dr ramzan jclub_importantpresentation for Medical.pptx

Important Presentation for Medical.
Pulmonary Arterial Hypertension (PAH) is a progressive and potentially fatal condition involving structural remodeling of the pulmonary blood vessels.

This remodeling leads to increased pulmonary vascular resistance and elevated pulmonary artery pressure, which can eventually cause right ventricular failure and death.

Current treatment options for PAH include:

Endothelin receptor antagonists

Phosphodiesterase-5 (PDE-5) inhibitors

Soluble guanylate cyclase stimulators

Prostacyclin-pathway agents

1. Dr Muhammad Ramzan Published in: Nejm PGR Medicine Unit 1 Published on 31 march 2025

2. INTRODUCTION Pulmonary arterial hypertension is a progressive, potentially fatal disease characterized by remodeling of the pulmonary vasculature, which results in increased pulmonary vascular resistance and pulmonary artery pressure and can ultimately lead to right ventricular failure and death. Established treatments for pulmonary arterial hypertension include endothelin-receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin-pathway agents.

3. Although randomized, placebo-controlled trials of existing therapies have shown delays in the time to clinical worsening, these findings primarily reflected functional deterioration rather than major events such as death, lung transplantation, and hospitalization for worsening pulmonary arterial hypertension. Sotatercept, a first-in-class activin -signaling inhibitor, offers a novel therapeutic alternative to vasodilators in the treatment of pulmonary arterial hypertension by binding proliferative members of the transforming growth factor β superfamily (e.g., activins ), targeting pulmonary vascular remodeling.

4. METHODOLOGY TRIAL DESIGN ZENITH was a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which the efficacy and safety of sotatercept was evaluated in patients with pulmonary arterial hypertension at high risk for death. Patients were randomly assigned in a 1:1 ratio to receive add-on subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; escalated to target dose, 0.7 mg per kilogram) or placebo every 21 days, in addition to stable maximum tolerated doses of double or triple therapy for pulmonary arterial hypertension.

5. INCLUSION CRITERIA Adults (18 to 75 years of age) Patients who had symptomatic WHO group 1 pulmonary arterial hypertension (idiopathic, heritable, drug- or toxin-induced, connective-tissue disease associated, or with simple congenital systemic to-pulmonary shunts ≥1 year after repair) in WHO functional class III or IV and had a REVEAL Lite 2 risk score of 9 or higher.

6. EXCLUSION CRITERIA Pulmonary arterial hypertension associated with portal hypertension, human immunodeficiency virus infection, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis; pulmonary arterial hypertension other than group 1; a left ventricular ejection fraction below 45%; clinically significant mitral or aortic valve disease; and other clinically significant coexisting conditions or laboratory abnormalities ( e.g.,platelet count of < 50000).

7. RESULTS The first patient was enrolled on December 1, 2021, and the primary completion date was July 26, 2024. A total of 173 patients under went randomization, including 1 patient who did not meet the eligibility criteria and underwent randomization in error. 86 were enrolled in the sotatercept group and 86 in the placebo group in the intention-to treat population. The median duration of follow up was 10 months in the sotatercept group and 7months in the placebo group.

8. PRIMARY AND SECONDARY END-POINTS The analysis of the primary efficacy end point focused on the occurrence of death from any cause, lung transplantation, or hospitalization lasting at least 24 hours for worsening pulmonary arterial hypertension as a first event for each patient. In this analysis, 15 patients (17.4%) in the sotatercept group and 47 patients (54.7%) in the placebo group had at least one such event ; the hazard ratio was 0.24 (95% confidence interval [CI], 0.13 to 0.43; P<0.001.

9. ADVERSE EVENTS Serious adverse events occurred in 53.5% of the patients in the sotatercept group and in 64.0% of those in the placebo group

10. DISCUSSION In the ZENITH trial, the efficacy and safety of sotatercept was evaluated in patients at high risk for death (WHO functional class III or IV and a REVEAL Lite 2 risk score ≥9), despite receiving double or triple therapy for pulmonary arterial hypertension. The interim analysis showed a 76% lower risk of a composite of death from any cause, lung transplantation, or hospitalization lasting at least 24 hours for worsening pulmonary arterial hypertension with sotatercept than with placebo.

11. The incremental efficacy of the addition of sotatercept to background pulmonary arterial hypertension therapy probably relates to the mechanism of action of sotatercept. By targeting the activin -signaling pathway, sotatercept improves the balance between growth-promoting factors and growth-inhibiting factors, addressing the core pathobiologic features of pulmonary arterial hypertension. The efficacy of sotatercept in this heavily treated population with advanced pulmonary arterial hypertension reflects its role in reducing the risk of major outcomes.

12. CONCLUSION Among high-risk adults with pulmonary arterial hypertension who were receiving the maximum tolerated dose of background therapy, treatment with sotatercept resulted in a lower risk of a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension than placebo.