Background/Purpose: Gout is associated with an increased risk of cardiovascular (CV) disease including myocardial infarction (MI), stroke and heart failure (HF). Although both probenecid and allopurinol have been available for treatment of gout for many decades, no studies have directly compared CV safety of these drugs.  Both drugs lower uric acid through different mechanisms and have other pharmacologic effects possibly tied to CV disease.

Methods: To determine comparative CV safety of probenecid versus allopurinol, we conducted a cohort study of gout patients enrolled in Medicare (2008-2013). Gout patients aged ≥65 years who initiated probenecid or allopurinol were identified with having continuous enrollment in Parts A/B/D for ≥1 year free of a given drug prior to the 1^st dispensing date (i.e., index date). Patients with ESRD, dialysis or renal transplant were excluded. The primary outcome was a composite CV endpoint of MI or stroke using a validated claims-based algorithm (PPV>94%). Secondary outcomes included MI, stroke, coronary revascularization, and HF. Follow-up time started from the day after the index date to the earliest CV endpoint, drug discontinuation, nursing home admission, death, or end of study period. To control for ≥50 potential confounders at baseline, probenecid initiators were matched to allopurinol initiators on a propensity score (PS) with a ratio of 1:3. Incidence rates (IR) and hazard ratios (HR) were estimated in the PS-matched cohort. We also conducted subgroup analyses among patients with no known CV disease or chronic kidney disease (CKD) at baseline.      

Results: We included a total of 9,722 probenecid initiators PS-matched on 29,166 allopurinol initiators with mean (± SD) age of 76 (± 7) years and 54% were men. All the baseline covariates were well-balanced between the two PS-matched groups. During the 365-day baseline period prior to the index date, 28% had evidence of CVD, 27% HF, 45% diabetes, and 28% CKD. 71% had any use of colchicine, 48% opioids, and 35% oral steroids at baseline. The IR of MI or stroke per 100 person-years was 2.29 in probenecid and 2.82 in allopurinol initiators with HR of 0.78 (95%CI 0.67-0.90). In the secondary analyses, probenecid was associated with a decreased risk of MI, stroke and HF exacerbation versus allopurinol (see Table). Subgroup analyses in probenecid initiators vs. allopurinol showed consistent results with HR of 0.82 (95%CI 0.67-0.99) for the composite CV endpoint of MI or stroke among those without baseline CV disease and HR of 0.84 (95%CI 0.70-1.01) in those without baseline CKD.        

Conclusion: In this large cohort study of 38,888 elderly gout patients enrolled in Medicare, use of probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke and HF exacerbation compared to allopurinol. Previous research has found direct positive CV effects of probenecid, suggesting that it should be investigated as a potential CV treatment.