{"id":38182,"date":"2013-08-28T21:10:02","date_gmt":"2013-08-29T01:10:02","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=news&#038;p=38182"},"modified":"2013-08-28T21:10:02","modified_gmt":"2013-08-29T01:10:02","slug":"new-actelion-drug-found-safe-and-effective-in-pulmonary-arterial-hypertension-but-does-it-save-lives","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2013\/08\/28\/new-actelion-drug-found-safe-and-effective-in-pulmonary-arterial-hypertension-but-does-it-save-lives\/","title":{"rendered":"New Drug Found Safe and Effective in Pulmonary Arterial Hypertension &#8212; But Does It Save Lives?"},"content":{"rendered":"<p>Macitentan, a\u00a0new 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. \u00a0The drug, a dual endothelin-receptor antagonist, is under development from\u00a0Actelion\u00a0as an enhanced version of bosentan (Tracleer).\u00a0The results of a phase 3 trial, SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), have now been\u00a0<a href=\"http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa1213917\">published in the\u00a0<em>New England Journal of Medicine<\/em><\/a>.<\/p>\n<p>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\u00a0(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:<\/p>\n<ul>\n<li>Placebo: 46.4%<\/li>\n<li>Macitentan 3 mg: 38.0% (hazard ratio compared with placebo: 0.70, CI 0.52-0.96, p=0.01)<\/li>\n<li>Macitentan 10 mg: 31.4%\u00a0\u00a0(HR compared with placebo:\u00a00.55, CI 0.39-0.76, p&lt;0.001)<\/li>\n<\/ul>\n<p>A similar pattern was observed for the secondary endpoint of death due to PAH or hospitalization for PAH:<\/p>\n<ul>\n<li>Placebo: 33.6%<\/li>\n<li>Macitentan 3 mg: 26.0% (HR compared with placebo: 0.67, CI 0.46-0.97, p=0.01)<\/li>\n<li>Macitentan 10 mg: 20.7%\u00a0 HR compared with placebo:\u00a00.50, CI 0.34-0.75, p&lt;0.001)<\/li>\n<\/ul>\n<p>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.<\/p>\n<p>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\u00a0that &#8220;macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension.&#8221;<\/p>\n<p>However, PAH researcher Stephen Archer takes issue with this claim:<\/p>\n<blockquote><p>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&#8217;s 1982\u00a0<em>NEJM<\/em> digoxin trial was considered &#8220;negative&#8221; 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 &#8220;reduction in mortality&#8221; &#8230; which has but one meaning.<\/p><\/blockquote>\n","protected":false},"excerpt":{"rendered":"<p>Macitentan, a\u00a0new 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. \u00a0The drug, a dual endothelin-receptor antagonist, is under development from\u00a0Actelion\u00a0as an enhanced version of bosentan (Tracleer).\u00a0The results of a phase 3 trial, SERAPHIN (Study with an Endothelin [&hellip;]<\/p>\n","protected":false},"author":196,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1,14],"tags":[1776,1942,1941,1940,1744],"class_list":["post-38182","post","type-post","status-publish","format-standard","hentry","category-general","category-heart-failure","tag-actelion","tag-bosenten","tag-dual-endothelin-receptor-antagonist","tag-macitentan","tag-pulmonary-arterial-hypertension"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/38182","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/users\/196"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=38182"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/38182\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=38182"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=38182"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=38182"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}