Allopurinol use reduced risk for myocardial infarction in Medicare beneficiaries
Allopurinol use reduced the risk of myocardial infarction in Medicare beneficiaries, according to recently published data. In addition, longer durations of allopurinol use led to further reductions.
“Allopurinol use seems to be associated with a potential benefit for reducing the risk of heart attacks in the Americans 65 years and older,” Jasvinder A. Singh, MD, associate professor of rheumatology at the University of Alabama at Birmingham School of Medicine, told Healio Rheumatology.
A previous study showed allopurinol reduced the risk for myocardial infarction (MI) (hazard ratio = 0.52), while another showed it increased the risk of cardiovascular events (hazard ratio = 1.25). To clarify these conflicting findings, Singh and colleagues performed a study on a random sample of patients with gout who were taking allopurinol and who received Medicare benefits between 2006 and 2012. The researchers adjusted their multivariable-adjusted Cox regression models for age, sex, race, Charlson comorbidity index (CCI) and cardio-protective medication use. The sensitivity analyses adjusted for hypertension, hyperlipidemia, diabetes and smoking.
Of 29,298 total episodes of allopurinol use, 5.3% were associated with MI. Allopurinol use was associated with a reduced risk for MI (hazard ratio = 0.85). In addition, longer durations of use were associated with a progressively reduced risk for MI. The hazard ratio was 0.98 between 1 and 180 days of allopurinol use, was 0.83 between 181 days and 2 years, and was 0.7 after 2 years. Factors associated with increased risk for MI included an age of at least 75 years, male gender, higher CCI score and angiotensin-converting enzyme inhibitor use.
These results suggest that allopurinol may have a cardio-protective effect, the researchers wrote. In addition, they wrote that future studies should examine the risk-benefit ratio of allopurinol use.
“Given that the study is observational, we are not sure whether this link is certain or is due to other reasons,” Singh said. “A randomized study will be needed to answer this question, regarding whether allopurinol can provide a benefit against the heart disease in the elderly.” – by Will Offit
Disclosures: Singh reports research grants from Takeda and Savient; and consultant fees from Takeda, Savient, Regeron, Merz, Bioiberica, Crealta, Allergan Pharmaceuticals, WebMD, UBM LLC and the American College of Rheumatology. Please see the full study for all other relevant financial disclosures.
Previous observational studies evaluating whether allopurinol reduces the risk of myocardial infarction have shown contradictory results. In this retrospective cohort study evaluating claims from a Medicare database, Singh and colleagues demonstrated allopurinol use in the elderly was associated with a 15% lower risk of myocardial infarction compared with nonusers. The cardioprotective effect was seen after 6 months of allopurinol therapy and a greater risk reduction was observed with longer duration of allopurinol use. The study included all patients started on allopurinol irrespective of the indication and 83% of the patients were identified as having a clinical diagnosis of gout.
This study suggests allopurinol may have a cardioprotective effect in the elderly. However, observational trials — even one as well done as this study — suffer from potential indication bias and a prospective randomized study will be necessary to confirm the results demonstrated in this study.
Several mechanisms have been proposed on how allopurinol may be responsible for the cardioprotective effect including antioxidant properties, improved endothelial function and reduced interleukin-1 levels. However, is it allopurinol that is playing a cardioprotective role or is the lowering of urate levels that is providing the benefit? Would other urate-lowering drugs have a cardioprotective effect?
This study raises the important question which is frequently debated: Should patients with asymptomatic hyperuricemia and other cardiovascular risk factors be treated with allopurinol or other urate-lowering drugs? Hyperuricemia and gout are associated with an increased risk of cardiovascular disease, and studies have suggested patients with controlled gout may have decreased cardiovascular morbidity and mortality compared with patients with uncontrolled disease. According to clintrials.gov, there is an ongoing trial comparing allopurinol to febuxostat on the cardiovascular risk in patients with gout, but this trial will only provide data on the comparative benefit or risk of these agents on cardiovascular outcomes.
Based on this study and other smaller studies suggesting a cardioprotective effect of allopurinol, it is time that a prospective randomized trial of allopurinol and/or other urate-lowering drugs be conducted in patients with asymptomatic hyperuricemia and other cardiovascular risk factors. A precedent for a trial of this nature exists with the ongoing evaluation of methotrexate in 7,000 patients with risk for cardiovascular disease enrolled in the Cardiovascular Inflammation Reduction Trial which is a collaborative effort between Brigham and Women’s Hospital and the National Heart, Lung and Blood Institute.
Cardiovascular disease remains the leading cause of death in the United States. Proper identification and treatment of cardiovascular risk factors are key when evaluating patients with rheumatologic diseases, including gout. Current evidence is limited on the clinical utility of treatment of asymptomatic hyperuricemia as a cardiovascular risk factor. Studies such as this publication suggesting potential benefit of lowering uric acid on cardiovascular risk support a properly conducted large-scale clinical trial of allopurinol or other urate-lowering drugs in this patient population.
Stanley Cohen, MD
University of Texas Southwestern Medical School
Margarita Fallena, MD
Texas Health Presbyterian Hospital
Disclosure: Cohen and Fallena report no relevant financial disclosures.