PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) Trial

Abstract

Heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (HF) accounts for approximately half of HF cases in the community, and the portion of HF with preserved ejection fraction (EF) is increasing.1 Patients with HFpEF have limited functional capacity and poor prognosis. With ongoing shifts in the age distribution of the population, the burden of HFpEF is projected to increase. To date, there is no proven therapy for HFpEF. There is an urgent need for effective therapies for HFpEF. To date, 3 randomized control trials in HFpEF have tested the impact of renin-angiotensin-aldosterone antagonists on clinical outcomes in HFpEF. None of these trials demonstrated benefit individually (Figure 1) or in a pooled analysis (n=8021).2 An aldosterone antagonist trial in HFpEF is ongoing (clinicaltrials.gov NCT00094302). A trial of the β-blocker nebivolol in HF patients with normal or reduced EF was underpowered but suggested a benefit of β-blocker in the relatively small subset of HFpEF patients (Figure 1).3 The digitalis investigation group (DIG) trial showed no reduction in mortality with digoxin in a small ancillary study of HFpEF patients.4 Figure 1. Previous randomized clinical trials in heart failure with preserved ejection fraction (HFpEF): Summary of the hazards ratios (95% CI) for the primary outcome measure of the large randomized placebo-controlled clinical trials in HFpEF to date. CHARM-Preserved indicates Candesartan in Patients With Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction; I-PRESERVE, Irbesartan in Patients With Heart Failure and Preserved Ejection Fraction; PEP-CHF, Perindopril in Elderly People With Chronic Heart Failure; SENIORS, Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure; DIG, Digitalis Investigation Group Trial. Although inadequate power or crossover may have contributed to negative findings in these trials, unique pathophysiology in HFpEF may mediate the differential response to neurohumoral …