Rebecca L. Attridge, Rebecca Moote, and Deborah J. Levine
KEY CONCEPTS
Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg at rest with a pulmonary wedge pressure (also known as pulmonary artery occlusion pressure) or left ventricular end-diastolic pressure (LVEDP) ≤15 mm Hg measured by right cardiac catheterization.
Diagnosis of PAH is growing due to increased awareness and knowledge of the disease state, leading to earlier and improved evaluation and identification.
Regardless of the etiology, be it unknown or related to an associated medical condition, subgroups of PAH are based on similar clinical and pathologic physiology.
The underlying cause of PAH is a complicated amalgam of endothelial cell dysfunction, a procoagulant state, platelet activation, vasoconstriction, loss of relaxing factors, cellular proliferation, hypertrophy, fibrosis, and inflammation.
Patients with PAH present with exertional dyspnea, fatigue, weakness, and exertion intolerance. As the disease progresses, symptoms of right heart dysfunction and failure, such as dyspnea at rest, lower extremity edema, chest pain, and syncope, are seen.
The only way to make a definitive diagnosis of PAH is by right heart catheterization. The right heart catheterization provides important prognostic information and can be used to assess pulmonary vasoreactivity prior to initiating therapy.
The goals of treatment are to alleviate symptoms, improve the quality of life, slow the progression of the disease, and improve survival.
A general goal of PAH treatment is to correct the imbalance between vasoconstriction and vasodilation and prevent adverse thrombotic events to improve oxygenation and quality of life.
Nonpharmacologic therapy is frequently used to address comorbid conditions that often accompany PAH.
Conventional therapy of PAH includes oral anticoagulants, diuretics, oxygen, and digoxin.
Prostacyclin analogs such as epoprostenol, treprostinil, and iloprost induce potent vasodilation of pulmonary vascular beds.
Endothelin receptor antagonists, bosentan and ambrisentan, improve exercise capacity, hemodynamics, and functional class in PAH.
Phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, are potent and highly specific drugs that have been shown to reduce mPAP and improve functional class.
Combination therapy in PAH may address more than one mechanism causing this disease. Combination therapy in clinical trials has provided additional benefit, but more studies are needed.
Pulmonary hypertension is a term describing a group of conditions relating to elevated blood pressure measured within the pulmonary artery. Pulmonary hypertension is not a specific diagnosis; rather it is a complex group of disorders relating to the pulmonary circulation. Pulmonary hypertension is classified into five groups according to the World Health Organization (WHO; see Table 17-1).1 Pulmonary arterial hypertension (PAH) or Group 1 pulmonary hypertension is a progressive disease characterized by an elevation in pulmonary arterial pressure and pulmonary vascular resistance. 
PAH may be defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg at rest, with a pulmonary wedge pressure (also known as a pulmonary artery occlusion pressure or left ventricular end-diastolic pressure [LVEDP]) ≤15 mm Hg measured by cardiac catheterization.2
TABLE 17-1 World Health Organization Classification of Pulmonary Hypertension
PAH may occur in the setting of underlying medical conditions or as an idiopathic disease (idiopathic PAH [IPAH]). Historically, medical treatment of PAH has been limited due to lack of effective, targeted therapy. Without medical therapy, IPAH portends a poor prognosis (median survival 2.8 years) after diagnosis.3 Prior to the availability of disease-specific therapy for IPAH, survival rates for 1, 3, and 5 years were 68%, 48%, and 34%, respectively.4Since the approval of epoprostenol in 1995, a number of new therapeutic options have been developed. In a recent epidemiologic study, survival rates for 1, 2, and 3 years in patients on targeted therapy were 83%, 67%, and 58%, respectively.5
EPIDEMIOLOGY
The prevalence of PAH is estimated to be 15 to 50 patients per million individuals. Unfortunately, only 15,000 to 20,000 of the afflicted patients have an established diagnosis of PAH and are currently receiving treatment. In a French registry study of more than 600 patient with PAH, Humbert found that the most common cause of PAH was IPAH (approximately 40%), followed by PAH associated with connective tissue diseases (15.3%), congenital heart disease (11.3%), portal hypertension (10.4%), and familial PAH (FPAH) (3.9%).6 However, diagnosis of PAH is growing due to increased awareness and knowledge of the disease state, leading to earlier and improved evaluation and identification.
ETIOLOGY
PAH most often originates with a predisposing state and one or more inciting factors that could be genetic or environmental exposures.7 Once a permissive environment exists, multiple mechanisms can be activated leading to vascular constriction, cellular proliferation, and a prothrombotic state resulting in PAH and its sequelae.8 PAH can be associated with numerous conditions as well as being an idiopathic condition (IPAH). The incidence of IPAH is estimated to be 5 to 6 per 1 million in North America and Europe, with a marked female predominance (male-to-female ratio, 1:1.7), and mean age at time of recognition is approximately 37 years, although there is considerable variation.8,9 Although uncommon in the United States, the commonest form of PAH worldwide is schistosomiasis followed by congenital heart disease and pulmonary hypertension of early childhood.10 Rheumatologic diseases such as scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and myositis are also associated with development of PAH. Patients with scleroderma who develop PAH, estimated between 7% and 12% of patients, have markedly worse outcomes in comparison to other PAH subgroups. Patients with human immunodeficiency virus (HIV) infection can develop PAH with a prevalence of 0.5%. In patients with liver disease, portal hypertension may cause concurrent pulmonary hypertension in an estimated 2% to 6% of patients.11 Multiple drugs and toxins have been associated with PAH but those that definitively precipitate PAH include anorexigens such as aminorex, fenfluramine, and dexfenfluramine.10,12 Other drugs considered to be likely or possible causative agents for PAH include amphetamines, L-tryptophan, cocaine, and certain chemotherapeutic agents (mitomycin C, carmustine, etoposide, cyclophosphamide, bleomycin).9 Heritable PAH (HPAH) includes both IPAH with germline mutations and familial cases without an identified mutation. Germline mutations seen in PAH include bone morphogenetic protein receptor 2 (BMPR2) and activin receptor-like kinase 1 (ALK-1). Genetic testing for these mutations may be offered and professional genetic counseling should be provided.11
PATHOPHYSIOLOGY
Regardless of etiology, all subgroups of PAH are based on similar clinical and pathologic physiology. 
The pathobiology of PAH involves several key biologic events, including endothelial cell dysfunction, a procoagulant state, platelet activation, constricting factors, loss of relaxing factors, cellular proliferation, hypertrophy, fibrosis, and inflammation—all combining to produce progressive and deleterious vascular remodeling (Fig. 17-1).13,14Multiple genetic mutations are known to contribute to the pathophysiology of PAH, including BMPR2, ALK-1, nitric oxide synthase (ec-NOS), carbamoyl-phosphate synthase gene, and 5-hydroxytryptamine (serotonin [5-HT]) transporter (5-HTT).13,15 A mutation of BMPR2 receptor is an aberration of signal transduction in the pulmonary vascular smooth muscle cell that is postulated to alter apoptosis favoring cellular proliferation. ALK-1 is part of the transforming growth factor-β superfamily and is seen in hereditary hemorrhagic telangiectasia and PAH.16 5-HTT is associated with pulmonary artery smooth muscle proliferation and is present in IPAH in the homozygous form in 65% of patients.17 Dysregulation of 5-HT synthesis mediated via tryptophan hydroxylases is closely linked to the hypoxic PAH phenotype in mice and may contribute to PAH development.18
FIGURE 17-1 Pulmonary arterial hypertension; potential pathogenetic and pathobiologic mechanisms. (ALK-1, activin receptor-like kinase 1 gene; BMPR2, bone morphogenetic protein receptor 2 gene; CPS, carbamoyl-phosphate synthase gene; ec-NOS, nitric oxide synthase gene; 5-HTT, serotonin transporter gene; HIV, human immunodeficiency virus. (Reproduced with permission from reference 30.)
Molecular, cellular, and genetic mechanisms are mediated by a variety of biologically active compounds, including prostacyclin (PGI2), endothelin-1 (ET-1), nitric oxide (NO), and 5-HT. PGI2 is a vasodilatory and antiproliferative substance that is produced by the endothelial cells, and the synthesis of PGI2 and its circulating levels are reduced in PAH. Furthermore, thromboxane, a vasoconstrictor, is increased in PAH. ET-1 is produced in the endothelium, and it possesses potent vasoconstrictor and mitogenic effects. ET-1 levels are increased in PAH and clearance is reduced. ET-1 acts via the endothelin receptors (ETA and ETB) to promote vascular smooth muscle proliferation and vasoconstriction.14,19 Plasma levels of ET-1 are correlated with severity of PAH and prognosis.20 NO is produced in the endothelium via NO synthase and leads to vasodilation and opening of cell membrane potassium channels to allow potassium ion efflux, membrane depolarization, and calcium channel inhibition. Voltage-dependent potassium channels are inhibited by a number of stimuli that promote PAH, including hypoxia and fenfluramine, resulting in downregulated potassium channels in patients with PAH. Entering calcium is a signal for release of sarcoplasmic calcium and activation of the contractile apparatus. NO promotes vasodilation through calcium channel inhibition. In PAH there is evidence of decreased NO synthase expression, leading to vasoconstriction and cell proliferation.21 Elevated 5-HT has been observed and vasoconstriction mediated via the increased expression of the 5-HT1B receptor is seen in PAH.8
Autoantibodies, proinflammatory cytokines, and inflammatory infiltrates may also participate in the pathogenesis of PAH. Coagulation is disordered in PAH as evidenced by increased levels of von Willebrand factor, plasma fibrinopeptide A, plasminogen activator inhibitor-1, 5-HT, and thromboxane. Furthermore, tissue plasminogen activator, thrombomodulin, NO, and PGI2 are decreased, leading to an imbalance favoring thrombosis. Endothelial dysfunction is the common denominator of mechanisms for PAH, and a variety of injuries, such as shear stress, inflammation, toxins, and hypoxia, are thought to be involved.10,13
The signs and symptoms of PAH are highly variable depending on the stage of the disease and comorbidities (Table 17-2). Symptoms may include exertional dyspnea, fatigue, and weakness. As the disease progresses, patients may experience dyspnea at rest, chest pain, presyncope, syncope, lower extremity edema, and abdominal bloating and distension. On physical exam, patients with PAH may have an accentuated component of S2 audible at the apex of the heart, midsystolic ejection murmur, palpable left parasternal lift, right ventricular S4 gallop, and a prominent “a” wave.10 Hepatojugular reflux, a diastolic murmur of pulmonary regurgitation, and a systolic murmur of tricuspid regurgitation may be present in advanced disease.9
TABLE 17-2 World Health Organization Functional Classification of Pulmonary Arterial Hypertension (PAH)
Several comorbidities and environmental factors play a role in the development of PAH and must be evaluated when establishing an initial diagnosis of PAH (Fig. 17-2). In patients with a clinical suspicion of PAH, Doppler echocardiography should be performed as a noninvasive screening test that can detect increased pulmonary pressures, although this study cannot be used to definitively diagnose PAH.22Echocardiography can also be used to assess treatment interventions and to follow disease progression.10 However, right heart catheterization is the definitive study to use in diagnosis of PAH and when patients are worsening clinically.15 Right heart catheterization provides important prognostic information and can be used to assess pulmonary vasoreactivity with the administration of fast-acting, short-duration vasodilators to determine the extent of vascular smooth muscle constriction and vasodilator response to calcium channel blockers (CCBs; strength of recommendation: A for IPAH; E/C for associated pulmonary arterial hypertension [APAH]).9 Table 17-3 lists the grading criteria for recommendations, and Table 17-4 lists commonly used agents and their dosages. The consensus definition of a positive response is defined as a reduction of mPAP by at least 10 mm Hg to a value of 40 mm Hg or less.23 Patients with an acute response (approximately 13% on initial testing) are most likely to have a beneficial hemodynamic and clinical response. These patients may be able to be treated with CCBs. However, about half of these patients lose an acute vasodilator response when tested 1 year later.24 Therefore, even this small group of patients who may be treated with CCBs must be followed closely for safety and efficacy. If the patient loses the acute vasodilator response, he or she needs to be switched to different PAH therapy. Patients who have a negative response on initial vasodilator testing are not candidates for treatment with CCBs.9,25
FIGURE 17-2 Evaluation of causes of PAH. (Adapted from Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–2537.)
TABLE 17-3 Relationship of Strength of Recommendation Scale to Quality of Evidence and Net Benefit
TABLE 17-4 Agents for Vasodilator Testing in Pulmonary Arterial Hypertension
Because PAH commonly occurs in the setting of connective tissue disease, serologic markers should be obtained to confirm or exclude these diagnoses.9,26 Liver function tests (LFTs) should also be evaluated due to the increased risk for PAH in patients with cirrhosis and portal hypertension. HIV is associated with an increased prevalence of PAH, and HIV testing should be done as part of the initial PAH workup.9Chronic thromboembolic pulmonary hypertension (CTEPH) should be evaluated with ventilation–perfusion lung scans and/or pulmonary angiography. Pulmonary function testing and arterial blood oxygenation should be evaluated. The diffusing capacity of carbon monoxide may be particularly helpful in systemic sclerosis and PAH.10 In patients with PAH, serial determinations of functional class, exercise capacity (assessed by the 6-minute walk distance), and serial biomarkers provide benchmarks for disease severity, response to therapy, and progression.9,26
CLINICAL PRESENTATION Pulmonary Arterial Hypertension
Symptoms
• Exertional dyspnea
• Fatigue
• Weakness
• Exertional chest pain
• Complaints of general exertion intolerance
• Dyspnea at rest as disease progresses
• Syncope
• Lower extremity edema
Symptoms of Related Conditions
• Paroxysmal nocturnal dyspnea as a result of left-sided heart disease
• Raynaud’s phenomenon, arthralgia, or swollen hands and other symptoms of connective tissue disease
• Orthopnea
• A history of snoring as reported by the patient’s partner may be a consequence of sleep-disordered breathing and can be associated with PAH
Symptoms of Disease Progression
• Leg swelling
• Abdominal bloating and distension
• Anorexia
• More profound fatigue
May develop as right ventricular dysfunction and triscuspid valve regurgitation evolve
Signs
• Accentuated component of S2 audible at the apex of the heart
• Early systolic ejection click
• Midsystolic ejection murmur
• Palpable left parasternal lift
• Right ventricular S4 gallop
• Prominent “a” wave
Signs of Advanced Disease
• Diastolic murmur of pulmonary regurgitation
• Holosystolic murmur of tricuspid regurgitation
• Hepatojugular reflux
• A pulsatile liver
• Right ventricular S3 gallop
• Marked distension of jugular veins
• Peripheral edema
• Hypotension
• Cool extremities suggesting markedly reduced cardiac output and peripheral vasoconstriction
• Diminished pulse pressure
• Cyanosis (suggests right-to-left shunting)
• Digital clubbing
• Rales
• Dullness
• Decreased breath sounds
• Accessory muscle use
• Wheezing
• Prolonged exhalation
• Peripheral venous insufficiency (suggests venous thrombosis or pulmonary thrombotic disease)
Diagnostic Tests
• Electrocardiogram for chamber enlargement
• Chest radiography to detect enlarged pulmonary arteries
• Doppler echocardiography to evaluate right ventricular/right atrial morphology and calculate right ventricular pressure and pulmonary arterial systolic pressure
• Magnetic resonance imaging may be used to exclude other diagnoses and evaluate right heart morphology
• Pulmonary function testing and arterial blood oxygenation
• Ventilation–perfusion scanning
• Computed tomography or magnetic resonance imaging can be used to exclude other diagnoses
• Right heart catheterization may be used to confirm the presence of PAH and to guide therapy
• Tests for connective disease or other risk factors
TREATMENT
Pulmonary Arterial Hypertension
Desired Outcomes
The goals of treatment are alleviation of symptoms, improvement in the quality of life, prevention of disease progression, and improvement in survival.1,9 While the first two outcomes are obtainable based on data from randomized trials, controversy exists over improvement in survival with current treatment regimens. Meta-analyses are conflicting; a 2007 meta-analysis of 16 trials demonstrated no mortality benefit in functional classes III/IV while a later 2009 study of 21 trials (6 of which were not included in the 2007 study) in predominately functional class III patients showed a 43% reduction in mortality.27 Unfortunately, overall mortality remained high.28 In addition, individual trials also show survival benefit, at least in the short term (i.e., 3 years).29
General Approach to Treatment
Treatment of PAH may be categorized into nonpharmacologic, pharmacologic, and surgical interventions. 
The principal endothelial abnormalities that are current pharmacologic therapeutic targets include (a) supplementing endogenous vasodilators, (b) inhibiting endogenous vasoconstrictors, and (c) reducing endothelial platelet interaction and limiting thrombosis. Nonpharmacologic therapy can be quite broad and should be used when clinically appropriate. Surgical therapy is indicated in certain situations and includes atrial septostomy, pulmonary thromboendarterectomy for CTEPH, and lung or heart–lung transplantation (for disease that is not responsive to medical therapy).1
Nonpharmacologic Therapy
Nonpharmacologic therapy is frequently used to address comorbid conditions that often accompany PAH. Patients with PAH should be counseled on several important points. Pregnancy should be avoided due to high morbidity and mortality rates in females with PAH during pregnancy and in the postpartum course.3 Immunization against influenza and pneumococcal disease should be provided.9Hypoxemia may aggravate vasoconstriction in patients with PAH; therefore, PAH patients may require supplemental oxygen, particularly when using air travel.30 Patients should adhere to a low-sodium diet to avoid fluid retention predisposing to right heart failure.31 Cardiopulmonary rehabilitation improves functional status and is safe and important for patients with PAH.32
Pharmacologic Therapy
The number of potential therapies for PAH has expanded dramatically in the last decade. In addition to adjunctive background therapy, multiple drugs have been developed specifically for treatment of PAH. Figure 17-3 illustrates the current recommended treatment algorithm based on the most recent guidelines.1,3
FIGURE 17-3 Treatment algorithm for pulmonary arterial hypertension (PAH). Designators (A), (B), (C), (D), (E/A), (E/B), and (E/C) are defined in Table 17-3. (APAH, associated pulmonary arterial hypertension; CCB, calcium channel blocker; FC, functional class; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension.) (Data from reference 1.)
Conventional Pharmacologic Treatment 
Conventional therapy includes oral anticoagulants, diuretics, oxygen, and digoxin.26 Anticoagulation with warfarin may be considered in patients with PAH, particularly if they have IPAH. The rationale for oral anticoagulants is based on the presence of traditional risk factors for venous thromboembolism, such as heart failure and sedentary lifestyle, as well as on the demonstration of thrombotic predisposition and thrombotic changes in the pulmonary microcirculation. The target international normalized ratio (INR) in most centers is 1.5 to 2.5.10,23 Anticoagulation is recommended for patients with IPAH (strength of recommendation: E/B).1,9
Loop diuretics such as furosemide are helpful adjunctive therapy in patients with decompensated right heart failure and associated findings of increased central venous pressure, abdominal organ congestion, peripheral edema, and ascites.9 Appropriate diuretic therapy in right heart failure provides symptomatic and clinical benefits in patients with PAH (strength of recommendation: E/A).9 Patients should be maintained at as close to a euvolemic state as possible.
Oxygen therapy with a goal oxygen saturation greater than 90% (0.90) may be beneficial in some patients, although there are no data regarding the long-term effects of oxygen treatment in PAH (strength of recommendation: E/A).9 Oxygen treatment is controversial in patients with PAH associated with shunts (i.e., Eisenmenger’s syndrome).
Digoxin may be used for patients with PAH with right heart failure as adjunctive therapy along with diuretics to control symptoms (strength of recommendation: E/C).9 There are no long-term trials and benefit is uncertain. Optimal plasma concentrations are unknown; however, in light of recent trials of digoxin in left systolic dysfunction, the typical target concentration is between 0.5 and 0.8 ng/mL (0.64 and 1 nmol/L). Patients on digoxin should receive periodic monitoring of potassium.
Specific Pharmacologic Therapy In recent years, there has been a surge in availability of drug therapy for the treatment of PAH. Figure 17-4 illustrates the timeline of drug approval over the past few decades.
FIGURE 17-4 Timeline of pulmonary arterial hypertension (PAH) medication approvals. Epoprostenol: 1995; treprostinil: SC 2002, IV 2004, inhaled 2009; iloprost: 2004; bosentan: 2001; ambrisentan: 2007; sildenafil: 2005; tadalafil: 2009.
Synthetic Prostacyclin and Prostacyclin Analogs 
PGI2 is produced predominantly by endothelial cells, and it induces potent vasodilation of all vascular beds. It is also a potent inhibitor of platelet aggregation and possesses cytoprotective and antiproliferative activities. PGI2 synthase expression is reduced in pulmonary arteries, and urinary excretion of PGI2 metabolites is reduced in PAH. Epoprostenol is a synthetic analog of PGI2 and has a short half-life of 3 to 5 minutes; consequently, it must be given by continuous IV infusion. Initiation of epoprostenol should be done in a hospital setting at low doses ranging from 2 to 4 ng/kg/min and increased at a rate limited by side effects (flushing, headache, diarrhea, jaw pain, backache, abdominal cramping, foot/leg pain, and hypotension). The two available products, Flolan® (now available generic) and Veletri®, have unique stability and reconstitution parameters; both pharmacists and patients should be aware of the differences and follow the manufacturer recommendations. Because of the short half-life of the drug, it is recommended that the patient have a backup supply of the drug and infusion pump.23 Because the drug must be administered by continuous infusion with a central venous catheter and pump, infection, catheter obstruction, and sepsis are potential complications. A Centers for Disease Control and Prevention study found that bloodstream infections occurred with epoprostenol and treprostinil in the range of 0.3 to 2.1 per 1,000 medicine days (approximately 1 infection every 3 years) when these drugs are given by the IV route. The target dose for the first 2 to 4 weeks is around 10 to 15 ng/kg/min, and periodic dose increases are then required to maximize efficacy. Optimal doses are variable but are in the range of 25 to 40 ng/kg/min.30,33 Observational series have documented an improvement in survival in patients with IPAH compared with either historical control or predicted survival based on the National Institutes of Health Registry equation.33–35 Based on current guidelines, epoprostenol is indicated for WHO functional class III and IV (strength of recommendation: A).1
Treprostinil (Remodulin) is a stable analog of PGI2 given for subcutaneous (SC) or IV infusion approved for functional classes II, III, and IV.33 The major advantages of treprostinil over epoprostenol include ease of use and increased safety due to a longer half-life, lowering the risk of rebound effects that may happen with drug interruption.19 Treprostinil has been shown to improve 6-minute walk distance and hemodynamics with outcomes that are similar to epoprostenol.36,37 In clinical trials, the greatest exercise improvement was observed in patients who were more compromised at baseline and in patients who could tolerate doses in the upper quartile (>13.8 ng/kg/min). The initial dose for treprostinil is 1.25 ng/kg/min by either the SC or the IV route. If not tolerated, the dose should be reduced to 0.625 ng/kg/min and retitration attempted at 4 weeks. If transitioning from epoprostenol to treprostinil, start with 10% of the epoprostenol dose. Dose may be increased by 1.25 ng/kg/min but no more than 2.5 ng/kg/min per week. Infusion site pain is common with the SC route, leading to discontinuation of the treatment in 8% of patients and limiting dose increase in other patients.30 Patients unable to tolerate SC can be transitioned to IV treprostinil.23 Other side effects are similar to epoprostenol. Based on international guidelines, treprostinil is recommended for functional class III (SC administration—strength of recommendation: B; IV administration—strength of recommendation: E/B), and functional class IV (SC administration—strength of recommendation: C; IV administration—strength of recommendation: E/B).1
In an effort to prevent complications and use of pumps and central venous catheters for PGI2 analog administration, aerosolized formulations were developed. The first approved formulation, iloprost (Ilomedin, Ventavis), is a PGI2 analog that is given by inhalation using a dosing system provided by the manufacturer (ADD system) with the initial inhaled dose being 2.5 mcg six to nine times per day up to every 2 hours during waking hours. The dose should be titrated and maintained at 5 mcg/dose if tolerated. In a 3-month, randomized, double-blind, placebo-controlled trial, iloprost via inhalation provided at least a 10% improvement in 6-minute walking distance and improvement in functional class.38 Inhaled iloprost can be cumbersome to use as each inhalation dose can take 4 to 10 minutes to administer. Patients should also be instructed to have a backup supply as iloprost has a short half-life, similar to epoprostenol.23 Adverse effects are similar to other PGI2 analogs with the exception of infectious complications related to catheter use for drug delivery. Inhaled iloprost is indicated for functional class III (strength of recommendation: A) and functional class IV (strength of recommendation: B), although many clinicians prefer using the IV or SC route in patients with more severe disease.1
The second aerosolized formulation, inhaled treprostinil (Tyvaso), was approved by the FDA in July 2009 to improve exercise capacity in functional class III patients. In a randomized, double-blind, 12-week trial, patients receiving inhaled treprostinil experienced a 20-m improvement in 6-minute walk distance compared with those on placebo (P <0.0006). All patients included in the trial were concurrently receiving bosentan or sildenafil for at least 3 months.39 An open-label extension of the trial found that inhaled treprostinil provided sustained benefit and was safe and efficacious over a 2-year period.40 The approved dosing of inhaled treprostinil is three breaths (18 mcg each) four times daily during waking hours. The dose may be titrated based on patient tolerance at 1- to 2-week intervals to maximum dose of nine breaths four times daily. Inhaled treprostinil requires less time to administer, but the formulation is more complicated to prepare than inhaled iloprost.23 While inhaled treprostinil avoids the infusion-related complications of the other PGI2 analogs, use is cautioned in patients with acute pulmonary infections or underlying lung disease. The most common adverse effects seen in clinical trials include throat irritation, cough, headache, nausea, dizziness, and flushing. Inhaled treprostinil may also cause systemic hypotension, and patients should be monitored carefully if they are concurrently on diuretics, antihypertensives, or other vasodilators.1
Endothelin Receptor Antagonists (ERAs) ET-1, a peptide produced primarily by the vascular endothelial cells, is characterized as a powerful vasoconstrictor and mitogen for smooth muscle. Activation of the ET-1 system has been shown in both plasma and lung tissue of PAH patients. Bosentan (Tracleer) is an orally active dual ETA and ETB receptor antagonist that improves exercise capacity, functional class, hemodynamics, echocardiographic and Doppler variables, and time to clinical worsening.41,42 In one of the larger studies with bosentan, patients were started on 62.5 mg twice daily for 4 weeks followed by 125 or 250 mg twice daily for a minimum of 12 weeks. Both doses were better than placebo, and the higher dose provided greater improvement in 6-minute walking distance. Increases in hepatic aminotransferases occurred in 11% of patients and were dose dependent.42 The mechanism of increased liver enzymes is thought to be competition by bosentan and its metabolites with the biliary excretion of bile salts, resulting in retention of bile salts that can be cytotoxic to hepatocytes. Because of this toxicity, bosentan is only available through a distribution program, the Tracleer Access Program.23 Bosentan should be started at 62.5 mg twice daily in adults and adolescents for 4 weeks. After 4 weeks of therapy, the dose should be increased to 125 mg twice daily. If LFTs are confirmed to be in the range of three to five times the upper limit of normal, reduce the daily dose or interrupt treatment. If LFTs return to pretreatment levels, bosentan may be continued or reintroduced if indicated. LFTs should be monitored at baseline and monthly thereafter, and monthly pregnancy testing is required in females (category X). Complete blood count should be monitored every 3 months as bosentan has been associated with anemia. Bosentan is indicated for WHO functional class II and III (strength of recommendation: A) as well as functional class IV (strength of recommendation: E/C).1
Ambrisentan (Letairis) is a once-daily selective ETA receptor antagonist that improves exercise capacity and hemodynamics and delays clinical worsening in PAH.43,44 Two large (n = 202 and 192) trials recently evaluated the efficacy of ambrisentan compared with placebo. In 12 weeks, both studies demonstrated a significant improvement in functional capacity at doses of 2.5, 5, and 10 mg daily (range of 31 to 59 m). However, greater response was seen with increased doses. All doses were well tolerated, with no patients on therapy experiencing an increase in LFTs >3 times the upper limit of normal. Similar to bosentan, ambrisentan is category X for pregnancy; the distribution program for ambrisentan is referred to as Letairis Education and Access Program (LEAP).23 Unlike bosentan, liver toxicity occurs very rarely with ambrisentan (0.8% in 12-week trials and 2.8% for up to 1 year).33 Common side effects include peripheral edema, nasal congestion, flushing, and palpitations. Treatment should be initiated with 5 mg once daily and increased to 10 mg once daily if required. Ambrisentan is recommended for WHO functional class II and III (strength of recommendation: A) and may be used for WHO functional class IV (strength of recommendation: E/C).1
Phosphodiesterase Inhibitors There are two phosphodiesterase-5 inhibitors available for the treatment of PAH—sildenafil (Revatio) and tadalafil (Adcirca). Sildenafil is a potent and highly specific phosphodiesterase-5 inhibitor that is approved for erectile dysfunction but also has been shown to reduce mPAP and improve functional class. Sildenafil exerts its pharmacologic effect by increasing the intracellular concentration of cyclic guanosine monophosphate, leading to vasorelaxation and antiproliferative effects on vascular smooth muscle cells. In a double-blind, placebo-controlled trial, sildenafil with conventional therapy significantly improved 6MWD and hemodynamic parameters at 12 weeks compared with placebo. A 1-year extension study showed a continued improvement in 6MWD of 51 m (95% CI 41 to 60).45 The FDA-approved dose is 20 mg by mouth three times per day; however, much higher doses are routinely used clinically. Common adverse effects include headaches, flushing, epistaxis, dyspepsia, and diarrhea. Changes in vision have been reported, including blue-tinted vision and sudden loss of vision. In the event of sudden loss of vision, the drug should be stopped. Concurrent nitrate therapy may lead to excessive blood pressure reduction, and this combination should be avoided. Based on the current guidelines, sildenafil is recommended for functional class II and III patients with PAH (strength of recommendation: A) in addition to functional class IV patients (strength of recommendation: E/C).1
Another phosphodiesterase-5 inhibitor, tadalafil (Adcirca), was approved by the FDA in 2009 for the treatment of PAH. In a 16-week study, tadalafil 40 mg daily significantly improved exercise capacity (an average of +33 m; P<0.01) and quality of life measures. Tadalafil 40 mg also improved the time to clinical worsening (P = 0.041), which has not been demonstrated with sildenafil. Fifty-three percent of patients in this study were also on background bosentan therapy. Treatment-naïve patients demonstrated not only greater improvement in exercise capacity than those on bosentan therapy (+44 m vs. 23 m) but also greater improvement on all secondary outcomes. One possible explanation is decreased tadalafil levels as bosentan is a potent CYP450 3A4 inducer. Higher doses of tadalafil may be required in patients on concurrent bosentan therapy.46 The most commonly reported adverse events were headache, myalgia, and flushing. The recommended dose is 40 mg by mouth once a day.46 Concurrent use with nitrate therapy should also be avoided with tadalafil. Current guidelines indicate tadalafil for functional class II and III (strength of recommendation: B) and functional class IV (strength of recommendation: E/C).1
Calcium Channel Blockers 
Since such a small number of patients have a positive response to acute vasodilator testing, CCBs are rarely used in the management of PAH. Approximately 13% of patients with IPAH will demonstrate an acute vasodilator response and may be initiated on CCB therapy; however, the number responding to long-term therapy is low (7%).24 CCBs should not be used in the absence of demonstrated acute vasoreactivity.1The preferred drugs are dihydropyridine CCBs as they lack the negative inotropic effects seen with verapamil. Diltiazem may be used in patients with tachycardia to slow heart rate through atrioventricular node blockade. If left ventricular systolic dysfunction is present, diltiazem and verapamil should not be used. Assessment of CCB therapy should occur soon after initiation, and if improvement in functional class to class I or II is not seen, additional or alternative PAH therapy must be initiated. In acute responders, CCBs may be used in WHO functional classes I to IV (strength of recommendation: B).1 The doses of these drugs are relatively high—that is, up to 120 to 240 mg/day for nifedipine and 240 to 720 mg/day for diltiazem—however, initial doses should be much lower and titrated upward to response.30
Combination Therapy Combination therapy is an attractive option to address the multiple pathophysiologic mechanisms in PAH, resulting in improvement in hemodynamics, symptoms, and exercise capacity. Unfortunately, use of combination therapy has not been shown to decrease mortality, admission for worsening PAH, lung transplantation, or escalation of PAH therapy.44 Combination therapy can be pursued by the simultaneous initiation of two (or more) treatments or by the addition of a second (or third) agent if previous treatment has been insufficient. Potential indications for combination therapy include signs of right heart failure, 6-minute walk distance <380 m, and persistent functional class III or IV symptoms despite active treatment. ERAs plus PDE-5 inhibitors, PDE-5 inhibitors with PGI2analogs, ERAs with PGI2 analogs, and all three classes used in combination have all shown improved functional outcomes.41,42,47–49 Sequential combination therapy is recommended for patients with inadequate clinical response to monotherapy; combinations of prostanoids, phosphodiesterase-5 inhibitors, and endothelin antagonists may be used (strength of recommendation: B).1 Initial combination therapy may be necessary in WHO functional class IV patients (strength of recommendation: E/C).1 More specific information concerning individual drugs used for PAH is shown in Tables 17-5 to 17-7.
TABLE 17-5 Drug Dosing Table
TABLE 17-6 Desired Treatment Outcomes
TABLE 17-7 Drug Monitoring Information
Evaluation of Therapeutic Outcomes
Response to treatment in PAH can be objectively measured by the 6-minute walk distance, echocardiography to assess pulmonary pressures, and right heart catheterization as the gold standard to assess ventricular function and pulmonary pressures (see Table 17-6). The WHO functional classification system is clinically useful, but correlations to hemodynamics may be imprecise. Other outcomes that are useful in clinical trials include hospitalization for exacerbations of PAH and the development of complications and death.
CONCLUSIONS
Significant advances have been made in elucidating the pathogenesis of PAH as well as in the evaluation and treatment of these patients over the past 2 decades. With approved targeted therapies such as ERAs, phosphodiesterase-5 inhibitors, and PGI2 analogs, clinical improvement is possible in most patients, leading to a better quality of life and delay of disease progression. Patient education is important to improve acceptance of this disease and referral to specialty care centers may provide the best outcomes.
ABBREVIATIONS
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