Clinical,hemodynamic,and safety outcomes of sotatercept in pulmonary arterial hypertension: a meta-analysis of randomized trials with time-to-event data

Abstract

Background:

Pulmonary arterial hypertension (PAH) remains progressive despite contemporary background therapy. Sotatercept is a novel activin signaling inhibitor that targets pulmonary vascular remodeling and may improve clinical and hemodynamic outcomes.

Objectives:

To evaluate the efficacy, hemodynamic effects, and safety of sotatercept in patients with PAH.

Design:

Systematic review and meta-analysis of randomized controlled trials (RCTs).

Data sources and methods:

Five electronic databases were searched through October 2, 2025, for eligible RCTs. Time-to-event outcomes were analyzed using pooled individual patient data with hazard ratios (HRs), while secondary outcomes were assessed using random-effects risk ratios (RRs) and mean differences (MDs), with 95% confidence intervals (CI). Trial-sequential analysis (TSA) evaluated the conclusiveness of results.

Results:

In four RCTs (n = 889), sotatercept reduced clinical worsening or death by 77% (HR 0.23, 95% CI 0.16–0.32, p < 0.001) and prolonged event-free survival by ~40 weeks. World Health Organization (WHO) functional class improved in 40.3% vs 24.3% (RR 1.71, 95% CI 1.32–2.21), and 6-minute walk distance increased by MD 30.27 m (95% CI 13.45–47.08), while pulmonary vascular resistance (PVR) declined significantly (MD −247 dyn·s·cm–⁵, 95% CI −301.7; −192.2). Serious adverse events were slightly less frequent with sotatercept (26.2% vs 31.7%, RR 0.83); however, total bleeding (37.9% vs 18.7%, RR 2.00), epistaxis (26.7% vs 5.4%, RR 4.89), and telangiectasia (19.8% vs 6.4%, RR 3.24) were more common. TSA revealed conclusiveness in clinical worsening, WHO functional class, and PVR, as well as increases in bleeding events and epistaxis.

Conclusion:

Sotatercept significantly improves clinical outcomes and extends event-free survival in PAH, with an acceptable safety profile; however, caution is warranted regarding bleeding events. These results support its role as an add-on therapy in PAH management.

Trial registration:

PROSPERO ID: CRD420251166414.

Plain language summary

New hope for pulmonary hypertension: sotatercept significantly improves exercise capacity and reduces disease progression

Pulmonary arterial hypertension (PAH) is a serious and progressive condition in which high blood pressure in the lungs places strain on the heart, often leading to heart failure and death. Current treatments help control symptoms but rarely stop the disease from getting worse. Sotatercept is a new medication that targets abnormal blood vessel growth and helps restore normal vessel function. This study combined results from four high-quality clinical trials including 889 adults with PAH who were already receiving standard therapy. Half the participants received sotatercept injections every three weeks, and the other half received placebo. Researchers looked at how long patients remained free from major disease events, such as hospitalization or worsening symptoms, and also measured exercise capacity and heart–lung function. Patients who received sotatercept were 77% less likely to experience disease worsening or death compared with those on placebo. On average, they could walk about 30 meters farther during a six-minute walk test, and their heart pressures and blood vessel resistance improved significantly. The drug also increased overall event-free survival by around 40 weeks. While most side effects were mild or moderate, nosebleeds and small visible blood vessel spots on the skin (telangiectasia) were more common with sotatercept, and a few patients experienced higher hemoglobin levels or mild decreases in platelets. Overall, sotatercept was well tolerated and showed strong evidence of improving daily function and reducing the risk of clinical deterioration. These findings support its use as an additional therapy for adults with PAH who continue to have symptoms despite standard treatments. Further long-term studies are recommended to confirm its impact on survival and long-term safety.

Keywords

clinical worsening hemodynamics meta-analysis pulmonary arterial hypertension sotatercept survival

Introduction

Pulmonary arterial hypertension (PAH) is a chronic and progressive condition that causes increased pressure in the pulmonary arteries, leading to right heart strain and heart failure if untreated. Despite advances in treatment, the disease still results in significant illness and death. To guide management and assess prognosis, clinicians rely on noninvasive tools such as the World Health Organization (WHO) functional class, six-minute walk distance (6MWD), and levels of natriuretic peptides to assess disease severity and guide therapy.^1,2

Current management typically combines drugs targeting the endothelin, nitric oxide, and prostacyclin pathways, such as endothelin-receptor antagonists, phosphodiesterase-5 inhibitors, or soluble guanylate cyclase (sGC) stimulators, and prostacyclin analogs. However, many patients remain symptomatic with limited exercise capacity and risk of clinical worsening, warranting the development of new therapies that modify disease progression and target alternative pathways, such as sotatercept.^1,3

Sotatercept is a new type of treatment that works by blocking activin signaling through an ActRIIA-Fc fusion protein, which binds certain transforming growth factor–β (TGF-β) family ligands. This action helps restore balance between growth-promoting and growth-inhibiting signals in the pulmonary arterial wall, improving vascular remodeling.^3,4 Building on this mechanism, randomized controlled trials (RCTs) have demonstrated that sotatercept significantly improves exercise capacity, WHO functional class, pulmonary vascular resistance (PVR), and NT-proBNP levels, supporting its role as an effective add-on therapy for PAH.^3–6 These landmark results led to its approval by the U.S. Food and Drug Administration in March 2024 for adults with PAH (WHO Group 1), marking the first therapy to target this signaling pathway.⁷

Recent reviews have further highlighted the biological and clinical relevance of sotatercept in PAH. Sotatercept acts as an ActRIIA-Fc ligand trap that binds selected activins and growth differentiation factors, thereby modulating the imbalance between pro-proliferative activin/SMAD2/3 signaling and anti-proliferative BMP/Bone Morphogenetic Protein Receptor Type II (BMPR2)/SMAD1/5/8 signaling implicated in pulmonary vascular remodeling. In addition, mechanistic evidence suggests crosstalk between activin signaling and established PAH treatment pathways, including endothelin, nitric oxide–cGMP, and prostacyclin signaling, while also explaining class-related hematologic effects such as increased hemoglobin and bleeding tendency. Clinically, sotatercept has been described as the first FDA-approved activin A receptor IIA inhibitor for PAH, supporting its emerging role as a disease-modifying add-on therapy beyond conventional vasodilator-based treatment.^8–10

To better understand its overall impact, we conducted a meta-analysis of RCTs with Kaplan–Meier to evaluate clinical, hemodynamic, and safety outcomes and guide its use in treatment planning.

Methods

Protocol registration

This systematic review and meta-analysis were conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions¹¹ and followed the PRISMA 2020 reporting guidelines (Supplemental Table 1).¹² The review protocol was prospectively registered in the PROSPERO database (CRD420251166414).

Data sources and search strategy

A comprehensive search of five electronic databases—PubMed, Scopus, Web of Science, EMBASE (via Ovid), and the Cochrane Library (CENTRAL)—was conducted by M.R.M and M.S.E. up to October 2, 2025. The search strategy combined Medical Subject Headings (MeSH) and free-text terms for keywords: “Pulmonary Arterial Hypertension” and “Sotatercept”. Details of the complete search process are provided in Supplemental Table 2. Additionally, we screened the reference lists of eligible studies to identify additional citations.

Eligibility criteria

We included only peer-reviewed RCTs with this PICO:

(i) Patients (P): Adult patients (⩾18 years) with confirmed PAH (WHO group 1) on background therapy (mono, double, or triple therapy).

(ii) Intervention (I): Add-on Sotatercept with target dose: 0.7 mg/kg (up-titrated or stable dose) subcutaneously every 3 weeks, plus stable background therapy.

(iii) Control (C): Matched placebo (saline) added to the same stable background regimen.

(iv) Outcomes (O): The primary outcomes included clinical worsening, which is a composite endpoint (death, lung transplantation, or unplanned hospitalization, ± atrial septostomy, prostacyclin escalation, or exercise capacity decline) (Supplemental Table 3), WHO functional class improvement, and 6MWD. The secondary outcomes included hemodynamic outcomes: (change in NT-proBNP levels, PVR, mean pulmonary arterial pressure (mPAP), and cardiac output); safety outcomes (all-cause mortality, any adverse event (AEs), serious AEs, drug-related AEs, headache, fatigue, nausea, diarrhea, dizziness, peripheral edema, total bleeding events, increased hemoglobin, thrombocytopenia, telangiectasia, epistaxis).

Studies were excluded if they were non-randomized, observational, single-arm, involved non-human or in vitro models, lacked relevant outcome data, were duplicate or interim reports, or investigated sotatercept in conditions other than PAH WHO group 1. Doses other than 0.7 mg/kg were also excluded.

Study selection

All citations were first imported into EndNote (Clarivate Analytics) for de-duplication, then uploaded into the Rayyan online software for blinded screening. Two reviewers (M.S.E. and A.W.K.) independently assessed titles and abstracts, followed by full-text reviews of potentially eligible studies. Any discrepancies were resolved through a third reviewer (M.R.M).

Data extraction

A pre-designed Excel spreadsheet was used for standardized data extraction. Three reviewers (A.W.K., M.S.E., and A.S.) independently collected the data from each eligible study, with disagreements resolved through a fourth reviewer (M.R.M.). The extracted information was categorized into three main domains:

Study Characteristics: Including (study ID, design, phase, blinding, number of centers, geographic location, total sample size, intervention, and comparator regimens, eligibility criteria (age, WHO functional class, background PAH therapy, and baseline risk stratification), and maximum follow-up duration).

Baseline Patient Characteristics: Extracted variables included (age, sex, race (White/Black), body mass index, time since PAH diagnosis, and classification of PAH (idiopathic, heritable, connective tissue disease–associated, drug/toxin-induced, or associated with corrected congenital heart defects). Functional status was captured via the WHO functional class (II or III), and background therapy was categorized as monotherapy, dual therapy, or triple therapy, including prostacyclin infusion. Additional baseline clinical parameters included 6MWD, NT-proBNP levels, mPAP, PVR, cardiac output, cardiac index, pulmonary artery wedge pressure (PAWP), hemoglobin, and estimated glomerular filtration rate (eGFR).

Study Outcomes: Efficacy, hemodynamic, and safety endpoints were extracted as predefined.

Quality assessment

Three independent reviewers (A.S., M.S.E., and A.W.K.) assessed the methodological quality of the included RCTs using the Cochrane Risk of Bias 2.0 (RoB 2) tool.¹³ This evaluation covered five key domains: the adequacy of the randomization process, deviations from intended interventions, completeness of outcome data, reliability of outcome measurement, and selective reporting of results. Each domain was rated as having either low risk, some concerns, or high risk. The overall RoB for each study was determined accordingly. Any disagreements between reviewers were resolved through discussion or by consultation with a third reviewer.

The certainty of the evidence across outcomes was assessed by two authors (M.S.E. and A.A.) using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.¹⁴ This system considers five dimensions: RoB, inconsistency, indirectness, imprecision, and publication bias. Where applicable, additional considerations such as large effect sizes or dose-response relationships were also taken into account. Based on these criteria, the strength of evidence for each outcome was categorized as high, moderate, low, or very low.

Statistical analysis

Meta-analysis

All analyses were conducted using R software (version 4.4.2), utilizing the “meta” and “metafor” packages for pairwise meta-analyses, which were performed using a random-effects model. Dichotomous outcomes were pooled with risk ratios (RRs) with 95% confidence intervals (CIs), while continuous outcomes were presented with mean differences (MDs) and corresponding 95% CIs.

Reconstructed time-to-event analysis

We reconstructed individual patient data (IPD) from published Kaplan–Meier survival curves using the “IPDfromKM” R package. With these reconstructed data, we fitted a Cox proportional hazards model to estimate the hazard ratios (HRs). We then merged all IPD across studies to calculate a pooled HR with 95% CI. In addition, we utilized the “survRM2” package to calculate the restricted mean survival time (RMST), enabling us to estimate and compare the lifetime lost across groups.

Heterogeneity and subgrouping

Heterogeneity across studies was assessed using the I² statistic and Cochran’s Q (Chi²) test. An I² value of 0%–30% was interpreted as low heterogeneity, 30%–50% as moderate, and >50% as indicative of substantial heterogeneity. Subgroup analyses were prespecified and conducted to explore potential effect modifiers based on two clinically relevant factors: (1) WHO functional class, categorized as mixed risk (functional class II or III) versus high risk (functional class III or IV); and (2) disease duration, categorized as recent-onset PAH (<1 year) versus established PAH (>7 years).

Sensitivity

First, a leave-one-out analysis was conducted by iteratively removing each trial from the pooled model to evaluate its influence on the overall effect. Second, we performed an IPD–based Kaplan–Meier sensitivity analysis excluding the ZENITH trial, which defined “clinical worsening” using a narrower composite endpoint (death, transplantation, or PAH-related hospitalization only). This analysis evaluated whether the exclusion of a trial with a more restrictive endpoint materially affected the pooled HR and restricted mean survival time (RMST) estimates.

Trial-sequential analysis

We conducted Trial-Sequential Analysis (TSA) using TSA software (version 0.9.5.10 beta) to evaluate whether the accumulated evidence was sufficient, thereby minimizing the risk of type I and II errors.¹⁵ TSA was performed with conventional thresholds (two-sided α = 0.05, 80% power, and anticipated relative risk reduction of 20%). The crossing of trial-sequential monitoring boundaries was interpreted as indicating that further studies may not be necessary. TSA performed as a complementary assessment of random errors in cumulative evidence and was not considered a substitute for the assessment of the certainty of evidence.

Results

Literature search results

A total of 903 articles were retrieved through a comprehensive electronic search. After removing duplicates, 467 articles were assessed for inclusion by title and abstract. After excluding 456 articles, 11 eligible studies were assessed for eligibility by full-text screening. Finally, 4 RCTs (3–6) were included in this meta-analysis. The PRISMA flow diagram is shown in Supplemental Figure 1.

Study characteristics

A total of four RCTs (3–6) were included, comprising 889 patients with PAH receiving background therapy. Sotatercept was administered subcutaneously, with most trials using a dose-escalation strategy (0.3–0.7 mg/kg), while the PULSAR trial uniquely applied a fixed 0.7 mg/kg dose throughout treatment. All studies were phase II or III, multicenter, double-blind trials. Notably, ZENITH enrolled patients with more advanced disease (WHO FC class II–IV), whereas the other three trials focused on patients with WHO class II or III only. In addition, there was variation in the background PAH therapy: some trials included patients on dual or triple therapy, while others allowed monotherapy. The duration of follow-up varied significantly, ranging from 6 months to 37 months. A comprehensive summary of trial characteristics is presented in Table 1.

Table 1.

Summary overview of the included trials.

Study ID	Study design	Blinding	Location (no. of centers)	Total	Study arms		Inclusion criteria				Max. follow-up
Study ID	Study design	Blinding	Location (no. of centers)	Total	Intervention	Comparator	Age (Y)	WHO FC class	Background TTT	Risk of death	Max. follow-up
McLaughlin 2025 (HYPERION)	Phase III, RCT	Double-blind	North America, South America, Europe, Asia-Pacific (152)	320	SC 0.3 mg/kg; escalated to 0.7 mg/kg	Matched placebo (saline)	18–75	II or III	Stable Prostacyclin infusion, dual or triple TTT for ⩾90 days	Intermediate or high	37.3 months
Humbert 2025 (ZENITH)	Phase III, RCT	Double-blind	North America, Europe, Australia, and Israel (53)	172	SC 0.3 mg/kg; escalated to 0.7 mg/kg	Matched placebo (saline)	18–75	III or IV	Stable Prostacyclin infusion, dual or triple TTT for ⩾30 days	High	10.6 months
Hoeper 2023 (STELLAR)	Phase III, RCT	Double-blind	North America, Europe, South Korea, Israel, Oceania, and South America (83)	323	SC 0.3 mg/kg; escalated to 0.7 mg/kg	Matched placebo (saline)	⩾18	II or III	Stable Prostacyclin infusion, mono, dual or triple TTT for ⩾90 days	Mixed	6 months
Humbert 2021 (PULSAR)	Phase II, RCT	Double-blind	United States, Israel, Brazil, Europe, Australia (40)	74	SC stable 0.7 mg/kg	Matched placebo (saline)	⩾18	II or III	Stable Prostacyclin infusion, mono, dual or triple TTT for ⩾90 days	Mixed	6 months

RCT, randomized controlled trial; SC, subcutaneous; TTT, treatment; WHO FC, World Health Organization functional class; Y, years.

A total of 451 patients in the sotatercept group and 438 patients in the placebo group. The majority were female (77%), with a mean age of 52.1 ± 15.7 years. Regarding functional class, 29.9% of patients were in WHO class II, 65.1% in class III, and 4.9% in class IV. The baseline mean of 6MWD was 359.3 ± 102.2 meters. In terms of background therapy, 35.1% of patients received prostacyclin infusion, 46.9% received dual therapy, and 50.8% received triple therapy. A detailed summary of baseline characteristics for study participants is presented in Table 2.

Table 2.

Baseline characteristics of the included trials.

Study ID	ZENITH 2025		PULSAR 2021		STELLAR 2023		HYPERION 2025
Group	Sotatercept	Placebo	Sotatercept	Placebo	Sotatercept	Placebo	Sotatercept	Placebo
Total, N	86	86	42	32	163	160	160	160
Female, N (%)	61 (70.9)	71 (82.6)	37 (88)	26 (81)	129 (79.1)	127 (79.4)	120 (75)	112 (70)
Age (Y), M (SD)	55.3 ± 14.3	53.5 ± 14.3	49.8 ± 15.1	45.6 ± 13.4	47.6 ± 14.1	48.3 ± 15.5	57.3 ± 15.4	55 ± 17.3
BMI (kg/m²), M (SD)	25.2 ± 5.8	25.8 ± 5.9	27.7 ± 6.6	27.3 ± 5.9	26.1 ± 5.7	26.6 ± 6.1	27.9 ± 5.9	27.8 ± 6.2
Time of diagnosis (Y), M (SD)	7.2 ± 5.6	8.2 ± 6.7	7.7 ± 5.6	7.7 ± 5.5	9.2 ± 7.3	8.3 ± 6.7	0.6 ± 0.26	0.58 ± 0.24
Causes of PAH, N (%)
Idiopathic	42 (48.8)	44 (51.2)	29 (69)	19 (59)	83 (50.9)	106 (66.2)	103 (64.4)	87 (54.4)
Heritable	11 (12.8)	7 (8.1)	5 (12)	7 (22)	35 (21.5)	24 (15.0)	11 (6.9)	8 (5.0)
Connective-tissue disease	22 (25.6)	26 (30.2)	6 (14)	3 (9)	29 (17.8)	19 (11.9)	39 (24.4)	58 (36.2)
Toxin-induced	6 (7.0)	5 (5.8)	2 (5)	1 (3)	7 (4.3)	4 (2.5)	4 (2.5)	4 (2.5)
Corrected congenital shunts	5 (5.8)	4 (4.7)	0	2 (6)	9 (5.5)	7 (4.4)	3 (1.9)	3 (1.9)
WHO FC class, N (%)
II	0 (0)	0 (0)	24 (57)	17 (53)	79 (48.5)	78 (48.8)	36 (22.5)	32 (20)
III	66 (76.7)	62 (72.1)	18 (43)	15 (47)	84 (51.5)	82 (51.2)	124 (77.5)	128 (80)
Background therapy, N (%)
Prostacyclin infusion	53 (61.6)	49 (57)	18 (43)	10 (31)	65 (39.9)	64 (40)	26 (16.2)	27 (16.9)
Monotherapy	7 (9)	3 (9)	4 (10)	3 (9)	9 (5.5)	4 (2.5)	0	0
Double therapy	21 (24.4)	27 (31.4)	14 (33)	12 (38)	56 (34.4)	56 (35)	116 (72.5)	115 (71.9)
Triple therapy	65 (75.6)	59 (68.6)	24 (57)	17 (53)	98 (60.1)	100 (62.5)	44 (27.5)	45 (28.1)
6-Minute walk distance, m	270.3 ± 104.8	270.7 ± 99.9	397.6 ± 91.6	409.1 ± 63.9	397.6 ± 84.3	404.7 ± 80.6	357.6 ± 90.9	352.3 ± 95.6
NT-proBNP (pg/ml), M (SD)	3603.1 ± 1924.9	4101.2/2687.3 ± 2771.2	870.5 ± 1608.7	870.2 ± 1213.3	1037.5 ± 2498.6	1207.8 ± 2694	1123.5 ± 2394.7	788.1 ± 1003.1
Mean PAP (mm Hg), M (SD)	57.0 ± 13.4	55.2 ± 12.1	50.1 ± 12.6	54.1 ± 13.4	53.0 ± 14.6	52.2 ± 13	N/A	N/A
PVR (dyn·sec cm^-5), M (SD)	883.2 ± 410.9	874.7 ± 344.2	755.9 ± 411.3	797.4 ± 322.6	781.3 ± 398.5	745.8 ± 313.5	939.3 ± 385.7	893.3 ± 406.7
Cardiac index (liters/min/m²), M (SD)	2.6 ± 0.6	2.6 ± 0.8	2.5 ± 0.47	2.5 ± 0.54	2.7 ± 0.6	2.7 ± 0.6	N/A	N/A
Cardiac output (L/min), M (SD)	4.7 ± 1.2	4.5 ± 1.4	4.6 ± 1.0	4.6 ± 0.83	4.9 ± 1.3	4.8 ± 1.2	N/A	N/A
PAWP (mm Hg), M (SD)	10.0 ± 3.3	9.8 ± 3.1	10 ± 3.1	10.4 ± 3	9.7 ± 3.2	9.8 ± 3.1	N/A	N/A
Hemoglobin (g/dL), M (SD)	12.9 ± 1.9	12.9 ± 1.9	13.5 ± 1.6	13.7 ± 1.8	13.9 ± 1.7	13.7 ± 1.6	13.4 ± 1.5	13.4 ± 1.7
eGFR (ml/min/1.73 m²), M (SD)	65.1 ± 24.6	73.5 ± 29.7	N/A	N/A	91.2 ± 34.6	88.3 ± 35.8	80.5 ± 27.8	86.3 ± 31.9

BMI, body mass index; CO, cardiac output; eGFR, estimated glomerular filtration rate; FC, functional class; M, mean; N, number; N/A, not available; NT-proBNP, N-terminal pro–B-type natriuretic peptide; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; WHO, world health organization; Y, year.

Risk of bias and certainty of evidence

All studies were judged to have an overall low RoB, as assessed using the RoB 2. A summary and graphical representation of the RoB assessment for the included studies are presented in Supplemental Figure 2. The GRADE rating results are shown in Table 3. According to the GRADE system, the strength of evidence was high for WHO functional class; moderate for all-cause mortality, PVR, total bleeding events, epistaxis, and serious AEs; low for 6MWD; and very low for NT-proBNP.

Table 3.

GRADE evidence profile.

Certainty assessment						№ of Patients		Effect		Certainty
No. of studies	RoB	Inconsistency	Indirectness	Imprecision	Other	Sotatercept	Placebo	Relative (95% CI)	Absolute (95% CI)	Certainty
6-Minute Walk Distance
4 RCTs	Not serious	Very serious^a	Not serious	Not serious	None	451	438	–	MD 30.27 m higher (13.45 higher to 47.08 higher)	⨁⨁〇〇, Low^a
WHO functional class
4 RCTs	Not serious	Not serious	Not serious	Not serious	None	182/451 (40.4%)	106/437 (24.3%)	RR 1.71 (1.32 to 2.21)	172 more per 1000 (from 78 more to 294 more)	⨁⨁⨁⨁, High
All-Cause Mortality
3 RCTs	Not serious	Not serious	Not serious	Serious^b	None	16/409 (3.9%)	26/406 (6.4%)	RR 0.63 (0.33 to 1.21)	24 fewer per 1000 (from 43 fewer to 13 more)	⨁⨁⨁〇, Moderate^b
Change in Pulmonary Vascular Resistance
3 RCTs	Not serious	Serious^c	Not serious	Not serious	None	291	278	–	MD 247 lower (301.71 lower to 192.16 lower)	⨁⨁⨁〇, Moderate^c
Change in N-terminal pro–B-type Natriuretic Peptide
4 RCTs	Not serious	Very serious^a	Not serious	Serious^d	None	451	438	–	MD 647 lower (1230 lower to 63.6 lower)	⨁〇〇〇, Very low^a,d
Total Bleeding Events
3 RCTs	Not serious	Not serious	Not serious	Serious^b	None	155/409 (37.9%)	76/406 (18.7%)	RR 2.00 (1.57 to 2.54)	187 more per 1000 (from 107 more to 288 more)	⨁⨁⨁〇, Moderate^b
Epistaxis
3 RCTs	Not serious	Not serious	Not serious	Serious^b	None	109/409 (26.7%)	22/406 (5.4%)	RR 4.89 (3.18 to 7.53)	211 more per 1000 (from 118 more to 354 more)	⨁⨁⨁〇, Moderate^b
Serious Adverse Effects
4 RCTs	Not serious	Not serious	Not serious	Serious^e	None	118/451 (26.2%)	139/438 (31.7%)	RR 0.83 (0.69 to 1.00)	54 fewer per 1000 (from 98 fewer to 0 fewer)	⨁⨁⨁〇, Moderate^e

I² > 75%; shows substantial heterogeneity.

Low number of events (if dichotomous) or a low number of patients (if continuous).

I² > 50%; shows significant heterogeneity.

A wide CI that does not exclude the appreciable risk of harm or benefit.

Crossing of no effect line (1), not excluding the risk of appreciable benefit/harm.

Boldface values indicate statistically significant pooled effect estimates. CI, confidence interval; GRADE, grading of recommendations assessment, development, and evaluation; MD, mean difference; RCT, randomized controlled trial; RoB, risk of bias; RR, risk ratio.

Primary outcomes

Efficacy clinical worsening

The pooled Kaplan–Meier curves for the cumulative risk of clinical worsening (Figure 1) included data from 815 patients (sotatercept: n = 409, placebo: n = 406). Sotatercept had a significantly 77% risk reduction from developing the composite endpoint compared with placebo (HR 0.23, 95% CI 0.16–0.32, p < 0.001; Figure 1). The RMST analysis demonstrated that patients treated with sotatercept had a longer event-free survival of 127.2 weeks (95% CI 121.7–132.8) versus 86.8 weeks (95% CI 79.7–94.1) for placebo, resulting in an MD of 40.3 weeks (95% CI 31.2–49.5, p < 0.001). The two-stage random-effects meta-analysis for the composite endpoint showed homogeneity among the included studies (I² = 0%) and confirmed a consistent benefit of sotatercept over placebo (HR 0.23; Figure 2(a)), with not both subgroups’ differences (p = 0.78, p = 0.74; Figure 2(a) and Supplemental Figure 3(a)).

Figure 1.

Cumulative hazard curve of the composite efficacy endpoint (clinical worsening) comparing Sotatercept versus placebo.

Figure 2.

Forest plots for primary and functional outcomes: (a) Clinical worsening. (b) WHO functional class. (c) 6-minute walk distance.

WHO FC class and 6MWD

Sotatercept showed a significant and homogeneous improvement in WHO FC class compared to the placebo (40.3% vs 24.3%; RR 1.71, 95% CI 1.32–2.21, p < 0.001, I² = 17%; Figure 2(b)). Regarding the 6MWD, sotatercept was associated with a significant increase (MD 30.27 m, 95% CI 13.45–47.08, P < 0.001), although heterogeneity was substantial (I² = 99.9%) (Figure 2(c)).

6MWD showed a significant difference regarding the risk of death subgrouping (p < 0.0001). Patients at high risk (WHO FC class III or IV) exhibited greater improvement in 6MWD (MD = +30.27 m; 95% CI, 13.45–47.08) compared with those at mixed risk (WHO FC class II or III) (MD = +22.78 m; 95% CI, 8.97–36.58; Figure 2(c)). In the PAH duration subgroup analysis, patients with recent-onset PAH showed less improvement in 6MWD (MD +30.27 m; 95% CI, 13.45–47.08) than those with established PAH (MD +37.44 m; 95% CI, 21.88–52.99; Supplemental Figure 3(c)). For WHO functional class improvement, no significant subgroup differences were observed in both analyses (p = 0.41, p = 0.07; Figure 2(b) and Supplemental Figure 3(b)).

The leave-one-out for 6MWD indicated that no single study was the primary source of heterogeneity, as I² remained at 99.9% in all scenarios (Supplemental Figure 4). However, the pooled MD varied from 22.8 m (after excluding Humbert et al.) to 37.4 m (after excluding McLaughlin et al.).

Secondary outcomes

Hemodynamic outcomes

Sotatercept showed a marked decrease in NT-proBNP levels (MD −646.90 pg/mL, 95% CI −1230.18 to −63.62, p = 0.03; I² = 100%; Figure 3(a)), a significant reduction in PVR (MD −246.93 dyn·s·cm–⁵, 95% CI −301.71 to −192.16, p < 0.001, I² = 69%; Figure 3(b)), and a significant decline in mPAP (MD −15.69 mmHg, 95% CI −19.37 to −12.01, p < 0.001, I² = 92.6%; Figure 3(c)). Regarding cardiac output, sotatercept demonstrated a significant improvement (MD 0.30 L/min, 95% CI 0.29–0.31, p < 0.001; I² = 47.8%; Supplemental Figure 5).

Figure 3.

Forest plots for biomarkers and hemodynamic outcomes: (a) Change in NT-proBNP. (b) Pulmonary vascular resistance. (c) Pulmonary artery pressure.

Regarding risk subgroup analysis, PVR showed subgroup difference (p = 0.049; Figure 3(b)). Patients at high risk (WHO FC class III or IV) exhibited a significantly smaller reduction (MD −246.9 dyn·s·cm–⁵, 95% CI, −301.7 to −192.2) compared with those at mixed risk (WHO FC class II or III) (MD −279.0 dyn·s·cm–⁵, 95% CI −339.6 to −218.4). High risk subgroup showed a significantly greater reduction in mPAP (MD −18.86 mmHg; 95% CI −19.08 to −18.64) compared with those at mixed risk (MD −13.77 mmHg; 95% CI −15.68 to −11.86; p for subgroup difference <0.001), as well as a greater reduction in NT-proBNP (MD −1,462.1 pg/mL, 95% CI −1470.4 to −1453.8) versus the mixed-risk group (MD −274.4 pg/mL, 95% CI −408.6 to −140.1, p for subgroup difference <0.001; Figure 3(c)). In contrast, in the PAH duration subgroup analysis, the difference in NT-proBNP reduction was not statistically significant (p for subgroup difference = 0.08; Figure 3(a)). For cardiac output, no significant difference was observed between the high-risk and mixed-risk subgroups (p for subgroup difference = 0.42; Supplemental Figure 5).

The leave-one-out indicated that omitting either Hoeper et al. or Humbert et al. resolved the heterogeneity for PVR (I² < 20%; Supplemental Figure 6). However, the pooled effect estimate for PVR after excluding Hoeper et al. showed less improvement (MD −217.5, p < 0.001), whereas excluding Humbert et al. yielded a greater improvement (MD −279, p < 0.001). For mPAP, the leave-one-out indicated that heterogeneity was resolved (I² = 0) by excluding Humbert et al. (MD −13.77, p < 0.001; Supplemental Figure 7). The leave-one-out did not indicate any resolution of heterogeneity for NT-proBNP (I² = 100% in all scenarios; Supplemental Figure 8).

Safety outcomes

The rate of serious AEs were slightly less in the sotatercept group (26.2% vs 31.7%, RR 0.83, 95% CI 0.69–1.00, p = 0.049, I² = 36%; Figure 4(a)), while any AEs was comparable between the sotatercept and placebo groups (88.7% vs 90.2%, RR 1.00, 95% CI 0.97–1.04, p = 1.000; I² = 0%; Figure 4(b)). Regarding all-cause mortality, sotatercept carried a 37% risk reduction without reaching statistical significance (3.9% vs 6.4%, RR 0.63, 95% CI 0.33–1.21, p = 0.18; Figure 4(c)). The analysis revealed minimal heterogeneity (I² = 2%).

Figure 4.

Forest plots for safety outcomes: (a) Serious adverse event. (b) Any adverse event. (c) All-cause mortality.

The sotatercept group showed an increased risk of drug-related AEs (32% vs 16.7%, RR 1.91, 95% CI 1.44–2.53, p < 0.001; I² = 0%; Supplemental Figure 9(a)). However, sotatercept showed no significant difference in headache (18.0% vs 16.7%, RR 1.08, 95% CI 0.81–1.44, p = 0.600, I² = 0%; Supplemental Figure 9(b)), dizziness (10.4% vs 9.1%, RR 1.57, 95% CI 0.85–2.88, p = 0.190, I² = 0%; Supplemental Figure 9(c)), fatigue (12.2% vs 11.6%, RR 0.89, 95% CI 0.60–1.31, p = 0.516, I² = 11%; Supplemental Figure 10(a)), nausea (11.3% vs 12.6%, RR 0.91, 95% CI 0.63–1.30, p = 0.60, I² = 0%; Supplemental Figure 10(b)), and diarrhea (10.0% vs 12.1%, RR 0.74, 95% CI 0.46–1.19, p = 0.201, I² = 0%; Supplemental Figure 11(a)). Importantly, peripheral edema occurred significantly less often with sotatercept compared with placebo (11.1% vs 21.6%, RR 0.54, 95% CI 0.34–0.86, p = 0.009, I² = 7%; Supplemental Figure 11(b)).

For hematologic events, both total bleeding episodes (37.9% vs 18.7%, RR 2.00, 95% CI 1.57–2.54, p < 0.001, I² = 6%; Figure 5(a)) and telangiectasia (19.8% vs 6.4%, RR 3.24, 95% CI 1.77–5.95, p < 0.001, I² = 38%; Figure 5(b)) occurred more frequently among patients receiving sotatercept. Similarly, sotatercept carried higher rates for epistaxis (26.7% vs 5.4%, RR 4.89, 95% CI 3.18–7.53, p < 0.001, I² = 0%; Figure 5(c)) and increased hemoglobin levels (10% vs 0.7%, RR 10.72, 95% CI 3.89–29.54, p < 0.001, I² = 0%; Supplemental Figure 12(a)), and thrombocytopenia (8.9% vs 4%, RR 2.03, 95% CI 1.02–4.03, p = 0.043, I² = 0%; Supplemental Figure 12(b)).

Figure 5.

Forest plots for bleeding-related adverse events: (a) Total bleeding events. (b) Telangiectasia. (c) Epistaxi.

Regarding the two subgroup analyses, the risk category subgroup and the PAH duration subgroup, no significant subgroup differences were observed for any of the safety outcomes (p for subgroup difference >0.05; Supplemental Figures 13–17).

Trial-sequential analysis

TSA for the composite endpoint (Supplemental Figure 18(a)), WHO functional class (Supplemental Figure 18(b)), and PVR (Supplemental Figure 18(d)) showed that the cumulative Z-curve crossed both the conventional and trial-sequential monitoring boundaries for the area of benefit, suggesting the sufficiency and the conclusiveness of our evidence for improving these outcomes with sotatercept. For 6MWD (Supplemental Figure 18(c)), the Z-curve crossed the trial-sequential but not the conventional boundaries, suggesting that the current evidence remains inconclusive. In contrast, TSA results for total bleeding events (Supplemental Figure 19(c)) and epistaxis (Supplemental Figure 19(d)) showed that the Z-curve crossed both boundaries in the area of harm, indicating the sufficiency of our evidence for increasing the risk of these AEs with sotatercept. Meanwhile, the Z-curve for mortality (Supplemental Figure 19(b)) and serious AEs (Supplemental Figure 19(a)) did not cross the conventional, trial-sequential, or futility boundaries, highlighting the need for further studies. However, these results should not be interpreted as definitive proof of effect, particularly given the limited number of trials, variation in endpoint definitions, and remaining clinical heterogeneity.

Discussion

Current PAH management follows a structured, goal-oriented approach guided by the 2022 ESC/ERS definition, mPAP > 20 mmHg, PVR > 2 Wood units, and pulmonary arterial wedge pressure ⩽15 mmHg, confirmed through right-heart catheterization. For newly diagnosed adults, international guidelines recommend initial oral combination therapy with an endothelin-receptor antagonist plus either a phosphodiesterase-5 inhibitor or sGC stimulator for low- or intermediate-risk patients, while high-risk individuals should receive parenteral prostacyclin-based therapy. Vasoreactivity testing is advised for idiopathic, heritable, or drug-induced PAH to identify candidates for high-dose calcium-channel blockers, whereas non-responders proceed directly to combination therapy.¹

In this meta-analysis, we tested the hypothesis that sotatercept provides a meaningful clinical benefit over placebo in PAH. Across four RCTs including 889 patients, sotatercept reduced the composite clinical endpoint by nearly three-quarters and extended event-free survival by about 40 weeks. All-cause mortality trended lower but was not statistically significant. Patients receiving sotatercept were about 70% more likely to improve by at least one WHO functional class and walked approximately 30 meters farther on the 6-minute test. Hemodynamically, sotatercept lowered PVR by around 247 dyn·s·cm–⁵, mPAP by 16 mmHg, reduced NT-proBNP levels, and modestly increased cardiac output.

Taken together, these findings support a plausible mechanism of right ventricular unloading with sotatercept, reflected by consistent reductions in pulmonary vascular resistance and mPAP, lower NT-proBNP levels, modest improvement in cardiac output, and improved functional outcomes. However, these results should not be interpreted as direct proof of reverse right ventricular structural remodeling from our aggregate meta-analysis, because right ventricular imaging endpoints were not consistently available across the included randomized trials. Rather, the available evidence suggests that sotatercept may improve the hemodynamic conditions that drive right ventricular strain, a hypothesis that should be further assessed in trials with standardized right ventricular imaging and longer follow-up.

Safety was broadly comparable, with slightly fewer serious AEs but higher rates of erythrocytosis, thrombocytopenia, telangiectasia, and bleeding or epistaxis, while peripheral edema was less frequent. TSA confirmed firm evidence for benefit in the composite endpoint, WHO class, and PVR, and firm evidence of harm for bleeding and epistaxis, whereas mortality, NT-proBNP, and walk distance results remained less conclusive.

The prevention signal is clear and compelling. Our meta-analysis showed about a 77% lower risk of composite clinical worsening) and roughly 40 extra weeks of event-free survival, while all-cause mortality trended lower but did not reach statistical significance. Ershed et al., in their meta-analysis, similarly reported consistent reductions in composite worsening, though mortality effects remained imprecise, supporting the same favorable direction as our findings.¹⁶ Shalabi et al. also observed fewer clinical events and a mortality reduction that met significance.¹⁷ Among individual trials, Hoeper et al., in the STELLAR phase III trial of 323 patients, demonstrated significant improvement in hierarchically tested outcomes, including time to death or clinical worsening. Likewise, Humbert et al., in the ZENITH phase III study of 172 high-risk patients, found a 76% lower risk of death, transplant, or PAH hospitalization with numerically fewer deaths.^4,5

This consistent benefit can be attributed to sotatercept’s rebalancing of TGF-β superfamily signaling by trapping activin-class ligands and enhancing BMPR2/ALK1 pathways. The result is a shift toward a more differentiated, less proliferative pulmonary arterial phenotype, leading to reduced vascular resistance, lower right-sided afterload, and delayed progression of clinical events, effects that manifest early in disease trajectories, even before mortality differences become statistically evident in moderate-duration randomized trials.¹⁸

Function improves as vascular load lightens. Our pooled results showed that patients were about 70% more likely to improve by at least one WHO functional class and gained roughly 30 meters in 6-minute walk distance (6MWD). Ershed et al., in their meta-analysis, found a +41 m increase in 6MWD and a twofold higher likelihood of WHO-class improvement,¹⁶ In the major trials, Hoeper et al., in STELLAR, reported a +40.8 m treatment effect on 6MWD at 24 weeks with improvement in eight of nine secondary endpoints. Humbert et al., in the PULSAR phase II trial, confirmed an additive 6MWD benefit on background therapy,⁵ and Waxman et al., in SPECTRA phase IIa, showed improved peak VO₂ and right-ventricular performance, reinforcing a consistent physiological response.¹⁹ This improvement likely arises because reducing PVR enhances right-ventricular–arterial coupling. At any given filling pressure, the right ventricle can generate a higher stroke volume, translating into longer walking distance and better functional class, while ongoing vascular and myocardial remodeling continues to stabilize hemodynamics.²⁰

The remodeling pattern is clear and consistent. Our study showed a drop in PVR by about 247 dyn·s·cm–⁵, a mPAP decrease of around 16 mmHg, a cardiac output rise of about 0.3 L/min, and an NT-proBNP fall of roughly 647 pg/mL. Ershed et al., reported similar findings with PVR reduction of about 233 dyn·s·cm–⁵ and mPAP decline of 15 mmHg, while Shalabi et al. confirmed a PVR drop of around 215 dyn·s·cm–5 and a significant NT-proBNP decrease, aligning closely with our results.¹⁷ In trials, Humbert et al., in PULSAR, showed PVR reduction as the main endpoint with matching 6MWD and biomarker improvements,⁵ and Hoeper et al., in STELLAR, extended these findings across multiple clinical outcomes.⁴ These improvements likely reflect the reversal of vascular remodeling. By blocking activin-driven smooth muscle growth and restoring endothelial signaling through BMPR2/ALK1 pathways, sotatercept widens distal arterioles, reduces right-ventricular afterload, and lowers wall stress, as seen in the NT-proBNP decline, a cohesive hemodynamic pattern captured in our pooled estimates.¹⁸

Beyond efficacy, the overall safety profile of sotatercept further reinforces its clinical value. In our results, serious AEs occurred about 17% less frequently with sotatercept compared with control, and peripheral edema was reduced by nearly half. However, several expected class-related effects were more common; the risk of drug-related AEs was almost doubled, bleeding episodes were about twice as frequent, telangiectasia appeared more than three times as often, and elevated hemoglobin occurred roughly ten times more frequently, while all-cause mortality showed no difference between groups. This safety profile closely aligns with the STELLAR trial, which consistently reported epistaxis or gingival bleeding, telangiectasia, thrombocytopenia, and higher hemoglobin among the most frequent events, with no increase in deaths during double-blind follow-up.⁴ These findings can be explained by sotatercept’s mechanism of action, in which ligand trapping at ActRIIA stimulates erythropoiesis, leading to higher hemoglobin levels, and may affect small blood vessels in the skin and mucosa, producing telangiectasias that sometimes bleed, particularly in patients predisposed to mucosal hemorrhage, while intermittent thrombocytopenia can further enhance bleeding risk.^21,22 In contrast, the reduction in peripheral edema is likely because of improved right-heart unloading and enhanced venous and lymphatic return as PVR decreases, paralleling broader gains in exercise capacity and biomarkers.²³ These safety signals, epistaxis, telangiectasia, and elevated hemoglobin, were confirmed by Preston et al. in their long-term extension study and exposure-adjusted analyses, which found no evidence of new or delayed toxicities; however, continued monitoring for potential late vascular effects remains advisable.²⁴

Clinical implications

For adults with PAH already receiving guideline-based therapy, our findings support adding sotatercept to improve exercise capacity, reduce pulmonary pressures, and lessen clinical worsening. In clinical practice, sotatercept may be best suited for WHO functional class II–III patients on dual or triple background therapy who remain above low-risk thresholds. This reflects the populations enrolled in the pivotal STELLAR (phase III) and PULSAR (phase II) trials. Follow-up at 12–24 weeks with repeat 6-minute walk distance, NT-proBNP, and updated risk assessment is recommended to confirm response and guide ongoing management consistent with ESC/ERS treatment pathways.¹

Safety monitoring can follow a straightforward, standardized checklist. Hemoglobin and platelet counts should be checked before each of the first five doses (longer if results are unstable) and periodically afterward; hold or reduce the dose if hemoglobin rises excessively or platelets fall. Patients should be counseled about possible nosebleeds or telangiectasia, and antithrombotic therapy should be reviewed to avoid unnecessary overlap. Major trials showed no excess of serious AEs versus placebo, supporting routine use with standard monitoring. In practice, maintain background ERA, PDE5i, or sGC-stimulator therapy ± prostacyclin as in the trials, and use sotatercept to help patients reach low-risk targets and reduce clinical worsening. Educate patients about self-injection every 3 weeks, the expected timing of benefits, and laboratory follow-up. At the center level, care pathways should define eligibility criteria, lab thresholds for dose adjustment, antithrombotic review, and follow-up schedules. As use expands, programs should also plan for equitable access and affordability.

Strengths and limitations

This meta-analysis has several important methodological and clinical strengths. It represents the most comprehensive quantitative evaluation of sotatercept in PAH to date, combining four RCTs (n = 889) that used consistent dosing (0.7 mg/kg) and background therapy. By reconstructing IPD from Kaplan–Meier curves, we achieved more precise time-to-event modeling of sotatercept’s clinical benefit. We also conducted leave-one-out sensitivity analyses, confirming that no single trial disproportionately influenced the pooled estimates. In addition, we conducted two subgroup analyses—based on baseline risk of death (WHO functional class) and disease duration—which consistently demonstrated treatment benefit across subpopulations. The addition of TSA strengthened the certainty of evidence by assessing conclusiveness and minimizing random error. Finally, evidence quality was evaluated using the GRADE framework, ensuring transparency and reliability, while heterogeneity remained low across major efficacy and safety endpoints.

This study also has several limitations. The total number of included trials and participants was modest, reflecting the novelty of sotatercept and limiting precision for rare safety events and mortality estimates. Although heterogeneity was minimal for most categorical outcomes, variability remained for continuous measures such as 6-minute walk distance and NT-proBNP, likely due to differences in baseline functional class, disease duration, and background therapy. While reconstructed time-to-event data provided a robust approximation, they cannot fully replace original individual-level data, and some estimation bias may remain. All included studies were industry-sponsored phase II or III trials with relatively short- to mid-term follow-up, which limits conclusions regarding long-term survival and bleeding risk. Although TSA was used to assess the risk of random error, its interpretation is limited by the small number of included trials and by assumptions regarding anticipated effect size and required information size. TSA cannot correct for clinical heterogeneity, differences in endpoint definitions, selective outcome availability, risk of bias, or publication bias. Therefore, TSA results in this review should be considered supportive and hypothesis-strengthening rather than definitive. Finally, the small number of available studies constrained the ability to formally assess publication bias.

Conclusion

Sotatercept demonstrates promising therapeutic potential in PAH. Pooled evidence from randomized trials indicates significant improvements in WHO functional class, exercise capacity, pulmonary hemodynamics, and NT-proBNP levels, with a marked reduction in the risk of clinical worsening. Although mortality benefits remain inconclusive, a favorable trend was observed. The treatment was generally well tolerated, with AEs consistent with its biological mechanism; however, bleeding and vascular-related events warrant caution. These findings support the use of sotatercept as an add-on to standard therapy. Nonetheless, larger, long-term trials are needed to confirm survival benefits and generalizability across broader patient populations.

Supplemental Material

sj-docx-1-tar-10.1177_17534666261459209 – Supplemental material for Clinical, hemodynamic, and safety outcomes of sotatercept in pulmonary arterial hypertension: a meta-analysis of randomized trials with time-to-event data

Supplemental material, sj-docx-1-tar-10.1177_17534666261459209 for Clinical, hemodynamic, and safety outcomes of sotatercept in pulmonary arterial hypertension: a meta-analysis of randomized trials with time-to-event data by Mohamed R. Murad, Ameer Awashra, Mohamed S. Elgendy, Ahmed Wahdan Kasem, Abdalhakim Shubietah and Fadi Safi in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Mohamed R. Murad

Ameer Awashra

Abdalhakim Shubietah

Data availability statement

All required data are included in the manuscript or the Supplemental material. Any additional data can be obtained from the corresponding author* upon a reasonable request.

Generative AI and AI-assisted technologies statement.

No generative AI or AI-assisted technologies were used in the preparation of this manuscript.

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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