August 28th, 2013
New Drug Found Safe and Effective in Pulmonary Arterial Hypertension — But Does It Save Lives?
Larry Husten, PHD
Macitentan, a new drug for pulmonary arterial hypertension (PAH), appears to be safe and effective, but it is unclear whether it offers any significant advantages over currently available drugs. The drug, a dual endothelin-receptor antagonist, is under development from Actelion as an enhanced version of bosentan (Tracleer). The results of a phase 3 trial, SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), have now been published in the New England Journal of Medicine.
In the trial, 742 patients with PAH were randomized to one of three groups: a daily dose of 3 mg of macitentan, a daily dose of 10 mg of macitentan, or placebo. The primary endpoint (the time to the first occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension) was significantly reduced in the two treatment arms:
- Placebo: 46.4%
- Macitentan 3 mg: 38.0% (hazard ratio compared with placebo: 0.70, CI 0.52-0.96, p=0.01)
- Macitentan 10 mg: 31.4% (HR compared with placebo: 0.55, CI 0.39-0.76, p<0.001)
A similar pattern was observed for the secondary endpoint of death due to PAH or hospitalization for PAH:
- Placebo: 33.6%
- Macitentan 3 mg: 26.0% (HR compared with placebo: 0.67, CI 0.46-0.97, p=0.01)
- Macitentan 10 mg: 20.7% HR compared with placebo: 0.50, CI 0.34-0.75, p<0.001)
At 6 months, the 6-minute walk distance had decreased by 9.4 m in the placebo group and increased by 7.4 m in the low-dose macitentan group and by 12.5 m in the high-dose group. These results are similar to those seen with other PAH drugs in earlier trials.
The authors write that previous drugs for PAH have been approved on the basis of short-term trials that have had exercise capacity as the primary endpoint. They claim that SERAPHIN is the first trial to test the long-term impact on morbidity and mortality of a PAH drug, and conclude that “macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension.”
However, PAH researcher Stephen Archer takes issue with this claim:
At first glance one would assume that this means fewer patients in the macitentan group died during the study. In fact the endpoint they refer to is a composite endpoint and the significance (versus placebo) is driven by reduced incidence of worsening PAH and hospitalization in the macitentan arm. In fact, the all-cause mortality rates are virtually identical to those in the placebo group (6.6 vs 6.8%). Cardiologists will recall that Haber’s 1982 NEJM digoxin trial was considered “negative” by many, even though digoxin significantly reduced hospitalizations in left heart failure patients, all because digoxin did not reduce mortality. So is SERAPHIN a negative trial? Or based on the predefined composite endpoint they chose, positive? By choosing an inhomogeneous endpoint (where outcomes are very dissimilar in impact to the patient-death vs hospitalization or worsening PAH) a bias is created toward a positive finding. Whether such composite endpoints are acceptable is a matter of opinion; however, improvement in this composite endpoint should not be called a “reduction in mortality” … which has but one meaning.
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As a member of the SERAPHIN Steering Committee and co-author on the study, and as a clinical investigator involved in study design in PAH, I would like to provide my perspective on the design of the SERAPHIN trial for this rare disease state.
The use of a composite end point increases the ability to capture clinically relevant events and, therefore, to demonstrate the true impact of a new treatment on the course of the disease. As has been recommended by experts in the PAH and clinical trials field, all reported morbidity and mortality events were adjudicated by an independent and blinded CEC. This approach enabled confirmation that events were clinically meaningful and ensured that the classification of events was consistent, adding to the robustness of the primary end point in SERAPHIN.
Additionally, because, PAH is a rare disease, conducting a statistically powered mortality study in PAH is not feasible given the requirement for the large number of patients and long study duration. Moreover, given that drugs and life-saving surgical procedures are available, it is unethical to withhold PAH therapy from patients experiencing disease progression as defined by the criteria used in SERAPHIN. These considerations prompted the development of a study design that used a clinically relevant composite end point, which included mortality, and allowed modification of therapy in the case of a morbidity event.
Finally, it should be noted that the SERAPHIN study looked at time to first event. Because most patients who die from PAH first deteriorate, death in these patients would not be reflected in the primary efficacy endpoint. There are compelling data, in fact, showing that morbidity events, including hospitalization and decline in exercise tolerance are associated with worse survival. Therefore, the study design of SERAPHIN was felt to be robust in addressing important long-term endpoints for patients with PAH
Richard N. Channick, M.D.
Associate Professor of Medicine
Harvard Medical School
Director, Pulmonary Hypertension Program
Massachusetts General Hospital