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


Advances in understanding the pathophysiology of IPAH have led to the development of several suitable pharmacologic treatment alternatives. Initially, calcium channel blockers were demonstrated to be efficacious in the small percentage of patients with IPAH who exhibit a favorable response to acute vasodilator challenge. Twenty years after the identification of endogenous prostacyclin, intravenous epoprostenol was approved by the FDA and is now a first-line treatment option in patients who are not candidates for calcium channel blocker therapy. Studies have shown that epoprostenol provides long-term benefits in exercise capacity, hemodynamic parameters, and survival.

Treprostinil, a stable prostacyclin analog, is an alternative to intravenous epoprostenol in patients who experience life-threatening catheter or delivery system complications or who cannot tolerate dosage escalations while receiving intravenous epoprostenol. Compared with administration of epoprostenol, administration of subcutaneous treprostinil is considerably less cumbersome and has fewer serious adverse effects related to drug delivery, although a long-term mortality benefit with treprostinil has not yet been proved.

Iloprost is an aerosolized prostanoid recently approved by the FDA for treatment of IPAH. It appears to be safe, effective, and well tolerated and may be considered a long-term treatment alternative. Like treprostinil, however, controlled studies addressing a substantive mortality benefit with iloprost have yet to be completed.

An increasing understanding of the multiple pathogeneses of IPAH led to the discovery of another target for drug therapy, and subsequently the endothelin-receptor antagonist bosentan was approved as the first orally administered drug available to treat IPAH. Although long-term studies on survival have not been completed, bosentan is considered a potential first-line treatment option in patients who do not respond to calcium channel blockers.

Finally, sildenafil is the newest drug available for IPAH, having received FDA approval in 2005. A phosphodiesterase type 5 inhibitor originally marketed for erectile dysfunction, sildenafil brings efficacy, convenience, and cost-effectiveness to the treatment of IPAH.

Indefinite therapy with epoprostenol or bosentan should be considered primary treatment for patients with IPAH who are in NYHA class III, and possibly class II, and are not suitable candidates for calcium channel blocker therapy. Based on current evidence, the benefit of subcutaneous treprostinil, inhaled iloprost, sildenafil, and oral beraprost appears to be less than that of intravenous epoprostenol or oral bosentan. Indefinite treatment with intravenous epoprostenol is the treatment of choice for patients with IPAH who are in NYHA class IV and are not candidates for calcium channel blocker therapy. Second-line alternative, or possibly combination, therapies in this case are bosentan, subcutaneous treprostinil, inhaled iloprost, and sildenafil.[10]

New agents are in various phases of development, and novel uses for existing drugs are being investigated. As our knowledge of the multifactorial pathogenesis of IPAH grows, it is anticipated that additional innovative treatment options will be discovered, promising a new era of hope for patients and the clinicians who care for them.