Pulmonary arterial hypertension (PAH) is a disease state characterized by vascular narrowing and increased pulmonary vascular resistance. Physical symptoms, which may include fatigue or weakness, exertional dyspnea, and peripheral edema, are often nonspecific and can mimic more common disorders encountered in clinical practice. Healthcare professionals have been limited in which medications could be used to treat this condition because clinical data have been scarce. Recently, multiple new classes of medications, many of which are very costly, have become available; these agents offer physicians more therapeutic options for the treatment of PAH. Managed-care organizations have been challenged with suggesting the appropriate place in therapy for these new agents, as well as ensuring their safe and cost-effective utilization. This review summarizes the data available for the drugs used to treat PAH, with the goal of helping organizations to make appropriate decisions regarding the proper use of these agents.
Pulmonary arterial hypertension (PAH) is a disease state characterized by vascular narrowing and increased pulmonary vascular resistance. Physical symptoms, which may include fatigue or weakness, exertional dyspnea, and peripheral edema, are often nonspecific and can mimic more common disorders encountered in clinical practice. Healthcare professionals have been limited in which medications could be used to treat this condition because clinical data have been scarce. Recently, multiple new classes of medications, many of which are very costly, have become available; these agents offer physicians more therapeutic options for the treatment of PAH. Managed-care organizations have been challenged with suggesting the appropriate place in therapy for these new agents, as well as ensuring their safe and cost-effective utilization. This review summarizes the data available for the drugs used to treat PAH, with the goal of helping organizations to make appropriate decisions regarding the proper use of these agents. (Formulary. 2007;42:287–293.)
Pulmonary arterial hypertension (PAH) is a relatively rare lung disorder in which the blood pressure in the pulmonary artery is increased far above normal levels, usually with no identifiable cause.1 Although many cases of PAH are idiopathic or familial, the disease may develop secondary to pregnancy, valvular heart disease, chronic thromboembolic disease, lupus, scleroderma, rheumatoid arthritis, vasculitis, or HIV.1 Among the >800,000 patients hospitalized with PAH between 2000 and 2002, 61% were women, and 34% were aged <65 years.1 In the United States alone, approximately 16,000 deaths and >250,000 hospital visits are attributed to PAH annually.1 These numbers have been steadily increasing over the past 15 years.1
Historically, the stages of PAH disease have been classified by the New York Heart Association (NYHA) and the World Health Organization (WHO). Both organizations base their classifications on the effect of the disease on the patient's ability to function (class I: no limitation of physical activity; class II: mild limitation of physical activity; class III: marked limitation of physical activity; class IV: inability to perform any physical activity).5 The WHO classification also takes into account the presence or absence of syncope. However, the 2 classification systems are generally used interchangeably; in this review, WHO classes will be used.
Calcium-channel blockers. CCBs have been used off-label since the 1980s in patients with PAH because of their vasodilating effects.6 Uncontrolled studies have demonstrated that long-term use of high-dose oral CCBs (nifedipine 172±41 mg or diltiazem 720±208 mg) prolongs survival among patients with an initial response to vasodilator therapy. However, this initial response to treatment with vasodilators is uncommon, occurring in approximately 10% of patients with idiopathic PAH and rarely in patients with PAH secondary to other conditions.6 Those patients who do not exhibit an initial response to vasodilator therapy are not likely to benefit from CCB therapy.6 Current American College of Chest Physicians (ACCP) guidelines recommend that patients with PAH (particularly those with idiopathic PAH) undergo an acute vasoreactivity challenge using a short-acting vasodilator such as intravenous epoprostenol, adenosine, or inhaled NO before treatment with CCBs. Patients demonstrating a positive response to vasodilator therapy, defined as a decrease of ≥10 mmHg to ≤40 mmHg, with an increased or unchanged cardiac output, should be considered for therapy with a long-acting CCB.7
Patients with decompensated right-sided heart failure should avoid treatment with CCBs. In patients with advanced left ventricular dysfunction, CCBs may worsen heart failure and increase mortality. CCBs should be avoided in patients with a cardiac index ≤2.1 L/min/m2, pulmonary arterial oxygen saturation ≤63%, and/or right atrial pressure ≥10 mmHg.
Current ACCP guidelines recommend starting with a low dose of CCB and slowly titrating to the maximum tolerated dose.7 Additionally, the British Cardiac Society guidelines recommend that CCBs should be initiated in a hospital setting, with careful monitoring of symptoms, blood pressure, oxygen saturation, and exercise tolerance.9 Limiting factors for dose escalation include systemic hypotension, bradycardia, and peripheral edema.
Nifedipine, diltiazem, verapamil, and amlodipine are commonly used CCBs; the choice of agent is generally based on heart rate at baseline. Nifedipine or amlodipine may be used in patients with relative bradycardia, whereas verapamil or diltiazem may be used in patients with tachycardia.7,10 In patients with left-sided heart failure, therapy with nifedipine or verapamil may exacerbate symptoms and lead to the deterioration of ventricular function; amlodipine is a dihydropyridine CCB that is not associated with increased mortality in patients with chronic heart failure.9
Prostacyclin analogues. Prostacyclin, or prostaglandin I2, is a metabolite of arachidonic acid produced in the vascular endothelium. In vascular smooth muscle tissue, prostacyclin induces relaxation and inhibits cell proliferation. In addition, prostacyclin is a powerful inhibitor of platelet aggregation.6 There is evidence suggesting that prostacyclin deficiency is involved in the pathogenesis of PAH. Clinical studies have explored the role of exogenous prostacyclin in the long-term treatment of moderate-to-severe PAH. Currently, 3 prostacyclin analogues are approved by FDA for the treatment of PAH: epoprostenol, treprostinil, and iloprost. Oral beraprost is approved for the treatment of PAH in Japan and is undergoing phase 3 trials in the United States for the same indication.7
Epoprostenol. Epoprostenol is approved by FDA for the treatment of WHO class III or IV PAH. This agent has a short half-life (<6 minutes) and disintegrates at an acidic pH.11 In addition, epoprostenol must be stored as a freeze-dried preparation due to instability at room temperature. Epoprostenol must be administered via continuous infusion through an indwelling central venous catheter (preferably a tunneled venous catheter).
Intravenous epoprostenol was studied in a prospective, multicenter, 12-week, open-label trial of 81 patients with WHO class III or IV idiopathic PAH.12 Patients were randomly assigned to receive either epoprostenol (intravenously infused at an initial rate of 2 ng/kg/min, with the rate increased in increments of 2 ng/kg/min every 15 minutes), in addition to conventional therapy (oxygen, diuretics, warfarin, and oral vasodilators) or conventional therapy alone. The mean maximum tolerated dose of epoprostenol was 9.2 ng/kg/min. Patients in the epoprostenol arm experienced a statistically significant improvement in function, manifested by a greater 6-minute walking distance (6MWD) score (an increase of 32 meters [m] in the epoprostenol group vs a decrease of 15 m in the conventional group; P<.003). In addition, patients receiving epoprostenol therapy demonstrated improvements in quality of life, hemodynamic measures, and survival.
More recently, 2 large cohort analyses of epoprostenol therapy in patients with WHO class III or IV idiopathic PAH were conducted, with historical controls used as the comparator group.13,14 Patients in these studies were treated with epoprostenol 21±7 ng/kg/min or 27±8 ng/kg/min.13,14 Patients treated with epoprostenol 27±8 ng/kg/min had a survival rate of 85% at 1 year, 65% at 3 years, and 55% at 5 years, a significant improvement when compared with the control group (P<.001 for all).14 In both studies, patients with a history of right-sided heart failure demonstrated poorer outcomes.13,14
A Cochrane review confirmed the efficacy of epoprostenol in treating patients with idiopathic PAH and PAH secondary to other conditions.15 This pooled analysis of published studies demonstrated that epoprostenol was associated with significant improvements in exercise capacity (difference in 6MWD, 90 m), cardiopulmonary hemodynamics, and WHO functional class compared with standard treatment. Most of the studies evaluating this agent were short in duration (3 months). However, 1 study that followed patients for an additional period of 18 months demonstrated that epoprostenol may be associated with tachyphylaxis.11 Patients taking epoprostenol for a prolonged period of time may therefore require a doubling of the dose every 6 to 12 months to achieve the same degree of symptom relief.
Because epoprostenol must be administered via continuous infusion, use of this agent has been associated with catheter-related infections, thromboembolism, and catheter obstruction. Abrupt discontinuation of the infusion may lead to life-threatening deterioration of PAH.7 Common side effects associated with epoprostenol treatment include headache, jaw pain, flushing, diarrhea, nausea, rash, and musculoskeletal pain. These side effects are generally dose related and may subside when the dose is decreased.7