Allopurinol and the risk of ventricular arrhythmias in the elderly: a study using US Medicare data

Abstract

BackgroundThere are no published human studies investigating whether the use of allopurinol, the most commonly used medication for the treatment of hyperuricemia in gout, the most common type of inflammatory arthritis in adults, has any beneficial effects on ventricular electrophysiology. The objective of our study was to assess whether allopurinol use is associated with a reduction in the risk of ventricular arrhythmias (VA).MethodsWe used the 5% random sample of Medicare beneficiaries from 2006–2012 to examine new allopurinol use and the risk of incident VA. Multivariable Cox regression analyses were adjusted for demographics (age, race, sex), comorbidity, cardiac medications, and conditions associated with VA. We calculated hazard ratios (HR) and 95% confidence intervals (CI).ResultsOf the 28,755 episodes of new allopurinol use, 2538 were associated with incident VA (8.8%). Among patients with incident VA, 54% were male, 78% were White, 75% had gout as the underlying diagnosis, and the mean Charlson–Romano comorbidity score was 4.8. The crude incidence of VA per 1,000,000 person-days declined as the duration of allopurinol use increased: 1–180 days, 151; 181 days to 2 years, 105; and > 2 years, 85. In multivariable-adjusted analyses, compared to non-use, allopurinol use was associated with lower HR of VA of 0.82 (95% CI, 0.76–0.90). Compared to allopurinol non-use, longer allopurinol use durations were significantly associated with lower multivariable-adjusted HR for VA: 1–180 days, 0.96 (95% CI, 0.85–1.08); 181 days to 2 years, 0.76 (95% CI, 0.68–0.85); and > 2 years, 0.72 (95% CI, 0.60–0.87). Multiple sensitivity analyses adjusting for cardiac conditions, anti-arrhythmic drugs and alternate definitions confirmed our findings with minimal/no attenuation of estimates.ConclusionAllopurinol use and use duration of more than 6 months were independently associated with a lower risk of VA. Future studies need to assess the pathophysiology of this potential benefit.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0816-6) contains supplementary material, which is available to authorized users.

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert

“…These collective findings are buttressed by many human observational studies that have reported association between elevated serum urate levels and CV disease event risk, all-cause mortality, and CHF (18–22). On the other hand, Mendelian randomization analysis, though possessing a variety of limitations, has not supported the concept that urate-lowering would lower the risk of CV disease (29).…”

“…With respect to pharmacologic lowering of serum urate levels, a large body of in vitro and in vivo evidence supports the notion of proinflammatory effects, and toxic effects in the vasculature, of high levels of soluble urate (28). These collective findings are buttressed by many human observational studies that have shown an association between elevated serum urate levels and CV disease event risk, all-cause mortality, and congestive heart failure (18)(19)(20)(21)(22). On the other hand, Mendelian randomization analysis, though possessing a variety of limitations, has not supported the concept that urate lowering lowers the risk of CV disease (29).…”

“…The CARES trial was double-blinded and randomized, with a state-of-the-art adjudication process for relevant CV disease end points. As such, it was designed to be free from confounding, performance bias, and detection bias, which are strengths compared to multiple prior observational studies of XOIs and CV disease in gout (18)(19)(20)(21)(22). The CARES trial enrolled a relevant study population (i.e., people with gout and established CV disease), and investigators were able to observe a sufficient number of relevant CV and mortality events during the study period.…”

“…On the other hand, Mendelian randomization analysis, though possessing a variety of limitations, has not supported the concept that urate lowering lowers the risk of CV disease (29). To date, studies of the treatment of hyperuricemia in humans, including use of XOIs, and assessment of CV disease, are inconclusive (22,23,28).…”

Promising effects of xanthine oxidase inhibition by allopurinol on autonomic heart regulation estimated by heart rate variability (HRV) analysis in rats exposed to hypoxia and hyperoxia

“…Beneficial effects of allopurinol, or its more stable metabolite oxypurinol, are evidenced in the case of vascular injury, inflammation [ 3 ], heart failure[ 4 ], ischemic heart disease [ 2 , 5 ], and also myocardial protection during cardiac or aortic surgery or post-ischemic reperfusion[ 6 ]. Experimental and clinical data indicated reduction of the risk of ventricular arrhythmias related to prolonged allopurinol use [ 7 , 8 ]. In contrast to favorable effects of various antioxidants observed in experimental studies and in a wide range of clinical settings, a number of randomized multi-center clinical trials performed over the last two decades, disclosed that chronic use of common commercially available antioxidants such as beta-carotene, vitamin A, vitamin E, vitamin C or selenium has been associated with critical cardiovascular events, sudden death and an increase of all-cause mortality [ 9 – 11 ].…”