Compelling Evidence of Long-Term Outcomes in Pulmonary Arterial Hypertension? A Clinical Perspective


The following are 10 points to remember from a review of clinical trials in pulmonary arterial hypertension (PAH):

1. PAH is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death.

2. There are currently three classes of drugs approved for the treatment of PAH: prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Each is approved for use on the basis of relatively small, short-term studies, yet it is common for each to be administered (alone or in combination) over the lifetime of a patient with PAH.

3. Twenty long-term (at least 1 year) open-labeled clinical trials were identified, including two studies of calcium channel blockers in persons considered vasodilator responders.

4. Long-term improved outcomes are associated with improved hemodynamics, including a moderate reduction in mean pulmonary artery and pulmonary vascular resistance with an increase in cardiac output. The latter are biased, considering they represent the outcome in persons who survived at least a year. Hemodynamic changes vary from robust to insignificant in individuals, suggesting that there are responders and nonresponders to each of the drug classes.

5. Despite missing data and survivor bias, there appears to be sustained improvement in exercise capacity, as measured by the 6-minute hall walk in a subpopulation of patients who remain on long-term therapy. Considering the variability in study design and handling of missing data, 6-minute walk changes should not be used to compare drugs within and between classes.

6. Because of the short duration of placebo-controlled studies, it is unclear if they support a true long-term survival advantage for medical therapy or if the risk reduction observed in this analysis was due to a relatively modest delay in mortality beyond the short-term observation periods of these studies. The effects of medical therapy on survival must still be inferred primarily from long-term observational studies and historical controls.

7. When using the National Institutes of Health (NIH) Registry formula to predict survival at 1, 2, 3, and 5 years (includes mean pulmonary artery pressure, mean right atrial pressure, and cardiac index), long-term observational studies conducted by the pharmaceutical industry show medical therapy to have a survival advantage.

8. Data from two large contemporary observational studies show a significant improvement in survival, and show that survival estimates as predicted by the NIH formula, may no longer be relevant and/or accurate in the current era of PAH-directed therapy.

9. In the Chicago PAH cohort, observed survival was 86%, 69%, and 61% at 1, 3, and 5 years, respectively. In 247 patients with idiopathic, familial, and anorexigen-associated PAH (i.e., etiologies similar to those in the NIH model), observed survival was significantly higher than NIH-predicted survival at 1 year (92% vs. 65%), 3 years (75% vs. 43%), and 5 years (66% vs. 32%), respectively. The French Registry observed survival rates approximately 10 percentage points higher than those predicted by the NIH formula.

10. The authors concluded that current medical therapies approved for the treatment of PAH can provide sustained benefits in hemodynamic function and exercise capacity. The cumulative evidence suggests that patients are living longer compared with untreated patients; the reasons are likely multifactorial. Although definitive evidence will require randomized and properly controlled long-term trials, the current evidence supports the long-term use of these drugs for the treatment of patients with PAH.


It is important to realize that clinical trials include idiopathic PAH, scleroderma, and congenital heart disease (most exclude HIV and portopulmonary hypertension); treatment response and survival vary considerably with the etiology of PAH; and the benefit or lack of benefit within each etiology is not clear from publications.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Acute Heart Failure, Pulmonary Hypertension

Keywords: Pulmonary Circulation, Cardiac Output, Vasodilator Agents, Hemodynamics, Heart Diseases, Registries, Receptors, Endothelin, Atrial Pressure, Survival Rate, Chicago, Heart Failure, Hypertension, Pulmonary, National Institutes of Health (U.S.), United States

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