Ravichandran, Ashwin Kumar

Abstract Rationale: Since the initial descriptions of pulmonary arterial hypertension (PAH), there has been a significant increase in PAH diagnoses among the geriatric population. Studies suggest that older PAH patients exhibit unique hemodynamic profiles and treatment responses. We hypothesized that patients ≥80 years old would have a unique clinical profile and worse outcomes. Methods: The Pulmonary Hypertension Association Registry (PHAR) is a prospective cohort of PAH and chronic thromboembolic pulmonary hypertension (CTEPH) patients new to care at a Pulmonary Hypertension Care Center in the US. Individuals <18 years of age and those with CTEPH were excluded. Clinical data, quality of life measures, and functional capacity were recorded at time of enrollment and at follow up visits. Octogenarians were defined as those ≥80 years old and non-octogenarians as <80 years old. Associations between age subgroups with the change in six-minute walk distance (6MWD), and worsened WHO functional class (WHO FC) at the next visit, and time to all-cause mortality were assessed using linear, binomial, and Cox regression, respectively. Results: The study sample included 87 PAH octogenarian patients and 2,583 non-octogenarian patients at enrollment. The Table shows that octogenarian PAH patients were of similar sex and race distribution as others, but had lower body mass index. Octogenarians were more likely to have idiopathic or CTD-related PAH, and differed from younger patients in terms of several sociodemographic variables. PAH treatment, WHO FC, quality of life, and hemodynamic also differed between the groups. Octogenarians had a lower change in 6MWD (-26m, 95%CI -52 – -2, p = 0.066) and worse WHO FC (2.0, 95%CI 1.1 – 3.8, p = 0.038) over time compared to other adults after adjustment for sex, BMI, PAH etiology, annual income, marital status, right atrial pressure, mean pulmonary artery pressure, and PAH treatment. Octogenarians had an increased risk of death compared to younger adults (hazard ratio 1.7, 95%CI 1.1 – 2.6, p = 0.022) after adjustment for covariates. Conclusions: While the eldest PAH patients may have some comparable features to younger patients, they are different in a variety of socioeconomic variables, disease type, hemodynamics, and number of PAH therapies. The eldest PAH patients demonstrate worse exercise and functional capacity with time and a 70% increased risk of death compared to younger patients. Further studies are needed to better characterize PAH in the elderly, as this may lead to more effective treatments and enhanced quality of life.

AbstractMacitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right‐heart catheterization hemodynamic variables, N‐terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty‐seven patients were randomized to macitentan (n = 28) or placebo (n = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo‐corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58–0.94; p = .0158). No statistically significant differences were observed in secondary endpoints. In a post‐hoc analysis, 66.7% of patients receiving macitentan achieved PVR <3 WU versus 40.0% receiving placebo (p = .0383). Macitentan was generally well tolerated; adverse events were consistent with those in previous PAH studies with macitentan. In conclusion, macitentan showed promising tolerability and significantly reduced PVR in PH patients with persistently elevated PVR after LVAD implantation. ClinicalTrials. gov identifier: NCT02554903.

AbstractMacitentan is an oral endothelin receptor antagonist for the management of pulmonary arterial hypertension (PAH). The OPsumit® USers Registry (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) medical chart review provide real‐world data for patients newly initiating macitentan. This study aims to describe the characteristics, safety profile, and clinical outcomes of PAH patients newly treated with macitentan in the combined OPUS/OrPHeUS data set. OPUS was a prospective, multicenter, long‐term, observational drug registry from April 2014 to June 2020. OrPHeUS was a retrospective, US, multicenter chart review: observation period October 2013 to March 2017. All analyses were descriptive. At registry closure in June 2020, the combined population consisted of 5654 patients, of whom 81.9% were diagnosed with PAH. For these 4626 patients, median duration of macitentan exposure observed was 14.5 (Q1 = 5.2, Q3 = 29.0) months; idiopathic PAH (54.8%) was the most common form of PAH; macitentan was initiated as monotherapy (37.9%), or as part of double (48.0%) or triple therapy (14.1%); discontinuation due to nonhepatic/hepatic adverse events occurred in 17.1%/0.3% of patients; 9.9% of patients experienced ≥1 hepatic adverse events; Kaplan–Meier estimates showed that at 1 year 59.9% (95% confidence interval: 58.3, 61.5) of patients were free from hospitalization and survival was 90.4% (89.3, 91.3). This analysis of real‐world data from the combined OPUS and OrPHeUS populations demonstrated that macitentan is well tolerated in a large, diverse population of PAH patients, with overall and hepatic safety profiles consistent with previous macitentan clinical trials.

Highly specialized left ventricular assist device care is not readily available in many areas, potentially limiting access to therapy. This retrospective analysis examines the relationship of outcomes by patient distance from implanting left ventricular assist device center within the Mechanical Circulatory Support Research Network. Zip codes were used to calculate patient distance, with the primary outcome of interest being 3-year survival by distance from the surgical center. Secondary outcomes included 90-day survival and incident event rates for the following: gastrointestinal bleeding, infection, cerebral event, and pump thrombosis. Across the four centers, there were 1184 patients supported for a median of 486 days. Overall survival was 91 ± 0.8% at 90 days and 61 ± 1.9% at 3 years, with worse 3-year survival in those living >90 vs . ≤90 miles from the ventricular assist device implant center (55 ± 3.0% vs . 64 ± 2.5, p = 0.019). Patients living >90 miles from an implant center were older, more likely to be implanted for destination therapy support, had a prior sternotomy, and had worse renal function than those living closer ( p <0.05 for all). After adjusting for these factors, albumin and center of implant, the hazard ratio did not reach statistical significance (hazard ratio = 1.2; p = 0.14). Except for gastrointestinal bleeding, the event rates for the secondary outcomes were higher for those living closer to the implanting center. Protocols should be designed for more frequent follow-up and increased shared care opportunities to ensure optimal outcomes are achieved in distant patients.