RAnoLazIne for the Treatment of Diastolic Heart Failure in Patients With Preserved Ejection Fraction: The RALI-DHF Proof-of-Concept Study
What is the impact of inhibiting late Na+ current using ranolazine on diastolic function in patients with heart failure with preserved ejection fraction (HFPEF)?
The RALI-DHF (RAnoLazIne for the Treatment of Diastolic Heart Failure) study was a prospective, randomized, double-blind, placebo-controlled small proof-of-concept study. Inclusion criteria were EF ≥45%, a mitral E-wave velocity/mitral annular velocity ratio (E/E′) >15 or N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration >220 pg/ml, a left ventricular end-diastolic pressure (LVEDP) ≥18 mm Hg, and time-constant of relaxation (tau) ≥50 ms. Patients were randomized to ranolazine (n = 12) or placebo (n = 8). Treatment consisted of intravenous infusion for 24 hours, followed by oral treatment for 13 days. Between-treatment comparisons of all exploratory efficacy endpoints were analyzed using the Wilcoxon rank sum test.
After 30 minutes of infusion, LVEDP (p = 0.04) and pulmonary capillary wedge pressure (p = 0.04) decreased in the ranolazine group, but not in the placebo group. Mean pulmonary artery pressure showed a trend toward a decrease in the ranolazine group that was significant under pacing conditions at 120 bpm (p = 0.02), but not for the placebo group. These changes occurred without changes in LV end-systolic pressure or systemic or pulmonary resistance, but in the presence of a small, but significant decrease in cardiac output (p = 0.04). Relaxation parameters (e.g., tau, rate of decline of LV pressure per minute) were unaltered. Echocardiographically, the E/E′ ratio did not significantly change after 22 hours. After 14 days of treatment, no significant changes were observed in echocardiographic or cardiopulmonary exercise test parameters. There were no significant effects on NT-proBNP levels.
The authors concluded that ranolazine improved measures of hemodynamics, but that there was no improvement in relaxation parameters.
This proof-of-concept study showed that ranolazine given intravenously for 24 hours in patients with HFPEF was safe and modestly improved some important measures of diastolic function with decreases in LVEDP and pulmonary capillary wedge pressure during resting conditions and a decrease in mean pulmonary artery pressure during paced conditions. However, after 14 days of oral treatment, there were no significant changes in noninvasive measures for diastolic function. Given the small number of patients studied and the multiple hypotheses tested, additional larger prospective studies are indicated to validate the beneficial effects of ranolazine on measures of hemodynamics and to assess clinical outcomes.
Keywords: Heart Failure, Diastolic, Piperazines
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