Perhexiline Therapy in Heart Failure With Preserved Ejection Fraction Syndrome

Randomised Double Blind Placebo Controlled Trial of Perhexiline in Heart Failure With Preserved Ejection Fraction Syndrome (HFpEF)

Up to half of all patients with clinical features of heart failure are found to have normal heart pumping function. Recently the investigators have shown that a drug called perhexiline markedly improved exercise capacity and symptoms in patients with heart failure associated with impaired cardiac pump function. In this proposal the investigators will assess whether perhexiline has beneficial effects in patients with heart failure and a normal heart pumping function.

Up to 50% of patients with symptoms of heart failure have a preserved left ventricular ejection fraction (HFpEF syndrome). Current therapy for systolic heart failure is targeted at inducing vasodilation and counteracting neuro-endocrine activation. There is a lack of a corresponding evidence base for the treatment of HEpEF. We have previously shown that perhexiline, an agent that increases the efficiency of energy production by shifting substrate utilization from free fatty acids towards glucose, was highly effective in improving exercise capacity, symptoms and cardiac function in patients with systolic heart failure. We have also recently shown that energy deficiency plays a major role in the pathophysiology of HFpEF. In this proposal we therefore aim to investigate the effectiveness of perhexiline in 70 HFpEF patients, in a 3 month randomised, double-blind, controlled trial. An interim analysis is planned after 20 patients.

Inclusion Criteria: HFpEF will be defined as: Clinical features consistent with heart failure LVEF ≥ 50%, with no evidence of significant valvular disease No hypertrophic cardiomyopathy, and no evidence of pericardial constriction Peak VO2 < 80% predicted, with RER>1 and with a pattern of gas exchange on metabolic exercise testing indicating a cardiac cause for limitation) Patients recruited will be in sinus rhythm Exclusion Criteria: BMI >35 Objective evidence of lung disease on formal lung function testing Reversible myocardial ischaemia on contrast-enhanced myocardial stress Echocardiography, and no evidence of exercise-induced mitral regurgitation (>2+) Impaired hepatic function; known hypersensitivity to perhexiline

Singh S, Beadle R, Cameron D, Rudd A, Bruce M, Jagpal B, Schwarz K, Brindley G, Mckiddie F, Lang C, Dawson D, Frenneaux M. Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome. Future Cardiol. 2014 Nov;10(6):693-8. doi: 10.2217/fca.14.62. Erratum In: Future Cardiol. 2015 Mar;11(2):245. Nightingale, Peter [removed].