Pharmacotherapy for Idiopathic Pulmonary Arterial Hypertension During the Past 25 Years

Anna M. Hackman, Pharm.D.; Thomas E. Lackner, Pharm.D., FASCP


Pharmacotherapy. 2006;26(1):68-94. 

In This Article

Abstract and Introduction

Objective: To review the current pharmacotherapy for idiopathic pulmonary arterial hypertension (IPAH).
Methods: A search of the primary literature was conducted by using MEDLINE, the National Institutes of Health medical research Web site (, and the United States Food and Drug Administration's Center for Drug Evaluation and Research Web site (
Results: Until the early 1980s, conventional therapy for IPAH consisted of anticoagulation, diuretics, digitalis extracts, and supplemental oxygen, yet the 5-year mortality rate remained at 66%. Calcium channel blocker therapy was introduced with the hope that it would improve survival in patients with IPAH, but it was found to be effective in only approximately 25% of patients. In 1996, intravenous epoprostenol was the first drug to show long-term benefit on hemodynamics, exercise capacity, and survival. However, administration of epoprostenol requires a permanently indwelling central venous catheter, and tachyphylaxis is common, necessitating continuous dosage escalations. Subsequently, treprostinil, a prostacyclin analog of epoprostenol that can be administered by continuous subcutaneous infusion, was introduced, followed by aerosolized iloprost, a prostacyclin analog for inhalation. An increasing understanding of the multiple pathogeneses of IPAH led to the discovery of another target for drug therapy, and bosentan, an orally administered agent, became the first endothelin-receptor antagonist approved for treatment of IPAH. Most recently, the phosphodiesterase inhibitor, sildenafil, has received approval from the United States Food and Drug Administration for the treatment of IPAH.
Conclusion: Recently developed pharmacotherapies offer greater effectiveness and safety than traditional agents for the treatment of IPAH.

As recently as the early 1980s, a diagnosis of idiopathic pulmonary arterial hypertension (IPAH, also known as primary pulmonary hypertension) was tantamount to a death sentence, with a mean survival time after diagnosis of 2.8 years.[1] This is a rare disease, with an incidence of only 1-2 persons/million, but it affects healthy adults in their prime, frequently in the third or fourth decade of life, and occurs in women 3 times more frequently than in men.

For almost a century, since Romberg first described the abnormal pulmonary vasculature findings of IPAH, the only drug therapy that improved survival was anticoagulation with warfarin.[2] Not until the 1980s were three significant advances made in the treatment of IPAH. First, in 1981 the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) established the Patient Registry for the Characterization of Primary Pulmonary Hypertension. This registry facilitated cooperation among 32 medical centers while screening nearly 200 patients to elucidate the clinical and pathologic characteristics of IPAH, opening the door to coordinated scientific scrutiny of this disease.[3,4] Shortly thereafter, the second advance occurred with the introduction of high-dose calcium channel blockers as therapy for IPAH. Vasodilatory effects in the pulmonary vasculature improved clinical symptoms, reduced pulmonary artery pressure, and caused regression of right ventricular hypertrophy. Unfortunately, this effect was seen in only the 20-30% of patients who exhibited pulmonary vascular responsiveness to acute vasodilator challenge.[5] The acute challenge itself, using agents such as hydralazine, diazoxide, phentolamine, or isoproteronol, posed serious risks due to the potential for prolonged systemic hypotension in patients who were already hemodynamically compromised.[6,7,8] Therefore, the third seminal event was the successful use of epoprostenol, a synthetic formulation of endogenous prostacyclin, a potent vasodilator, in testing acute pulmonary vascular responsiveness in patients with pulmonary hypertension. Because of its short half-life, epoprostenol offered a safer alternative for vasodilator challenge without the potential for sustained, life-threatening systemic hypotension seen with previously used agents, and it quickly became the reference standard in pulmonary vascular testing.[3,9]

Recently, at the request of the American College of Chest Physicians, the current body of evidence regarding IPAH was reviewed and summarized, then evaluated by an international panel of experts. The resultant guidelines published in 2004 include recommendations on screening, early detection and diagnosis, and medical and surgical therapies for and prognosis of IPAH, along with grading of the evidence, benefits to the patient, and strength of the recommendations.[10] Although IPAH remains an incurable disease, in the past 2.5 decades, significant advances have been made in our understanding of its pathophysiology, in recently available treatment options for this condition, and, consequently, in the overall prognosis for patients.