ABC | Volume 113, Nº3, September 2019

Review Article Calderado et al. Pulmonary hypertension Arq Bras Cardiol. 2019; 113(3):419-428 Figure 2 – Pathophysiological pathways in pulmonary hypertension and specific therapy. Green lines: possible combinations; Red lines: Not recommended combination; Blue dotted line: Potential for substitution therapy, within the same pathway. ERA: endothelin receptor antagonist; PDE5i: Phosphodiesterase type 5 inhibitor; sGC: Soluble Guanylate Cyclase. Modified from Dos Santos Fernandes CJC, et al. 37 ERA PDE5i Prostanoids sGC stimulants Riociguat Bosentan Ambrisentam Macitentan Selexipag Treprostinil Iloprost Epoprostenol Sildenafil Tadalafil primary outcome) and decreased systemic resistance after 3 weeks of treatment, with no changes in pulmonary vascular resistance, pulmonary artery pressure or pulmonary capillary pressure (also a primary endpoint). However, the patients who received the medication had more clinical decompensation, notably the highest dose groups. 43 The same medication was studied again in 642 patients with FC II-IV HF and LVEF < 35%. There was no right heart catheterization monitoring. Patients were randomized for placebo or darusentan (5 doses) for 6 months. The primary outcome of the study was LV diastolic volume changes measured using cardiac resonance imaging. The selective inhibitor of endothelin receptor had no impact on cardiac remodelling or in the clinical parameters, again with a tendency towards higher decompensation of heart failure with moderate to higher doses of the medication studied. 44 Another study, with bosentan, assessed the impact of the medication in high dosage (500 mg 2x/day) and for an extended period of time (26 weeks) in 370 patients with advanced HF, in FC III or IV and with LVEF < 35%. The primary outcome was clinical worsening. The study was interrupted precociously due to the high incidence of hepatotoxicity, so that less than half of the case reports had completed the 26 weeks of follow-up. This data is important since, in general, there was no difference between the bosentan and placebo groups, but for those patients who completed the 6 months of follow-up, the use of bosentan was associated with clinical improvement. We do not have the hemodynamic data of the mentioned study. 45 So far we have discussed studies that analysed patients with LV systolic dysfunction, and mostly, though not entirely, PH registries (not always by right heart catheterization). If on one hand there seems to be hemodynamic improvement in the early stage of endothelin receptor inhibitor therapy, on the other hand, there may be clinical decompensation, probably due to hydrosaline retention. In the medium-term, sustained usage can bring clinical benefits, as suggested in the latest study discussed above. 45 Recently, the results of the MELODY-1 study (Macitentan in subjects with combined prE‑ and post‑capiLlary PH due to left ventricular DYsfunction) can be incorporated into the discussion on the role of inhibitors of endothelin receptors in the treatment of patients with PH due to left ventricular dysfunction. 46 Although this is a pilot study, with small casuistry, it is the first study carried out from hemodynamic confirmation of group 2 PH to randomization. The authors limited the study to patients with group 2 PH, along with the hemodynamic criteria of post- and pre-capillary componentes of PH (pulmonary vascular resistance > 3Wood units and diastolic pulmonary gradient > 7 mmHg). A total of 63 patients were randomly assigned to macitentan or placebo. There was more fluid retention or clinical worsening in the macitentan group, especially due to the first criterion: 22.6% X 12.5%. After 12 weeks, no difference was observed between the groups in relation to the hemodynamic parameters, BNP or 6 min walk test. Although the authors selected, among the patients with HF, the subgroup more likely to benefit from specific medication for PAH, they also observed worsened evolution when they used it, 47 which is nowadays one of the strongest evidence against the use of inhibitors of endothelin receptors in group 2 PH. Phosphodiesterase type 5 inhibitors In 2007, Lewis et al. 48 randomized 34 patients with FC II‑IV heart failure and LVEF ≤ 40% to receive sildenafil or placebo for 3 months. The patients who received sildenafil improved HF functional class, aerobic capacity, the distance in the 6-minute walk test and showed significant reduction in pulmonary vascular resistance in relation to the basal values, with no increase in pulmonary capillary pressure or change in cardiac index. 48 Meanwhile, encouraging case reports were published on hemodynamic improvements through treatment with sildenafil in candidates for cardiac transplantation, with reduced pulmonary vascular resistance and cardiac outcome improvement. 49 424