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Safety, efficacy, and clinical utility of macitentan in the treatment of pulmonary arterial hypertension.

ABSTRACT: Pulmonary arterial hypertension is a progressive, debilitating disease caused by a dysregulation of the pulmonary vascular tone that inevitably leads to right heart failure and death without treatment. Until relatively recently, the treatment options for those afflicted by pulmonary arterial hypertension were limited; today, a greater understanding of the pathophysiology behind this disease has led to several evidence-based therapies that can improve pulmonary function and quality of life for these patients. One of the primary mediators of pulmonary vascular tone is endothelin-1, which is a potent and long-lasting vasoconstrictor. Macitentan is a second-generation endothelin receptor antagonist that acts selectively as a pulmonary vasodilator without the significant side effects noted with previous endothelin receptor antagonists. This review focuses on the mechanism of action and pharmacokinetics of macitentan, as well as the adverse effects, efficacy, and clinical uses of macitentan in the clinical trials to date. In addition, the authors briefly review clinical trials currently underway to illustrate possible future directions for the use of macitentan.

SUBMITTER: Monaco TJ

PROVIDER: S-EPMC4876803 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Safety, efficacy, and clinical utility of macitentan in the treatment of pulmonary arterial hypertension.

Monaco Thomas J TJ Davila Carlos D CD

Drug design, development and therapy 20160518

Pulmonary arterial hypertension is a progressive, debilitating disease caused by a dysregulation of the pulmonary vascular tone that inevitably leads to right heart failure and death without treatment. Until relatively recently, the treatment options for those afflicted by pulmonary arterial hypertension were limited; today, a greater understanding of the pathophysiology behind this disease has led to several evidence-based therapies that can improve pulmonary function and quality of life for th ...[more]

PMID: 27274200

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Project description:Even though pulmonary arterial hypertension (PAH) remains an incurable disease, the combination of PAH-specific therapies allowed evolving from symptom-based strategies to others aiming to move patients to low-risk conditions. Endothelin-1 (ET-1) receptor antagonists emerged as specific-PAH drugs that can be used in combination with other specific therapies. This work aimed to perform a prospective clinical assessment of patients with PAH that switched from bosentan to macitentan (POTENT), due to inadequate response. POTENT is a prospective, open-label, single-arm, uncontrolled study including PAH patients from our ongoing SAUDIPH registry. It enrolled 50 PAH patients divided as follows: idiopathic/heritable pulmonary arterial hypertension (I/HPAH); n = 24; PAH associated with congenital heart disease, n = 19; PAH associated with connective tissue diseases, n = 5; and pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH), n = 2. At baseline, most patients were in World Health Organization Functional Class (WHO FC) II/III (52.0%). After switching to macitentan, patients were more likely to be in WHO FC I/II (78%) and 22% of the overall cohort moved to a lower risk condition, with three low risk stratification parameters. Mean 6-min walking distance increased about 34 m after 12 months, with a significant mean change over time (12.63 ± 11.69 at month 3 vs. 40.75 ± 12.57 at month 12, p = 0.002). Most haemodynamic parameters decreased over time, with corresponding negative mean changes (p < 0.001). The safety of macitentan was confirmed by the absence of anaemia and liver injury; clinical worsening was observed only in a small group of patients. In general, macitentan might be a valid alternative to bosentan in PAH stable patients on combination therapy with insufficient clinical response, and presenting intermediate and high-risk parameters. We anticipate that studying this strategy in PAH subgroups would further clarify its potential and limitations.

Project description:BackgroundThe evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.MethodsAmong consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.ResultsTwenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.ConclusionTriple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.

Project description:IntroductionEvaluating overall survival in randomized controlled trials (RCTs) can often be confounded by bias introduced by treatment switching. SERAPHIN was a large RCT that evaluated the effects of long-term treatment with the endothelin receptor antagonist macitentan in patients with pulmonary arterial hypertension. In an intent-to-treat (ITT) analysis, a non-significant decrease in the risk of all-cause mortality up to study closure was reported with macitentan 10 mg versus placebo. As patients could switch treatment when experiencing symptoms of disease progression, this analysis attempts to adjust for the confounding effects on overall survival.MethodsThe inverse probability of censoring weighted (IPCW) and rank-preserving structural failure time (RPSFT) models were used to estimate the treatment effect on overall mortality had there been no treatment switching in SERAPHIN. Time to all-cause death was evaluated up to study closure. Treatment switching was defined as patients in the placebo group switching to open-label macitentan 10 mg, and patients in the macitentan 10 mg group prematurely discontinuing macitentan.ResultsBy study closure, 73.2% (183/250) of patients in the placebo group had switched to macitentan 10 mg. Among these patients, exposure time to macitentan 10 mg represented 28.2% of total study treatment exposure (cumulative exposure 134.6 patient-years). At study closure, 24.8% (60/242) of patients in the macitentan 10 mg group were not receiving open-label macitentan; mean time not receiving macitentan was 44.3 weeks. The adjusted hazard ratios (HR) for overall survival using the IPCW and RPSFT methods were lower (HR 0.42, 95% confidence interval [CI] 0.22, 0.81; p = 0.009, and HR 0.33, 95% CI 0.04, 2.83, respectively) than the ITT unadjusted HR (0.80, 95% CI 0.51, 1.24).ConclusionThese results from the current analyses indicate that in SERAPHIN, the standard ITT analysis was confounded by treatment switching resulting in an underestimation of the benefit of macitentan 10 mg on overall survival. By adjusting for switching, the IPCW and RPSFT models estimated a 58% and 67% reduction in risk of mortality, respectively, with macitentan 10 mg versus placebo.Trial registrationClinicalTrials.gov identifier: NCT00660179.

Project description:BackgroundRiociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH.MethodsRandomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test.ResultsFour studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed.ConclusionsWe confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.

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Safety, efficacy, and clinical utility of macitentan in the treatment of pulmonary arterial hypertension.

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Safety, efficacy, and clinical utility of macitentan in the treatment of pulmonary arterial hypertension.

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