Sleep Quality, Nutrient Intake, and Social Development Index Predict Metabolic Syndrome in the Tlalpan 2020 Cohort: A Machine Learning and Synthetic Data Study.

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.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

A machine learning approach to personalized predictors of dyslipidemia: a cohort study.

Introduction: Mexico ranks second in the global prevalence of obesity in the adult population, which increases the probability of developing dyslipidemia. Dyslipidemia is closely related to cardiovascular diseases, which are the leading cause of death in the country. Therefore, developing tools that facilitate the prediction of dyslipidemias is essential for prevention and early treatment. Methods: In this study, we utilized a dataset from a Mexico City cohort consisting of 2,621 participants, men and women aged between 20 and 50 years, with and without some type of dyslipidemia. Our primary objective was to identify potential factors associated with different types of dyslipidemia in both men and women. Machine learning algorithms were employed to achieve this goal. To facilitate feature selection, we applied the Variable Importance Measures (VIM) of Random Forest (RF), XGBoost, and Gradient Boosting Machine (GBM). Additionally, to address class imbalance, we employed Synthetic Minority Over-sampling Technique (SMOTE) for dataset resampling. The dataset encompassed anthropometric measurements, biochemical tests, dietary intake, family health history, and other health parameters, including smoking habits, alcohol consumption, quality of sleep, and physical activity. Results: Our results revealed that the VIM algorithm of RF yielded the most optimal subset of attributes, closely followed by GBM, achieving a balanced accuracy of up to 80%. The selection of the best subset of attributes was based on the comparative performance of classifiers, evaluated through balanced accuracy, sensitivity, and specificity metrics. Discussion: The top five features contributing to an increased risk of various types of dyslipidemia were identified through the machine learning technique. These features include body mass index, elevated uric acid levels, age, sleep disorders, and anxiety. The findings of this study shed light on significant factors that play a role in dyslipidemia development, aiding in the early identification, prevention, and treatment of this condition.

Portopulmonary Hypertension: An Updated Review.

Portal hypertension may have major consequences on the pulmonary vasculature due to the complex pathophysiological interactions between the liver and lungs. Portopulmonary hypertension (PoPH), a subset of group 1 pulmonary hypertension (PH), is a serious pulmonary vascular disease secondary to portal hypertension, and is the fourth most common subtype of pulmonary arterial hypertension. It is most commonly observed in cirrhotic patients; however, patients with noncirrhotic portal hypertension can also develop it. On suspicion of PoPH, the initial evaluation is by a transthoracic echocardiogram in which, if elevated pulmonary pressures are shown, patients should undergo right heart catheterization to confirm the diagnosis. The prognosis is extremely poor in untreated patients; therefore, management includes pulmonary arterial hypertension therapies with the aim of improving pulmonary hemodynamics and moving patients to orthotopic liver transplantation (OLT). In this article, we review in detail the epidemiology, pathophysiology, process for diagnosis, and most current treatments including OLT and prognosis in patients with PoPH. In addition, we present a diagnostic algorithm that includes the current criteria to properly select patients with PoPH who are candidates for OLT.

Riociguat in children with pulmonary arterial hypertension: The PATENT-CHILD study.

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml (n = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

Long-Term Safety, Tolerability and Survival in Patients with Pulmonary Arterial Hypertension Treated with Macitentan: Results from the SERAPHIN Open-Label Extension.

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.

Differences in health policies for drug availability in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension across Latin America.

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.

Riociguat in the Treatment of Pulmonary Arterial Hypertension.

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.

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. METHODS: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. FINDINGS: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. INTERPRETATION: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. FUNDING: Bayer AG, Merck Sharp & Dohme.

Macitentan in the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an uncommon but lethal and progressive disease in which prostacyclin, nitric oxide and endothelin-1 pathways are disturbed and contribute to the pathophysiology of this disease. Endothelin receptor antagonists are a class of drugs that have been approved as PAH therapy. Macitentan is a lipophilic, tissue specific, dual receptor antagonist with a higher potency than bosentan and a reduced risk of hepatic injury. Macitentan has shown a reduction in morbidity and mortality due to PAH at long-term follow-up and improvements in hemodynamics, exercise capacity and functional class at the short term. Its main adverse events are nasopharyngitis, bronchitis and an increased risk of anemia. We review the clinical data of macitentan and its use in PAH.

Angiotensin converting enzyme 2 and angiotensin (1-7) axis in pulmonary arterial hypertension.

BACKGROUND: In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood. METHODS: We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically. RESULTS: Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL-1 versus 0.19, 0.10-0.37 pmol·mL-1; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL-1 versus 12.9, 9.55-19.9 ng·dL-1; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL-1 versus 4.07, 2.82-6.73 pmol·mL-1; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL-1 versus 4.53, 1.47-14.3 ng·mL-1; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL-1 versus 5.97, 3.1-17.8 nmol·mL-1; p<0.001). No significant differences were found among the three different aetiological forms of PAH. CONCLUSIONS: The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.

Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Integrating Data From Randomized Controlled Trials and Observational Studies to Assess Survival in Rare Diseases.

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

Risk stratification and medical therapy of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) remains a severe clinical condition despite the availability over the past 15 years of multiple drugs interfering with the endothelin, nitric oxide and prostacyclin pathways. The recent progress observed in medical therapy of PAH is not, therefore, related to the discovery of new pathways, but to the development of new strategies for combination therapy and on escalation of treatments based on systematic assessment of clinical response. The current treatment strategy is based on the severity of the newly diagnosed PAH patient as assessed by a multiparametric risk stratification approach. Clinical, exercise, right ventricular function and haemodynamic parameters are combined to define a low-, intermediate- or high-risk status according to the expected 1-year mortality. The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy. Further treatment escalation is required in case low-risk status is not achieved in planned follow-up assessments. Lung transplantation may be required in most advanced cases on maximal medical therapy.

Evaluation of Macitentan in Patients With Eisenmenger Syndrome.

BACKGROUND: Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. METHODS: Patients with Eisenmenger syndrome aged ≥12 years and in World Health Organization functional class II-III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline. RESULTS: Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5; P=0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of ≥2 g/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group). CONCLUSIONS: Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01743001.

Advances in medical therapy for pulmonary arterial hypertension.

PURPOSE OF REVIEW: The purpose of this review is to demonstrate advances in the medical treatment of pulmonary arterial hypertension (PAH). Reviewed will be the evidence that favors the use of risk assessment in the treatment of PAH. Optimization of combination therapy depending on the risk or worsening will be reviewed. Finally, recent advances in new treatment strategies will be mentioned. RECENT FINDINGS: The use of therapies in sequence or in combination for the treatment of PAH has been shown to decrease morbidity and mortality. Tailoring these treatment strategies to a risk of worsening has been shown to decrease mortality and time to clinical worsening because of PAH. In addition, there have been several advances in the development of other medications separate from the three known pathogenic pathways in PAH. SUMMARY: In the last 15 years, 12 specific therapies have been approved for PAH. These therapies target three separate pathogenic pathways [the endothelin (ET), nitric oxide (NO) and prostacyclin (PGI2)]. As a result, treatment guidelines have tailored the treatment of PAH with these medications either as single drug therapy or in combination. Recently, other treatment pathways have been explored as new strategies for the treatment of PAH.

Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality.

BACKGROUND: Registry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been formally evaluated in randomized controlled trials. OBJECTIVES: The purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies. METHODS: For each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark. RESULTS: In the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR. CONCLUSIONS: These results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [SERAPHIN]; NCT00660179; Selexipag [ACT-293987] in Pulmonary Arterial Hypertension [GRIPHON]; NCT01106014).

Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial.

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.