Systematic Review of the Efficacy and Safety of Perhexiline in the Treatment of Ischemic Heart Disease

Abstract

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)

Metabolic Modulation With Perhexiline in Chronic Heart Failure

“…Nevertheless, pharmacological studies have identified the optimal plasma therapeutic range for perhexiline, and by using an inexpensive and effective blood test, side effects associated with this drug are virtually eliminated. 33,35,43 The results of the current study therefore establish that perhexiline exerts significant benefits on V O 2 max, LVEF, symptomatic status, LV function at rest and during peak stress, and skeletal muscle energy metabolism in patients with stable CHF. The improvement in V O 2 max, which was larger than that seen in patients treated with angiotensin-converting enzyme inhibitors, 8,9 occurred in addition to optimal medical therapy.…”

Metabolic Mechanisms in Heart Failure

“…158 The fact that these side effects are easily avoided by dose titration of plasma levels has led to its renaissance for refractory angina in Australia and New Zealand with restricted use in Europe. 159 In a randomized, double-blinded study of 56 optimally medicated HF patients over 8 weeks, perhexiline improved symptoms, peak exercise While these agents have explicit and unequivocal metabolic benefits, a dearth of clinical trials exists in this area. None of these agents is yet indicated specifically for the treatment of insulin resistance in heart failure.…”

The pathophysiology of heart failure: a tale of two old paradigms revisited

“…Perhexiline, another more powerful pFOXi that reduces transport of FFAs into mitochondria by inhibiting carnitine palmitoyltransferase-1 (CPT-1) (Fig 6 32 ), was a successful antianginal agent in the 1970s. 33 It fell out of favour in the same decade due to unexplained cases of hepatotoxicity and neurotoxicity. In the ensuing decades, the basis of this toxicity has been attributed to abnormal metabolism of perhexiline in a small group of patients, labelled 'poor metabolisers,' due to defects in the CYP2D6 liver microsomal enzymes.…”

“…Strict monitoring of levels of perhexiline in plasma is now known to allow its use with abolition of all toxicity. 33 In our randomised double-blind trial of 56 patients with ischaemic and non-ischaemic cardiomyopathy, perhexiline (monitored and adjusted according to levels in plasma) led to significant improvements in the primary endpoint of maximum oxygen consumption (from 16.1±0.6 ml/kg/min to 18.8±1.1 ml/kg/min; p<0.001), left ventricular ejection fraction (from 24±1% to 34±2%; p<0.001), and quality of life (Fig 7). These improvements are almost unprecedented whether judged against other pharmacological therapies or mechanical therapies.…”