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Cardiovascular Risks of Probenecid vs. Allopurinol for Gout
Study Questions:
What is the comparative cardiovascular safety of probenecid and allopurinol for treatment of gout in patients ≥65 years old?
Methods:
The authors conducted a cohort study using Medicare claims data for patients aged ≥65 years from 2008-2013 who were initiated on treatment with probenecid or allopurinol. The primary outcome was the composite endpoint of hospitalization for myocardial infarction (MI) or stroke. Secondary outcomes included MI, stroke, coronary revascularization, mortality, and heart failure. Patients who used pegloticase or rasburicase, suffered from end-stage renal disease, or were on dialysis were excluded. Subjects were studied from the day after index use of probenecid or allopurinol until the occurrence of death, the primary outcome, the end of study database period, insurance disenrollment, nursing home admission, or 30 days following drug discontinuation or change to the other study drug. Multiple covariates associated with severity of gout and cardiovascular risk were assessed, and propensity score matching was used to control for the >65 potential confounders.
Results:
Of the >2.8 million patents identified, after applying inclusion and exclusion criteria, there were 339,870 who initiated a uric acid-lowering drug. In this cohort, 9,722 started probenecid and 303,936 started allopurinol. After propensity matching with a 1:3 fixed ratio, 100% of probenecid and 9.6% of all allopurinol initiators were included in the study cohort. The mean age was 76 ± 7 years, 79% were white, and 54% were male. Baseline characteristics in both groups included cardiovascular disease (28%), heart failure (27%), chronic kidney disease (28%), and diabetes (46%). The median follow-up for the primary outcome (as-treated analysis) was 188 days (interquartile range [IQR], 61-469 days) for probenecid initiators and 358 days (IQR, 103-854 days) for allopurinol initiators. During the follow-up period, the incidence rate of the composite endpoint of MI or stroke per 100 person-years was 2.36 (95% confidence interval [CI], 2.05-2.71) among probenecid initiators and 2.83 (95% CI, 2.67-2.99) among allopurinol initiators. The hazard ratio (HR) of the primary outcome was 0.8 (95% CI, 0.69-0.93) in the probenecid group compared to the allopurinol group. Secondary outcomes were also lower in the probenecid group compared to the allopurinol group for MI (hazard ratio [HR], 0.81; 95% CI, 0.67-0.99), stroke (HR, 0.72; 95% CI, 0.57-0.90), and all-cause death (HR, 0.87; 95% CI, 0.76-0.997). The incidence rate of hospitalization for HF decompensation in patients with established HF was lower in the probenecid group compared to the allopurinol group (HR, 0.91; 95% CI, 0.83-0.997).
Conclusions:
In a large cohort study of 38,888 elderly Medicare patients with gout, use of probenecid appears to be associated with a modest decrease in MI, stroke, and admission for heart failure exacerbation compared to allopurinol.
Perspective:
Patients with gout are at increased risk for cardiovascular disease, although it remains unclear whether uric acid plays a causative role in development of cardiovascular disease. Prior observational studies have shown conflicting results (primarily with allopurinol) regarding reducing the risk of future cardiovascular disease. Until now, no data existed regarding the effects of probenecid on cardiovascular disease. This large cohort study presents data suggesting that probenecid use as compared to allopurinol is associated with a modest decrease in certain cardiovascular events. Given this is a nonrandomized observational study, it is subject to residual/unmeasured confounding, and causality cannot be proven. Future prospective, randomized, interventional studies are needed to evaluate the effect of probenecid and allopurinol on cardiovascular outcomes, and if present, to determine the mechanism(s) by which these medications affect cardiovascular risk.
Keywords: Acute Coronary Syndrome, Allopurinol, Cardiovascular Diseases, Diabetes Mellitus, Geriatrics, Gout, Heart Failure, Kidney Failure, Chronic, Myocardial Infarction, Myocardial Revascularization, Primary Prevention, Probenecid, Risk Factors, Stroke, Uric Acid
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