The US Food and Drug Administration’s approval of sotatercept (Winrevair®) in March 2024 arrived with great excitement given its unique mechanism of action and proven efficacy on top of existing medications for pulmonary arterial hypertension (PAH).1 Many providers encounter patients with PAH who are currently treated and may be candidates for sotatercept treatment. Understanding when to consider sotatercept and how to use it has become a critical part of the care of this serious condition.
A quick PAH primer
PAH severity is stratified based on noninvasive risk score tools as low, intermediate, and high risk.2 In contemporary US registry data, the overall survival is still suboptimal, with three-year mortality of approximately 28% for intermediate-risk and 55% for high-risk patients with PAH.3 The core objective in the treatment of PAH is to move and maintain patients in the low-risk category.2 Low-risk status corresponds to a one-year mortality under 5%.
The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL) risk calculator and its streamlined version, REVEAL Lite 2, are widely used tools. REVEAL Lite 2 relies on six noninvasive variables including functional class, vital signs (systolic BP and heart rate), 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) or BNP, and renal function.3 A score of ≤5, 6-7, and ≥8 define low, intermediate, and high risk, respectively.
Echocardiography supplements the risk stratification by providing information on the right ventricular structure and function, and improving precision.4 Other investigations such as cardiopulmonary exercise test, cardiac magnetic resonance imaging, and hemodynamic assessment can help guide treatment decisions, particularly when traditional risk scoring tools are discordant.2
Sotatercept: What makes it different?
Sotatercept is a novel pulmonary antihypertensive (NoPAH). Traditional therapies like prostacyclin and its analogues, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE5) inhibitors have antiproliferative benefit in addition to strong pulmonary vasodilatory properties.3 In contrast, sotatercept inhibits activin signaling, functioning as a ligand trap for activins and growth differentiation factors.5 PAH is characterized by reduced signaling through the bone morphogenetic protein receptor type II (BMPR2) pathway, which leads to unopposed activin activity.5 That tilt toward pro-proliferative signaling drives smooth muscle growth, medial thickening, and the characteristic vascular remodeling observed in PAH.6 Sotatercept counteracts these effects by rebalancing these impaired signaling pathways, favoring physiological repair rather than unchecked proliferation.5
Trial data: A consistent signal
Sotatercept has met the primary trial end points in all randomized, placebo-controlled studies in which it was tested. PULSAR, the phase 2 study, showed dose-dependent effects.7 At 0.7 mg/kg, patients saw a 34% reduction in PVR, with marked improvement in 6MWD and reduction in NT-proBNP levels.1
STELLAR, the pivotal phase 3 trial, enrolled 323 patients with long-standing PAH, with nearly 60% on triple therapy and 40% on parenteral prostacyclin analogues.3, 8–9 In this context, sotatercept improved 6MWD by 34 meters and met eight of nine hierarchical secondary end points, including an 84% reduction in time to death or clinical worsening.8
The ZENITH trial included patients with PAH at higher risk, in World Health Organization functional class III to IV with REVEAL Lite 2 scores of ≥ 9 and on maximal conventional PAH therapy.10 The trial was stopped early in the interim analysis for overwhelming efficacy, with a 76% relative risk reduction in the composite end point of death, transplant, or hospitalization due to PAH.11
The HYPERION trial, published in 2025, studied patients with a recent diagnosis (during the last year) of PAH at intermediate to high-risk, treated with double or triple PAH therapy.12 Sotatercept produced a 76% risk reduction in the primary end point of clinical worsening (composite of death, lung transplantation, atrial septostomy, unplanned hospitalization for PAH, and deterioration in exercise performance due to PAH).13
Notably, sotatercept demonstrates a favorable number needed to treat (NNT): an NNT of 4 to prevent one clinical worsening event in ZENITH and an NNT of 5 in HYPERION—substantially better than historical NNTs for other PAH therapies.14
The SOTERIA trial, an ongoing open-label study evaluating long-term safety, tolerability, and efficacy of sotatercept in PAH, showed sustained treatment benefit at roughly 15 months of follow-up, with a low rate (2.6%) of serious adverse events.15–16
How it fits into current treatment
Immediately following diagnosis, the PAH treatment algorithm is unchanged (ie, dual oral therapy for low and intermediate-risk patients and addition of parenteral prostacyclin analogues for high-risk patients).3 Modifications occur at reassessment. For intermediate-low-risk patients who have not achieved low-risk status after three to six months of dual oral therapy, sotatercept becomes an option alongside nonparenteral prostacyclin pathway agents or replacing PDE5 inhibitors with soluble guanylate cyclase stimulators.14
Given the multiplicity of options, the decision of which alternative to use remains debatable, even among experts. In this context, the STELLAR trial demonstrated robust improvements in 6MWD and reduction in clinical worsening events, mostly driven by reductions in the need for rescue therapy initiation, hospitalizations, and PAH progression.17 In contrast, the GRIPHON (testing selexipag on a background of single or dual PAH therapy) and FREEDOM-EV (testing oral treprostinil on a background a single PAH therapy) trials were larger, longer-term studies with composite morbidity-mortality primary end points.18–19 These trials showed a 40% and 26% reduction in clinical worsening events, respectively, but more modest 6MWD improvements.14
What about patients already on maximal therapy not yet at goal?
This is where STELLAR demonstrated additional sotatercept benefits. Patients on triple therapy, including parenteral prostacyclin analogues, had significant clinical improvements from sotatercept.5 Sotatercept can also be added for patients on parenteral prostacyclin who remain at high risk, based on data from the ZENITH trial.11
What to expect and how to monitor treatment
Sotatercept is generally well tolerated, with only 1.8% of patients discontinuing therapy for adverse effects in STELLAR.8 Common adverse effects include epistaxis, telangiectasias, headache, dizziness, rash, and diarrhea. Hemoglobin elevations and thrombocytopenia occurred in roughly 6% of patients. Bleeding events were reported in about 21% of study patients and were usually mild and manageable.17
Pericardial effusion has emerged as an important real-world side effect. Recent case series report new or worsening pericardial effusions, particularly in patients with connective tissue disease associated PAH, an underlying effusion, and those treated with prostacyclin analogues.20–22 Interestingly, STELLAR and ZENITH did not show an increase in pericardial effusions compared with placebo.20,23 SOTERIA supports a generally stable, long-term safety profile without an increased incidence of pericardial effusion.16 In practice, if a pericardial effusion is thought to be associated with sotatercept, it is reasonable to pause sotatercept and consider reintroduction at a lower dose once the effusion has resolved or stabilized, in the context of close echocardiographic monitoring.
Using evidence in real conversations
Translating clinical data into patient-centered terms helps with shared decision-making. A few useful points:
- Instead of quoting hazard ratios, telling patients that “sotatercept helped people walk about 30 more meters in six minutes, roughly the length of a grocery store aisle” is more relatable.
- Highlighting the reduction in hospitalizations is appreciated by patients.
- A subcutaneous injection every three weeks fits easily into many patients’ routines.
- It is better tolerated compared with other drugs approved and improving quality of life.
- Understanding a patient’s lifestyle, work schedule, and goals help guide the discussion and decision on the best treatment approach.
So what is our role?
Sotatercept represents real progress, but the efficacy of the medication depends on the adequate recognition and treatment of patients with PAH. Underdiagnosis and undertreatment remain common challenges in PAH. It remains essential to adequately distinguish PAH from other forms of pulmonary hypertension in which sotatercept, or other PAH therapies, has not been studied or are not beneficial. High-risk patients not on parenteral prostacyclin need timely treatment with prompt initiation of aggressive PAH therapies to improve outcomes. Comorbidities such as obesity, hypertension, diabetes, and atrial fibrillation are common but do not contraindicate PAH therapy.14
Real-world phenotypes like multimorbidity and heart failure with preserved ejection fraction overlap remain understudied; however, the phase 2 CADENCE trial in patients with combined post- and pre-capillary pulmonary hypertension reported meaningful PVR reductions, offering early proof of concept for group 2 disease and prompting phase 3 studies.24–25
For now, sotatercept offers clinicians a novel therapy that meaningfully improves outcomes. Using it thoughtfully, integrating it into risk-based care, and ensuring timely referral to expert centers are the ways pulmonologists can make a big difference in patients’ lives.
This article was originally published in the Spring 2026 issue of CHEST Physician.
References
1. Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021;384(13):1204-1215. doi:10.1056/NEJMoa2024277
2. Sahay S, Visovatti S, Tonelli AR, et al. International Society for Heart and Lung Transplantation (ISHLT) consensus statement on risk stratification in pulmonary arterial hypertension. J Heart Lung Transplant. 2025;44(11):e73-e131. doi:10.1016/j.healun.2025.04.015
3. Sahay S, Chakinala MM, Kim NH, Preston IR, Thenappan T, Mclaughlin VV. Contemporary treatment of pulmonary arterial hypertension: a US perspective. Am J Respir Crit Care Med. 2024;210(5):581-592. doi:10.1164/rccm.202405-0914SO
4. Verma D, Estrada RA, Sahay S. The role of imaging in risk assessment for pulmonary arterial hypertension. Curr Opin Cardiol. 2025;40(5):327-334. doi:10.1097/HCO.0000000000001238
5. Cascino TM, Sahay S, Moles VM, McLaughlin VV. A new day has come: sotatercept for the treatment of pulmonary arterial hypertension. J Heart Lung Transplant. 2025;44(1):1-10. doi:10.1016/j.healun.2024.09.021
6. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023;61(1):2200879. doi:10.1183/13993003.00879-2022
7. A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH). ClinicalTrials.gov. NCT03496207. https://clinicaltrials.gov/study/NCT03496207
8. Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558
9. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11) (STELLAR). ClinicalTrials.gov. NCT04576988. https://clinicaltrials.gov/study/NCT04576988
10. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sotatercept When Added to Maximum Tolerated Background Therapy in Participants With Pulmonary Arterial Hypertension (PAH) World Health Organization (WHO) Functional Class (FC) III or FC IV at High Risk of Mortality (ZENITH). ClinicalTrials.gov. NCT04896008. https://www.clinicaltrials.gov/study/NCT04896008
11. Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025;392(20):1987-2000. doi:10.1056/NEJMoa2415160
12. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sotatercept When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy in Newly Diagnosed Intermediate- and High-Risk PAH Patients (HYPERION). ClinicalTrials.gov. NCT04811092. https://www.clinicaltrials.gov/study/NCT04811092
13. McLaughlin VV, Hoeper MM, Badesch DB, et al. Sotatercept for pulmonary arterial hypertension within the first year after diagnosis. N Engl J Med. 2025;393(16):1599-1611. doi:10.1056/NEJMoa2508170
14. Chin KM, Gaine SP, Gerges C, et al. Treatment algorithm for pulmonary arterial hypertension. Eur Respir J. 2024;64(4):2401325. doi:10.1183/13993003.01325-2024
15. An Open-label Long-term Follow-up Study to Evaluate the Effects of Sotatercept When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH (MK-7962-004/A011-12) (SOTERIA). ClinicalTrials.gov. NCT04796337. https://www.clinicaltrials.gov/study/NCT04796337
16. Preston IR, Badesch D, Ghofrani HA, et al. A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: interim results of SOTERIA. Eur Respir J. 2025;66(1):2401435. doi:10.1183/13993003.01435-2024
17. Hoeper MM, Gomberg-Maitland M, Badesch DB, et al. Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies. Eur Respir J. 2025;65(5):2401424. doi:10.1183/13993003.01424-2024
18. A Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study Assessing the Safety and Efficacy of Selexipag on Morbidity and Mortality in Patients With Pulmonary Arterial Hypertension (GRIPHON). ClinicalTrials.gov. NCT01106014. https://clinicaltrials.gov/study/NCT01106014
19. Phase III Clinical Worsening Study of UT-15C in Subjects With Pulmonary Arterial Hypertension (PAH) Receiving Background Oral Monotherapy (FREEDOM-EV). ClinicalTrials.gov. NCT01560624. https://www.clinicaltrials.gov/study/NCT01560624
20. Sahay S, Villasmil Hernandez N, Al Aaraj Y, et al. Pericardial effusions and sotatercept therapy in pulmonary arterial hypertension: a multicentre, real-world experience. Eur Respir J. 2025;66(4):2501040. doi:10.1183/13993003.01040-2025
21. Tager D, Highland KB, Aulak KS, Haber L, Tonelli AR. Pericardial effusion and prostacyclin analog toxicity after initiation of sotatercept. Pulm Circ. 2025;15(3):e70141. doi:10.1002/pul2.70141
22. McKenna AM, Hill NS, Farber HW. A case series: pericardial effusion in patients treated with sotatercept. Pulm Circ. 2025;15(3):e70162. doi:10.1002/pul2.70162
23. Hoeper MM, Preston IR, Gomberg-Maitland M, et al. Pericardial effusion in sotatercept phase 3 trials: insights from STELLAR and ZENITH. Eur Respir J. 2025;66(3):2500768. doi:10.1183/13993003.00768-2025
24. A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effects of Sotatercept Versus Placebo for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) Due to Heart Failure With Preserved Ejection Fraction (HFpEF) (CADENCE). ClinicalTrials.gov. NCT04945460. https://www.clinicaltrials.gov/study/NCT04945460
25. Merck announces positive topline results from phase 2 CADENCE study evaluating WINREVAIR (sotatercept-csrk) in adults with combined post- and precapillary pulmonary hypertension due to heart failure with preserved ejection fraction. November 18, 2025. https://www.merck.com/news/mercks-winrevair-sotatercept-csrk-met-primary-endpoint-in-phase-2-cadence-study-in-adults-with-combined-post-and-precapillary-pulmonary-hypertension-cpcph-due-to-heart-failure-w/
