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Adverse cardiovascular effects of allopurinol are related to the use of high doses.

W e congratulate the authors for conducing a randomized controlled trial (RCT) [1] that helps to shed light into such a controversial question. The authors observed that the deleterious cardiovascular effects of allopurinol may be related to the fact that most patients were normouricemic, and so the reduction in uric acid level, which has antioxidant properties, could have detrimental effects. Although this a reasonable explanation, there may be other possible causes to the results observed in this study. Two studies in heart failure, the OPT-CHF [2] and the EXACT-HF [3], tested oxypurinol (active metabolite of allopurinol) and allopurinol, respectively, at high doses (600 mg/day) in comparison with placebo. Despite the results of the OPT-CHF suggesting possible harm with oxypurinol, the authors observed in subgroup analysis a potential beneficial effect in patients with hyperuricemia ( 9.5 mg/dl). This subgroup presented a reduction in uric acid of approximately 30% in relation to baseline (which was 11.4 mg/dl) [2]. So, with the hope that allopurinol could do better in hyperuricemic patients, the EXACT-HF [3] study was performed including exclusively patients with uric acid at least 9.5 mg/dl. Mean uric acid level (11.0 mg/dl at baseline) reduced 38.5% in the allopurinol arm. However, the results were once again disappointing: the number of patients with improved heart failure was numerically lower with allopurinol (13 versus 19% in placebo). Considering the results of both studies, the prospects for the use of highdose allopurinol in heart failure are not good. It may be worth reminding that in both studies the prevalence of use of furosemide, which increases significantly the serum levels of oxypurinol [4], was about 90%. In addition to the study by Gingles et al. [1], two recent RCTs tested the effect of high-dose allopurinol on vascular function. Borgi et al. [5] compared high-dose allopurinol (most patients received 600 mg/day) and placebo in nonhypertensive obese or overweight individuals with mean uric acid of 6.1 mg/dl. There was a 50% reduction in serum uric acid level in allopurinol group, but there was a numerical worsening in endothelial-dependent (EDV) and endothelial-independent vasodilation (EIV) comparing with placebo. The Apex trial [6] was a cross-over RCT of allopurinol 600 mg and placebo in patients with cardiac syndrome X (mean uric acid, 5.4 mg/dl). At the end of 6 weeks, allopurinol reduced serum uric acid by 48% but failed to improve EDV and EIV in relation to placebo. These results are similar to those reported by Gingles et al. [1], which included patients with controlled hypertension and left ventricular hypertrophy. Over 12 months, allopurinol 600 mg/day failed to improve EDV, significantly increased the levels of TBARS (thiobarbituric acid reactive substances, markers of oxidative stress) and impaired the regression of left ventricular hypertrophy. It is currently believed that the potential cardiovascular benefits of allopurinol lie in its antioxidant effect by inhibiting endothelium-bound xanthine oxidase and/or in its hypouricemiant effect [7,8], despite the fact that evidence for the latter mechanism is fading [7,9]. Focusing on the antioxidant effect, there is evidence that almost maximum attainable inhibitory effect on xanthine oxidase activity occurs at low concentrations of oxypurinol (40 mmol/l) [10,11]. Stamp et al. [4] observed that the mean concentration of oxypurinol in individuals taking an average dose of allopurinol of 220 mg/day was 88 mmol/l. So, doses generally used in clinical practice are much higher than those necessary to produce a significant blockade of endothelial xanthine oxidase activity. Therefore, low doses of allopurinol (<200 mg/day) should be generally enough for obtaining the desired antioxidant effect. On the other hand, the use of high-dose allopurinol may be related to an increased incidence of serious adverse events in comparison to lower doses [12]. In a recent metaanalysis, doses greater than 300 mg were related to absence of cardiovascular benefits, whereas lower doses showed a protective effect [12]. Once the plateau of a therapeutic effect is reached, higher doses can only increase the intensity and frequency of adverse events. Higher concentrations of oxypurinol (>100–150 mmol/l) may be associated with higher oxidative stress. Oxypurinol at high concentrations can itself be a substrate for myeloperoxidase released by neutrophils, generating a radical capable of oxidizing uric acid to allantoin [13] and produce deleterious effects. Furthermore, there is evidence, at least in predisposed individuals, of a dose-dependent immune system activation associated with increasing concentrations of oxypurinol [14]. There is growing evidence that activation of the immune system (including hypersensitivity reactions) plays an important role in the pathogenesis of atherosclerosis [15,16]. In the EXACT-HF study [3], as much as 10% of the patients on allopurinol developed allergic-like skin reactions. The study by Gingles and colls [1], along with other recent publications, adds to the evidence that high-dose allopurinol can actually cause deleterious cardiovascular effects. RCTs comparing the cardiovascular effects and oxidative stress markers between different allopurinol dose regimens (including doses 200mg/day) are urgently needed.