Chest
Volume 130, Issue 4, October 2006, Pages 1198-1202
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Clinical Commentary
The Current Treatment of Pulmonary Arterial Hypertension: Time to Redefine Success

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In the past decade, three classes of medications have been approved for the treatment of pulmonary arterial hypertension. A review of the clinical trial data for the prostanoids, endothelin antagonists, and phosphodiesterase-5 inhibitors has shown that all agents have similar efficacy on the 6-min walk distance over 12 to 16 weeks, which was the primary end point in the randomized clinical trials. However, little is known about their long-term efficacy or about how these drugs affect the underlying disease, if at all. Successful therapy is currently defined as an improvement in exercise tolerance over a 4-month period. Future trials need to better characterize how therapies affect the pulmonary vasculature pathologically, biologically, and hemodynamically, and whether survival is actually improved.

Section snippets

The Natural History of PAH

The natural history of untreated idiopathic PAH (IPAH) was well-characterized by the National Institutes of Health Registry on Primary Pulmonary Hypertension1 as it was conducted in an era when therapy largely consisted of diuretics and supplemental oxygen. Patients with PAH present with dyspnea with effort, limited exercise capacity, and signs and symptoms that were consistent with right heart failure. On cardiac catheterization, these patients uniformly will have a markedly elevated pulmonary

Is Pulmonary Arterial Hypertension Reversible?

To ascertain a realistic end point in therapeutic trials, we need to determine what type of treatment effect is possible. The obvious question becomes whether the disease is indeed reversible, and/or whether there is a certain stage at which the potential for reversibility becomes lost.

The experience with calcium channel blockers for the treatment of PAH holds some insights. The long-term effectiveness of calcium channel blocker therapy relates to a select group of patients with PAH whose

What Have We Achieved With Approved Therapies?

In the past 10 years, there have been three classes of drugs that have become approved by the regulatory authorities as a treatment of PAH. They include the prostanoids,10, 11, 12, 13 the endothelin receptor antagonists,14 and the phosphodiesterase-5 inhibitors.15 However, these therapies were approved not because they lowered pulmonary artery pressure, but because they allowed patients to perform better on a 6-min walk test, which was the primary end point in the trials. It is valid to ask

How Should We Evaluate the Treatments of PAH?

IV epoprostenol therapy has been studied considerably following its approval in 1995. There is little doubt that it produces long-term beneficial effects in patients with advanced PAH, yet its mechanism of action remains a mystery. It has been characterized as a vasodilator,20, 21 an inotrope,22 an anticoagulant,23 and a growth factor inhibitor,24 but there are no histopathologic data on how it affects the pulmonary vasculature in humans with PAH. By comparison, we know even less about the

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    Dr. Rich is also a part-time salaried consultant to United Therapeutics Corporation.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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