{"id":138807,"date":"2025-04-02T21:19:26","date_gmt":"2025-04-03T01:19:26","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=138807"},"modified":"2026-01-28T19:05:21","modified_gmt":"2026-01-29T00:05:21","slug":"zenith-trial-sotatercept-significantly-reduces-major-morbidity-and-mortality-events-in-high-risk-pah-patients","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=138807","title":{"rendered":"ZENITH Trial: Sotatercept Significantly Reduces Major Morbidity and Mortality Events in High-Risk PAH Patients"},"content":{"rendered":"<p><b>Key Points:<\/b><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Pulmonary arterial hypertension (PAH) is a progressive disease with poor outcomes despite advancements in therapy.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Sotatercept, a novel activin signaling inhibitor, targets vascular remodeling in PAH and has previously demonstrated efficacy in improving hemodynamics and clinical outcomes.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">The Phase 3 ZENITH trial showed that sotatercept significantly reduced the risk of <\/span><span style=\"font-weight: 400;\">composite of death from any cause, lung transplantation, or hospitalization (\u226524 hours) for worsening pulmonary arterial hypertension<\/span><span style=\"font-weight: 400;\"> by 76% compared to placebo in high-risk PAH patients (WHO FC III\/IV) on maximum tolerated background therapy.<\/span><\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p><span style=\"font-weight: 400;\">Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by pulmonary vascular remodeling, increased pulmonary pressures, and high mortality rates. Despite recent therapeutic advancements, outcomes remain poor, particularly for patients with advanced disease (WHO functional class [FC] III\/IV). Sotatercept, a first-in-class activin signaling inhibitor, has shown promise in addressing the underlying vascular remodeling of PAH.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Building on the success of the STELLAR trial, which demonstrated improvements in exercise capacity and hemodynamics in PAH patients with WHO FC II\/III, the ZENITH trial evaluated sotatercept in patients at higher risk of mortality. Results were presented by Dr. Marc Humbert from Universit\u00e9 Paris-Saclay at ACC 2025 as a late-breaking clinical trial and simultaneously published in <\/span><i><span style=\"font-weight: 400;\">The New England Journal of Medicine<\/span><\/i><span style=\"font-weight: 400;\">.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">This Phase 3, multicenter, double-blind, placebo-controlled trial enrolled 172 adult patients with WHO FC III or IV PAH and pulmonary vascular resistance (PVR) <\/span><span style=\"font-weight: 400;\">\u2265<\/span><span style=\"font-weight: 400;\">400 dynes\u00b7s\u00b7cm-5 who were receiving maximum tolerated background PAH therapy. Patients were randomized 1:1 to receive sotatercept (0.3 mg\/kg, titrated to 0.7 mg\/kg) or placebo every three weeks in addition to their stable PAH regimen.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">The primary endpoint was time to first major morbidity or mortality event, defined as all-cause death, lung transplantation, or PAH-related hospitalization of <\/span><span style=\"font-weight: 400;\">\u2265<\/span><span style=\"font-weight: 400;\">24 hours. Secondary endpoints included overall survival, transplant-free survival, NT-proBNP reduction, improvement in WHO FC, mean pulmonary artery pressure, and changes in the REVEAL Lite 2.0 risk score.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">At a median follow-up of 10.6 months (range, 0.3-26.1), sotatercept significantly reduced the risk of major morbidity and mortality events by 76% compared to placebo (HR=0.24; 95% CI, 0.13-0.43; p&lt;0.0001). Major events occurred in 17.4% of sotatercept-treated patients versus 54.7% in the placebo group, leading to early trial termination due to overwhelming efficacy.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Safety analyses showed no treatment discontinuations due to adverse events. Deaths occurred in 7 patients (8.1%) in the sotatercept arm versus 13 patients (15.1%) in the placebo arm. Lung transplantation was required in 1 patient (1.2%) receiving sotatercept versus 6 patients (7.0%) in the placebo group, and PAH-related hospitalizations were lower in the sotatercept group (9.0% vs. 50.0%).<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Dr. Humbert highlighted the significance of these findings: &#8220;The ZENITH trial is the first PAH study with a primary endpoint exclusively comprising major outcomes\u2014all-cause death, lung transplantation, and hospitalization for PAH. These results reinforce the potential of WINREVAIR (sotatercept) as a practice-changing therapy for a broad spectrum of PAH patients.&#8221;<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Key Points: Pulmonary arterial hypertension (PAH) is a progressive disease with poor outcomes despite advancements in therapy. Sotatercept, a novel activin signaling inhibitor, targets vascular remodeling in PAH and has previously demonstrated efficacy in improving hemodynamics and clinical outcomes. The Phase 3 ZENITH trial showed that sotatercept significantly reduced the risk of composite of death [&hellip;]<\/p>\n","protected":false},"author":40615,"featured_media":138808,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[898,8],"tags":[899,45,47,185],"ppma_author":[1069],"class_list":{"0":"post-138807","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-acc-2025","8":"category-news","9":"tag-acc-2025","10":"tag-conference","11":"tag-featured","12":"tag-news","13":"author-hassan-adam-alhassan-md"},"authors":[{"term_id":1069,"user_id":40615,"is_guest":0,"slug":"hassan-adam-alhassan-md","display_name":"Hassan Adam Alhassan MD","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/8cc8318e58bf0ad1548b042cbb04e2e62466d8fe5780d7b1f138246f2c21b2b5?s=96&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138807","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/users\/40615"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=138807"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138807\/revisions"}],"predecessor-version":[{"id":138809,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138807\/revisions\/138809"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/138808"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=138807"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=138807"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=138807"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=138807"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}