Development of macitentan for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event-driven morbidity and mortality study of treatment-naive and background PAH therapy-treated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class II and III PAH patients. Macitentan reduced the incidence of the composite end point of PAH-related hospitalizations and mortality and improved WHO FC and exercise capacity (6-min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.

Five-Year outcomes of patients enrolled in the REVEAL Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right-sided heart failure, decreasing functional status, and poor survival. The present study characterizes the 5-year survival in the United States of a new and previous diagnosis of PAH in patients stratified by baseline functional class (FC). The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is a 55-center observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH. METHODS: The REVEAL Registry enrolled newly and previously diagnosed patients aged ≥ 3 months with WHO group 1 PAH consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients aged ≥ 18 years. RESULTS: Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively. CONCLUSIONS: Patient survival of advanced PAH remains poor at 5 years despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients.

OBJECTIVE: Voriconazole is a broad-spectrum triazole antifungal agent under investigation for opportunistic infections that often target immunosuppressed patients. This study investigated the effect of voriconazole on the pharmacokinetics of cyclosporine (INN, ciclosporin). METHODS: This was a randomized, double-blind, placebo-controlled, crossover study in kidney transplant recipients with stable renal function who were receiving cyclosporine (150-375 mg/d). During the first study period (7.5 days), subjects in group A received concomitant voriconazole (200 mg every 12 hours); group B received a matched placebo. After a washout period (>or=4 days), subjects were crossed over to the other treatment regimen. RESULTS: In the 7 subjects who completed both regimens, concomitant administration with voriconazole resulted in a 1.7-fold increase in mean cyclosporine area under the plasma concentration-time curve within a dosage interval (AUC(tau); 90% confidence interval, 1.47 to 1.96). Cyclosporine maximum observed plasma concentration (C(max)) and the time to the first occurrence of C(max) (t(max)) were not affected in a clinically significant manner, but plasma trough concentration (C(min)) was higher in the presence of voriconazole than with placebo. The mean increase in cyclosporine C(min) in subjects who ceased to participate in the study was 2.48-fold (range, 1.88 to 3.03). There were 7 subjects who stopped participating in the study during voriconazole administration. Six of these subjects discontinued the study for reasons that were considered to be drug related, and the majority were attributable to increased cyclosporine levels. Although not serious, all causality-related adverse events were more frequent during voriconazole administration than during placebo administration. CONCLUSIONS: Mean cyclosporine AUC(tau) increased 1.7-fold in the presence of voriconazole. Therefore, when voriconazole is initiated in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be halved and that blood cyclosporine concentrations be carefully monitored. When voriconazole is discontinued, blood cyclosporine concentrations should be monitored and the cyclosporine dose increased, if necessary.

Characterization of first-time hospitalizations in patients with newly diagnosed pulmonary arterial hypertension in the REVEAL registry.

BACKGROUND: Hospitalization is an important outcome in pulmonary arterial hypertension (PAH), shown previously to correlate with survival. Using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), we sought to characterize first-time hospitalizations and their effect on subsequent hospitalization and survival in patients with newly diagnosed disease. METHODS: Patients with newly diagnosed PAH (n = 862, World Health Organization group 1) were evaluated for first-time hospitalization. The hospitalizations were categorized as PAH related or PAH unrelated based on the case report form. Categories for PAH-related and PAH-unrelated hospitalization were defined before independent review. Patient demographics and disease characteristics are described as well as freedom from hospitalization and survival. RESULTS: Of 862 patients, 490 (56.8%) had one or more hospitalizations postenrollment: 257 (52.4%) PAH related, 214 (43.7%) PAH unrelated, and 19 (3.9%) of undetermined causes. The most common causes of PAH-related hospitalization were congestive heart failure and placement/removal of a central venous catheter. Patients with PAH-related hospitalizations were more likely to receive parenteral therapy, be in functional class III/IV, and have higher risk scores before hospitalization at enrollment. Following discharge, 25.4% ± 3.2% and 31.0% ± 4.0% of patients with PAH-related and PAH-unrelated first hospitalization, respectively, remained hospitalization-free for 3 years (P = .11). Survival estimates at 3 years postdischarge were 56.8% ± 3.5% and 67.8% ± 3.6% (P = .037) for patients with PAH-related and PAH-unrelated hospitalization, respectively. CONCLUSIONS: In the REVEAL Registry, PAH-related hospitalization was associated with relatively more rehospitalizations and worse survival at 3 years. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.