1Universitätsklinikum Schleswig-Holstein Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin Lübeck, Deutschland; 2Universitätsmedizin Greifswald Klinik und Poliklinik für Innere Medizin B Greifswald, Deutschland; 3Universitätsklinikum Schleswig-Holstein Lübeck, Deutschland
Background: In the latest pulmonary hypertension guidelines (2022) both endothelin receptor antagonists (ERAs), Macitentan and Ambrisentan, are recommended in combination with tadalalfil (a phosphodiesterase type 5 inhibitor (PDE5i)) as a class I indication for patients with pulmonary arterial hypertension (PAH, PH class I). However, there is a lack of head-to-head trials of ERAs in PAH. Thus, we compared the effectiveness of macitentan versus ambrisentan in combination therapy with a PDE5i.
Methods: Systematical search in MEDLINE and EMBASE yielded 4 randomized controlled trials, 4 observational prospective studies and one retrospective observational study evaluating the safety and efficacy of either macitentan or ambrisentan in combination therapy with a PDE5i for treatment of PAH fulfilling the inclusion criteria for meta-analysis. The primary efficacy endpoint was the improvement in six-minute walking distance (6MWD). Further efficacy endpoints were the relative reduction in NTproBNP and the relative reduction in pulmonary vascular resistance (PVR). Safety endpoints were mortality as well as the occurrence of severe adverse events (SAEs) and SAEs leading to treatment discontinuation. A network meta-analysis using the RCTs was performed to evaluate the primary efficacy endpoint. Additional endpoints were also calculated using single-arm meta-analyses to include observational studies that did not have placebo groups.
Main Results: 923 patients were included, comprising 371 who received ambrisentan in combination with a PDE5i, 256 who received macitentan in combination with a PDE5i, and 340 who received a PDE5i and placebo. Considering primary efficacy endpoint both network metanalysis and single-arm metanalysis showed an improvement of 6MWD by both ERAs in combination with PDE5i compared to PDE5i and placebo (Figure A-B). A trend towards a higher improvement in 6MWD by macitentan + PDE5i (mean improvement 43.53 m [95% CI, 41.73-45.32m]) compared to ambrisentan + PDE5i (mean improvement 33.43 m [95% CI, 19.02-47.84m]) was not statically significant (p=0.11). However, the percentage decrease in NTproBNP was significantly higher in macitentan + PDE5i group (mean -73.21 % [95% CI, -78.38- -68.03%]) compared with ambrisentan + PDE5i (mean -34.37 % [95% CI, -45.29- -23.46%], p<0.01, Figure C). No difference in percentage decrease of PVR was observed (44.49% [95% CI, 37.74% - 51.25% for macitentan + PDE5i vs 47.10% [95% CI, 27.02% - 67.19%, p=0.81). Also, regarding mortality, there was no difference between macitentan + PDE5i and ambrisentan + PDE5i group (Figure D). No difference in SAEs occurrence was displayed between macitentan + PDE5i (24% [95% CI, 15-34%]) and ambrisentan + PDE5i (20% [95% CI, 6-48%], p=0.76). A trend towards lower discontinuation rates in macitentan + PDE5i group (9% [95% CI, 5-21%] vs. 19% [95% CI, 9-37%]) was not statistically significant (p=0.11).
Conclusion: Both macitentan and ambrisentan are effective in combination with a PDE5i in patients with PAH. The higher reduction of NTproBNP and a trend towards an increased improvement of 6MWD by macitentan could however represent a tentative indication for a possible higher efficacy of macitentan, which should be further investigated in future randomized controlled head-to-head studies.