Allopurinol, an old drug with new benefits in CKD and angina

The renal research is the first to show that allopurinol treatment in patients with chronic kidney disease (CKD) decreases inflammation, slows the progression of kidney disease, and reduces patients’ risk of experiencing a cardiovascular event or being hospitalized.

Allopurinol is a drug used primarily to treat individuals with excess uric acid. Hyperuricemia can lead to gout and, in extreme cases, kidney failure. Elevated uric acid may also increase risk of developing hypertension and heart disease. Patients with CKD–who most often die from heart disease.

To investigate, Marian Goicoechea, PhD, Jose Luño, MD, Hospital General Universitario Gregorio Marañón, in Madrid, Spain) and their colleagues conducted a prospective, randomized trial of 113 CKD patients who received either allopurinol (100 mg/day) or who continued taking their usual therapy. The researchers assessed kidney disease progression, cardiovascular events and hospitalizations among patients in the study over two years.

The blood levels of uric acid and C-reactive protein significantly decreased in patients treated with allopurinol. In the control group, kidney function declined after two years, but in the allopurinol-treated group, kidney function improved. Allopurinol treatment slowed down kidney disease progression regardless of patients’ age, gender, and diabetes status; their blood levels of uric acid and C-reactive protein; the amount of  protein patients lost in the urine; and the other types of medications patients used. In addition, compared with usual therapy, allopurinol treatment reduced the risk of cardiovascular events by 71% and the risk of hospitalizations by 62%.

While allopurinol has significant potential benefits for CKD patients, “these results have to be confirmed in larger prospective trials and are the basis for a hypothesis that still needs to be tested,” the authors wrote.

Study co-authors include Soledad García de Vinuesa, Ursula Verdalles, Caridad Ruiz-Caro, Jara Ampuero, Abraham Rincón, and David Arroyo of Hospital General Universitario Gregorio Marañón.

Allopurinol in angina pectoris

Another study (2) in the Lancet shows that the drug prolongs exercise capacity in chronic stable angina, and could thus be a cheap alternative to conventional treatments. The study, from Professor Allan D Struthers, University of Dundee, UK, and colleagues.

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.”

References

1. The article, entitled “Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk,” will appear online at http://cjasn.asnjournals.org/ on June 10, 2010, doi10.2215/CJN.01580210.
2. Norman A, Ang DSC, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina:a randomized, placebo controlled crossover trial. Lancet 2010 published online 8 June 2010. DOI:10.1016/so140-6736(10)60391-1.

Recommended reading

• Berbari AE. The role of uric acid in hypertension, cardiovascular events, and chronic kidney disease. European Society of Hypertension Newsletter. Update on Hypertension Management. 2010;11(No 49);1-2.