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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. ispartof: ADVANCES IN THERAPY vol:39 issue:9 pages:4374-4390 ispartof: location:United States status: published

Background: Little is known regarding the impact of socioeconomic factors on the use of evidence-based therapies and outcomes in patients with heart failure with reduced ejection fraction across Asia. Methods: We investigated the association of both patient-level (household income, education levels) and country-level (regional income level by World Bank classification, income disparity by Gini index) socioeconomic indicators on use of guideline-directed therapy and clinical outcomes (composite of 1-year mortality or HF hospitalization, quality of life) in the prospective multinational ASIAN-HF study (Asian Sudden Cardiac Death in Heart Failure). Results: Among 4540 patients (mean age: 60±13 years, 23% women) with heart failure with reduced ejection fraction, 39% lived in low-income regions; 34% in regions with high-income disparity (Gini ≥42.8%); 64.4% had low monthly household income (P interaction Conclusions: These findings highlight the importance of socioeconomic determinants among patients with heart failure in Asia and suggest that attention should be paid to address disparities in access to care among the poor and less educated, including those from wealthy regions. Registration: URL: https://clinicaltrials.gov ; Unique Identifier: NCT01633398.

Background Data comparing outcomes in heart failure ( HF ) across Asia are limited. We examined regional variation in mortality among patients with HF enrolled in the ASIAN ‐HF (Asian Sudden Cardiac Death in Heart Failure) registry with separate analyses for those with reduced ejection fraction ( EF ; Methods and Results The ASIAN ‐ HF registry is a prospective longitudinal study. Participants with symptomatic HF were recruited from 46 secondary care centers in 3 Asian regions: South Asia (India), Southeast Asia (Thailand, Malaysia, Philippines, Indonesia, Singapore), and Northeast Asia (South Korea, Japan, Taiwan, Hong Kong, China). Overall, 6480 patients aged >18 years with symptomatic HF were recruited (mean age: 61.6±13.3 years; 27% women; 81% with HF and reduced r EF ). The primary outcome was 1‐year all‐cause mortality. Striking regional variations in baseline characteristics and outcomes were observed. Regardless of HF type, Southeast Asians had the highest burden of comorbidities, particularly diabetes mellitus and chronic kidney disease, despite being younger than Northeast Asian participants. One‐year, crude, all‐cause mortality for the whole population was 9.6%, higher in patients with HF and reduced EF (10.6%) than in those with HF and preserved EF (5.4%). One‐year, all‐cause mortality was significantly higher in Southeast Asian patients (13.0%), compared with South Asian (7.5%) and Northeast Asian patients (7.4%; P Conclusions This first multinational prospective study shows that the outcomes in Asian patients with both HF and reduced or preserved EF are poor overall and worst in Southeast Asian patients. Region‐specific risk factors and gaps in guideline‐directed therapy should be addressed to potentially improve outcomes. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 01633398.

OBJECTIVES: This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH). BACKGROUND: PAH is a progressive, life-threatening disease often requiring hospitalization. METHODS: In the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated. RESULTS: Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms. CONCLUSIONS: Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension

Idiopathic Pulmonary Arterial Hypertension (IPAH) is a serious disorder of unknown etiology with limited therapeutic options. Sildenafil has been shown to decrease symptoms, improve hemodynamics and quality of life. Its impact on survival is uncertain. We studied the efficacy of sildenafil in improving survival in patients with IPAH.Data on survival of patients with IPAH was collected from prospectively maintained registry at our hospital from January 1999 to December 2005. Thirty nine patients who were treated with conventional therapy including digoxin, diuretics, anticoagulants and calcium channel blockers prior to January 2001 served as historical controls (control group). One hundred and thirty nine patients received sildenafil additionally from January 2001 (sildenafil group). All patients in sildenafil group showed improvement in symptoms. Survival of patients in sildenafil group was significantly better compared to historical controls receiving only conventional therapy. It was 89%, 43% and 19% in the control group Vs 93%, 75% and 54% in the sildenafil group at the end of 1, 3 and 5 years respectively (P Value=0.0002). Sildenafil was well tolerated and none of the patients had to discontinue the treatment.Sildenafil when added to conventional therapy improves symptoms as well as survival significantly compared to conventional therapy alone. Further randomized controlled trials are needed to evaluate its impact on survival when used either alone or in combination with other drugs.

Purpose of review Pulmonary arterial hypertension (PAH) has been a disease with limited treatment options and poor prognosis. This article reviews the recent advances that took place in the medical management of PAH. Recent findings Sildenafil is a type 5 cGMP-specific phosphodiesterase inhibitor originally developed to treat erectile dysfunction. Multiple uncontrolled and randomized controlled trials have proven that it is useful in the treatment of PAH and it was approved by the US Food and Drug Administration. The switch from continuous intravenous infusion of epoprostenol to subcutaneous infusion of treprostinil has been proven feasible and safe. Bosentan has been shown effective as a monotherapy and it also improves survival in patients with functional classes III and IV. In smaller clinical trials bosentan has improved symptoms in different forms of PAH. Combinations of drugs of different classes such as prostanoids, endothelin receptor blockers and sildenafil are tested, and such a strategy improves both symptoms and survival. Animal models and anecdotal clinical experience suggest the possibility of using imatinib mesylate in PAH. Summary With the approval of sildenafil, treatment options for this difficult disease have improved significantly. Combinations of drugs of different groups are promising and need further exploration.

Non-surgical transpericardial approach for catheter-based epicardial radiofrequency ablation of post-infarction left ventricular tachycardia has been described as an alternative and additive procedure to standard endocardial technique for delivery of radiofrequency energy in difficult situations. We report our initial experience with this approach in three patients of post-infarction recurrent ventricular tachycardia, refactory to multiple antiarrhythmic drugs. Ablation was successful in terminating the tachycardia in two and in modifying the circuit to be amenable for control with single antiarrhythmic drug in one patient. There were no serious acute or long-term complications related to the procedure. Epicardial approach is an effective and safe adjunct to standard endocardial ablative technique for patients of post-infarction ventricular tachycardia.

In a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire.Primary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH.After initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100 mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment.Twenty-two patients completed the study. Exercise time increased by 44% from 475 +/- 168 s at the end of placebo phase to 686 +/- 224 s at the end of sildenafil phase (p0.0001). With sildenafil, cardiac index improved from 2.80 +/- 0.9 l/m2 to 3.45 +/- 1.1 l/m(2) (p0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/- 17.82 mm Hg to 98.50 +/- 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil.Sildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.

The prevalence of risk factors for atherosclerosis is increasing in India due to changing socioeconomic factors and lifestyles. Data for the state of Andhra Pradesh are scanty in this regard.The prevalence of conventional risk factors for atherosclerosis was prospectively assessed in a unique sample of 3307 workers of a political party drawn from all over the state of Andhra Pradesh. Demographic, anthropometric, clinical and laboratory data were collected prospectively over a period of 6 months. The mean age of the subjects was 43.12+/-9.5 years, 2955 (88%) were males and 385 (12%) females. The prevalence of risk factors was as follows: diabetes in 810 (24%); hypertension in 924 (28%); lipid abnormality in 1908 (58%); smoking in 805 (24%) and positive family history in 555 (17%). Obesity was prevalent in 1178 (36%) of the population. All coronary risk factors, excepting family history, were significantly more prevalent in males [diabetes: 777 (26%) v. 34 (9%), p0.001; hypertension: 833 (28%) v. 72 (19%), p0.001; lipid abnormality: 1729 (59%) v. 172 (45%), p0.001; smoking: 801 (27%) v. 7 (2%), p0.001; and family history: 497 (17%) v. 60 (16%), p=0.54]. Region-wise analysis showed a high prevalence of diabetes in the Andhra and Rayalaseema regions, hypertension in the Andhra region, and smoking in the Rayalaseema region. Lipid disorders were equally prevalent in all the regions.The present report shows a disturbing burden of coronary risk factors in the study population. There is an urgent need to undertake population-based measures to reverse the trend.