McConnell, John W.

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.

AbstractDual combination therapy with a phosphodiesterase‐5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate‐risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open‐ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from −5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus‐based recommendations may be helpful to clinicians and beneficial for patients when evidence‐based guidance is unavailable.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health‐related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis‐10 (E10) and SF‐12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty‐one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow‐up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six‐minute walk distance (IRR 1.66, 95%CI 1.04–2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six‐minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

Abstract Rationale Obesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations, and survival is not well understood. Objectives To assess the effect of obesity on HRQoL, hospitalizations, and survival in patients with PAH. Methods We performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed-effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 and emPHasis-10. We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status. Results A total of 767 subjects were included (mean age of 57 years, 74% female, 33% overweight, and 40% with obesity), with median follow-up duration of 527 days. Overweight patients and patients with obesity had higher baseline emPHasis-10 scores (worse HRQoL), which persisted over time (P < 0.001). Patients who are overweight and obese have a trend toward increased incidence of hospitalizations compared with normal-weight patients (IRR, 1.34; 95% confidence interval [95% CI], 0.94–1.92 and IRR, 1.33; 95% CI 0.93–1.89, respectively). Overweight patients and patients with obesity had lower risk of transplant or death compared with normal-weight patients (HR, 0.45; 95% CI, 0.25–0.80 and HR, 0.39; 95% CI, 0.22–0.70, respectively). Conclusions In a large multicenter, prospective cohort of PAH, patients who were overweight or obese had worse disease-specific HRQoL despite better transplant-free survival compared with normal-weight patients. Future interventions should address the specific needs of these patients.

Abstract Rationale Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. Objectives To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. Methods The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Results Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (−5.4; 95% CI, −8.1 to −2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Conclusions Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.