystolic ejection murmur resulting from turbulent transvalvular pulmonary flow Palpable left parasternal lift caused by the impulse of the hypertrophied high-pressure right ventricle Right ventricular S 4 gallop Prominent jugular A wave, which suggests high right ventricular filling pressure In addition, signs of more advanced PAH disease include 45 : Diastolic murmur of pulmonary regurgitation Holosystolic murmur of tricuspid regurgitation, which is audible at the lower left sternal border and increases during inspiration Tricuspid regurgitation, as indicated by an increased jugular venous pressure with accentuated V waves, hepatojugular reflux, and a pulsatile liver Right ventricular failure, as indicated by a right ventricular S 3 gallop, prominent distension of the jugular veins, an enlarged and pulsatile liver, peripheral edema, and abdominal distension Reduced cardiac output and vasoconstriction, as indicated by hypotension, reduced pulse pressure, and cool extremities The following findings, detected during the examination, can provide some clues into possible underlying symptom causes 45 : Cyanosis is indicative of right-to-left shunting, severely decreased cardiac output, or severe impairment in intrapulmonary gas transfer. Cyanosis is also present in 20% of patients with idiopathic PAH Digital clubbing is suggestive of congenital heart disease or pulmonary veno-occlusive disease but is rare in idiopathic PAH Fine rales, accessory muscle use, wheezing, or prolonged exhalation indicate pulmonary parenchymal or airway disease Obesity, enlarged tonsils, and kyphoscoliosis (ie, lateral curvature of the spine with rotation of the vertebrae) may be possible underlying causes of a hypoventilatory syndrome Scleroderma skin changes, other rashes, arthritis, nail-fold capillary abnormalities, and other related signs suggest the presence of a connective tissue disorder Peripheral venous insufficiency or obstruction calls for further evaluation for pulmonary thromboembolic disease and venous thrombosis An electrocardiogram (ECG) may be performed and typically shows right ventricular hypertrophy and right atrial dilation in Figure 5: Flow chart for evaluating suspected pulmonary hypertension. RVE, RAE, RVSP left heart disease VHD CHD Echocardiogram, ECG LFTs and clinical evidence of cirrhosis and portal htn Portopulmonary hypertension Functional test RH catheterization Vasodilator test Chest x-ray HIV test HIV patients with PAH. 44 However, the ECG lacks sufficient sensitivity and specificity to accurately confirm or exclude PAH. Differential diagnosis If findings from the clinical history and physical examination suggest pulmonary hypertension, further evaluation of the patient proceeds in a series of required supplemental tests to identify or exclude other possible causes. Figure 5 shows an algorithm for the differential diagnosis of PAH. 13 The progression of tests begins with echocardiography and ends with right-heart catheterization, which is an absolute requirement for confirming a PAH diagnosis. 3,43,45 Table 8, page 14, summarizes the purpose and key findings of blood tests and required diagnostic tests. 40 ECG and echocardiogram. Findings from the ECG and echocardiogram may help identify or exclude left-heart disease, valvular heart disease, or congenital heart disease. Although not useful as a screening tool, the ECG can provide information about the degree of right ventricular hypertrophy, right-heart dilation, and the presence of arrhythmias. 45 Doppler echocardiography is an essential tool for evaluating PAH because it provides estimates of right ventricular systolic pressure and can assess right atrial enlargement, right ventricular enlargement, and pericardial infusion. 45 However, Doppler echocardiography can underestimate or overestimate the presence of pulmonary hypertension; thus, additional testing is required. 13,46 Chest radiography. Although most patients with PAH have a normal chest radiograph, this test can help reveal any abnormal anatomic features that may be caused by PAH, such as central pulmonary artery enlargement or right ventricular enlargement. 44,45 The chest radiograph can also help identify other Emphysema fibrosis thoracic abnl Autoantibody tests Scleroderma SLE RA vasculitis Sleep disorder Ventilationperfusion scan, angiography Chronic thromboembolism Solid arrows indicate the suggested progression of tests. Dotted arrows indicate potential underlying causes, alternative diagnoses, or characteristics of pulmonary hypertension that can be determined by the test. Abbreviations: abnl, abnormality; CHD, congenital heart disease; ECG, electrocardiogram; LFTs, liver function tests; htn, hypertension; PFTs, pulmonary function tests; RA, rheumatoid arthritis; RAE, right atrial enlargement; RH, right heart; RVE, right ventricular enlargement; RVSP, right ventricular systolic pressure; SLE, systemic lupus erythematosus; VHD, valvular heart disease. Source: Figure 3. McLaughlin V V, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1422. Reprinted with permission. PFTs Sleep study

10 14 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 15 possible associated conditions, such as chronic obstructive pulmonary disease (eg, emphysema), pulmonary venous hypertension, restrictive pulmonary disease, or chronic thromboembolic disease. Pulmonary function tests. Pulmonary function tests are necessary in the evaluation of all patients with pulmonary hypertension to help exclude or define any contributing airway or parenchymal Table 8: Screening and diagnostic tests for evaluation of suspected pulmonary hypertension and notable findings. Blood tests Antinuclear antibody assay HIV Liver function test Diagnostic tests Chest radiography Electrocardiography Echocardiography Pulmonary function testing Overnight oximetry Ventilation-perfusion lung scan 6-minute walk test Cardiopulmonary exercise test Right-heart catheterization Purpose Tests necessary for all evaluations Screen for connective tissue disease (eg, scleroderma, systemic lupus erythematosus, rheumatoid arthritis) that may be associated with PAH Screen for HIV-associated PAH Screen for liver disease that may be associated with PAH (eg, portopulmonary hypertension) Findings Enlargement of central pulmonary arteries disease. 44,45 Approximately 20% of all patients with chronic pulmonary embolism will show evidence of reduced lung volumes (<80% predicted) with testing. Among patients with limited systemic sclerosis, approximately 1 in 5 will have a subnormal diffusing capacity for carbon monoxide (DL CO ). 44 A DL CO <55% of predicted levels may indicate the patient is at higher risk for future development of PAH. Right ventricular enlargement Marked tapering of peripheral arteries Right ventricular hypertrophy and strain Right axis deviation Right atrial enlargement Tricuspid regurgitation velocity (used to estimate right ventricular systolic pressure) Decreased acceleration time (<100 ms) or increased pulmonary regurgitant velocity (increased mean pulmonary arterial pressure) Increased tricuspid regurgitation velocity at time of pulmonary valve opening (increased right ventricular diastolic pressure) Increased ratio of tricuspid regurgitation velocity to right ventricular outflow tract time-velocity integral or increased pulmonary resistance (increased [PEP/AcT]/TT) Notching or cessation of right ventricular outflow tract flow in mid-systole (increased pulmonary vascular resistance) Increased severity of tricuspid regurgitation (right ventricular enlargement and altered geometry) Coronary sinus dilation (increased right atrial pressure) Dilation of inferior vena cava dilation with reduced or absent collapse on inspiration (increased right atrial pressure) Right ventricular hypertrophy and dilation, right atrial enlargement, straightened interventricular septum, decreased deceleration time of early diastolic transmitral flow (right ventricular pressure overload) Increased right ventricular index of myocardial performance (right ventricular dysfunction, decreased ejection time, increased isovolumic intervals; correlates with survival) Pericardial effusion (association with right-heart failure, decreased exercise tolerance, and poor 1-year survival) Left heart valvular or (systolic or diastolic) myocardial disease, shunt (causal or contributory cardiac disease) Obstructive or restrictive lung disease Diffusing capacity Screen for sleep disorders and nocturnal hypoxemia Rule out vascular obstruction (CTEPH) Provide baseline measure of activity level and estimate prognosis Provide baseline measure of activity level Oxygen saturation for superior vena cava, inferior vena cava, right atrial, right ventricular, pulmonary arterial pressure Right atrial pressure (indicative of right ventricular filling pressure, tricuspid regurgitation), right ventricular pressure (right ventricular filling and function) Pulmonary arterial pressure Pulmonary capillary wedge pressure or left ventricular end-diastolic pressure Cardiac output Pulmonary vascular resistance Systemic blood pressure and heart rate Response to short-acting vasodilator (likelihood of responding to CCB treatment) Abbreviations: AcT, acceleration time; CCB, calcium-channel blocker; CT, computed tomography; CTEPH, chronic thromboembolic pulmonary hypertension; HIV, human immunodeficiency virus; PEP, pre-ejection period; TT, total systolic time. Sources: Adapted with permission from Table 2, McGoon MD, Kane GC. Pulmonary hypertension: diagnosis and management. Mayo Clin Proc. 2009;84:195. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;17: CASE STUDY Initial presentation A 39-year-old Caucasian female is referred to you by her primary care provider because of progressive shortness of breath with exertion. Patient history. She is part owner of a small business and delivered a healthy child 9 months ago. She notes that she has been under significant stress lately because of financial problems at work. In addition, she has not lost all the weight she gained during the pregnancy and has not had the time to continue her usual exercise regimen. The patient complains of shortness of breath while attempting various activities. She can walk only 1 block without stopping and becomes dyspneic when climbing a flight of stairs and while dressing and bathing. Past medical history. Her past medical history includes 2 normal pregnancies, with no complications during delivery, and seasonal allergies, for which she needs over-the-counter (OTC) remedies occasionally. Physical examination. On examination, the patient is overweight (body mass index [BMI]=32) but not morbidly obese, and vital signs are unremarkable. Oxygen saturation at rest while breathing room air is 98%. Lungs are clear; there is no peripheral edema or clubbing. There is a questionable increase in the second heart sound, but because of the patient s body habitus, it is difficult to hear. Case study question #1 Which of the following tests would not be appropriate in the initial evaluation of this patient s shortness of breath? A. Posteroanterior (PA) and lateral chest radiograph B. 12-lead electrocardiogram (ECG) C. Allergy testing D. Pulmonary function testing Case study answer #1 The chest radiograph is normal in most patients with PAH; however, this test may help identify abnormal Sleep study. Testing with overnight oximetry can reveal the presence of a sleep disorder, such as apnea or hypopnea. 44 Ventilation/perfusion (V/Q) scan and angiography. A ventilation/ perfusion scan is essential for identifying or excluding CTEPH, which is a potentially curable cause of pulmonary hypertension. 44 Scans from patients with CTEPH typically show at least 1 segmental-sized or larger perfusion abnormality. A normal ventilation/perfusion scan means that CTEPH is probably not the cause of pulmonary hypertension, and the patient is more likely to have idiopathic PAH. However, findings suggestive of CTEPH anatomic features associated with PAH, such as central pulmonary artery enlargement or right ventricular enlargement. 44,45 In addition, the chest radiograph can reveal the presence of other possible conditions, including chronic obstructive pulmonary disease, pulmonary venous hypertension, restrictive pulmonary disease, or chronic thromboembolic disease. The ECG is not diagnostic, but this test is useful for determining the degree of right ventricular hypertrophy, right heart dilation, or the presence of arrhythmias. 45 Pulmonary function tests are required in the evaluation of all patients with suspected pulmonary hypertension to help identify any contributing airway or parenchymal disease. 44,45 Allergy testing is not likely to be helpful in this setting; therefore, the best choice is answer C. Findings. In this patient, the chest radiograph was normal. The ECG revealed an early R-wave progression. Pulmonary function tests were normal except for a mild decrease in carbon monoxide diffusing capacity (DL CO ) (66% predicted). Case study question #2 Which test would you order next? A. Ventilation/perfusion (V/Q) scan B. Exercise stress test C. Echocardiogram D. Connective tissue serologies Case study answer #2 A ventilation/perfusion scan can help reveal the presence of chronic thromboembolic pulmonary hypertension (CTEPH); however, findings suggestive of CTEPH can be falsepositives for other conditions and require additional testing with angiography. 44 Patients with idiopathic PAH are likely to have a normal ventilation/perfusion scan. Exercise stress testing may help determine the degree of functional impairment. Doppler echocardiography provides estimates of right ventricular systolic pressure and can reveal right atrial enlargement, right ventricular enlargement, and pericardial infusion. 45 Connective tissue serologies can help identify the presence of connective tissue diseases that increase the risk of PAH. While all the tests listed are reasonable selections for determining underlying causes in patients with suspected pulmonary hypertension, answer C, the echocardiogram, would be the best test to confirm your suspicions. require additional follow-up to define the underlying pathology because they may represent false-positives for other conditions, such as pulmonary veno-occlusive disease, pulmonary artery sarcoma, or large-vessel pulmonary vasculitis. 44 Angiography can provide further definition of pulmonary arteries to confirm a CTEPH diagnosis. Autoantibody tests. Blood tests should be conducted in order to identify or exclude conditions associated with pulmonary hypertension. 45 Autoantibody tests can reveal the presence of connective tissue disease, such as scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or vasculitis. 13,45

11 16 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 17 HIV test. All patients with PAH that cannot be attributed to any other cause should be tested for HIV infection. 45 Liver function tests. Because pulmonary hypertension is associated with hepatic impairment, all patients should undergo testing of liver function. In addition, patients should be clinically evaluated for presence of cirrhosis and portal hypertension, which can be associated with portopulmonary hypertension. 13 Right-heart cardiac catheterization. Right-heart catheterization is necessary to confirm the PAH diagnosis and establish disease severity. 43,45 This test assesses pulmonary artery pressure, right atrial pressure, pulmonary venous pressure, pulmonary blood flow, and mixed venous oxygen saturation. 45 Right-heart catheterization also allows the clinician to calculate pulmonary vascular resistance. In addition, it can be used to detect and quantify any existing intracardiac shunting. Vasodilator test. Vasodilator testing should be performed in most patients at the time of right-heart cardiac catheterization. 13 Short-acting agents (eg, adenosine, inhaled nitric oxide, epoprostenol) are typically used. Calcium-channel blockers (CCBs) should be avoided for vasodilator testing because in that setting, they carry a risk of serious life-threatening hemodynamic Table 9: Screening and diagnostic tests for evaluation of suspected pulmonary hypertension and notable findings. Supplemental test Arterial blood gases Brain natriuretic peptide assessment Chest CT (contrast enhanced) Chest CT (high resolution) Connective tissue disease serologies Exercise echocardiography Exercise echocardiography with right-heart catheterization Genetic testing and counseling Lung biopsy Polysomnography Pulmonary angiography Transesophageal echocardiography Uric acid and troponin measurements Vasodilator testing Volume loading Purpose Help determine ventilation function and gas exchange Provides measure of right ventricular failure and may function as a prognostic index If chronic thromboembolic pulmonary hypertension is suspected, provides further definition of anatomy of pulmonary arteries Assessment for interstitial lung disease Clotting studies Assessment for coagulopathy in chronic thromboembolic disease Assessment for scleroderma, systemic erythematous lupus, rheumatoid arthritis Assessment for left-heart disease Assessment for possible abnormal response when any other explanation for symptoms is lacking Screen for PAH if multiple family members are affected Only advisable in rare patients Further define sleep disorder If chronic thromboembolic pulmonary hypertension is suspected, provides further definition of pulmonary arteries Provides further definition of valvular and septal anatomy Aid in assessing prognosis Response to short-acting vasodilator Helps define hemodynamic profile changes. 44 The response to vasodilator administration reflects the degree to which vasoconstriction is contributing to pulmonary hypertension and the likelihood that the patient will respond to PAH treatment with CCBs. 13 A positive response is defined as a decrease in mean pulmonary arterial pressure of 10 mm Hg to a value of <40 mm Hg without a concurrent decrease in cardiac output. 43 Vasodilator testing is not necessary for patients who would not be candidates for treatment with CCBs, such as those with marked increases in right atrial pressure or decreases in cardiac output, overt right heart failure, and those in FC IV. 13 Functional test. Assessing exercise capacity is an important component of PAH evaluation. As discussed previously, symptom severity, as determined by functional class, is predictive of survival. 29 The 6-minute walk test (6MWT) is recommended for functional assessment in PAH, although other tests are available. 45 The 6MWT measures how far patients can walk on a level surface in that time period. 47 The distance covered decreases with increasing functional class severity and pulmonary vascular resistance. 47 Supplemental tests may be performed to help clarify the diagnosis or characterize associated conditions. Those tests are listed in Table 9. Abbreviations: AcT, acceleration time; CT, computed tomography. Sources: Adapted with permission from Table 2, McGoon MD, Kane GC. Pulmonary hypertension: diagnosis and management. Mayo Clin Proc. 2009;84:195. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;17: CASE STUDY As described in the initial case presentation, the chest radiograph in this patient was normal. In addition, the ECG revealed an early R-wave progression, and pulmonary function tests were normal except for a mild decrease in carbon monoxide diffusing capacity (DL CO ) (66% predicted). Additional testing showed the echocardiogram to be markedly abnormal with an estimated right ventricular systolic pressure (RVSP) >75 mm Hg. Case study question #3 Which of the following is needed in order to further evaluate this patient s presumed pulmonary hypertension? A. A detailed social history looking for possible recreational drug use, especially methamphetamine and/or cocaine, and an HIV test B. Thyroid-stimulating hormone (TSH) level, free T4 level, hepatic panel, assessment for hypercoagulable state, antinuclear antibody (ANA) test, rheumatoid factor (RF) test C. V/Q scan, high-resolution computed tomography (HRCT) D. 6-minute walk test (6MWT) E. All of the above Case study answer #3 Recent data from the University of California at San Diego suggest there is an increased risk of PAH among recreational drug users, particularly among users of methamphetamine. 21 Although the exact mechanism is unknown, it is theorized that methamphetamine and other stimulants cause release of norepinephrine and serotonin, leading to pulmonary vasoconstriction and proliferation of pulmonary arterial smooth muscle cells. 21 Several studies have reported an association between autoimmune thyroid disease (hyperthyroidism and hypothyroidism) and PAH, which indicates that testing for thyroid abnormalities is warranted. 48,49 Liver function testing is necessary to determine any previous exposure to hepatitis B or C virus; however, it is important to remember that liver function tests do not always reflect the degree of liver injury, especially with hepatitis C infection. Because the risk of PAH is increased in patients with connective tissue disease, screening tests for ANA and RF should be performed. 44 Screening for clotting diatheses is also indicated, particularly if CTEPH is suspected. 44 To eliminate CTEPH as a possible cause of pulmonary hypertension, performing a V/Q scan is essential; patients who have normal V/Q scans are more likely to have PAH. 44 HRCT can provide a detailed view of the lung parenchyma and thereby help uncover occult interstitial lung disease. 44 Although debate continues about the routine use of the 6MWT, 12,50 it is still considered an important component of evaluation. 45 Clinical trial evidence suggests that the 6MWT is predictive of survival in idiopathic PAH 51 ; in one study, desaturation 10% during the 6MWT increased mortality risk almost 3 times during a follow-up period of 26 months. 52 In addition, the distance walked during the 6MWT is inversely correlated with New York Heart Association (NYHA) functional class severity. 47 All tests listed are indicated for further characterizing PH; therefore, answer E is the best selection. Findings. The patient denies use of recreational drugs. HIV testing, hepatic panel, ANA, RF, TSH, and screening for a hypercoagulable state are all nonrevealing. The V/Q lung scan is read as very low probability for pulmonary embolus. Additionally, the HRCT is negative, and the patient has no history suggestive of sleep apnea. Case study question #4 What would be your next step in the evaluation of this patient? A. Stress echocardiogram B. Brain natriuretic peptide test C. Treadmill stress test D. Right-heart catheterization Case study answer #4 Right-heart catheterization is the essential diagnostic test for identifying pulmonary hypertension and localizing the process to the pulmonary arterial circulation. Typically, the transpulmonary gradient (the difference between mean pulmonary artery pressure and pulmonary capillary wedge pressure) is greater than 14 mm Hg; the difference between the pulmonary artery diastolic pressure and the wedge pressure is greater than 5 mm Hg. Questions regarding abnormal left ventricular diastolic compliance (distensibility) and its contribution to elevated pulmonary artery pressure can be evaluated by using volume or exercise challenge during the right-heart catheterization. Administration of a volume bolus to a poorly compliant left ventricle should increase the wedge pressure and cause an increased V wave on the wedge tracing, indicating a nonidiopathic cause for PH, such as diastolic dysfunction. Your next step would be to confirm your suspicions using right-heart catheterization, answer D. Findings. The right-heart catheterization is performed by your local cardiologist. Results are as follows: Right atrial pressure: 12 mm Hg

12 18 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 19 Key Learnings CASE STUDY (cont d) Right ventricular (RV) pressure: 72/4 mm Hg Pulmonary artery pressure (PAP): 77/38 mm Hg (mean 50 mm Hg) Pulmonary capillary wedge pressure (PCWP): 11 mm Hg Cardiac output/cardiac index (CO/CI): 4.6 L/min/2.3 L/min/m 2 Pulmonary vascular resistance (PVR): 678 dyn. sec. cm 5 Systemic vascular resistance (SVR): 1122 dyn. sec. cm 5 The patient showed no acute vasodilator response. Case study question #5 This patient appears to have idiopathic PAH. What would be the most important piece of prognostic information obtained from the right-heart catheterization? A. Right atrial pressure: >20 mm Hg B. Mean pulmonary artery pressure: 75 mm Hg C. Right ventricular venous saturation: 60% D. Pulmonary vascular resistance: 13.3 Woods units Case study answer #5 The right atrial pressure is an extremely significant parameter. A value >20 mm Hg is associated with higher risk of mortality. 29,43 Thus, answer A is the best choice. Case study question #6 Which of the following is false regarding vasodilator challenge testing and the data obtained from it? A. Vasodilator challenge testing may be performed with short-acting vasodilators; approved agents are inhaled nitric oxide, IV adenosine, or IV epoprostenol B. A positive vasodilator response is defined as a decrease in mean pulmonary artery pressure (mpap) 10 mm Hg and a final mpap 40 mm Hg, with a stable or increased cardiac output C. All patients should receive vasodilator challenge testing because CCB therapy may be indicated D. Vasodilator challenge testing identifies a subgroup of patients with pulmonary hypertension who may benefit from long-term CCB therapy and whose disease progression and survival may differ significantly from the majority of patients with idiopathic PAH Case study answer #6 CCBs are negative inotropes that can have deleterious effects in patients already suffering from right ventricular dysfunction. 53 It has been demonstrated that the risk of vasodilator challenge can outweigh the benefit in patients with NYHA class 4 heart failure, overt right heart failure, or advanced hemodynamics (such as elevated right atrial pressure [RAP] and/or CI <2.0 L/ min/m 2 ). 13,43 Not all patients should receive CCB testing; therefore, answer C is the best choice. Case study question #7 Your next step is to refer the patient to a pulmonary hypertension center for treatment. In the interim, the patient asks whether PAH might be genetic and whether that means she should worry about her children. (She had, of course, been doing research on the Internet and wants to know whether she and her children should be tested for a mutation in the BMPR2.) Current information on the BMPR2 gene suggests the following: A. Patients with a mutation in the BMPR2 gene nearly always develop PAH B. BMPR2 is the only genetic mutation conferring an increased risk of developing PAH C. BMPR2 mutations are not helpful for identifying family cohorts at increased risk for the disease D. The genetic penetrance (number of individuals with the prospective mutation who express the disease phenotype) for BMPR2 mutations varies widely as low as 10%-20% in some families, while higher in others. Therefore, testing for BMPR2 is not an efficient way to screen for PAH Case study answer #7 Research into family cohorts and into other genetic mutations conferring risk for PAH is ongoing. Current recommendations for testing have not been rigidly established, are controversial, and are considered most useful as a research tool. Because penetrance is low and mutations are variable, 54 testing will identify the mutation but not clearly define the patient s risk for developing the disease; therefore, answer D is the best choice. n Screening for PAH may be appropriate for patients with a family history of pulmonary hypertension, congenital heart disease, connective tissue disease, HIV infection, or sickle cell disease n Diagnosis of PAH includes taking the patient s clinical history and extensive testing, and requires confirmation by right-heart catheterization n Dyspnea is a hallmark symptom, affecting the majority of patients. Other symptoms include fatigue, weakness, angina, abdominal distension, and peripheral edema. Syncope may occur and is a sign of more severe disease n The diagnostic process begins with a clinical workup to evaluate for comorbid conditions, family history, and past exposure to stimulants, anorexigens, and toxins n The stepwise progression of tests begins with echocardiography and ends with right-heart catheterization n Findings from the ECG and echocardiogram (Doppler) may identify or exclude left-heart disease, valvular heart disease, or congenital heart disease as causes of clinical symptoms and provide crucial information about the degree of right ventricular hypertrophy, rightheart dilation, and the presence of arrhythmias n Chest radiograph can reveal any abnormal anatomic features that may be caused by PAH, such as central pulmonary artery enlargement or right ventricular enlargement, and identify other possible associated conditions, such as chronic obstructive pulmonary disease (eg, emphysema), pulmonary venous hypertension, restrictive pulmonary disease, or chronic thromboembolic disease n Pulmonary function tests are necessary in order to exclude or define any contributing airway or parenchymal lung disease PAH TREATMENT MODALITIES There is no cure for PAH. Current treatments are directed at raising functional class, improving quality of life, and prolonging survival of the patient. 40,43,55 Response to therapy may be assessed by periodically evaluating functional class and performing the 6MWT, echocardiography of right-heart function, or right-heart catheterization. 13,43 As diagnosing PAH and treatment selection are complex, experts continue to recommend referring PAH patients to specialized centers for management. 40,55 The main approaches to managing PAH are lifestyle modification, general or conventional treatment, and vascular-directed treatment. Surgical intervention consisting of lung transplantation or atrial septostomy is a final option for patients who fail all pharmacological therapies. 40,55 DIAGNOSIS OF PAH n Testing with overnight oximetry can uncover an undiagnosed sleep disorder n A ventilation/perfusion scan can identify or exclude CTEPH, which is a potentially curable cause of pulmonary hypertension n Autoantibody tests can reveal the presence of connective tissue disease, such as scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or vasculitis n All patients with unexplained PAH should be tested for HIV infection n All patients should undergo liver function tests n Right-heart catheterization is required to confirm the PAH diagnosis. This test assesses pulmonary arterial pressure, right atrial pressure, pulmonary venous pressure, pulmonary blood flow, and mixed venous oxygen saturation. Right-heart catheterization also allows the clinician to calculate pulmonary vascular resistance. In addition, it can be used to detect and quantify any existing intracardiac shunting n Vasodilator testing with short-acting agents should be performed in most patients at the time of right-heart catheterization. A positive response is defined as a decrease in mean pulmonary arterial pressure of 10 mm Hg to a value of <40 mm Hg. Vasodilator testing is not necessary for patients who show marked increases in right atrial pressure or decreases in cardiac output, overt right-heart failure, and those in FC IV n All patients should undergo functional assessment with the 6MWT n Supplemental tests may be performed to clarify the diagnosis or identify associated conditions Lifestyle Modifications Patients are usually advised to avoid intense physical activity that can precipitate syncope. 13 However, a regular exercise program that allows for gradual buildup may be beneficial. A recent study demonstrated that among PAH patients (80% of whom were in FC III or IV) already receiving standard drug regimens, those who participated in a 15-week program consisting of both aerobic exercise and resistance training achieved greater improvements in walking distance, quality of life, and functional class as compared with controls. 56 Travel to high altitude areas should be avoided. If patients have to travel by air, many will need supplemental oxygen. 40 Medications that can cause vasoconstriction, such as those for sinus congestion or colds should be stopped and avoided. 40 Patients should be immunized against influenza and pneumococcal pneumonia. Pregnancy should be avoided because it is associated with a high risk of maternal death. 1

13 20 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 21 General Treatment General treatment for PAH focuses on supportive or adjunctive therapies, including use of oxygen, anticoagulants (eg, warfarin), diuretics, and digoxin. 13,40,55 Supplemental oxygen may improve functioning and improve arterial oxygen concentration in some patients. 40 Evidence suggests that anticoagulation therapy improves survival in idiopathic PAH. 13,40 Warfarin treatment is generally recommended for most patients unless they have an underlying condition that precludes its use, such as portal hypertension or connective tissue disease, which increase the risk of gastrointestinal bleeding. 13 Diuretics are used to relieve fluid overload due to right ventricular failure. 40 Loop diuretics and potassium-sparing agents are often required and should be accompanied by sodium and fluid restriction. Although data supporting its use in PAH are lacking, digoxin may be prescribed to address low cardiac output or right ventricular failure. 13,40 Vascular-directed Treatment Vascular-directed treatments share a common goal: to reduce pulmonary vascular resistance, pressure, and related symptoms, and thereby increase the patient s tolerance of physical activity in order to lengthen survival. 40 Vascular-directed therapies have demonstrated efficacy in improving exercise tolerance, although there is some debate about whether these drugs significantly increase survival rates. 57 Even so, it is important to note that all mortality data in the trials included in the meta-analysis were based on the use of historical controls. A more recent analysis of clinical trial data indicates that survival rates have increased significantly since PAH-specific drugs were introduced; the 3-year survival rate has risen from approximately 40% in the 1980s to the current rate of approximately 80%. 58,59 Currently, there is no evidence to suggest a survival benefit is conferred by one drug class over any other. 59 Calcium channel blockers Treatment with CCBs may benefit a small subset of patients who have a positive response to vasodilator testing. 40 However, the proportion of patients who respond to vasodilator testing is smaller than previously believed. 60 A retrospective analysis of patients with idiopathic PAH found that less than 13% of patients responded to vasodilator testing with a >20% decrease in both mean pulmonary arterial pressure and pulmonary vascular resistance. 60 Furthermore, among those who responded, nearly 50% did not benefit from CCB treatment. 60 If a patient does respond to vasodilator testing, CCB options include diltiazem, nifedipine, and amlodipine. 1 Verapamil should be avoided because of its negative inotropic effect. Patients should be followed closely and switched to other PAH therapies if improvement to FC I or II does not become evident. Prostanoids Prostanoids target the prostacyclin pathogenic pathway (Figure 4). The currently available agents in the United States are epoprostenol, treprostinil, and iloprost. Epoprostenol was first approved for treatment of FC III or IV in 1995, and substantial clinical evidence supports its efficacy in idiopathic and associated forms of PAH. 40 It is a potent, short-acting vasodilator that inhibits platelet aggregation and reduces pulmonary vascular resistance. 61 Treatment of PAH patients with epoprostenol results in greater improvements in symptoms, hemodynamics, and survival as compared with conventional therapy. 61 However, epo- prostenol administration is complex and requires training for the patient. It must be administered continuously through an indwelling central line; sudden interruption of the infusion can result in death. 40 Epoprostenol is also associated with dosedependent adverse effects, including headache, flushing, diarrhea, nausea, lower extremity pain, and rash. 40 Central-linerelated complications, thrombosis, ascites, and thrombocytopenia can also occur. Treprostinil has properties similar to epoprostenol but can be administered subcutaneously as well as intravenously. 40,62 It is also available as an inhalation solution. The efficacy of treprostinil in improving exercise capacity and survival has been shown in clinical trials. 40,62-64 The side-effect profile of treprostinil is similar to that of epoprostenol; however, subcutaneous treprostinil can cause severe pain at the infusion site, which may be dose-limiting. 40 Iloprost is administered via inhalation 6 to 9 times a day. 13 Studies of patients with idiopathic and associated forms of PAH show that iloprost improves exercise capacity, functional class, and hemodynamics. 65,66 The long-term efficacy of inhaled iloprost as a monotherapy is yet to be determined. 13,67 Iloprost s side effects are similar to those of epoprostenol. 13 Endothelin receptor antagonists Endothelin receptor antagonists target the endothelin pathogenic pathway by nonselectively blocking both ET A and ET B, or selectively blocking ET A. 34,40 The endothelin receptor antagonists are administered orally. The currently available agents in the United States are bosentan and ambrisentan. 68 Sitaxsentan is not yet approved in the United States but is included in this discussion because it appears in the medical literature. Bosentan is a twice-daily oral sulfonamide endothelin receptor antagonist that binds to both ET A and ET B. 69 Bosentan is indicated for treatment of PAH patients with FC II, III, or IV symptoms. 69 Among patients with FC III or IV, compared with placebo, bosentan treatment increased the distance covered in the 6MWT, improved functional class, lessened dyspnea, and slowed time to clinical progression. 70 Side effects of bosentan include anemia, edema, flushing, and headache. 40,69,70 In addition, approximately 11% of patients treated with bosentan experience elevations in liver aminotransferases at least 3 times the upper limit of normal. 69 Thus, monthly liver function tests are required with bosentan therapy. 40 Drug-drug interactions have been noted with cyclosporine, estrogen-based oral contraceptives, glyburide, ketoconazole, lopinavir/ritonavir, rifampicin, sildenafil, simvastatin, tacrolimus, and warfarin. 40,69 Ambrisentan is a once-daily oral nonsulfonamide endothelin receptor antagonist that selectively binds to ET A. 71 Ambrisentan is indicated for treatment of PAH patients with FC II or III symptoms. 71 Findings from dose-ranging and placebo-controlled clinical trials indicate that ambrisentan treatment improves hemodynamics, symptoms, and exercise capacity in patients with idiopathic or associated forms of PAH. 72,73 In addition, ambrisentan appears to improve functional class and quality of life, as well as delay time to clinical progression. 73 Ambrisentan is well tolerated, and most adverse events reported in clinical trials are categorized as mild to moderate. 73 The most common side effects are flushing, headache, nasal congestion, peripheral edema, and sinusitis. 71 In addition, in ambrisentan clinical trials, elevations in liver aminotransferases at least 3 times the upper limit of normal were observed in 0.8% of patients in 12-week studies and 2.8% of patients in studies extending out to 1 year. 71 Monthly monitoring of liver function is required in patients treated with ambrisentan. 71 Drug interactions may occur with cyclosporine A, inducers of uridine 59-diphosphate glucuronosyltransferases, organic anion transport protein, and P-glycoprotein. 71 Ambrisentan has no clinically relevant interaction with warfarin, sildenafil, omeprazole, ketoconazole, or the ethinyl estradiol and norethindrone components of oral contraceptives. 71,74-76 Sitaxsentan is a once-daily, oral sulfonamide ET A -specific selective endothelin receptor antagonist that is not yet approved in the United States. 77,78 Sitaxsentan may be used for the treatment of PAH in patients with FC III symptoms who have not responded to conventional therapy and patients with FC II symptoms who have not responded to conventional therapy and for whom there are no other treatment options. 78 Clinical trials have shown that in patients with idiopathic or associated forms of PAH, sitaxsentan 100 mg improves walking distance and functional class, as compared with placebo. 77,79 The most common side effects associated with sitaxsentan include headache, peripheral edema, nasal congestion, nausea, and constipation. 78 In clinical trials, elevations in liver aminotransferases more than 3 times the upper limit of normal occurred in 2% of patients treated with sitaxsentan 100 mg and appear dose related. 78 Monthly monitoring of liver function is required. 78 Sitaxsentan is contraindicated for use with cyclosporine, and warfarin dosage must be reduced if given concomitantly with sitaxsentan. 78 No clinically significant reactions have been observed with digoxin, fluconazole, ketoconazole, nelfinavir, nifedipine, omeprazole, the ethinyl estradiol and norethindrone components of oral contraceptives, or sildenafil. 78 Phosphodiesterase-5 inhibitors Phosphodiesterase-5 (PDE5) inhibitors were originally used for the treatment of erectile dysfunction. 1 They are potent vasodilators that target the nitric oxide pathway in PAH. The PDE5 inhibitors currently approved for PAH treatment in the United States are sildenafil and tadalafil. Clinical trial evidence has Table 10. Determinants of risk. Lower risk (good prognosis) Clinical evidence of RV failure No Yes Progression of symptoms Gradual Rapid WHO functional class II, III IV demonstrated that sildenafil improves functional capacity and symptoms in patients with idiopathic and associated forms of PAH. 80 Adverse events include dyspepsia, flushing, headache, and nosebleeds. 40,80 One recent clinical trial showed that in patients with idiopathic or associated forms of PAH who were either on background therapy with bosentan or who were not on background therapy with bosentan, tadalafil improved exercise capacity and health-related quality of life. 81 However, tadalafil improved the distance covered in the 6MWT to a lesser extent in the group on background therapy with bosentan than in the group not on background therapy with bosentan. Side effects included headache, myalgia, and flushing. Nitrates are contraindicated in patients taking PDE5 inhibitors because of the risk of severe hypotension. 40 PAH TREATMENT STRATEGIES Updated recommendations from expert panels on the treatment of PAH have recently become available, along with treatment algorithms. These include the proceedings of the th World Symposium on Pulmonary Hypertension 55 and the 2009 Expert Consensus Document on Pulmonary Hypertension. The 2009 document was released jointly by the American College of Cardiology Foundation (ACCF) Task Force and the American Heart Association (AHA) in collaboration with the American College of Chest Physicians (ACCP), the American Thoracic Society, and the Pulmonary Hypertension Association. The ACCF/AHA document made general treatment recommendations based on vasodilator response and assessment of risk. 43 The 4th World Symposium on Pulmonary Hypertension algorithm also incorporates vasodilator response but makes recommendations according to WHO functional class. 55 ACCF/AHA Treatment Algorithm The ACCF/AHA treatment algorithm for PAH takes into account vasodilator testing response and factors that contribute to categorizing a patient as at high or low risk (Table 10). 43 The flow chart begins with general treatment measures for all patients with PAH. The next step in selecting treatment depends on the response to vasodilator testing. As described previously, all patients undergo vasodilator testing unless they are severely ill or have contraindications for CCB therapy. Those showing a positive response are treated with oral CCB therapy and evaluated Higher risk (poor prognosis) 6 minute walk distance Longer (>400 meters) Shorter (<300 meters) Cardiopulmonary exercise testing Peak VO 2 >10.4 ml/kg/min Peak VO 2 <10.4 ml/kg/min Echocardiography Minimal RV dysfunction Pericardial effusion, significant RV enlargement/dysfunction, right atrial enlargement Hemodynamics RAP <10 mm Hg, CI >2.5 L/min/m 2 RAP >20 mm Hg, CI <2.0 L/min/m 2 Brain natriuretic peptide Minimally elevated Significantly elevated CI, cardiac index; RAP, right atrial pressure; RV, right ventricular; VO 2, average peak oxygen uptake during exercise. Source: Table 2. McLaughlin V V, Archer SL, Badesch DB, et al. J Am Coll Cardiol. 2009;17:1585.

14 22 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 23 The 4th World Symposium on Pulmonary Hypertension Algorithm The 4th World Symposium on Pulmonary Hypertension was held in Dana Point, California, in February The proceedings were recently published and include an evidence-based treatment algorithm for PAH (Figure 6). 55 This algorithm generally follows that developed by the ACCF/AHA consensus group, including the strategy of starting with general treatment measures and vasodilator testing. 55 However, the World Symposium algorithm makes treatment recommendations based on functional class and grades each recommendation according to the quality of evidence and the net benefit of therapy. 55 For example, for patients in FC II who are nonresponders to vasodilator testing, the algorithm recommends first-line treatment with endothelin receptor antagonists (eg, ambrisentan or bosentan) or the PDE5 inhibitor sildenafil. The weight of this recommendation is graded A: a strong recommendation. These drugs are also strongly recommended as first-line options for FC III; epoprostenol, treprostinil, and iloprost are also recommended. A grade A is also given to the recommendation for IV epoprostenol for patients in FC IV. The World Symposium also recognized that treatment selecfor response. Patients who show a sustained response to CCBs continue treatment, with periodic follow-up. Patients who do not show a sustained response are treated similarly to patients who did not respond positively to vasodilator testing. Selecting treatment for patients who do not respond to vasodilators takes into consideration clinical variables that place a patient at higher (FC IV) or lower risk (FC II), as shown in Table 10. Patients at low risk who do not respond to vasodilator testing may be initially treated with endothelin receptor antagonists or PDE5 inhibitors. 40,43 Patients at low risk whose disease progresses may then be treated with intravenous or subcutaneous prostacyclin analogues. 40,43 Those patients at high risk who do not respond positively to vasodilator testing may be initially treated with prostacyclin analogues (preferably intravenously for more severely ill patients), possibly combined with endothelin receptor antagonists or PDE5 inhibitors. 40,43 All PAH patients, both those at low and high risk, are periodically reevaluated for response. More invasive therapies may be required as the disease progresses. Surgical intervention may be needed for patients who fail all pharmacological interventions. 40,43 Figure 6. The 4th World Symposium on Pulmonary Hypertension evidence-based treatment algorithm. Oral anticoagulants (E/B) IPAH/HPAH diuretics (E/A) oxygen* (E/A) digoxin (E/C) supervised rehabilitation (E/B) ACUTE RESPONDER WHO class I-IV Amlodipine, diltiazem, nifedipine (B) Sustained response (WHO I-II) Yes Strength of recommendation A Strong recommendation E/A Strong recommendation on the basis of expert opinion only B Moderate recommendation E/B Moderate recommendation on the basis of expert opinion only C Weak recommendation E/C Weak recommendation on the basis of expert opinion only D Negative recommendation E/D Negative recommendation on the basis of expert opinion only I No Amlodipine, diltiazem, nifedipine (B) Supportive therapy and general measures Expert referral (E/A) Acute vasoreactivity test (A for IPAH) (E/C for APAH) Sequential combination therapy + (B) Prostanoids + (B) PDE-51 NONRESPONDER No recommendation possible (inconclusive) + (B) ERA Avoid excessive physical exertion (E/A) birth control (E/A) psychological and social support (E/C) infection prevention (E/A) Strength of recommendation WHO class II WHO class III WHO class IV A Ambrisentan, bosentan, sildenafil INADEQUATE CLINICAL RESPONSE Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil Epoprostenol IV B Sitaxsentan, tadalafil Sitaxsentan, tadalafil, treprostinil SC Iloprost inh C Beraprost Treprostinil SC E/B E/C Iloprost IV, treprostinil IV Not approved Treprostinil inh+ Treprostinil inh+ INADEQUATE CLINICAL RESPONSE Iloprost IV, treprostinil IV, initial combination therapy (see below) Ambrisentan, bosentan, sildenafil, sitaxsentan, tadalafil Atrial septostomy (E/B) and/or lung transplant (E/A) Abbreviations and symbols: *To maintain oxygen at 92%. + Investigational, under regulatory review. APAH, associated pulmonary arterial hypertension; ERA, endothelin receptor antagonist; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5; SC, subcutaneous; WHO, World Health Organization. Sources: Figure 1. Barst RJ, Gibbs SR, Hossein A, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S81. Table 1. Barst RJ, Gibbs SR, Hossein A, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S82. Table 11: Arguments for and against combination therapy in PAH. Arguments for use of combination therapy Targets multiple pathogenic pathways Provides synergistic effects of different agents Avoids treatment-limiting toxicities associated with monotherapy of certain agents May prevent PAH disease and/or symptom progression Delays recourse to invasive therapy or transplantation Arguments against use of combination therapy No convincing data from randomized clinical trials No indication of which combination works best against which monotherapy regimen No data for determining which patients are best candidates No evidence for which combination therapy regimen should be used in which patient population No evidence for long-term safety and tolerability Sources: Barst RJ, Gibbs SR, Hossein A, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S78-S84. O Callaghan DO, Gaine SP. Combination therapy and new types of agents for pulmonary arterial hypertension. Clin Chest Med. 2007;28:177. McLaughlin V V, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;17: CASE STUDY Case study question #8 The patient experiences a slow progression of symptoms over 4 to 6 weeks. Right-heart catheterization is repeated at the pulmonary hypertension center. Results are as follows: RAP: 17 mm Hg RV pressure: 77/7 mm Hg PAP: 80/35 mm Hg (mean 50 mm Hg) PCWP: 12 mm Hg CO/CI (by Fick equation): 4.20 L/min and 2.1 L/min/ m 2, respectively PVR: 724 dyn sec cm 5 6MWT: 315 m The patient also expresses a reluctance to go on any intravenous regimen. Which of the following treatment regimens, given this patient s apparent risk profile and preference, would be most appropriate? A. Sildenafil and diuretics B. Combination therapy with tadalafil, IV epoprostenol or IV treprostinil, diuretics, and warfarin C. An endothelin receptor antagonist, diuretics, and anticoagulation with warfarin (target international normalized ratio [INR]: 2-3) D. Subcutaneous treprostinil, sildenafil, diuretics, and anticoagulation with warfarin (target INR: 2-3) Case study answer #8 The endothelin receptor antagonists (ambrisentan and bosentan) and PDE5 inhibitors (sildenafil and tadalafil) are recommended for managing PAH patients in FC II or III who are at lower risk for more rapid disease progression and development of right-heart failure. 43 This patient has had slow progression of her symptoms, and a right-heart catheterization not consistent with right-heart failure. In this case, most pulmonary hypertension specialists would elect a less aggressive therapeutic regimen that includes an oral therapy, such as an endothelin receptor antagonist or PDE5 inhibitor, along with general treatment measures comprising diuretics and warfarin. Beginning with an oral therapy is appropriate and leaves the option open for switching to a prostanoid if symptoms progress. Were the patient started on an intravenous prostanoid and improved dramatically, options would be limited for switching to an oral therapy. Transitioning from a prostanoid to an oral therapy is very controversial and should be attempted only when patients meet strict criteria Evidence from randomized controlled clinical trials is lacking for anticoagulation therapy in this setting, but a collection of small studies as early as the 1970s identified anticoagulation as benefitting patients with idiopathic PAH. 40,43 Therefore, anticoagulation therapy is considered appropriate for patients with idiopathic PAH and possibly for some patients with associated PAH that have limited cardiopulmonary reserve and no potential contraindication. 40,43 Diuretics are commonly used to control right ventricular volume 43 ; however, there are no data regarding the comparative effects of different diuretics in PAH. There is considerable interest in treating this multifactorial disease with agents that target multiple pathways or with combination therapy. In the PAH patient population, the 3 best defined pathways involve prostacyclin synthesis (therapeutic target for prostanoids), abnormalities in endothelin signaling (therapeutic target for endothelin receptor antagonists), and abnormalities in the generation and concentration of nitric oxide (therapeutic target for PDE5 inhibitors). However, the use of combination therapy as initial management has not been studied, is controversial, and needs to be much more precisely defined. Considering the patient s disease status and expressed preference, the best choice is answer C.

15 24 CSI:PAH DIAGNOSIS AND MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION 25 tion must include factors in addition to functional class, such as approval status, route of administration, patient preference, sideeffect profile, and clinical judgment. 55 Emerging Strategies in PAH Management Combination therapy Although data from randomized clinical trials are limited, patients who do not respond adequately to PAH monotherapy may benefit from treatment with a combination of approved agents. 40,43 In most cases, a second agent is added to an existing monotherapy regimen as the patient begins to deteriorate. 36 Less commonly, a patient may be started on therapy with 2 or more agents. A number of arguments can be made for and against implementing combination therapy in PAH; these are listed in Table 11, page n The objectives of current PAH treatments are to improve quality of life and prolong survival. The main treatment approaches are lifestyle modification, general or conventional treatment, and vascular-directed treatment n Lifestyle modification includes participation in a regular moderate exercise program, avoidance of high altitude areas, discontinuation of vasoconstrictive medications, and for women, avoidance of pregnancy. General treatment includes supportive or adjunctive therapies, such as supplemental oxygen, anticoagulants, diuretics, and digoxin n Vascular-directed treatments are medications that target the pathological processes in the pulmonary vasculature. These include CCBs, prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 (PDE5) inhibitors n CCBs are appropriate only for the small subset of patients who respond positively to vasodilator testing. CCB options include diltiazem, nifedipine, and amlodipine. Verapamil should not be used n Prostanoids target the prostacyclin pathogenic pathway. Options include epoprostenol, treprostinil, and iloprost. Epoprostenol must be administered continuously through an indwelling central line. Side effects include headache, flushing, diarrhea, nausea, lower extremity pain, and rash. Treprostinil has properties similar to epoprostenol but can be administered subcutaneously as well as intravenously. It is also available as an inhalation solution. Iloprost is administered via inhalation 6 to 9 times a day, and side effects are similar to those of epoprostenol n Endothelin receptor antagonists are orally administered agents that target the endothelin pathogenic pathway by nonselectively blocking both ET A and ET B, or selectively blocking ET A. Available agents in the United States are bosentan and ambrisentan. Bosentan is a twice-daily, nonselective endothelin receptor antagonist that is indicated for FC II, III, or IV symptoms. Side effects of bosentan include anemia, edema, flushing, and headache. Monthly liver function tests are required with bosentan therapy. Ambrisentan is a once-daily endothelin receptor antagonist that selectively binds to ET A and is Key Learnings PAH TREATMENT STRATEGIES 23; Table 12, page 25, lists the most common combinations of agents. Combination therapy may simultaneously target multiple pathogenic pathways, reduce the risk of treatment-limiting toxicity of monotherapy, delay symptom progression, or postpone recourse to invasive therapy or surgery. 36 However, evidence showing the benefit of combination therapy as compared with monotherapy is lacking, as are data regarding which specific combinations to use and in what types of patients, as well as possible long-term drug-drug interactions. Although limited, some clinical trial data have shown the benefits of combination therapy with endothelin receptor antagonists and prostanoids or PDE5 inhibitors, 88 or prostanoids and PDE5 inhibitors. 87,89 However, some trials have failed to show significant differences from monotherapy, including the Combination indicated for the treatment of PAH patients with FC II or III symptoms. The most common side effects are flushing, headache, nasal congestion, peripheral edema, and sinusitis. Monthly monitoring of liver function is required in patients treated with ambrisentan n PDE5 inhibitors are vasodilators that target the nitric oxide pathway and were originally used for the treatment of erectile dysfunction. The PDE5 inhibitors approved for PAH in the United States are sildenafil and tadalafil. Adverse events include dyspepsia, flushing, headache, and nosebleeds n Patients who have a positive response to vasodilator testing may be given a treatment trial with an oral CCB; those who have a sustained response can continue treatment, with periodic evaluation n According to the ACCF/AHA consensus group on PAH, selection of treatment for patients who do not respond to vasodilator testing is based on whether the patient is considered at higher (FC IV) or lower risk (FC II or III). Initial options for high-risk patients include prostanoids, possibly combined with endothelin receptor antagonists or PDE5 inhibitors. Initial options for low-risk patients include endothelin receptor antagonists or PDE5 inhibitors. More invasive therapies may be required as the disease progresses n According to the 4th World Symposium on Pulmonary Hypertension, the selection of treatment for patients who do not respond to vasodilator testing is based on functional class, taking into consideration other factors, such as patient preference and the medication s side effects and approval status. Treatment recommendations are graded according to the quality of evidence supporting their use and the net benefit to the patient. First-line options strongly recommended for FC II patients are ambrisentan, bosentan, and sildenafil. These drugs are also strongly recommended as first-line options for FC III, along with IV epoprostenol and inhaled iloprost n Although conclusive evidence is lacking, combination therapy may be given to patients who do not adequately respond to monotherapy n Other agents under investigation for PAH treatment include antiproliferative agents, antihypertensives, statins, selective serotonin reuptake inhibitors, immunosuppressants, and anti-inflammatory drugs Table 12: Common combination regimens for PAH. Endothelin antagonists + prostanoids Endothelin antagonists + PDE5 inhibitors PDE5 inhibitors + prostanoids Bosentan or ambrisentan + epoprostenol Bosentan or ambrisentan + sildenafil Sildenafil + epoprostenol Bosentan or ambrisentan + iloprost Bosentan + tadalafil Sildenafil + iloprost Sildenafil + treprostinil PDE5, phosphodiesterase-5. Sources: O Callaghan DO, Gaine SP. Combination therapy and new types of agents for pulmonary arterial hypertension. Clin Chest Med. 2007;28:177. Galie N, Brundage BH, Ghofrani A, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119: Therapy of Bosentan and aerosolized Iloprost in Idiopathic Pulmonary Arterial Hypertension (COMBI) trial, which evaluated the benefits of adding inhaled iloprost to bosentan therapy. 90,91 Large-scale studies are needed to confirm the benefits of specific combinations. Several trials are under way to further evaluate the role of combination therapy in PAH. 40 Investigational Agents Novel agents are under investigation for use in PAH treatment and management. Rather than targeting the 3 pathways known to contribute to PAH pathogenesis, these therapies are directed at other possible underlying mechanisms. 40 Examples include antiproliferative agents, antihypertensives, statins, selective serotonin reuptake inhibitors, immunosuppressants, and antiinflammatory agents. Whether any of these classes will demonstrate efficacy in PAH treatment remains to be determined. None are currently approved for treating patients with PAH. CONCLUSIONS PAH is a serious disease that requires early diagnosis and appropriate management to slow progression and improve survival. At this time there is no cure for PAH. Although the prevalence of PAH is low, it is expected to increase, particularly in developing countries and among patients exposed to specific stimuli. Thus, physicians need to maintain a high index of suspicion for PAH in their patients, especially those who present with dyspnea of unknown cause. If a physician suspects or identifies PAH, in most cases the patient should be referred to a center specializing in pulmonary hypertension. Although research is still ongoing, knowledge of the pathophysiology of PAH has grown significantly within the past several years, laying a foundation for the development of more targeted and effective therapies. 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17 28 CSI:PAH 76. Richards DB, Walker GA, Mandagere A, et al. Effect of ketoconazole on the pharmacokinetic profile of ambrisentan. J Clin Pharmacol. 2009;49: Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47: Thelin (sitaxsentan sodium tablets) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada, Inc: November 4, Available at: our%20products/prescription%20pharmaceuticals/default. asp?s=1&id=56&doc=enmonograph. Accessed on July 7, Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169: Galie N, Ghofrani HA, Torbicki A, et al, for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353: Galie N, Brundage BH, Ghofrani A, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119: Kim NH, Channick RN, Rubin LJ. Successful withdrawal of long-term epoprostenol therapy for pulmonary arterial hypertension. Chest. 2003;124: Suleman N, Frost AE. Transition from epoprostenol and treprostinil to the oral endothelin receptor antagonist bosentan in patients with pulmonary hypertension. Chest. 2004;126: Steiner MK, Preston IR, Klinger JB, et al. Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension. Chest. 2006;130: Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24: McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174: United Therapeutics. Triumph-1 Trial of Viveta in pulmonary arterial hypertension meets primary endpoint. November 1, Available at: cfm?releaseid= Accessed on July 7, Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24: Simonneau G, Rubin L, Galie N, et al, for the Pulmonary Arterial Hypertension combination Study of Epoprostenol Sildenafil (PACES) Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension. Ann Intern Med. 2008;149: Hoeper M, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;4: United Therapeutics. Freedom-C trial of oral treprostinil in pulmonary arterial hypertension fails to meet primary endpoint. November 17, Available at: releasedetail.cfm?releaseid= Accessed on July 7, 2009.

18 PAH Case Study Investigation (CSI) Diagnosis and Management of Pulmonary Arterial Hypertension Case Review Monograph