Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Computational platform for doctor-artificial intelligence cooperation in pulmonary arterial hypertension prognostication: a pilot study.

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous and complex pulmonary vascular disease associated with substantial morbidity. Machine-learning algorithms (used in many PAH risk calculators) can combine established parameters with thousands of circulating biomarkers to optimise PAH prognostication, but these approaches do not offer the clinician insight into what parameters drove the prognosis. The approach proposed in this study diverges from other contemporary phenotyping methods by identifying patient-specific parameters driving clinical risk. Methods: We trained a random forest algorithm to predict 4-year survival risk in a cohort of 167 adult PAH patients evaluated at Stanford University, with 20% withheld for (internal) validation. Another cohort of 38 patients from Sheffield University were used as a secondary (external) validation. Shapley values, borrowed from game theory, were computed to rank the input parameters based on their importance to the predicted risk score for the entire trained random forest model (global importance) and for an individual patient (local importance). Results: Between the internal and external validation cohorts, the random forest model predicted 4-year risk of death/transplant with sensitivity and specificity of 71.0-100% and 81.0-89.0%, respectively. The model reinforced the importance of established prognostic markers, but also identified novel inflammatory biomarkers that predict risk in some PAH patients. Conclusion: These results stress the need for advancing individualised phenotyping strategies that integrate clinical and biochemical data with outcome. The computational platform presented in this study offers a critical step towards personalised medicine in which a clinician can interpret an algorithm's assessment of an individual patient.

Derivation of a Risk Score (REVEAL-ECHO) Based on Echocardiographic Parameters of Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Multiparametric risk assessment tools determine mortality risk in patients with pulmonary arterial hypertension (PAH) by combining invasive and noninvasive variables so management strategies can be tailored to individuals. RESEARCH QUESTION: Can a risk score based on common echocardiographic parameters risk-stratify patients with PAH? STUDY DESIGN AND METHODS: A Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) echocardiographic risk score (REVEAL-ECHO) was derived using retrospective echocardiographic data from 2,400 adult patients with PAH enrolled in the REVEAL registry database. A stepwise Cox regression model identified echocardiographic parameters significantly predictive of survival. Values were assigned to each selected parameter based on survival at 12 months' follow-up (Kaplan-Meier estimates). The REVEAL-ECHO risk score was the sum of individual values. Patients were categorized as having low, intermediate, or high risk based on Kaplan-Meier-predicted 12-month survival. RESULTS: The risk score included four echocardiographic parameters-right ventricular (RV) chamber enlargement, reduced RV systolic function, tricuspid regurgitation severity, and pericardial effusion-and accounted for PAH etiology. Higher REVEAL-ECHO risk scores signaled lower probability of 12-month survival. Statistically significant separation of mortality risk was observed among the risk strata: intermediate vs low (hazard ratio [HR], 1.43; 95% CI, 1.17-1.75; P = .0004) and high vs low (HR, 2.60; 95% CI, 2.19-3.10; P < .0001). Augmentation of the REVEAL Lite 2 risk calculator with REVEAL-ECHO risk scores achieved separation of REVEAL Lite 2 into four risk groups and identified a subgroup of patients with a low REVEAL Lite 2 risk score who were at higher risk (intermediate-low risk) and a subgroup of patients with an intermediate REVEAL Lite 2 risk score who also were at higher risk (intermediate-high risk). INTERPRETATION: A REVEAL-ECHO risk score, derived using four echocardiographic parameters, may discriminate risk further when used as an adjunct to current risk assessment scores. Further validation is required.

Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension.

BACKGROUND: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.

The evolving landscape of pulmonary arterial hypertension clinical trials.

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.

Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension - An analysis of FREEDOM-EV.

BACKGROUND: Risk scores integrate clinical variables emphasizing symptoms, exercise capacity, and measures of cardiac strain to predict clinical outcome better than any single value in pulmonary arterial hypertension (PAH). Risk scores have demonstrated prognostic utility for outcomes in registries, and recent studies have suggested that they are also therapy-responsive in controlled trials. METHODS: FREEDOM-EV, a global, placebo-controlled, event-driven study, randomized 690 PAH participants 1:1 to oral treprostinil (TRE) or placebo. Clinical assessments were performed every 12 weeks to calculate the non-invasive French risk assessment (FRA), 4-strata COMPERA, REVEAL 2.0, and REVEAL Lite 2; median follow-up was 58 weeks. The Week 12 risk scores were used to predict time to clinical worsening (from Week 12) with Kaplan-Meier product-limit estimates. Log-rank test was used to calculate the statistical difference among risk categories, and mediation analysis tested the hypothesis that improvements in risk score contributed to reduced likelihood for clinical worsening. We assessed the previously proposed "net clinical benefit" (achievement of FRA low-risk status and absence of clinical worsening). RESULTS: Both REVEAL scores, COMPERA, and FRA at Week 12 predicted subsequent clinical worsening better than baseline risk. Mediation analysis demonstrated that Week 12 risk score reduction explained part of TRE's effect on clinical worsening, especially for those with higher baseline risk. TRE assigned participants were more likely to achieve the previously proposed "net clinical benefit" at Weeks 24 and beyond. Few participants who achieved 'net clinical benefit' had subsequent clinical worsening. CONCLUSIONS: Contemporary risk scores were therapy responsive in FREEDOM-EV and early improvements predicted subsequent outcomes. This post hoc analysis suggests that risk scores may be a surrogate for clinical worsening.

Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.

OBJECTIVE: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. METHODS: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. RESULTS: GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. CONCLUSIONS: The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

Association of Early Aspirin Use With In-Hospital Mortality in Patients With Moderate COVID-19.

Importance: Prior observational studies suggest that aspirin use may be associated with reduced mortality in high-risk hospitalized patients with COVID-19, but aspirin's efficacy in patients with moderate COVID-19 is not well studied. Objective: To assess whether early aspirin use is associated with lower odds of in-hospital mortality in patients with moderate COVID-19. Design, Setting, and Participants: Observational cohort study of 112 269 hospitalized patients with moderate COVID-19, enrolled from January 1, 2020, through September 10, 2021, at 64 health systems in the United States participating in the National Institute of Health's National COVID Cohort Collaborative (N3C). Exposure: Aspirin use within the first day of hospitalization. Main Outcome and Measures: The primary outcome was 28-day in-hospital mortality, and secondary outcomes were pulmonary embolism and deep vein thrombosis. Odds of in-hospital mortality were calculated using marginal structural Cox and logistic regression models. Inverse probability of treatment weighting was used to reduce bias from confounding and balance characteristics between groups. Results: Among the 2 446 650 COVID-19-positive patients who were screened, 189 287 were hospitalized and 112 269 met study inclusion. For the full cohort, Median age was 63 years (IQR, 47-74 years); 16.1% of patients were African American, 3.8% were Asian, 52.7% were White, 5.0% were of other races and ethnicities, 22.4% were of unknown race and ethnicity. In-hospital mortality occurred in 10.9% of patients. After inverse probability treatment weighting, 28-day in-hospital mortality was significantly lower in those who received aspirin (10.2% vs 11.8%; odds ratio [OR], 0.85; 95% CI, 0.79-0.92; P < .001). The rate of pulmonary embolism, but not deep vein thrombosis, was also significantly lower in patients who received aspirin (1.0% vs 1.4%; OR, 0.71; 95% CI, 0.56-0.90; P = .004). Patients who received early aspirin did not have higher rates of gastrointestinal hemorrhage (0.8% aspirin vs 0.7% no aspirin; OR, 1.04; 95% CI, 0.82-1.33; P = .72), cerebral hemorrhage (0.6% aspirin vs 0.4% no aspirin; OR, 1.32; 95% CI, 0.92-1.88; P = .13), or blood transfusion (2.7% aspirin vs 2.3% no aspirin; OR, 1.14; 95% CI, 0.99-1.32; P = .06). The composite of hemorrhagic complications did not occur more often in those receiving aspirin (3.7% aspirin vs 3.2% no aspirin; OR, 1.13; 95% CI, 1.00-1.28; P = .054). Subgroups who appeared to benefit the most included patients older than 60 years (61-80 years: OR, 0.79; 95% CI, 0.72-0.87; P < .001; >80 years: OR, 0.79; 95% CI, 0.69-0.91; P < .001) and patients with comorbidities (1 comorbidity: 6.4% vs 9.2%; OR, 0.68; 95% CI, 0.55-0.83; P < .001; 2 comorbidities: 10.5% vs 12.8%; OR, 0.80; 95% CI, 0.69-0.93; P = .003; 3 comorbidities: 13.8% vs 17.0%, OR, 0.78; 95% CI, 0.68-0.89; P < .001; >3 comorbidities: 17.0% vs 21.6%; OR, 0.74; 95% CI, 0.66-0.84; P < .001). Conclusions and Relevance: In this cohort study of US adults hospitalized with moderate COVID-19, early aspirin use was associated with lower odds of 28-day in-hospital mortality. A randomized clinical trial that includes diverse patients with moderate COVID-19 is warranted to adequately evaluate aspirin's efficacy in patients with high-risk conditions.

Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Management of Women With Congenital or Inherited Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 2/5.

Maternal morbidity and mortality continue to rise in the United States, with cardiovascular disease as the leading cause of maternal deaths. Congenital heart disease is now the most common cardiovascular condition encountered during pregnancy, and its prevalence will continue to grow. In tandem with these trends, maternal cardiovascular health is becoming increasingly complex. The identification of women at highest risk for cardiovascular complications is essential, and a team-based approach is recommended to optimize maternal and fetal outcomes. This document, the second of a 5-part series, will provide practical guidance from pre-conception through postpartum for cardiovascular conditions that are predominantly congenital or heritable in nature, including aortopathies, congenital heart disease, pulmonary hypertension, and valvular heart disease.

Implantable system for treprostinil and lung transplantation: case series from delivery for pulmonary arterial hypertension study.

The implanted system for treprostinil has been described in previous publications. There is no information published about how to handle this system around lung or heart-lung transplantation. We present the experience from the DelIVery for Pulmonary Arterial Hypertension study. Seven subjects from five pulmonary arterial hypertension centers were included in this retrospective chart review. All subjects were participating in the previously described DelIVery for pulmonary arterial hypertension study. Seven subjects with implanted pumps have been listed for lung or heart-lung transplant. Six subjects underwent lung or heart-lung transplantation and one remains on the transplant list. Three different methods of patient management for transplant were used. In three subjects, the implanted system was filled with saline prior to transplantation and treprostinil was infused via an external system. Three subjects had their drug-filled implanted pump and catheter system explanted at the time of transplant. One patient had the drug-filled implanted system removed prior to being listed for transplantation. Four subjects were hospitalized while waiting for transplantation. In conclusion, the implanted system for treprostinil is an important advance in the care of pulmonary arterial hypertension subjects. The experience described here provides three effective strategies for managing the implanted system around lung or heart-lung transplantation. The optimal strategy will depend on patient characteristics and lung transplant program preferences and wait list times.

Sotatercept for the Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).

Contemporary Pharmacotherapeutic Approach in Pulmonary Arterial Hypertension.

Since the 1973 World Symposium on Pulmonary Hypertension, advancements in the understanding of pathophysiology and pathobiology have led to a myriad of pharmacotherapies for the disease. This article journeys through the development of therapeutic approaches for pulmonary arterial hypertension.