Multi-Centre Experience on the Use of Perhexiline in Chronic Heart Failure and Refractory Angina: Old Drug, New Hope

Thanh Trung Phan; Ganesh Nallur Shivu; Anirban Choudhury; Khalid Abozguia; Chris Davies; Ulasini Naidoo; Ibrar Ahmed; Zaheer Yousef; John Horowitz; Michael Frenneaux


Eur J Heart Fail. 2009;8(9) 

In This Article

Abstract and Introduction


Aims The objective of this study is to report on our 5-year collective experience on the use of perhexiline in the UK, in patients with chronic heart failure (CHF) and/or refractory angina with respect to 'real-life' drug side effects and toxicity, therapeutic drug level monitoring, 5 year mortality outcomes and predictors of response to perhexiline therapy.
Methods and results Data on clinical history, perhexiline monitoring, follow-up, and mortality were retrospectively collated from centralized perhexiline databases from two tertiary referral centres. A total of 151 patients were on perhexiline therapy at two UK tertiary referral centres. At 3–4 months, 68.8% of patients had drug level within the therapeutic range and 20.8% were above the therapeutic range. A total of 58.9% of patients reported to have felt better on the perhexiline (responders). The presence of refractory angina was an independent predictor of response to perhexiline therapy (odds ratio 2.84, 95% confidence interval 1.28–6.32, P = 0.01). Five-year mortality was non-significantly different between patients with refractory angina, CHF, or both (20.5, 31.0, and 38.4%, P = 0.20, respectively).
Conclusion Perhexiline therapy provides symptomatic relief in the majority of patients with minimal side effects or toxicity. Careful therapeutic level monitoring for dose titration is important to prevent acute and chronic toxicity. Patients with refractory angina were more likely to be responders.


The prevalence of chronic heart failure (CHF) is increasing and it is a leading cause of morbidity and mortality in developed countries and an emerging one in the developing world. The mortality of CHF at 5 years remains about 50%, which is similar to the prognosis for many cancers and is worse than this in more severe CHF.[1] Despite considerable advances in neuro-humoral modulation therapy,[2] the limits of this approach have already been encountered.[3] Thus, there is an urgent need for novel therapeutic approaches. Ironically, our search for a future therapy has led us to look to the past. An old drug, a metabolic modulator called perhexiline was first introduced into Europe nearly 30 years ago for the adjunctive treatment of angina.[4]

Perhexiline was first introduced in the 1970s as an anti-anginal agent effective at relieving symptoms of angina, improving exercise tolerance, and increasing workload needed to induce ischaemia. The drug works in part by modifying myocardial substrate utilization from fatty acids to carbohydrates, which is energetically more efficient for the heart to metabolize.[5] By the early 1980s there were reports of hepatotoxicity[6] and peripheral neuropathy[7] with perhexiline use. These effects were later shown to occur in patients who were 'slow hydroxylators' secondary to a polymorphic variant of the cytochrome P-450 enzyme (CYP2D6) which metabolizes the drug.[8] However, this toxicity can be completely avoided by maintaining drug plasma concentration between 0.15 and 0.60 mg/L.[9] Perhexiline has both acute (<2 weeks) and chronic (>3 months) potential toxicity as well as predictable effect on lowering blood glucose levels which, in diabetics, can potentially induce the development of hypoglycaemia. Both acute and chronic toxicity are essentially plasma-level related, but they are not confined to 'slow hydroxylators' only.[10]

In the UK, perhexiline is available off licence, on a named patient and named consultant cardiologist basis. In some parts of the world, particularly Australia, perhexiline is quite widely used in the treatment of refractory angina and unstable angina, with excellent results.[11] In addition, recently, our group have demonstrated the beneficial short-term effects of perhexiline in patients with CHF (of both ischaemic and non-ischaemic aetiology) in a phase 2 double-blind, randomized, placebo-controlled trial.[12] This has led to our centres using perhexiline therapy in highly symptomatic otherwise optimally treated patients with CHF and/or refractory angina. To date there is, however, very limited published long-term clinical data on the use of perhexiline in patients with CHF and/or refractory angina. In this study we aim to report on our 5-year collective experience on the use of perhexiline in patients with CHF and/or refractory angina, with a focus on 'real-life' drug side effects and toxicity, therapeutic drug level monitoring, 5-year mortality outcomes, and predictors of response to perhexiline therapy.