Macitentan a promising therapy in inoperable CTEPH
The dual endothelin-receptor antagonist macitentan shows promise in improving haemodynamics and exercise capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), according to results of the phase II MERIT-1* trial presented at ERS 2017.
In this multicentre (36 hospitals in 16 countries), double-blind trial, 80 patients (mean age 57.5 years, 64 percent female, 38 percent Asian) with inoperable CTEPH, WHO functional class II-IV with resting pulmonary vascular resistance (PVR) ≥400 dyn.s/cm5, 6-minute walk distance (6MWD) of 150–450 m, and mean pulmonary arterial pressure and pulmonary arterial wedge pressure of ≥25 mmHg and ≤15 mm Hg, respectively, were randomized 1:1 to receive once-daily oral doses of macitentan (10 mg) or placebo for 24 weeks. Sixty-one percent of patients were on pulmonary arterial hypertension (PAH) medications at baseline.
Resting (geometric mean) PVR was significantly improved at week 16 in patients assigned to macitentan compared with those on placebo (73.0 percent vs 87.2 percent of baseline, a reduction of 206 and 86 dyn.s/cm5 from baseline, respectively; geometric means ratio 0.84, 95 percent confidence interval, 0.70–0.99; p=0.041). [Lancet Respir Med 2017;doi:10.1016/S2213-2600(17)30305-3; ERS 2017, abstract OA1984]
At week 24, 6MWD increased by 35.0 m and 1.0 m from baseline in the macitentan and placebo groups, respectively (p=0.033), though macitentan did not appear to confer any effect on Borg dyspnoea score compared with placebo (least-squares mean difference -0.39; p=0.35). None of the patients on macitentan experienced worsening of WHO functional class compared with three in the placebo group (odds ratio, 0.21; p=0.096).
The findings were consistent regardless of the use of PAH therapies at baseline among the patients, pointing to a potential benefit of combining macitentan with other PAH therapies, the researchers said.
“[T]he consistency of results found in patients with and without background treatment encourages future trials on combination therapy with CTEPH,” said Dr Adam Torbicki from the Center for Postgraduate Medical Education, Otwock, Poland, in a commentary. [Lancet Respir Med 2017;doi:10.1016/S2213-2600(17)30342-9]
Serious adverse event (AE) incidence was lower among patients on macitentan compared with placebo (8 percent vs 18 percent). The most common AE in both groups was peripheral oedema (23 percent vs 10 percent of patients on macitentan and placebo, respectively), while other AEs in the macitentan group were decreased haemoglobin (15 percent), pain in extremity (8 percent), and upper respiratory tract infection (8 percent). One patient in each group experienced haemoptysis and three patients on placebo experienced hypotension.
“Surgical removal of the thromboembolic obstructions [in CTEPH] with pulmonary endarterectomy is the recommended treatment of choice for most patients and is potentially curative in some patients,” said the researchers. However, many patients are not eligible or choose not to undergo the surgery, they said.
“The similarities between histological changes in the microvasculature of patients with CTEPH and in those with PAH provide a rationale for the use of therapies for PAH in patients with inoperable CTEPH,” the researchers said.
“[A]though MERIT provided two important messages – namely that a drug that acts on the endothelin pathophysiological pathway can be successfully applied in nonoperable CTEPH, and that combination therapy is likely to be useful also in CTEPH, and therefore requires further research – we are still far from finding the optimal way through the vascular labyrinth of CTEPH,” concluded Torbicki.