ABC | Volume 114, Nº1, January 2019

Review Article Fernandes et al. Heart Failure with Preserved Ejection Fraction Arq Bras Cardiol. 2020; 114(1):120-129 6. Digoxin Digoxin is also part of the therapeutic algorithm in HFrEF, although it is not the first-line therapy. 3 A potential benefit in patients with diastolic dysfunction and HFpEF could arise from its neurohormonal action. The Effects of Digoxin on Morbidity and Mortality in Diastolic Heart Failure, the “DIG PEP” trial, 23 showed no effect on the natural history endpoints, such as mortality and hospitalizations. Although it was associated with a trend toward reduction in HF hospitalizations, it did not affect the overall results, partly because of a non-significant increase in the risk of hospitalization for unstable angina. 7. Nitrates and Nitrites Another pathophysiological mechanism involved in HFpEF is the deregulation of the NO-sGC-cGMP-PKG pathway. A possible therapeutic approach would consist in the use of drugs that act at this level, such as nitrates, phosphodiesterase-5 inhibitors, riociguat and vericiguat. The Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction, the “NEAT- HFpEF” trial, 24 evaluated an isosorbide mononitrate regimen, using increasing doses, for 6 weeks. In addition to the lack of improvement in quality of life or NT-proBNP levels, there was a reduction in daily activity level and increasedHF symptoms. Other mechanisms eventually limit the hemodynamic benefits of organic nitrates and predispose patients to excessive hypotension and other adverse effects. The hypothesis that the results would be better with inorganic nitrates (NO3) was tested in a pilot study that assessed exercise capacity and the impact on vasculature and skeletal muscle, using NO3-rich beetroot juice. Although the primary endpoint was not reached, the results seemed to be positive. 25 It will be important to confirm the results in larger, long-term trials. 8. Sildenafil Inhibition of phosphodiesterase-5 seems to reverse cardiac remodeling and improve vascular, neuroendocrine and renal function, with clinical improvement in patients with idiopathic pulmonary arterial hypertension (PAH) and HFrEF. The Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction, the “RELAX” trial, 26 evaluated these parameters in patients with HFpEF, comparing sildenafil with placebo for 24 weeks. Not only was there no improvement in exercise capacity, clinical status, cardiac remodeling or diastolic function, but also the renal function and NTproBNP, endothelin-1 and uric acid levels were adversely affected. In the subgroup of patients with HFpEF and severe pulmonary vascular disease, the results might perhaps be different and more encouraging. 5 9. sCG Stimulators (Riociguat and Vericiguat) Pulmonary hypertension (PH) is frequently seen in patients with HF and has been shown to be a major determinant of worse outcomes, thereby representing a potential novel therapeutic target in HFpEP. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator. Its vasodilatory, antifibrotic, antiproliferative and antiinflammatory effect has shown to be efficient in pulmonary arterial hypertension and chronic thromboembolic PH with LV systolic dysfunction. The Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure, the “DILATE-1” trial, 27 evaluated its effect in patients with PH and diastolic dysfunction. It was an initial study, which assessed a small number of patients and used single doses of riociguat. Despite being well tolerated and improving exploratory hemodynamic and echocardiographic parameters, further studies with larger sample sizes and longer duration are needed to assess its long-term clinical effect. In the Vericiguat in patients withworsening chronic heart failure and preserved ejection fraction, the “SOCRATES‑Preserved” trial, 28 12 weeks of treatment with vericiguat also did not change the primary endpoints, NT-proBNP levels and LA volume. Some potential to improve quality of life has been suggested, particularly at higher doses, which may be tested in further studies, possibly with higher doses, longer follow-up and additional endpoints. Iron Supplementation FAIR 40 (NCT03074591) 2019 Ferric Carboxymaltose IV vs placebo 200* LVEF ≥ 45%, NYHA II‑III, diastolic dysfunction, iron deficiency, Hb 9-14g/dL 52 weeks Evaluation of exercise capacity, quality of life, NYHA functional class, mortality and HF hospitalizations SGLT2 Inhibitors EMPERIAL Preserved 46 (NCT03448406) 2019 Empagliflozin vs. placebo 300* LVEF > 40%, NYHA II‑IV, NT‑proBNP > 300pg/mL, 6 min‑walking distance ≤ 350 metros 12 weeks Assessment of exercise capacity measured by the 6 min‑walking distance Preserved-HF 47 (NCT03030235) 2019 Dapagliflozin vs. placebo 320* LVEF ≥ 45%, NYHA II‑III, NT‑proBNP ≥ 225pg/mL or BNP ≥ 75 pg/mL 12 weeks NT-proBNP evaluation EMPEROR-Preserved 48 (NCT03057951) 2021 Empagliflozin vs. placebo 6000* LVEF > 40%, NYHA II‑IV, NT‑proBNP > 300pg/mL 38 months Evaluation of CV death and HF hospitalization AMI: acute myocardial infarction; CAD: coronary artery disease; CO: cardiac output; CV: cardiovascular; HF: heart failure; HR: hazard ratio; LA: left atrium; LVEF: left ventricle ejection fraction; mPAP: mean pulmonary artery pressure; NYHA: New York Heart Association; PAP: pulmonary artery pressure; PCWP: Pulmonary Capillary Wedge Pressure; 95% CI: 95% confidence interval; * Estimated target number. 125