Real‐World Performance of Sotatercept in PAH Patients With Cardiopulmonary Comorbidities: A Retrospective Single Center Experience

ABSTRACT

Landmark trials of sotatercept in pulmonary arterial hypertension (PAH) excluded patients with significant cardiopulmonary comorbidities. To evaluate the real‐world effectiveness and safety of sotatercept in patients with Group I PAH and cardiopulmonary comorbidities. We conducted a single‐center prospective observational study of adults with PAH on stable background therapy who initiated sotatercept between August 2024 and April 2025. Clinical, echocardiographic, and adverse event data were collected at baseline, 3 months, and 6 months. Forty‐five patients (mean age 59.1 years old; 88.8% female) were included. Common comorbidities include CAD (44.7%), HTN (40.4%), ILD (23.4%), and COPD (12.7%). Most patients were on triple background pulmonary vasodilator therapy (63.8%). At 6‐month follow‐up, oxygen requirement at rest improved from 4.64 to 3.20 L/min (p = 0.001), 6MWD increased by 20 meters (310.5 ± 142.4 m to 330.4 ± 132.3 m, p = 0.01). REVEAL Lite 2 scores improved, with over half the cohort achieving or maintaining low risk status. Adverse effects were mild, including epistaxis and increased hematocrit. Sotatercept appears safe and clinically beneficial in PAH patients with cardiopulmonary comorbidities.

1. Introduction

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right ventricular failure [1]. Despite advancements in therapy, one‐, two‐, and 3‐year all‐cause mortality rates remain high at 8%, 16%, and 21%, respectively, even among patients on guideline‐directed therapy [2].

Cardiopulmonary comorbidities such as hypertension, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD) affect over 50% of patients with PAH [3, 4] and are linked to diminished responses to PAH therapy, namely, phosphodiesterase inhibitors (PDE‐5) and endothelin receptor antagonists (ERAs), lower likelihood of achieving low‐risk status, and higher mortality [5]. Importantly, patients with these complex phenotypes are often excluded from clinical trials, presenting ongoing challenges in therapeutic decision‐making.

Sotatercept, a first‐in‐class activin signaling inhibitor, has demonstrated significant improvements in functional capacity, hemodynamics, and all‐cause mortality in pivotal trials STELLAR [6] and ZENITH [7]. As a disease‐modifying agent that reverses vascular remodeling, sotatercept represents a major therapeutic advance. However, its generalizability is limited due to the exclusion of patients with significant cardiopulmonary comorbidities in these trials.

We aimed to assess the clinical and hemodynamic effects of sotatercept in a cohort of PAH patients with cardiopulmonary comorbidities, offering insights into its effectiveness and safety in this previously unstudied population.

2. Methods

We conducted a retrospective observational study at a single academic center between August 2024 and April 2025. Eligible patients were age ≥ 18 years, with confirmed group I PAH by right heart catheterization (RHC) [mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units], on stable background therapy for at least 3 months, and evidence of at least 1 pulmonary or cardiovascular comorbidity. Cardiovascular and pulmonary comorbidities were defined in accordance with the 2022 ESC/ERS/ISHLT/ERN‐LUNG task force for the diagnosis and treatment of pulmonary hypertension [8] (Figure 1). Patients were excluded if they were pregnant, breast feeding, or if they were enrolled in any other PAH clinical trials. All patients received subcutaneous sotatercept every 3 weeks in accordance with the STELLAR protocol.

Figure 1.

Definition of cardiopulmonary comorbidities. HFpEF: heart failure with preserved ejection fraction, LHD: left heart disease, OSA: obstructive sleep apnea.

Clinical data including cardiopulmonary comorbidities, oxygen use, 6‐min walk distance (6MWD), echocardiographic parameters, and REVEAL Lite 2 risk scores were collected at baseline, 3 months, and 6 months from the electronic medical record using a standardized template. The study protocol was approved by the Institutional Review Board (IRB 202401101). Statistical analysis included descriptive metrics, paired t‐tests, and repeated measures ANOVA with significance set at p < 0.05.

3. Results

Among 160 patients with PAH at our center, 92 initiated sotatercept during the study period. Of these, 47 patients had at least one cardiac or pulmonary comorbidity. Two patients were excluded: one discontinued sotatercept due to injection site rash after the second dose, and the other died after receiving the first dose. A total of 45 patients were included in the final analysis.

3.1. Baseline Characteristics

The cohort had a mean age of 59.1 ± 17.3 years and was predominantly female (88.8%) and white (84.4%). Most patients were WHO functional class II (57.7%) or III (40%), and 20% were receiving parenteral prostacyclin. The most common PAH subgroup was connective tissue disease‐associated (CDT) (35.6%), followed by idiopathic (28.8%) and hereditary PAH (17,7%). 25 patients (55.5%) were on oxygen supplementation (mean O2 at rest 4.6 L). Detailed demographic and hemodynamic data are described in Table 1.

Table 1.

Baseline demographic and clinical characteristics.

Demographics
Age (years)	59.09 ± 17.34
Female	40 (88.8%)
Race
White	38 (84.4%)
Hispanic	5 (11.1%)
Asian	2 (4.4%)
BMI (kg/m2)	27.88 ± 7.202
Clinical Status
WHO Functional Class
I	0 (0%)
II	26 (57.7%)
III	18(40%)
IV	1 (2.2%)
REVEAL Lite 2 score
Low	18 (40%)
Intermediate	11 (21%)
High	16 (31%)
PAH subgroups
Idiopathic	13 (28.8%)
Hereditary	8 (17,7%)
Drug induced	2 (4.4%)
Connective Tissue Disease	16 (35.5%)
Congenital Heart Disease	3 (6.6%)
Pulmonary veno‐occlusive disease (PVOD)	2 (4.4%)
Portopulmonary Hypertension (PoPH)	1 (2.2%)
Background Therapy
Monotherapy	3 (6.6%)
Dual Therapy	13 (28.8%)
Triple Therapy	30 (66.7%)
Parenteral Prostacyclin	9 (20%)
Baseline Hemodynamic profile
RA (mmHg)	8.8 ± 4.2
mPAP (mmHg)	46.6 ± 17.4
PCWP (mmHg)	10.8 ± 4.3
CO(TD) (L/min)	4.3 ± 1.8
CI(TD) (L/min/m2)	2.4 ± 0.8
PVR (Wood Units)	9.3 ± 6.0
SvO2%	65.1 ± 8.2
SVI (ml/min)	30.0 ± 10.5
PAC (ml/mmHg)	1.6 ± 1.0
Total	45

3.2. Cardiopulmonary Comorbidities

The most common left heart diseases included: coronary artery disease (44.7%), hypertension (40.4%), and heart failure with preserved ejection fraction (38.3%). The most common arrhythmia was atrial fibrillation (10 patients, 22%). The distribution of all comorbidities can be found in Figure 2.

Figure 2.

Distribution of cardiopulmonary comorbidities in patients with PAH.

ILD (23.4%) and COPD (12.7%) were the most common pulmonary comorbidities. Among the patients with PAH and ILD, only 4 cases were associated with CTD. In both sub‐groups (PAH‐ILD and PAH‐COPD), hemodynamic assessment at diagnosis was consistent with group I PAH (PVR > 5, mPAP > 40) and the degree of DLCO reduction and/or hypoxia were deemed out of proportion to lung parenchymal involvement. Detailed pulmonary function tests, HRCT and RHC data for both PAH‐ILD and PAH‐COPD are summarized in Tables 2 and 3.

Table 2.

Characteristics of patients with PAH and ILD.

PFT	Parameter	Mean
	FVC (L)	1.82
	FVC % Predicted	70.0%
	FEV1 (L)	1.39
	FEV1 % Predicted	71.1%
	TLC (L)	3.7
	TLC % Predicted	71.6%
	DLCO (mL/min/mmHg)	6.09
	DLCO % Predicted	32.6
HRCT	Radiographic pattern	%
	UIP/Probable UIP	4 (36%)
	NSIP/Probable NSIP	3 (18%)
	CPFE	3 (18%)
	Unclassified ILD	3 (18%)
RHC	Parameters
	RA mmHg	6
	Mean PAP mmHg	43
	PCWP mmHg	10.5
	PVR Wood Units	12.6
	CO L/min	3.2
	CI L/min/m2	1.96

Table 3.

Characteristics of patients with PAH and COPD.

PFT	Parameter	Mean
	FVC (L)	2.04
	FVC % Predicted	84.5%
	FEV1 (L)	1.4
	FEV1 % Predicted	75.127%
	TLC (L)	3.8
	TLC % Predicted	85.6%
	DLCO (mL/min/mmHg)	5.7
	DLCO % Predicted	31.3
HRCT	Emphysema	%
	Mild (< 25%)	1 (18%)
	Moderate (25%–50%)	3 (50%)
	Severe (50%–75%)	2 (32%)
	Very Severe (> 75%)	0 (0%)
RHC	Parameters
	RA mmHg	10.1
	Mean PAP mmHg	43.3
	PCWP mmHg	11.8
	PVR Wood Units	7.8
	CO L/min	4.2
	CI L/min/m2	2.1

3.3. Clinical Outcomes

Over a median follow‐up of 6 months, patients experienced modest improvement in clinical parameters. Across the cohort, the average 6 min walk distance (6MWD) increased from 310.5 to 330.4 mts (p = 0.01). Similarly, nadir desaturation during 6MWT improved from 88.2% to 89.1% (p = 0.23). Additionally, patients requiring oxygen supplementation experienced a 1.4 L reduction at rest (p < 0.001) and 0.5 L reduction with exertion (p < 0.34) (Tables 4 and 5).

Table 4.

Paired Samples t‐test comparing clinical outcomes at baseline and follow‐up.

	N	Baseline	Follow up	Interval (days)	p‐value
6MWT
Distance in mt	40	310.5 ± 142.4	330.43 ± 132.27*	184.4 ± 95.7	0.01
Nadir O2%	40	88.2 ± 6.1	89.1 ± 4.9	184.4 ± 95.7	0.232
Echocardiogram
TR Velocity (cm/s)	17	330.4 ± 97.1	285.3 ± 115.8*	212.4 ± 94.2	0.002
TAPSE (cm)	30	18.8 ± 3.9	18.8 ± 4.2	212.4 ± 94.2	0.959
RVSP (mmHg)	12	67.9 ± 29.3	51.7 ± 25.2*	212.4 ± 94.2	0.014
S’ cm/s	7	10.5 ± 2.3	10.4 ± 2.8	212.4 ± 94.2	0.841
Stroke Volume (ml)	13	63.8 ± 12.1	59.8 ± 12.8	212.4 ± 94.2	0.404
Reveal Lite 2.0
Total	45	6.11 ± 2.36	5.24 ± 2.01	137.3 ± 52.8	< 0.001
Low		18 (40%)	24 (53%)
Intermediate		11 (21%)	14(31%)	137.3 ± 52.8	0.012
High		16 (31%)	7(16%)

Table 5.

Changes in oxygen requirements before after initiation of sotatercept.

Parameter	Baseline	Follow up	Mean difference	95% CI of difference	p‐value
Resting O₂ (L/min)	4.64	3.20	–1.44 L/min	–2.05 to –0.84	< 0.001
Exertional O₂ (L/min)	5.72	5.20	–0.52 L/min	–1.00 to –0.04	0.034

The mean REVEAL Lite 2 risk scores improved from 6.11 ± 2.36 to 5.24 ± 2.01 (p < 0.001). Thirteen patients moved down one risk category, while four shifted upward. Overall, the proportion of patients at low risk increased from 40% to 53% (p = 0.012), and those at high risk decreased from 31% to 16% (Figure 3).

Figure 3.

REVEAL Lite 2 risk score before and after sotatercept.

A third of the patients had improvement in WHO FC at 6 months including nine patients moving from FC III to FC II and five patients achieving FC I status (x2 = 9.11, d(f)=3, p = 0.028.) (Figure 4).

Figure 4.

WHO FC classification before and after sotatercept.

Right ventricular (RV) function was assessed via echocardiogram in 17 patients. Tricuspid Valve regurgitation (TVR) jet velocity decreased from 330.4 to 285.3 cm/s (p = 0.002), and RV systolic pressure (RVSP) decreased from 67.9 to 51.7 mmHg (p = 0.014). TAPSE, S’ velocity and left ventricle stroke volume remained stable (Table 4).

A subgroup analysis of sixteen patients with complete follow‐up at 3 and 6 months supported trends observed in the full cohort (Table 6). Though 6MWD did not reach statistical significance across time points (ANOVA p = 0.21), it increased steadily (355.6 m → 375.0 m → 381.5 m). Reductions in TVR jet velocity (p = 0.025) and RVSP (p = 0.045) remained significant. S’ velocity improved slightly (p = 0.035), reflecting subtle improvement in RV longitudinal function.

Table 6.

Repeated measures ANOVA of clinical parameters at baseline, 3 months, and 6 months.

	N	Baseline	3 months	6 months	p‐value	Post‐hoc
6MWT
Distance in mt	16	355.6 ± 136.6	375.0 ± 119.7	381.5 ± 122.5	0.214
Nadir O2%	16	88.8 ± 5.9	90.1 ± 4.8	89.4 ± 5.7	0.383
Echocardiogram
TR Jet	6	391.2 ± 88.1	346.5 ± 122.2	305.7 ± 60.9	0.025	FU2 < Baseline
TAPSE	9	17.7 ± 3.7	19.0 ± 5.5	16.3 ± 3.5	0.232
RSVP	6	86.7 ± 29.4	64.5 ± 31.1	52.2 ± 17.0	0.045	FU2 < Baseline
S'	3	9.43 ± 1.2	10.0 ± 2.1	10.6 ± 1.1	0.035	FU2 < Baseline
Stroke Volume	3	65.9 ± 17.2	56.7 ± 8.1	64.0 ± 17.1	0.856

Mild side effects included epistaxis, increased hemoglobin concentration, and mild thrombocytopenia that did not warrant discontinuation of treatment. Symptoms of excessive pulmonary vasodilation (headaches or flushing) improved with de‐escalation of background therapy. At 6 months, prostacyclin dose reduction was possible in eight out of nine patients.

4. Discussion

In this retrospective, real‐world study, we found that the addition of sotatercept to background PAH therapy in patients with PAH and cardiopulmonary comorbidities was effective and well tolerated. Despite being a population traditionally considered less likely to benefit from PAH‐specific therapy, patients experienced improvement in several clinically relevant parameters, including WHO FC, risk stratification, 6MWT distance, oxygen requirements, and echocardiographic markers of RV function.

Our cohort was representative of a real‐world PAH population, with CTD‐PAH as the most common subtype, followed by IPAH and HPAP [9], and a distribution of cardiopulmonary comorbidities that aligns with reports from larger retrospective studies [4]. Most patients had moderate to severe pulmonary hypertension, as reflected by WHO FC II or III, baseline hemodynamic profile, and use of parenteral prostacyclin.

Evaluation at three and 6 months showed improvement in several functional and hemodynamic outcomes. Follow‐up 6MWT distance improved by 20mt, a modest increase compared to previous studies [6]. A clinical and statistical significant reduction in oxygen requirement was observed among oxygen users. While requirements on exertion remained unchanged, patients were able to walk longer distances without worsening desaturation. Moreover, patients reported higher energy levels and more engagement with physical activity.

Echocardiography assessment showed reductions in RV pressure with preserved function. Improvements in oxygenation at rest, but not exertion, reflect the expected fixed ventilatory and cardiovascular impairment in this population.

Most notably, we observed significant changes in REVEAL Lite 2 risk scores and a trend towards improvement in WHO FC. Over half of the cohort remained or achieved low‐risk status during the study period, despite having comorbid conditions like ILD, COPD, or heart failure, factors typically associated with poor therapeutic response [10]. The REVEAL Lite 2 score was an appropriate tool for this analysis, as it was derived from the PAH registry data and retains accuracy in patients with comorbidities [9, 11]. These findings suggest that sotatercept may alter trajectory even in complex PAH phenotypes, further supporting STELLAR post‐hoc findings [12].

Furthermore, sotatercept was well tolerated, with a safety profile consistent with prior reports. The burden of comorbid conditions in our cohort mirrors real‐life PAH populations, making these findings especially relevant to clinical practice.

Important limitations in this study include small sample size, retrospective observational design and incomplete imaging, and invasive hemodynamic assessment. Nonetheless, this study highlights sotatercept's promising role this challenging population. Larger prospective studies to confirm these findings are needed.

5. Conclusion

Sotatercept appears to be a safe and effective therapeutic addition for patients with Group I PAH and cardiopulmonary comorbidities. In a population traditionally considered less likely to respond to PAH‐specific therapies, our study observed improvements in functional capacity, right ventricular parameters, and risk reclassification. These findings uncover the possibility of extending the clinical applicability of sotatercept beyond carefully selected trial populations. Further prospective studies are needed to confirm these findings.

Funding

The authors received no specific funding for this work.

Conflicts of Interest

AA declares a relationship with Merc & Co Inc, United Therapeutics and Savara Inc that includes consulting or advising.

Ethics Statement

This study was conducted in accordance with the ethical standards of the institutional and national research committees and with the Declaration of Helsinki. The protocol for this retrospective observational study was reviewed and approved by the Institutional Review Board of the University of Florida (IRB# 202401101). Given the retrospective nature of the study, the IRB granted a waiver of informed consent. All data were handled in compliance with institutional privacy policies and applicable regulations to ensure confidentiality and protection of patient information.

Gomez Rojas O, Mitchell S, Peterson JA, Kalra S, Bryant A, Ataya A, “Real‐World Performance of Sotatercept in PAH Patients With Cardiopulmonary Comorbidities: A Retrospective Single Center Experience,” Pulmonary Circulation 60 (2025): 1‐6. 10.1002/pul2.70226.