© 2004 American Thoracic Society
Selective or Nonselective Endothelin Receptor Blockade in Pulmonary Arterial HypertensionImperial College London London, United Kingdom Pulmonary arterial hypertension can be a progressive debilitating disease and the treatment options are inadequate. Recent attention has focused on two new drug targets for the management of the condition, endothelin receptors, and phoshodiesterase type 5. The studies with bosentan, an orally active, nonselective endothelin receptor antagonist, have been encouraging. Twice daily administration to patients with pulmonary arterial hypertension of idiopathic or scleroderma etiology led to a reduction in pulmonary artery pressure, increased exercise capacity, and improved functional class over 3 months of treatment (1). In a larger study, however, the margin of improvement, as judged by an increase in 6-minute walk distance of only 44 m over placebo at 4 months, clearly indicates that there is room to do better. Sixasentan is an oral endothelin receptor antagonist that exhibits selectivity for the ETA over the ETB receptor subtype. In theory, sparing blockade of the ETB receptor on vascular endothelial cells could unmask an indirect vasodilator effect of the endothelins, mediated through nitric oxide and prostacyclin release, and facilitate endothelin clearance. Barst and coworkers now report their data from a 3-month placebo-controlled study with sixasentan (100 mg or 300 mg once daily) in 178 patients with pulmonary arterial hypertension, classified as idiopathic, related to connective tissue disease or related to a congenital systemic to pulmonary shunt (3). The study employed cardiopulmonary exercise testing, or more specifically, percent-predicted peak oxygen consumption, as its primary endpoint. The higher dose of sixasentan produced a small increase (3.1%) compared with placebo. Both doses of active treatment increased 6-minute walking distance over placebo (mean effect, 34 m) at 3 months and improved pulmonary vascular resistance, cardiac index, and functional class, with no advantage evident from the higher dose. Adverse effects, however, and notably interference with warfarin metabolism, via inhibition of CYP2C9, were more common with 300 mg daily. The 6-minute walk test has proven an extremely valuable non-invasive test for evaluating patients with moderate-to-severe pulmonary hypertension in multicenter clinical studies. But how do we interpret a modest increase in 6-minute walk distance when accompanied by little evidence of improvement in cardiopulmonary exercise parameters? It is recognized that the two tests measure different abilities. Cardiopulmonary exercise testing is symptom-limited and examines maximal exercise performance while the 6-minute walk is time-limited and measures exercise capacity performed at the patient's own pace. The two investigations have been viewed as complementary, but despite evidence from one cross-sectional study of a good correlation between them (4), two independent clinical trials have now found discrepancies when used as a measure of therapeutic response (3, 5). The 6-minute walk distance is thought to be a better index of the patient's ability to perform activities of daily living and is an independent predictor of mortality. A statistically significant increase in mean 6-minute walk distance is not the same as, and is often smaller than, a clinically significant increase in an individual patient. Nonetheless, the improvement seen with bosentan, particularly when judged against a decline in the placebo group, was sufficient to gain a license for the treatment of functional class III pulmonary arterial hypertension. A similar decline in 6-minute walk distance was observed with placebo in the sixasentan study and so the gain observed with active treatment is also likely to be biologically and clinically significant. The authors urge caution when comparing their results with those of studies with other treatments. Trials with other agents have confined their assessment to patients with idiopathic or connective tissue–related disease in New York Heart Association functional class III or IV and a mean 6-minute walk distance of less than 450 m (5–8). The sixasentan study included patients with congenital heart disease and 33% were in functional class II with a 6-minute walk distance greater than 450 m before treatment. A concern is that the inclusion of patients with a milder form of the condition may have a "ceiling effect" on the benefit to be observed from the drug. To address this, the authors conducted a subgroup analysis in those patients that met the traditional enrolment criteria and found that the improvement in 6-minute walk distance over placebo increased to 65 m. While this is useful information, it was not a prespecified analysis, and the question of whether selective ETA inhibition is superior to nonselective inhibition can only be addressed in a head-to-head comparator study. Ideally, such a study would also include the opportunity to test the concept that selective ETA antagonism is associated with greater improvement in endothelial function and lower endothelin levels. Clearly there is a need for other readily measurable surrogate clinical endpoints with a broader dynamic range that enables the detection and monitoring of early stages of the condition. Echocardiography can provide a number of indices of right-heart function (9), but the right ventricle is not easily seen in all patients and the technique is unlikely to satisfy a requirement to detect early disease. MRI gives striking views of the right ventricle (10), but is expensive, not widely available, and not suitable for all patients. This leaves circulating markers, such as brain natriuretic peptide (11), cardiac troponins (12), and uric acid levels (13). Elevated plasma levels of each of these predict poor survival, but, used in isolation, they lack specificity and, particularly in the case of cardiac troponins, only detect the very severe forms of the disease. Pulmonary hypertension is a complex disease. There is increasing interest in the use of multiple markers that represent various components of the disease pathway in the expectation that such a combination is likely to reflect more accurately the underlying disease process. Such a combination may emerge for biomarkers already available, but in this era of proteomics there is the exciting prospect that new ones will emerge. Clinical experience with endothelin receptor blockade in pulmonary arterial hypertension is still relatively young. Bosentan has proven a welcome addition to our therapeutic formulary and data are emerging with respect to improved life expectancy on this drug, but it is not a cure. It is not effective in all patients, and many physicians are beginning to experiment with it in combination with other therapies in an attempt to arrest the disease. Three months is a rather short period in which to gain a full appreciation of the merits of a new drug. At first sight, sixasentan does not appear to offer any major advantage over bosentan in terms of safety or efficacy and it is more likely to emerge as an alternative rather than a superior treatment. Nonetheless, the early data suggests sixasentan deserves the benefit of further study. FOOTNOTES Conflict of Interest Statement: M.R.W. has lectured on endothelin at a meeting sponsored by Actelion. REFERENCES
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