Bosentan for Early Pulmonary Hypertension
Abstract & Commentary
By Michael H. Crawford, MD
Source: Galia N, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-2100.
The endothelin receptor antagonist bosentan has been shown to improve exercise tolerance, hemodynamics, and clinical deterioration in trials of patients with advanced symptoms due to pulmonary hypertension (WHO functional class III and IV). The EARLY study tested the hypothesis that bosentan would have a similar benefit in WHO FC II patients. This multicentered trial involved such patients, age > 12 years with pulmonary hypertension due to a variety of causes and either a six-minute walk distance < 80% of normal or < 500 m with a Borg dyspnea index of ³ 2 and a pulmonary vascular resistance of ³ 320 dym/s/cm5. Only treatment with sildenafil, calcium blockers, and anticoagulants were allowed. Inclusion criteria were met in 185 patients; 93 were randomized to bosentan and 92 to placebo for six months. The primary endpoints were the six-minute walk test and pulmonary vascular resistance (determined invasively). There were 22 patients who dropped out of the trial; 81 completed in the bosentan group and 82 in the placebo group. The most common reason for discontinuation was adverse events in the bosentan group (mainly liver dysfunction) and worsening pulmonary hypertension in the placebo group. At six months, the average pulmonary vascular resistance was 83% of the baseline value in the bosentan group and 108% in the placebo group (p < .001). Mean six-minute walk distance increased by 11 m in the bosentan group and decreased by 8 m in the placebo group (p = NS). Serious adverse events occurred in 13% of the bosentan patients and 9% of the placebo patients. Most common were syncope in the bosentan group and right heart failure in the placebo group. Galie et al concluded that bosentan therapy is, overall, beneficial for WHO class II patients with pulmonary hypertension.
Commentary
Often, pulmonary hypertension is rapidly progressive, resulting in right heart failure and death. Early treatment might be expected to slow this progression. Thus, treating mildly symptomatic patients with an effective agent for more advanced disease is a reasonable hypothesis to test. Two primary endpoints were chosen: a clinical one (six-minute walk test) and a hemodynamic one (pulmonary vascular resistance). Significant changes in the hemodynamic endpoint were achieved because of an average 3 mmHg drop in mean PA pressure and a 90 mL/min/m2 increase in cardiac index. If you guessed that such small changes in hemodynamics would not affect symptoms much, you are correct. Although there were treads for improved clinical benefits on bosentan (six-minute walk distance, number worsening) statistical significance was not achieved.
In addition to the small hemodynamic benefit, there are other reasons why clinical parameters were not significantly impacted. These were mildly symptomatic patients, albeit with significant pulmonary hypertension (mean PAP 52 mmHg), with six-minute walk distances of 435 m, as compared to previous trials that did show benefit where walk distances were 314-398 m. Significant changes in less sick patients may be harder to achieve. However, the experience in the placebo patients, 13% of whom worsened in six months vs 3% in the bosentan group, confirms that this is a progressive disease if you have mild symptoms. There was only one death in each group, so mortality could not be assessed.
Patients, on average, felt better on bosentan. Those on bosentan had a lower incidence of worsening functional class and improved quality-of-life questionnaire results. There were adverse events in both groups. The most common adverse event in the bosentan group was abnormal liver function tests, which are usually reversible with dosage reduction or discontinuation of bosentan. Worsening pulmonary hypertension was common in the placebo group. Clearly, this is a progressive disease, at least in those with symptoms, and bosentan appears to retard this progression, even in patients already on therapy (one-third on calcium blockers, 15% on sildenafil).
There are limitations to this study. Almost all the patients were classified as white. Most had idiopathic pulmonary hypertension; few had HIV (< 5%). In general, there were not enough patients in the various etiologic subgroups to determine if bosentan is superior for one etiology vs another. The follow-up was relatively short (six months), so it is possible that significant differences in clinical outcome could have occurred with longer follow-up. In summary, mildly symptomatic patients with significant pulmonary hypertension should be considered for bosentan therapy since the benefits seem to outweigh the risks.
The endothelin receptor antagonist bosentan has been shown to improve exercise tolerance, hemodynamics, and clinical deterioration in trials of patients with advanced symptoms due to pulmonary hypertension (WHO functional class III and IV).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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