ABC | Volume 113, Nº3, September 2019

Review Article Calderado et al. Pulmonary hypertension Arq Bras Cardiol. 2019; 113(3):419-428 Other small studies have also demonstrated hemodynamic benefits in patients with LV systolic dysfunction who received silnadefil, even after the first dose. 50 Nonetheless, there are no data of randomized multicenter studies available to establish the impact of sildenafil on patients with LV systolic dysfunction. In the Sildenafil Versus Placebo in Chronic Heart Failure (SilHF) study, still in progress, patients with HF and Group 2 PH (echocardiographic criterion) and LVEF < 40% are randomized to receive sildenafil 40 mg 3x/day or placebo. 51 This will be an important study, though the lack of hemodynamic monitoring through right catheterization may be a problem for the interpretation of the results. The impact of sildenafil when compared with placebo throughout 12 weeks was tested in patients with heart failure with preserved ejection fraction. In this multicenter study, 216 patients were randomized and there was no difference in the primary outcome (peak consumption of O 2 ) or in the clinical Picture. 52 We do not have the data on right heart catheterization and therefore we do not know the exact number of patients in group 2 PH. Finally, the subgroup of patients with valvular heart disease deserves special attention. Most patients with significant aortic valvular disease and almost all patients with symptomatic mitral insufficiency have PH. Even after correction of the valvular disease, some patients remain with PH and others who did not have PH before surgical treatment can develop the disease evolutionarily . Recently, the impact of sildenafil in patients with residual PH, after heart valve surgery, was assessed in a multicenter randomized study. 3 A total of 200 patients with a mean pulmonary arterial pressure ≥ 30 mmHg and with no signficant valve injury were randomized to receive sildenafil 40 mg every 8 hours or placebo, for 6 months. The composite outcome of death, admission to hospital for decompensated heart failure or functional worsening occurred more often in the sildenafil group compared with the placebo group (OR 0.39; CI 0.22-0.67; p < 0.001), mainly at the expense of more admissions for decompensed HF. It is important to highlight that, although the etiology of the cardiomyopathy was valvular disease, and only patients with no significant residual valvular injury had been randomized, the hemodynamic data indicate characteristics of group 2 PH, with combined pre- and post‑capillary PH; in a little more than half of the patients (57%), pulmonary resistance was greater than 3 Wood units. Thus, althought early data from small case reports performed in single-centers encourage the use of sildenafil in grupo 2 PH, there is no evidence supporting its routine recommendation. Riociguat Riociguat acts on the same pathway as phosphodiesterase type 5 inhibitors, directlty stimulating guanylate cyclase, in addition to having an established role in the management of patients with PH due to chronic pulmonary thromboembolism (group 4) and in pulmonary arterial hypertension. Its role in group 2 PH has been recently tested in the LEPHT study. 53 The patients had symptomatic HF, with LFEF ≤ 40% and PH measured by right heart catheterization. A total of 201 patients were radomized to receive riociguat (3 different doses) or placebo. There was no difference in the mean pulmonary artery pressure between the groups (primary endpoint), but the group who received riociguat 2 mg three times daily showed increased cardiac index and reduced systemic and pulmonary vascular resistance. No difference was observed in relation to the functional class or in the composite outcome of death or admission for decompensated heart failure. Thus, so far, there is no indication for the routine use of any of the specific medications for group 1 PH in individuals with group 2 PH. In selected cases, when, after optimization of cardiomyopathy, with special attention to volemia, PH remains with pre-capillary component apparent on cardiac catheterization, the decision upon the use of specific medication should be individualized, in a reference center, preferably , in the context of clinical study to deliver more evidence. Pulmonary hypertension due to Pulmonary Disease and/or Hypoxia (Group 3) It is considered the second most common cause of PH and the pulmonary diseases most commonly associated with PH are: chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease and combined pulmonary fibrosis and emphysema. 54 Although there is high prevalence of increased pulmonary artery pressure in patients with chronic pulmonary diseases, only a small minority of these patients present with severe PH, characterized by mPAP > 35 mmHg. In some patients with pulmonary disease and HP, especially in patients with mild pulmonary disease, but with severe PH, it may be difficult to determine whether PH is caused by pulmonary disease or related to concomitant pulmonary vascular disease. 55 Until now, there is no evidence that the specific medications used in PAH are beneficial for the treatment of Group 3 PH, and patients with suspected associated vascular disease should be referred to reference centers. Chronic thromboembolic pulmonary hypertension (CTEPH) and other diseases of pulmonary artery obstruction (Group 4) CTEPH is the main disease of group 4, and is characterized by chronic obstruction of pulmonary artery and vascular remodelling due to pulmonary thromboembolism. It is the only potentially curable form of PH, once effective pulmonary thromboendarterectomy is perfomed. For this reason, it is always necessary to investigate chronic pulmonary thromboembolism in patients with PH, and refer the diagnosed cases to a reference center. 56 In cases of contraindicated surgery or persistent PH after surgery, there is evidence in favor of the use of riociguat. 57 Macitentan also provides clinical and hemodynamic benefits for patients with CTEPH with no surgical indication. 58 Full anticoagulation is always recommended, even after surgery; diuretic and oxigen are indicated in case of heart failure and hypoxemia, respectively. 11 should be considered for patients who are not candidate for surgical intervention. 59 Pulmonary hypertension with unclear multifactorial mechanisms (Group 5) Group 5 includes several diseases which may behave similarly to other groups, but whose mechanisms associated with the development of PH are not clear yet. Thus, treatment is heterogeneous and essentially focused on the underlying disease. 60 425