SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients ...with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors PDE-5i). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio HR 0.62; 95% confidence level CL 0.43–0.89;
p
= 0.009). Furthermore, patients receiving macitentan and background therapy had a 37% reduction in the risk of being hospitalized for PAH (HR 0.63; 95% CL 0.41–0.96) compared with patients receiving background therapy only (placebo arm). Macitentan treatment in combination with background therapy was also associated with improvements in exercise capacity, functional class, cardiopulmonary hemodynamics, and health-related quality of life compared with background therapy alone. The safety profile of macitentan as part of a combination therapy regimen was consistent with that of macitentan in the overall SERAPHIN population. The SERAPHIN study has provided evidence that combination therapy with macitentan and a PDE-5i is effective and well tolerated in the management of PAH. Based on these data, and those from subsequent long-term trials, combination therapy is increasingly recognized as an important treatment option for improving long-term outcomes in PAH.
Clinical trial registration number: NCT00660179
Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a ...new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.
We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.
A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval CI, 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.
Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).
Patients with pulmonary arterial hypertension who achieve a six-minute walk distance of 380-440 m may have improved prognosis. Using the randomized controlled trial of macitentan in pulmonary ...arterial hypertension (SERAPHIN), the association between six-minute walk distance and long-term outcomes was explored.
Patients with six-minute walk distance data at Month 6 were dichotomized as above or below the median six-minute walk distance (400 m) and assessed for future risk of pulmonary arterial hypertension-related death or hospitalization and all-cause death. Additionally, six-minute walk distance values at baseline, Month 6 and the change from baseline to Month 6 were categorized by quartiles. All associations were analyzed by the Kaplan-Meier method using a log-rank test and Cox regression models.
Patients with a six-minute walk distance >400 m vs. ≤400 m at Month 6 have a reduced risk of pulmonary arterial hypertension-related death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). The risk was also lower for patients with higher quartiles of six-minute walk distance at baseline or Month 6 (baseline: hazard ratio Q4 (>430 m) vs. Q1 (≤300 m) 0.23; 95% confidence interval 0.15-0.36; Month 6: hazard ratio Q4 (>455 m) vs. Q1 (≤348 m) 0.33; 95% confidence interval 0.19-0.55). In contrast, six-minute walk distance changes at Month 6 were not associated with the risk of pulmonary arterial hypertension-related death or hospitalization (p = 0.477). These findings were consistent when adjusted for known confounders. Similar results were observed for the risk of all-cause death up to end of study.
Patients with pulmonary arterial hypertension walking >400 m had better long-term prognosis. Although changes in six-minute walk distance were not associated with long-term outcomes, assessing absolute six-minute walk distance values remains important in the clinical management of patients with pulmonary arterial hypertension.
This study investigated the relationship between Metabolic Syndrome (MetS), sleep disorders, the consumption of some nutrients, and social development factors, focusing on gender differences in an ...unbalanced dataset from a Mexico City cohort. We used data balancing techniques like SMOTE and ADASYN after employing machine learning models like random forest and RPART to predict MetS. Random forest excelled, achieving significant, balanced accuracy, indicating its robustness in predicting MetS and achieving a balanced accuracy of approximately 87%. Key predictors for men included body mass index and family history of gout, while waist circumference and glucose levels were most significant for women. In relation to diet, sleep quality, and social development, metabolic syndrome in men was associated with high lactose and carbohydrate intake, educational lag, living with a partner without marrying, and lack of durable goods, whereas in women, best predictors in these dimensions include protein, fructose, and cholesterol intake, copper metabolites, snoring, sobbing, drowsiness, sanitary adequacy, and anxiety. These findings underscore the need for personalized approaches in managing MetS and point to a promising direction for future research into the interplay between social factors, sleep disorders, and metabolic health, which mainly depend on nutrient consumption by region.
Background Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in ...patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated. Methods Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed. Results At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio HR, 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score. Conclusions Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown. Trial Registry ClinicalTrials.gov; No.: NCT00660179 ; URL: clinicaltrials.gov.
Pulmonary arterial hypertension (PAH) is a severe clinical condition that significantly affects patients’ quality of life and survival. Since the emergence of prostanoids 45 years ago, different ...drugs acting on vasoconstriction/vasodilation mechanisms have been developed for the treatment of PAH. Current evidence shows that better results occur when combined therapy is initiated up-front with periodic and systematized evaluations for escalation and switching. Among these strategies, riociguat has a relevant role, supported by the results of several clinical studies. This document issues recommendations by a panel of experts who analysed and discussed the indications and limitations for riociguat in PAH in different institutions of the Mexican health system.
Introduction
In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of ...morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients.
Methods
Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set.
Results
Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years).
Conclusions
This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy.
Trial Registration
ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.
Data on demographic characteristics and therapeutic approaches in Latin American pulmonary arterial hypertension (PAH) patients are scarce. Pulmonary Hypertension Mexican registry (REMEHIP) is a ...multicenter Mexican registry of adult and pediatric patients, including prevalent and incident cases. Objective: assess clinical characteristics, treatment trends, and in‐hospital outcomes. Inclusion: age >2 years, diagnosis of pulmonary hypertension (PH) (groups 1 and 4), right heart catheterization with mPAP ≥25 mmHg, PWP ≤ 15 mmHg, and PVR > 3 Wood unit (WU). We included 875 PH patients, 619 adults, 133 pediatric idiopathic PAH (IPAH), and 123 chronic thromboembolic pulmonary hypertension (CTEPH) patients. We enrolled 48.4% of the incident and 51.6% of the prevalent adult and pediatric patients. PAH adults: age 43 ± 15, females 81.9%, functional class (FC) (I/II) 66.5%, 6‐min walk distance (6MWD) 378 ± 112 m, mPAP 57.3 ± 19.0 mmHg, confidence interval (CI) 3.3 ± 1.5 L/min/m2, PVR 12.0 ± 8.1 WU. PAH pediatrics: age 9 ± 5, females 51.1%, FC (I/II) 85.5%, 6MWD 376 ± 103 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 16.4 ± 13.5 WU. CTEPH: age 44 ± 17, females 56.1%, FC (I/II) 65.5%, 6MWD 369 ± 126 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 10.5 + 6.5 WU. When we analyzed the IPAH group separately, it sustained a high functional class I/II incidence. REMEHIP shows better functional class in young females with severe PAH than in American and European patients. Also, PAH pediatric patients had a better functional class than other registries. However, our registry also shows that our population's access to specific pharmacologic treatments is still far from optimal.
Massive angiographic pulmonary embolism (PE) with right ventricular dysfunction (RVD) is associated with a high early mortality rate. The therapeutic alternatives for this condition include ...thrombolysis, surgical embolectomy, or percutaneous mechanical thrombectomy (PMT). We describe our experience using PMT in patients with massive PE and RVD with unsuccessful thrombolysis, increased bleeding risk, or major contraindications for thrombolytic therapy.
Clinical, hemodynamic, and angiographic parameters prior to and following PMT were evaluated. Our primary objective was to describe the incidence of in-hospital cardiovascular death, and of major and minor complications. Mid-term outcomes included analysis of occurrence of cardiovascular death, recurrent pulmonary embolism, change of New York Heart Association functional class, and hospital readmission.
From July 2004 to May 2007, 69 patients were referred to the cardiac catheterization laboratory with a diagnosis of acute PE, 18 of whom met the criteria for massive PE and are the subject of this study. All patients underwent thrombus fragmentation using a pigtail catheter that was complemented in 13 patients with thrombus aspiration. A percutaneous thrombectomy device (Aspirex; Straub Medical; Wangs, Switzerland) was used in 11 patients. Hemodynamic, angiographic, and blood oxygenation parameters improved after the procedure. A significant increase was observed for systolic systemic BP (74.3 ± 7.5 mm Hg vs 89.4 ± 11.3 mm Hg, p = 0.001) mean ± SD, as was a decrease in mean pulmonary artery pressure (37.1 ± 8.5 mm Hg vs 32.3 ± 10.5 mm Hg, p = 0.0001). The in-hospital major complications rate was 11.1%; one patient died from refractory shock, and one patient had intracerebral hemorrhage with minor neurologic sequelae. No cardiovascular deaths or recurrent pulmonary thromboembolism were documented during clinical follow-up (12.3 ± 9.4 months).
In patients with massive PE, RVD and major contraindications to thrombolytic therapy, increased bleeding risk, failed thrombolysis, or unavailable surgical thrombectomy, PMT appears to be a useful therapeutic alternative.
Treatment for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in Latin America differs between countries, with regard to disease etiology, health insurance coverage, ...and drug availability. A group of experts from Latin America, met to share regional experiences and propose possible lines of collaboration. The available evidence, regional clinical practice data, and the global context of the proceedings of the 6th World Symposium on Pulmonary Hypertension, held in Nice, France, in February 2018, were analyzed. Here, we discuss some priority concepts identified that could guide transnational interaction and research strategies in Latin America: (1) despite being evidence‐based, the 6th World Symposium on Pulmonary Hypertension proceedings may not be applicable in Latin American countries; (2) proactive identification and diagnosis of patients in Latin America is needed; (3) education of physicians and standardization of appropriate treatment for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension is vital; (4) our clinical experience for the treatment strategy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension is based on drug availability in Argentina, Brazil, Colombia and México; (5) there are difficulties inherent to the consultation of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, and access to treatment; (6) the importance of data generation and research of Latin American‐specific issues related to pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension is highlighted.
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