medwireNews: The dual endothelin receptor antagonist macitentan significantly improves pulmonary vascular resistance (PVR) in people with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) compared with placebo, show the results of the republished study.
Among the 40 study participants randomly assigned to receive oral macitentan 10 mg/day, PVR was reduced by 71.5% after 16 weeks of treatment, equating to a mean decrease of 255 dyn∙s/cm⁵, from 934 dyn∙s/cm⁵ at baseline.
This compared with a mean PVR decrease of 82 dyn·s/cm⁵ (87.6%) for the 40 participants assigned to placebo, whose mean baseline PVR was 988 dyn·s/cm⁵.
Hossein-Ardeschir Ghofrani, from the University of Giessen in Germany, and colleagues note in The Lancet Respiratory Medicine that the improvements in PVR with macitentan treatment “were consistent in patients already receiving pulmonary arterial hypertension therapy at baseline, primarily phosphodiesterase type-5 inhibitors.”
MERIT-1 appears in the journal again more than 6 years after its initial publication, and subsequent retraction when Ghofrani and colleagues discovered errors in the hemodynamic data, explain Adam Torbicki and Marcin Kurzyna, from Europejskie Centrum Zdrowia Otwock in Poland, in an accompanying comment.
The subsequent correction and confirmation of the primary efficacy analysis has “provided us with an opportunity to review the enormous progress that has been made in the management of CTEPH since 2017, making this diagnosis less concerning in terms of quality of life and life expectancy than ever before,” they remark.
All 80 MERIT-1 participants – aged a mean of 57.5 years – had right heart catheterization approximately 1 month before randomization and were judged by an adjudication committee to have inoperable CTEPH based on the surgical accessibility of the organized thrombi, as assessed by scans and angiograms.
In addition to improvements in PVR, those taking macitentan had significantly better exercise capacity at week 24 of treatment, with a least squares mean increased 6-minute walking distance of 35 m versus 1 m in the placebo group.
Ghofrani et al also report significant improvements in exploratory endpoints and other cardiopulmonary hemodynamic variables in the macitentan group than the placebo group, including no worsening of World Health Organization functional class at week 24 (0.0 vs 7.5%), an increase in cardiac output at week 16 (mean 0.81 L/min vs a 0.02 L/min decrease), and higher rates of freedom from pulmonary hypertension-related disease progression at week 24 (95.0 vs 87.5%).
Overall, 8% of the macitentan and 18% of the placebo group experienced serious adverse events. For the macitentan group, these were one case each of acute right ventricular failure, peripheral edema, and weight increase, and these are “consistent with those previously reported with macitentan in pulmonary arterial hypertension,” comment the researchers.
Torbicki and Kurzyna acknowledge that “[a]lthough new evidence about drug treatment in CTEPH remains scarce, the management landscape has changed dramatically since the initial MERIT-1 publication. The changes reflect the rapid development of interventional therapy, which has closed the treatment gap between operable and non-operable CTEPH.”
For example, balloon pulmonary angioplasty (BPA), as well as combined approaches such as unilateral BPA followed by contralateral pulmonary endarterectomy. Indeed, “[s]electing a well balanced multimodality treatment strategy is the challenge faced everyday by multidisciplinary teams in CTEPH expert centres,” they say, adding that “[o]ne of the current areas of uncertainty is the benefit of pretreatment with drugs before CTEPH interventions.”
The commentators conclude that the progress made in CTEPH management since the study was originally published “gives hope and courage to researchers, clinicians, and patients facing other forms of pulmonary hypertension without equally effective multimodal therapeutic approaches at present.”
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