News Release

40-year-old gout drug Allopurinol could be used to treat angina

Peer-Reviewed Publication

The Lancet_DELETED

Allopurinol has been used to treat gout for more than four decades. And a new study published Online First and in an upcoming Lancet shows that the drug prolongs exercise capacity in chronic stable angina, and could thus be a cheap alternative to conventional treatments. The Article is written by Professor Allan D Struthers, University of Dundee, UK, and colleagues.

Angina pectoris is severe chest pain due to ischaemia (a lack of blood and hence oxygen supply) to the heart muscle, generally due to obstruction or spasm of the coronary arteries. Coronary artery disease, the main cause of angina, is due to atherosclerosis (build-up of material in the arteries which can cause such obstructions). Chronic stable angina substantially reduces quality of life, with one in three patients having an angina 'attack' at least once a week. Chronic stable angina affects 4—5% of all adult males in the UK.

Experimental evidence on allopurinol suggests that it inhibits the enzyme xanthine oxidase, which in turn reduces the energy used by the heart in each beat or 'stroke'. If such an effect also occurs in man, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris, since it would allow more oxygen and energy to reach heart tissue suffering inadequate blood supply in angina patients. In this study, the authors assessed whether high-dose allopurinol prolongs exercise capability in patients with chronic stable angina.

65 patients (aged 18-85 years) with clinically diagnosed coronary artery disease, a positive exercise tolerance test*, and stable chronic angina pectoris (for at least 2 months) were recruited into a double-blind, randomised, placebo-controlled, crossover study in a hospital and two infirmaries in the UK. Patients were assigned to allopurinol (600 mg per day) or placebo for 6 weeks and then crossed over to take placebo or allopurinol, so that each patient received both treatments in a randomised fashion. The primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain.

In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s from a baseline of 232 s, and placebo increased it to 249 s. The absolute difference between allopurinol and placebo was 43 s. Allopurinol increased median total exercise time** to 393 s from a baseline of 301 s, and placebo increased it to 307 s, giving an absolute difference between groups of 58 s. Allopurinol also increased the time to chest pain from a baseline of 234 s to 304 s, and placebo increased it to 272 s, an absolute difference between groups of 38 s. No adverse effects of treatment were reported.

The authors say: "Allopurinol is inexpensive compared with some other antianginal drugs such as ranolazine and ivabradine, and has a favourable long-term (>40 years) safety record for the treatment of gout. Compared with older antianginal drugs (nitrates, β blockers), allopurinol is better tolerated because it does not reduce blood pressure or heart rate, and does not cause many side-effects, such as headaches and tiredness, that occur frequently with nitrates and β blockers."

They conclude: "High-dose allopurinol significantly prolonged the time to ST depression, the total exercise time, and the time to angina in patients with chronic stable angina during a standard exercise test, suggesting that endogenous xanthine oxidase activity contributes somehow to exercise-induced myocardial ischaemia. These results also show that high-dose allopurinol prolongs exercise in stable angina pectoris…on the basis of our results, allopurinol is a useful anti-ischaemic treatment option in patients with angina that has the advantage of being inexpensive, well tolerated and safe in the long term. The precise place of allopurinol in the management of angina pectoris now needs to be explored further, but this drug might be especially appealing for use in developing countries where coronary artery disease is rapidly increasing in frequency and where access to expensive drugs or invasive treatments (angioplasty and bypass surgery) is often restricted."

In an accompanying Comment, Dr Henry J Dargie, Scottish Advanced Heart Failure Service, Golden Jubilee National Hospital, Clydebank, West Dunbartonshire, UK and Western Infirmary, Glasgow, UK and Dr Renjith Antony Scottish Advanced Heart Failure Service, Golden Jubilee National Hospital, Clydebank, West Dunbartonshire, say: "Although further work is needed to confirm allopurinol's putative anti-ischaemic effects and to better understand its mechanism of action, allopurinol joins a growing list of compounds that tests the conventional wisdom on what constitutes antianginal therapy. Although prevention of coronary artery disease remains important, protecting the heart muscle from ischaemia is a logical and pragmatic approach to a disabling condition for which several mechanisms might be responsible."

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Professor Allan D Struthers, University of Dundee, UK. T) +44 (0) 1382 632180 E) a.d.struthers@dundee.ac.uk

Dr Henry J Dargie, Scottish Advanced Heart Failure Service, Golden Jubilee National Hospital, Clydebank, West Dunbartonshire, UK and Western Infirmary, Glasgow, UK. Contact by e-mail. E) h.dargie@clinmed.gla.ac.uk

For full Article and Comment, see: http://press.thelancet.com/allopurinol.pdf

Note to editors: *A positive exercise test detects when, during exercise in angina, the heart runs out of oxygen. The patient is attached to an ECG monitor and then exercised. ST depression on the heart tracing is the sign that the heart has run out of oxygen and the time to ST depression is therefore the time it takes during exercise for the heart to run out of oxygen.

**Exercise carried on briefly after ST depression. The endpoints (time to ST depression, time to chest pain and total exercise time) are related to each other in each patient but they are not exactly the same times.


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