Perhexiline was introduced about 30 years ago and rapidly gained a reputation for efficacy in the management of
angina pectoris. However, hepatic and neurological adverse effects associated with
perhexiline administration led to a marked decline in its use. The
drug was originally classified as a coronary
vasodilator, and later as a
calcium channel antagonist, but recent data suggests that it acts as a cardiac metabolic agent, through inhibition of the
enzyme,
carnitine palmitoyltransferase-1 (CPT-1). Given the
drug's unique anti-ischemic action and favorable hemodynamic profile, together with an improved understanding of the mechanisms underlying the adverse effects of the
drug and the clear clinical need for additional
therapies in refractory patients,
perhexiline is currently being re-appraised as a potentially useful agent in the management of severe
myocardial ischemia.
Perhexiline is being considered for registration or re-registration in a number of countries and is being evaluated in a large-scale clinical trial in elderly patients with
aortic stenosis and
myocardial ischemia. This systematic review examines the evidence from available published literature in relation to the efficacy and tolerability of
perhexiline in the treatment of
cardiac disease. While there is a lack of well designed controlled trials using objective end-points to determine efficacy (almost all trials used a crossover design, included small numbers of patients and had limited statistical analysis of results), there is consistency in the data available that
perhexiline is considerably more effective than placebo when used as monotherapy. Furthermore, it affords additional symptom relief in those already receiving maximal conventional anti-anginal
therapy. However, there is a paucity of trials demonstrating the efficacy of low dosages of
perhexiline (100 to 200 mg/day) in patients with refractory
angina pectoris. Available evidence also suggests that the incidence of adverse events can be minimised, and the efficacy maintained, by keeping plasma
perhexiline concentrations within a therapeutic range (150 to 600 micro g/L)