Ranolazine for the treatment of heart failure with preserved ejection fraction: background, aims, and design of the RALI-DHF study

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF), formerly referred to as diastolic heart failure (DHF), accounts for >50% of all HF patients. So far, there has been no specific treatment for impaired left ventricular (LV) relaxation. Data from in vitro and animal studies indicate that ranolazine improves diastolic function by inhibiting the late sodium current.

Hypothesis: RAnoLazIne for the Treatment of Diastolic Heart Failure (RALI-DHF) is a prospective, single-center, randomized, double-blind, placebo-controlled proof-of-concept study to determine if ranolazine compared with placebo will be more effective in improving diastolic function in patients with HFpEF.

Methods: Twenty patients with HFpEF (EF ≥ 50% and ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity [E/E'] >15 or N-terminal pro-type brain natriuretic peptide >220 pg/mL) will be randomized to receive ranolazine or placebo in a 1.5:1 ratio during their catheterization if the LV end-diastolic pressure is ≥18 mm Hg and the time constant of relaxation (τ) is ≥50 ms. Treatment will consist of intravenous infusion of study drug (or placebo) for 24 hours, followed by oral treatment for a total of 14 days.

Endpoints: The study will include the following exploratory endpoints: (1) change from baseline to 30 minutes from initiation of intravenous study drug administration during cardiac catheterization hemodynamic parameters at both resting and paced (120 beats per minute) conditions: τ, LV end-diastolic pressure, and dP/dt(min) .; and (2) change from baseline to day 14 in E/E', maximal oxygen consumption, and N-terminal pro-type brain natriuretic peptide.

Conclusions: The RALI-DHF study is designed as a translational study to bridge the gap between basic science and therapeutics and to determine if ranolazine, compared with placebo, will be more effective in improving diastolic function in patients with HFpEF.

Trial registration: ClinicalTrials.gov NCT01163734.

© 2011 Wiley Periodicals, Inc.

Figures

Figure 1

Schema during study‐drug infusion. Abbreviations: ECHO, echocardiography; PK, pharmacokinetic.

Figure 2

Schedule of events. Abbreviations: cath, catheterization; CPET, cardiopulmonary exercise test; ECG, electrocardiogram; ECHO, echocardiography; iv, intravenous; NT‐proBNP, N‐terminal pro‐type brain natriuretic peptide; PK, pharmacokinetic.