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 recommendations, and given the clinical heterogeneity, absence of pathognomonic criteria and the multiplicity of differential diagnoses, there are several challenges and uncertainties to be faced. 5 Treatment Unlike HFrEF, no treatment has yet shown a reduction in morbidity or mortality. Therefore, current recommendations are based on symptom relief with diuretics, screening and treatment of comorbidities. 3 Diuretics are recommended in case of congestion, for symptom relief, regardless of the LVEF. 3 They are widely used, especially loop diuretics, even though there are no specific recommendations concerning which diuretic therapy should be followed. 8 Several clinical trials have studied the effect of drugs proven to be effective in HFrEF for the treatment of patients with HFpEF (Table 1-A). 1. Beta-blockers (BB) The Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure, the “SENIORS” trial, 9 evaluated the effect of nebivolol in patients over 70 years with a history of HFrFE and HFpEF (LVEF > 35%). Despite the reduction in morbidity and mortality, most patients had reduced LVEF (mean 36%) and a history of coronary artery disease and, thus, it was not possible to extrapolate the results to patients with true HFpEF. In a meta-analysis performed later, the BB were the only drugs able to reduce cardiovascular and all-cause mortality. 10 However, patients with different LVEF were included, so the obtained results might possibly have been due to pleiotropic effects in patients with HFmrEF. Recently, our group showed the role of BB in patients with acute coronary syndrome and HFmrEF, demonstrating a reduction of in-hospital mortality, as well as myocardial revascularization. 11 2. Angiotensin-converting enzyme inhibitor (ACEI)/ Angiotensin receptor blocker (ARB) In spite of the proven efficacy in patients with HFrFE, post‑AMI, hypertension and/or high cardiovascular risk, the benefit in patients with HFpEF is limited. 12 The Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction, the “ CHARM-Preserved ” trial, 13 showed that candesartan, despite reducing hospital admissions, had no impact on cardiovascular mortality when compared to placebo. The perindopril in elderly people with chronic heart failure, the “PEP-CHF” trial 14 evaluated the impact of perindopril in patients with diastolic HF, showing no statistical benefit on long-term mortality or hospitalization. However, it appeared to improve symptoms, exercise capacity and HF hospitalization, particularly in younger patients with a history of AMI or hypertension. In addition, irbesartan showed no benefits in terms of mortality, hospitalizations or quality of life assessed in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction, the “I-PRESERVE” trial. 12 Another clinical trial showed that 12 months of enalapril had no effect on exercise capacity, aortic distensibility, ventricular parameters or quality of life. 15 3. Mineralocorticoid/aldosterone receptor antagonists (MRA) Activation of the mineralocorticoid receptors contributes to the pathophysiology of HF through sodium and water retention, potassium loss, endothelial dysfunction, inflammation, fibrosis, and hypertrophy. 16 These patients would be expected to benefit fromMRA use. The Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction, the “ALDO‑DHF” trial, 16 showed advantages in structural reverse cardiac remodeling and improved diastolic function, but did not affect maximal exercise capacity, patient symptoms, or quality of life. The study did not have enough power to evaluate the effect of spironolactone on HF hospitalizations or mortality. The Spironolactone for Heart Failure with Preserved Ejection Fraction, the “TOPCAT” trial, 17 added more information and assessed the clinical impact of spironolactone on HFpEF. Although it did not significantly reduce the primary outcome (cardiovascular death, cardiac arrest or HF hospitalization), a subgroup analysis revealed benefits in patients with elevated natriuretic peptide levels. These results have led current American guidelines to consider spironolactone in selected groups of patients with symptomatic HFpFE, particularly those with high natriuretic peptide levels, aiming to reduce hospitalizations (Class IIb). 18 4. Angiotensin receptor neprilysin inhibitor (ARNI) Increasing natriuretic peptide levels with ARNI is expected to improve myocardial relaxation, natriuresis, vasodilation and attenuation of sympathetic and fibrotic activity, aiming to improve cardiac function and symptoms. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction ”, the PARAMOUT” 19 trial: a phase II study, randomized 301 patients with HFpEF to receive either ARNI or valsartan. The primary endpoint, which was the change in NT-proBNP levels at 12 weeks, was significantly better in the sacubitril/valsartan group. At 36 weeks, there was also a reduction in left atrial (LA) volume, a marker of LV filling pressures, and an improvement in the NYHA functional class. Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction, the “PARAGON” 20 trial: a phase III study, will assess the clinical benefit and safety of this drug in chronic symptomatic patients with HFpEF. 5. Ivabradine An elevated heart rate (HR) is a predictive factor of worse outcomes and increased mortality in patients with heart failure, including those with HFpEF. Ivabradine is a specific and selective inhibitor of the sinoatrial node, if current , and thereby decreases HR in patients with sinus rhythm. 21 In patients with HFpEF, short-term treatment increased exercise capacity by improving LV filling pressures. 22 As these patients are mostly symptomatic during exercise, therapies targeting hemodynamic changes during exercise may be useful. The Effect of ivabradine in patients with heart failure with preserved ejection fraction, the “EDIFY” trial, 21 evaluated the effect of the drug over 8 months. Unlike the previous study, there was no improvement in the evaluated parameters (diastolic function, exercise capacity and NT-proBNP reduction). Future studies may show benefits in certain subgroups. 122