Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association | Circulation
Burden Of PAH Weighs Heavy Worldwide
Three decades of data from the Global Burden of Disease Study were analyzed for trends in global, regional, and national burdens in pulmonary arterial hypertension (PAH).
Female individuals and older adults, especially if they live in an economically disadvantaged sociodemographic index (SDI) area, are more likely to be adversely affected by pulmonary arterial hypertension (PAH), highlighting the ongoing burden of PAH despite an overall decline in age-standardized incidence rates (ASIRs) of this rare and progressive type of pulmonary hypertension and severe cardiovascular condition.
PAH continues to present a significant, global health burden despite treatment and diagnosis advances, and its true impact on the 192,000 patients living with this condition remains a major global health threat.1
Data on incidence, prevalence, mortality rates, and disability-adjusted life-years (DALYs) from 1990 to 2021 from the Global Burden of Disease Study—covering 204 countries and regions—were used for a new systematic analysis published recently in BMJ Open.2 This investigation dove deeper compared with previous studies, in that it included stratified SDI classifications and assessments of regions with limited health care access.
Principal Findings of InterestThere was an exponential leap in global incidence and prevalence of PAH between 1990 and 2021: 85.62% and 81.46%, respectively. However, the ASIR rate (per 100,000 persons) was steady, changing an estimated 0.05% annually (95% CI, 0.03%-0.07%) over the same period. Drilling down to SDI, results varied between high-SDI regions and low-SDI regions. From high- to low-SDI regions, these results were seen:
Disease ASIRs were greatest in Central Europe (0.47) and lowest in North America (0.30), notable increases were seen in Central Europe and the Caribbean (0.40% and 0.27%, respectively), and the most significant drop was seen in Western Sub-Saharan Africa (1.15%).
The global pattern of PAH is complex and uneven, with regions seeing substantial variation and marked inequality between high-income nations and developing countries.Image Credit: © Richelle-stock.Adobe.Com
County-level variations were significant, too, with the study authors attributing these to "differences in health care quality, disease awareness, and diagnostic capabilities across countries." Stable ASIRs were seen in high-SDI countries (0.47 and 0.37 in France and Germany, respectively) but trended up and down among low- and low-middle SDI countries (Ethiopia, 1.0 per 100,000; Benin, 1.32% decrease per year).
For female and male individuals, incident PAH cases increased 86% in each group, but the estimated annual percentage change was slightly higher in females: 0.06% vs 0.03%.
When sociodemographic information was considered, moderate total case increases were seen in high-SDI (48.36%) and high-middle SDI (50.85%) regions. A sharp contrast was seen for this outcome when investigating as such in middle-, low-middle, and low-SDI regions, which had substantial increases of 106.43%, 119.21%, and 120.38%, respectively.
Among the regions included in the Global Burden of Disease Study 2021, the largest overall increase in cases was seen with 214.21% in Western Sub-Saharan Africa, even though there was a small decline in its age-standardized prevalence rate, from 3.22 to 2.97 per 100,000 population. Eastern Europe experienced a 6.52% drop in cases and a prevalence rate that fell from 3.21 to 2.83 per 100,000. A stark contrast was seen in the United Arab Emirates and Qatar, which had total case increases of 615.52% and 717.15%, respectively.
"High-SDI countries generally demonstrated more modest increases while maintaining relatively stable [age-standardized prevalence rates]," the authors wrote.
For mortality outcomes, total global deaths rose 48.36% from 1990 to 2021, despite the estimate annual percentage change drop of 0.57% and the age-standardized mortality rate also falling, from 0.35 to 0.27 deaths per 100,000 population.
Overall, global DALYs dropped from 687,419 cases to 642,419 cases between 1990 and 2021, or 6.59%. Building on these results, age-standardized DALYs fell from 13.21 to 8.24 per 100,000, or 37.62%. In particular, substantial improvement was seen in high-middle SDI regions, which experienced a 22.09% drop in DALY totals.
ConclusionsThe pattern is complex and uneven, the study authors explained, when getting to the heart of the global burden of PAH. Regions saw substantial variation, and there was marked inequality between high-income nations and developing countries.
Notable contributions to these disparate outcomes come from environmental exposures, increasing rates of sedentary behaviors and dietary changes, tobacco consumption, urbanization, economic development, and comorbid health conditions, such as infectious diseases and nutritional deficiencies. In addition, certain regions have access to more advanced health care options, such as treatment and diagnostic capabilities, while others have to deal with within-region variations in substance use patterns.
The authors' solution is 3-fold, they explain.
"Strengthening health care systems, improving diagnostic and treatment capabilities, and focusing on high-risk groups," they wrote, "are crucial steps towards reducing the global impact of PAH and achieving equitable health outcomes."
References
1. Leary PJ, Lindstrom M, Johnson CO, et al. Global, regional, and national burden of pulmonary arterial hypertension, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Respir Med. 2025;13(1):69-79. Doi:10.1016/S2213-2600(24)00295-9
2. Wu X, Suo S, Su X, et al. Trends in pulmonary arterial hypertension: insights from Global Burden of Disease 1990–2021. BMJ Open. 2025;15(3):e095348. Doi:10.1136/bmjopen-2024-095348
Sotatercept Reduces Major Events In High-Risk PAH Patients
Sotatercept-csrk reduced the risk of major morbidity and mortality events in adults with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) functional class (FC) 3 or 4 at high risk of mortality, according to published results from the ZENITH trial.
Sotatercept is a recombinant activin receptor type IIA-Fc fusion protein designed to bind to activin A and other TGF- β superfamily ligands resulting in vascular proliferation regulation. It is currently approved under the brand name Winrevair™ for the treatment of adults with PAH (WHO Group 1) to increase exercise capacity, improve WHO FC, and reduce the risk of clinical worsening events.
The double-blind, placebo-controlled phase 3 ZENITH study (ClincialTrials.Gov Identifier: NCT04896008) enrolled 172 patients with WHO FC 3 or 4 PAH and a high 1-year risk of mortality (Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2.0 risk score ≥9) who were receiving maximum tolerated background therapy.
Study participants were randomly assigned to receive subcutaneous sotatercept (n=86) or placebo (n=86) every 21 days with background PAH therapy. The primary endpoint was the time to first confirmed morbidity or mortality event defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of at least 24 hours.
Findings showed sotatercept reduced the relative risk of major morbidity and mortality events by 76% (hazard ratio [HR], 0.24 [95% CI, 0.13-0.43]; P <.0001) compared with placebo. In the sotatercept arm, 17.4% of patients experienced at least 1 major morbidity or mortality event vs 54.7% of those in the placebo arm. The median duration of follow-up was 10.6 months (range, 0.3-26.1) and 7.1 months (range, 0.7-24.2) in the sotatercept and placebo groups, respectively.
Death from any cause (8.1% vs 15.1%), lung transplantation (1.2% vs 7.0%), and hospitalization for worsening PAH (9.3% vs 50.0%) occurred less frequently in the sotatercept group compared with the placebo group.
Notably, overall survival, a key secondary endpoint, did not reach the heightened statistical significance threshold at the interim analysis (HR, 0.42 [95% CI, 0.17-1.07]; P =.0313).
The most common adverse events reported with sotatercept were epistaxis and telangiectasia.
"The ZENITH study represents the first PAH clinical trial with a primary endpoint comprised entirely of major outcome measures – all-cause death, lung transplantation and hospitalization for PAH," said Dr Marc Humbert, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999. "Winrevair had a significant and clinically meaningful impact on the composite of these outcomes, and together with the growing body of evidence from the clinical development program, these data support the practice-changing potential of Winrevair for a broad range of patients with PAH."
Previously, Merck announced that the ZENITH trial would be stopped early based on strong efficacy data. All study patients were offered the opportunity to receive sotatercept through the open-label, long-term extension SOTERIA study (ClinicalTrials.Gov Identifier: NCT04796337).
Trial Supports Sotatercept As Standard Of Care For High-risk Patients With PAH
March 31, 2025
2 min read
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Key takeaways:CHICAGO — Sotatercept, an activin signaling inhibitor, was associated with improved outcomes in patients with advanced pulmonary arterial hypertension at high risk for death, a speaker reported.
The results of the phase 3, multicenter, double-blind, randomized, placebo-controlled ZENITH trial of sotatercept-csrk (Winrevair, Merck) for patients with WHO functional class III or IV PAH were presented the American College of Cardiology Scientific Session and simultaneously published in The New England Journal of Medicine.
Sotatercept reduced risk for adverse outcomes in patients with advanced pulmonary arterial hypertension. Image: Adobe Stock
"The idea was to evaluate efficacy and safety in a more advanced patient population than previous trials," Aaron B. Waxman, MD, director of the pulmonary vascular disease program at Brigham and Women's Hospital, told Healio. "The main difference is that these patients, all based on REVEAL scoring, were intermediate high to high risk, whereas the prior study looked at a standard population of functional class II and III, and while they had significant disease, not nearly as sick as this patient population."
In March 2024, the FDA approved sotatercept for the treatment of adults with WHO group I and WHO functional class II or III PAH taking background PAH therapy.
The approval was based on the results of the phase 3, randomized, double-blind, placebo-controlled STELLAR trial presented at ACC.23, in which sotatercept reduced risk for death and clinical worsening of PAH compared with placebo.
In the ZENITH trial, the effects of sotatercept every 3 weeks were compared with placebo in a cohort of 172 patients with WHO functional class III or IV PAH and high 1-year risk for death already receiving maximally tolerated background therapy (mean age, 54 years; 77% women; 87% white). High risk for death was defined as REVEAL Lite 2 risk score of 9 or more.
Participants assigned to sotatercept started at a dose of 0.3 mg/kg body weight and were escalated to a target dose 0.7 mg/kg.
The primary composite endpoint included hard outcomes such as all-cause death, lung transplantation or PAH hospitalization, all starting 24 hours from treatment initiation.
As Healio previously reported, the phase 3 ZENITH trial was halted early due to strong efficacy data reported during an interim analysis in November.
The researchers reported an incidence of at least one component of the primary endpoint in 17.4% of the sotatercept group and 54.7% of the placebo group, which translated to a hazard ratio of 0.24 (95% CI, 0.13-0.43; P < .0001).
Because the trial was halted early, the investigators made no formal comparisons between trial groups for the individual components of the composite primary endpoint.
Numerically, there were fewer occurrences of the individual components of the primary endpoint in the sotatercept arms compared with placebo:
Aaron B. Waxman
"Forty-seven patients in the placebo group had at least one event. Survival was also really quite impressively different, which was one of the main reasons for ending the study early," Waxman told Healio. "We felt it was unethical to continue this study after such an impressive improvement. So with the early termination, it had a loss to statistical power for the secondary endpoints and also limited long-term safety data."
The most common adverse events among those assigned to sotatercept were nosebleed and telangiectasia — spider veins — according to the presentation.
"Despite the limitations of shutting the study down early, it provides compelling evidence, as far as efficacy of sotatercept for reducing major mortality and morbidity in this high-risk patient population," Waxman said. "It confirms what we saw with the phase 3 trial and supports its implementation as standard of care in these spaces."
Reference: Sources/DisclosuresCollapse Source: Humber M, et al. Clinical and investigative horizons I. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).Disclosures: The ZENITH trial was funded by Merck. Waxman reports no relevant financial disclosures.
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