Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims

In this study of Medicare claims we found that allopurinol use was independently associated with a lower risk of an incident MI. Compared to patients who did not use allopurinol, new allopurinol users had a 15 % lower hazard of an incident MI. We also found that a longer duration of allopurinol use was associated with a greater risk reduction in hazard for an incident MI, i.e., allopurinol use durations of 0.5–2 years and >2 years was associated with a 17 % and 30 % reduced hazard of an incident MI. Our study provides robust evidence of MI risk reduction with allopurinol use and suggests that it may have a cardioprotective action. Several study findings merit further discussion.

In previous studies, allopurinol use was associated with a 48 % reduction in the hazard (HR, 0.52) for an incident non-fatal MI using a Spanish database [16] versus a 25 % increase in the hazard (HR, 1.25) of a cardiovascular event requiring hospitalization (including MI, hypertension, stroke, etc.) in Taiwanese patients with gout [17]. The study showing an increased risk included a composite cardiovascular outcome (more diverse than MI) and used a prevalent user (rather than an incident user) design, both of which may have led to the lack of observation of a protective effect for MI [17]. On the other hand, the study by de Abajo et al. showing a protective allopurinol effect used a case-control study with matching (a less robust study design) and was limited to non-fatal MI, but used an incident user design [16]. The contradictory evidence from two population-based studies indicated that more evidence that is robust was needed, which will be crucial in deciding whether allopurinol use reduces the risk of MI or not. Other studies have shown a beneficial effect of allopurinol use (versus non-use) on mortality [20‐22], heart failure readmission or death [23], and overall cardiovascular outcomes (including, but not limited to, MI) in patients with chronic kidney disease [24]; however, none specifically assessed MI only. A randomized, placebo-controlled, crossover trial included 65 adults with angiographically documented CAD, a positive exercise tolerance test, and stable chronic angina pectoris and randomized them to allopurinol (600 mg per day) or placebo for 6 weeks before crossover [13]. Allopurinol statistically significantly increased the median time to ST depression versus placebo (p = 0.0002; difference 43 s) and median total exercise time versus placebo (p = 0.0003) [13] showing its cardioprotective effect, providing one potential mechanism of the benefit we demonstrated. Similarly, a study comparing allopurinol to placebo in heart failure failed to show any benefit of allopurinol to placebo in patients with reduced ejection fraction  [25].

Our finding of a reduction in the risk of MI with allopurinol use in the elderly is based on a rigorous methodological approach using an incident user design. Use of a representative sample, adjustment for multiple covariates and potential confounders, and the robustness of estimates in sensitivity analyses, leads us to believe that our study findings are likely accurate and support a potential cardioprotective effect of allopurinol. To our knowledge, our study is amongst the first studies in the elderly population that show that allopurinol use is associated with a reduction in the risk of MI.

The mechanism of reduction in MI risk with allopurinol may be multi-fold. The anti-oxidant action of allopurinol [26‐32] may be responsible for improving cardiac contractile function and preventing MI, similar to its beneficial effect on the progression of post-ischemic cardiomyopathy in mice [33]. Allopurinol improves endothelial function in renal failure, diabetes, sleep apnea, and heart failure [8‐12, 34‐43], also confirmed in a recent meta-analysis [44]. These mechanisms may delay the progression of atherosclerosis and/or prevent plaque instability [45]. Clinically, allopurinol has an anti-ischemic action in patients with stable, chronic angina [13], is associated with a reduction in left ventricular mass in patients with diabetes [14] and heart disease [15], and with a reduction in blood pressure [46, 47], which are potential mechanisms for its cardioprotective action. Other mechanisms of action for allopurinol include decreased macrophage interleukin 1-beta (IL1β) secretion upon the activation of NLRP3 inflammasome [48, 49], and the impairment in CD36-mediated TLR4/6-IRAK4/1 signaling [50], mechanisms that may contribute to cardiac risk [51].

Another important study finding was that the duration of allopurinol use was associated with a dose-dependent reduction in MI risk. In particular, compared to non-use, longer allopurinol use duration of >6 months to 2 years and >2 years were each associated with an independent reduction in the hazard of MI of 17 % and 30 %, respectively (HRs, 0.83 and 0.70). Surprisingly, allopurinol use <6 month was not associated with any reduction in the risk of MI, which might indicate a threshold of 6-month use for preventing MI. The reduction in hazard showed a response-gradient, which provides further support for the protective effect of allopurinol on incident MI, seen previously where long-term allopurinol use was associated with a lower hazard of cardiovascular events (including MI) at 0.43 (95 % CI, 0.21–0.88; p = 0.02) in an open-label extension of a randomized study [52]. Thus, longer term allopurinol use seems to be cardioprotective in patients with gout. Further support for a dose-response relationship for allopurinol use duration for cardioprotection is evident by observations of lower mortality risk in heart failure patients [22] and lower MI risk in the general population [16] with high-dose compared to low-dose allopurinol use. Whether the risk/benefit ratio of allopurinol becomes favorable due to potential cardioprotection in patients with asymptomatic hyperuricemia (without gout) remains to be seen.

The greatest reductions in the hazard of MI with allopurinol exposure were noted in those aged 65–74 and ≥85 years, those of female gender, and those of Black race, another interesting finding which needs confirmation and further study. A greater benefit in the elderly and a racial minority is particularly interesting, since these groups are usually at higher risk of worse MI outcomes [53, 54].

Our study has several strengths and limitations. Despite our efforts to control for various confounders, our study is subject to potential residual confounding due to the cohort study design. To avoid this bias, we controlled for multiple potential confounders and performed multiple sensitivity analyses that supported the robustness of our findings. Second, our database lacked information on other risk factors, such as over the counter aspirin use, body mass index and diet components, which can be viewed as risk factors for MI; however, risk reduction was confirmed in analyses adjusted for other traditional CAD risk factors including hypertension, hyperlipidemia, diabetes, and smoking, and in models that additionally adjusted for aspirin use (by prescription), and other cardiac and gout medications. Third, the number of MI events may have been too low to detect statistical significance of findings in certain subgroups, i.e., type II error; availability of the entire dataset would likely have overcome this limitation. However, use of a national 5 % Medicare sample is a standard approach in epidemiological research [55, 56], and we had in excess of 1500 events for the main analyses. Limited resources prevented us from analyses of 100 % Medicare data.

Fourth, the Medicare data do not allow us to investigate why allopurinol was prescribed and, although we know that 83 % of allopurinol users in our study had a diagnosis of gout, specific reasons for its use are not known and likely included other conditions such as hyperuricemia without gout, metabolic syndrome, renal stones, tumor lysis syndrome, etc. However, regardless of the reason for allopurinol prescription, our observation of its beneficial effect is generalizable to all US elderly who use allopurinol. We also showed with sensitivity analyses that these effects were similar in magnitude for elderly Americans with gout who used allopurinol. Finally, these data are derived from Medicare, and can only be generalized to the US elderly population, not the US general population. Fifty percent of the elderly using allopurinol are female, which is different to the usual institutional cohorts of allopurinol users dominated by men, since these studies include patients from all age groups; however, our sample is that of all US elderly aged 65 years and older.

Strengths of the study included the use of a representative US population, the ability to control for the common MI risk factors, robustness of findings in multiple sensitivity models, the use of an incident user design to avoid the biases of prevalent user design, and the examination of both the allopurinol exposure and the duration of allopurinol use.