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A retrospective comparison of two established gout medications suggested that patients receiving probenecid (Probalan) have a lower cardiovascular risk than peers on the standard therapy of allopurinol (Zyloprim), researchers reported from a government-funded study.

Already at higher risk of cardiovascular disease, patients with gout nonetheless did have fewer myocardial infarctions (MIs) and strokes when they took probenecid in lieu of allopurinol (2.36 per 100 person-years versus 2.83 per 100-person years, HR 0.80, 95% CI 0.69-0.93), according to Seoyoung Kim, MD, ScD, MSCE, of Brigham and Women's Hospital in Boston, and colleagues.

As reported online in the , the rates of other adverse outcomes similarly favored probenecid recipients. These were as follows:

• MI: 1.40 per 100-person years versus 1.64 per 1oo-person years (HR 0.81, 95% CI 0.67-0.99)
• Stroke: 0.96 per 100 person-years versus 1.27 per 100 person-years (HR 0.72, 95% CI 0.57-0.90)
• Heart failure exacerbation among those with baseline heart failure: 36.88 per 100 person-years versus 37.05 per 100 person-years (HR 0.91, 95% CI 0.83-0.997)
• Mortality: 2.91 per 100 person-years versus 3.25 per 100 person-years (HR 0.87, 95% CI 0.76-1.00)

"These results were consistent in the subgroup analyses of patients without baseline cardiovascular disease or those without baseline chronic kidney disease [CKD]," the authors noted.

Writing in an , Michael Givertz, MD, also of Brigham and Women's Hospital, added that the findings "were observed on top of background cardioprotective therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (61%), beta-blockers (43%), and statins (54%)."

Kim and colleagues said that although both probenecid and allopurinol have been available for a long time for the management of gout, to the best of their knowledge, this is the first study that has evaluated the cardiovascular effect of probenecid in a direct comparison with allopurinol in a population-representative cohort of gout patients.

The study included gout patients enrolled in Medicare who started probenecid (n=9,722) or allopurinol (n=29,166) from 2008 to 2013. Participants had a mean age of 76, and 54% of the total were males. All were required to have been off the medications for at least 1 year before the index dispensing date.

Median follow-up was 118 days for the patients treated with probenecid and 358 days for those on allopurinol. Out of 180 days, the median number of days covered for the probenecid arm was 39.8% and 87.3% for allopurinol; by 365 days, these rates fell to 26.1% and 82.2%, respectively.

That the probenecid group was much less adherent to prescribed therapy is one reason to raise questions about the biological plausibility of the study's primary results, suggested Givertz.

"More importantly, these observational data are hypothesis-generating only. Although it might be tempting to use the data by Kim et al to alter clinical practice (e.g., prescribe probenecid rather than allopurinol to older patients with gout), there remain practical hurdles of uricosuric therapy including renal contraindications (CKD and nephrolithiasis), dosing, and gastrointestinal side effects."

The researchers acknowledged that probenecid is known to increase the concentration of some drugs such as antibiotics and NSAIDs when used concomitantly, but drug interactions between probenecid and statins or other cardiovascular drugs were not reported.

In addition, the team said, their retrospective study was subject to residual confounding despite propensity-score matching for baseline differences -- i.e., the probenecid group started off with less CKD and heart failure, for example. Moreover, the study groups took relatively low doses of their gout medication.