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 Table 1 – A) Main studies performed in patients with HFpEF using effective drugs in the treatment of the HFrEF; B) New drugs and new approaches in HFpEF A Clinical Trial Year Intervention Patients, n Major inclusion criteria Mean follow-up Main conclusions Beta Blockers SENIORS 9 2005 Nebivolol vs. placebo 2128 ≥70 years, mean LVEF of 36%, 35% with LVEF > 35%, 68% CAD 1,8 years Well tolerated and effective in reducing mortality and CV hospitalization (HR 0.86, 95%CI: 0.74–0.99; p = 0.039) ACEI/ARB CHARM Preserved 13 2003 Candesartan vs. placebo 3023 >18 years, LVEF > 40%, NYHA II-IV 3 years Tends towards a reduction in CV mortality and HF hospitalization ( unadjusted HR 0.89 95%CI: 0.77‑1.03, p = 0.118; adjusted 0.86 [0.74-1·0], p = 0.051) PEP-CHF 14 2006 Perindopril vs. placebo 850 ≥70 years, HF under diuretic therapy, diastolic dysfunction, without systolic or valvular dysfunction 2,1 years No difference in mortality or CV hospitalization (HR 0.92 95%CI: 0.70-1.21, p = 0.545). Some improvements in symptoms, exercise capacity and HF hospitalization in the first year of follow-up (younger patients with AMI or hypertension) I-PRESERVE 12 2008 Irbesartan vs. placebo 4128 >60 years, LVEF > 45%, NYHA II-IV 4.1 years No difference in mortality or CV hospitalization (HR 95%CI: 0.86-1.05, p = 0.35) Enalapril 15 2010 Enalapril vs. placebo 71 70 ± 1 years (80% women), LVEF ≥ 50%, Compensated HF and controlled Hypertension 1 year No impact on exercise capacity (p = 0.99), aortic distensibility (p = 0.93), ventricular volume and mass (p = 1) or quality of life (p = 0.07) MRA Aldo –DHF 16 2013 Spironolactone vs. placebo 422 ≥50 years, LVEF ≥ 50%, NYHA II-III, diastolic dysfunction 1 year Improved diastolic function (E/e' p < 0.001, ventricular remodeling p = 0.09 and neurohormonal activation; p = 0.03). Did not improve exercise capacity, symptoms or quality of life (p = 0.03) TOPCAT 17 2014 Spironolactone vs. placebo 3445 ≥50 years, LVEF ≥ 45%, Symptomatic HF, hospitalization within last 12 months or elevated natriuretic peptides 3.3 years No reduction in CV mortality, cardiac arrest or HF hospitalization (HR 0.89, 95%CI: 0.77-1.04, p = 0.14). Some benefit in terms of natriuretic peptide levels ARNI PARAMOUNT 19 2012 Sacubitril/ valsartan vs. valsartan 301 LVEF ≥ 45%, NYHA II‑III and NT‑proBNP > 400 pg/ml 12 and 36 weeks Reduction in NT-proBNP at 12 weeks (HR 0.77, 95%CI: 0.64-0.92, p = 0.005); LA volume reduction (p = 0.003) and NYHA class improvement (p = 0.05) at 36 weeks PARAGON 20 2019* Sacubitril/ valsartan vs. valsartan 4300 LVEF ≥ 45%, NYHA II‑IV, elevated natriuretic peptides and evidence of structural heart disease >2 years Evaluation of CV mortality and HF hospitalizations Ivabradine If- Channel Inhibitors 22 2013 Ivabradine vs. placebo 61 LVEF ≥ 50%, diastolic dysfunction, NYHA II-III, sinus rhythm, HR ≥ 60 bpm, exercise capacity <80% for age and gender 7 days Increased exercise capacity (p = 0.001), with improvement in hemodynamic status during the exercise (p = 0.004); improved LV filling pressure (p = 0.02) EDIFY 21 2017 Ivabradine vs. placebo 179 LVEF ≥ 45%, NYHA II-III, sinus rhythm, HR ≥70 bpm, NT‑proBNP ≥ 220 pg/mL (BNP ≥ 80 pg/mL 8 months No improvement in diastolic function (HR 1.4 90%CI: 0.3-2.5, p = 0.135), exercise capacity (p = 0.882) or NT-proBNP level (HR 1.01, 90%CI: −0.86-1.19; p = 0.882) 123