Macitentan In Pulmonary Arterial Hypertension Research Articles

Macitentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease (CTD-PAH): Real-World Evidence from the Combined OPUS/OrPHeUS Dataset.

Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. gov Graphical abstract available for this article.

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses. The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of -15mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. REPAIR NCT02310672.

Treatment with macitentan for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD): real-world experience from the combined OPUS and OrPHeUS data sets

Abstract Introduction Restrictive inclusion criteria can exclude some CHD-PAH patients from clinical trials. The OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers (OrPHeUS) data sets provide real-world data in PAH patients newly started on macitentan, including patients with CHD-PAH regardless of defect type. Purpose To describe the characteristics, safety and clinical outcomes of CHD-PAH patients newly treated with macitentan. Methods OPUS is a prospective, US, multicentre, observational drug registry ongoing since April 2014. OrPHeUS was a retrospective, US, multicentre chart review; observation period Oct 2013–Mar 2017. This analysis reports information on CHD-PAH patients in the combined OPUS/OrPHeUS data set, descriptively compared with idiopathic/heritable PAH (I/HPAH) patients. Results As of Sept 2019, there were 4268 PAH patients with follow-up data, of whom 264 (6%) had CHD-PAH and 2396 (56%) had I/HPAH. For CHD-PAH and I/HPAH patients respectively at macitentan initiation: median age (Q1, Q3) was 48 (36, 62) and 65 (53, 73) years; 199 (75%) and 1748 (73%) were female; 67/114 (59%) and 802/1301 (62%) were WHO functional class III/IV; median (Q1, Q3) 6-minute walk distances were 350 (274, 420) and 289 (195, 375) m for the 82 and 840 patients with measurements; median (Q1, Q3) time from PAH diagnosis to macitentan initiation was 37.3 (4.5, 113.1) and 7.4 (1.4, 38.3) months; and 99 (38%) and 1056 (44%) initiated macitentan as monotherapy. The number of patients with ≥1 hepatic adverse event (HAE) was similar for CHD-PAH and I/HPAH (22 [8%] and 184 [8%]), as were the adverse event (AE) profiles (collected from OPUS only). Exposure, discontinuations, outcomes and most common AEs are shown in the table. Conclusions In general, compared with I/HPAH patients, CHD-PAH patients were younger and a greater proportion had prevalent disease than I/HPAH patients. Safety and outcomes were similar between the groups. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd

Patient Characteristics and Treatment Patterns with Macitentan in Pulmonary Arterial Hypertension: Insights from the OPUS Registry

Purpose To describe the real-world use and safety profile of macitentan in patients with pulmonary arterial hypertension (PAH) enrolled in the OPsumit® USers registry (OPUS; NCT02126943). Methods OPUS is an ongoing long-term, prospective, multicenter, observational drug registry of patients newly treated with macitentan in the USA. Patient characteristics, treatment patterns, safety of macitentan and survival were analyzed for PAH patients. Results As of April 2018, OPUS included 1455 PAH patients with follow-up data. At enrollment, median (range) age was 62 (13-92) years and 75.2% were female. The median (Q1, Q3) time from PAH diagnosis was 6.2 (1.5, 37.0) months. WHO functional class (FC) was assessed in 1062 patients, 39.3% were in FC I/II and 60.7% in FC III/IV; median (Q1, Q3) 6-minute walk distance, assessed in 620 patients, was 305 (206, 383) meters. Use of macitentan in double or triple combination therapy regimens is shown in the Table. Median (Q1, Q3) exposure to macitentan was 11.6 (3.9, 22.2) months and macitentan was discontinued by 28.7% of patients, with adverse events (AEs) as the most common reason. At least 1 AE was experienced by 1076 (74.0%) patients; the most common were dyspnea (18.2%), headache (9.5%) and peripheral edema (8.8%). In total, 485 (33.3%) patients experienced ≥1 hospitalization. The Kaplan-Meier survival estimates (95% CI) were 91% (90, 93) at 12 months and 84% (82, 87) at 24 months. Conclusion OPUS represents the largest cohort of patients newly treated with macitentan, providing insight into macitentan use in the real-world. These analyses show that macitentan is most commonly initiated as monotherapy or in combination with a phosphodiesterase type 5 inhibitor in PAH. The safety profile of macitentan in OPUS is consistent with that observed in clinical trials.

PCV2 - Characterizing Patients Treated With Macitentan For Pulmonary Arterial Hypertension (PAH) In The U.S. Opsumit Users Registry (OPUS)

Health plans look beyond randomized controlled trials (RCTs) in making formulary decisions. There are three approved endothelin receptor antagonists, but no head-to-head trials. Real world evidence (RWE) informs the application of RCT results to healthcare decision making by assessing care and patient outcomes in routine clinical practice. RWE is derived from registries, medical records, pragmatic trials, and claims databases. OPUS registry (NCT02126943) is a US-based, multi-center, longitudinal, observational drug registry of newly treated macitentan patients. The objective of this analysis is to describe clinical characteristics, co-morbidities, and treatment of PAH patients with macitentan. Patients newly treated with macitentan (initiated < 30 days prior to enrollment visit) were included in the registry, regardless of prior or concomitant PAH therapy. Planned observation period was at least one year. Data collected at enrollment or follow-up included: demographics, clinical characteristics, outcomes, adverse events, macitentan treatment and registry discontinuation. As of June 2017, 1136 patients with PAH had follow-up data--74.2% females and 25.8% males. Of this cohort, 44.5% of patients were > 65 years of age; 57.9% patients had idiopathic PAH, and 24.9%, PAH associated with connective tissue disease. Common baseline comorbidities included: hypertension (52.6%), edema (24.5%), signs of right heart failure (15.8%), and diabetes mellitus (22.5%). Median exposure to macitentan was 9.6 months. Macitentan was initiated as monotherapy in 41.7%, and double or triple combination therapy in 58.2% of patients. Most common adverse events were dyspnea (18.0%) and peripheral edema (8.9%). 12.4% of patients experienced ≥1 PAH-related hospitalization. OPUS reports macitentan use and safety in real world clinical settings. Reported comorbidities are consistent with other large registries and claims analyses. Macitentan is initiated most commonly as double or triple combination therapy. PAH related hospitalizations were lower than previously reported in both claims analysis and registries.

Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the SYMPHONY Trial

Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity. Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known-group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated. Data from 278 patients (79%female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach's alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r]= 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies. ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov.

OPUS Registry: Switching to Macitentan From Other Endothelin Receptor Antagonists (ERAs)

To describe the real-world use of macitentan in pulmonary arterial hypertension (PAH) patients who switched from another ERA.

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

BackgroundPatients 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.MethodsPatients 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.ResultsPatients 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.ConclusionsPatients 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.

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

Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document.

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug–drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH.

Early Experience of Macitentan for Pulmonary Arterial Hypertension in Adult Congenital Heart Disease

Endothelin receptor antagonists (ERA) have been recognised as effective therapy for pulmonary arterial hypertension in congenital heart disease (CHD-PH), and Eisenmenger syndrome (ES) since The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (Breathe 5) study. A new dual receptor antagonist - Macitentan - is currently undergoing trials to determine its efficacy in simple ES. To date there is little information on this therapy in CHD and we report our first experience, some with more complex diseases. Data was collected prospectively from September 2014. Patients with CHD-PH were started on or converted to macitentan if they required therapy with phosphodiesterase 5 inhibitor (PDE5i) or if there was insufficient response or a reaction to bosentan, especially those with trisomy 21. Patients were seen approximately three months after starting therapy to assess echocardiography, six minute walk test, clinical response and tolerability. All patients underwent monthly liver tests initially, but this was reduced to three-monthly in Q4 2015. Fifteen patients with CHD-PH (eight male, seven female) were started on macitentan, median (range) age 38 (23-61) years, and eight patients with Down's syndrome. Eight patients had complex CHD with one having unoperated double inlet left ventricle with ventriculo-arterial discordance, one had double outlet right ventricle and six with complete atrio-ventricular septal defect. Six patients were ERA naïve and nine patients changed from bosentan to macitentan in order to achieve improved drug-drug interaction. Median length of time of treatment with macitentan is 289 (0-694) days to date. One discontinued due to rash and feeling unwell; one was unable to comply with medication due to learning difficulties and one died soon after commencing rescue therapy. This last patient was functional class IV with oxygen saturation of 67% at rest, with right heart failure and was unable to perform a walk test before commencing therapy. All patients who remained on therapy had significant increase in six minute walk test from median 286 (120-426) to 360m (150-450)(p <0.05), most notably in those treatment naïve. Functional class median remained at 3 but the range was reduced (1-3). Resting oxygen saturations improved from median 83 range (77-95%) at rest to 91 (77-96%) and at end walk from 78 (48-90%) to 79 (62-96%). Tricuspid regurgitant peak Doppler derived pressure drop did not change (as expected) at 4.6 (4.3-5.5)m/s. There were no episodes of liver dysfunction. The introduction of this new therapy has been simple and mostly well tolerated in our sick group of patients. With the usual reservations concerning the open-label nature of our observations, macitentan has good signals regarding oxygen saturations and encouraging signals relating to efficacy.

From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement?

From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement?

Change of sildenafil plasma concentrations after transition from bosentan to macitentan in pulmonary arterial hypertension

Change of sildenafil plasma concentrations after transition from bosentan to macitentan in pulmonary arterial hypertension

Macitentan in pulmonary arterial hypertension: The SERAPHIN trial.

Major limitations of pulmonary arterial hypertension (PAH) drug trials include the small number of enrolled patients, short term follow up (12-16 weeks), and lack of morbidity and mortality primary endpoints. The recently published SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial represents an important landmark in the history of clinical trials in PAH being the largest and longest clinical study conducted thus far in PAH patients with morbidity and mortality events as primary endpoint. SERAPHIN trial investigated whether long-term treatment with the new endothelin receptor antagonist macitentan would reduce the risk of mortality and morbidity in PAH patients.

Actelion set to launch macitentan for pulmonary arterial hypertension

Actelion set to launch macitentan for pulmonary arterial hypertension