Cumulative Incidence Curves of the Composite Endpoint of MI or Stroke

Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients with Gout. Seoyoung C. Kim, Tuhina Neogi, Eun Ha Kang, Jun Liu, Rishi J. Desai, MaryAnn Zhang, Daniel H. Solomon. Journal of the American College of Cardiology Mar 2018, 71 (9) 994-1004; DOI: 10.1016/j.jacc.2017.12.052

Inflammation plays a critical role in the pathogenesis of both gout and cardiovascular disease (CVD). It is well known that patients with gout are at an increased risk of CVD, including myocardial infarction (MI), stroke, and heart failure (HF). While it remains controversial whether uric acid is causally linked to the development of CVD, beneficial effects have been reported for allopurinol, the most commonly used urate-lowering drug, on lowering blood pressure and improving endothelial function and metabolic profile. Probenecid is another, older drug used for gout. It works as a competitive inhibitor of the organic anion transporter, producing uricosuria, as well as an inhibitor of pannexin 1 channels, an ATP release channel involved in the assembly and activation of the inflammasome. The NLRP3 inflammasome plays a critical role in production of IL-1β, which drives the inflammatory cascade that results in acute gout. Thus, it is possible that probenecid may have positive effect in gout patients not only by lowering serum urate levels, but also by reducing production of IL-1β.

In a recently published study, Dr. Seoyoung Kim and colleagues examined the comparative cardiovascular safety of two drugs used for gout prevention – probenecid and allopurinol – in a cohort of Medicare patients with gout. They identified patients who initiated probenecid or allopurinol and examined the risk of a composite cardiovascular endpoint of hospitalization for MI or stroke. To account for potential differences in the two cohorts at baseline, propensity score (PS) matching was used. They then estimated the incidence rate (IR) and hazard ratio (HR) of the outcomes in the PS matched cohort.

A total of 9,722 probenecid initiators were PS-matched to 29,166 allopurinol initiators with a ratio of 1:3. The mean age was 76 (±7) years, 54 percent were male, and 79 percent were white. At baseline, cardiovascular and other comorbidities were common in both groups, including CVD (28%), HF (27%), CKD (28%) and diabetes (46%), as was the use of gout-related medications, including colchicine (71%), oral steroids (35%), NSAID (44%), and opioids (48%). As expected, use of colchicine was observed mostly at the time of urate-lowering treatment initiation.

The occurrence of the primary composite CV endpoint (hospitalization for MI or stroke) was common in both groups with an IR of 2.36 per 100 person-years for probenecid initiators and 2.83 per 100 person-years for allopurinol initiators. The HR for the primary CV endpoint decreased in probenecid versus allopurinol initiators at 0.8 (95% CI 0.69-0.93). Cumulative incidence plots showed consistent results with a log rank test p-value of 0.003. Probenecid was also associated with a decreased risk of MI, stroke, HF exacerbation and mortality versus allopurinol. Our subgroup analyses of patients without baseline CVD or those without baseline chronic kidney disease also showed consistent findings.

Based on this large cohort of 38,888 elderly gout patients, treatment with probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke and HF exacerbation compared to allopurinol. Potential beneficial effects of IL-1β inhibition on CVD have been hypothesized, and the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial in fact showed that canakinumab, an IL-1β inhibitor, lowered the CV risk in patients with prior heart attack and inflammatory atherosclerosis. Given the high CV morbidity and mortality in gout patients, our study suggests a need for further research on potential beneficial effects of probenecid on the high CV morbidity and mortality of patients with gout.