Background Gout gives rise to increased risk of adverse cardiovascular outcomes. Gout attacks can be effectively prevented with urate lowering drugs such as allopurinol, and allopurinol further potentially reduces the cardiovascular risk. Whether treatment to a target level of uric acid is required to reduce cardiovascular risk is not known.
Objectives We sought to investigate the effect of achieving target plasma urate with allopurinol on cardiovascular outcomes in a case control study nested within long-term users of allopurinol.
Methods We identified all long-term users of allopurinol in Funen County, Denmark. Among these, we identified all cases of cardiovascular events (Antiplatelet trialist's Collaboration composite endpoint) and sampled 4 controls to each case from the same population. The cases and controls were compared with respect to whether they reached a urate target below 0.36 mmol/l on allopurinol. The derived odds ratios were controlled for potential confounders available from data on prescriptions, laboratory values or in- and outpatient contacts.
Results No association of treatment-to-target urate level below 0.36 mmol/l and cardiovascular events were found. Adjusted odds ratio for cardiovascular event between cases and controls was 1.01 (95% confidence interval 0.80 - 1.29). No significant effect was seen in any subgroup when stratifying by age, gender, renal function, allopurinol dose or the achieved urate level. Overall, the doses of allopurinol used in this study were low (mean $≈ $140 mg/d).
Conclusions In our study, we were unable to demonstrate any effect of the achieved urate level in patients treated with allopurinol on cardiovascular events. However, the results are hampered by the low doses of allopurinol used. Possible explanations include that higher allopurinol doses are required to achieve cardiovascular risk reduction or that the putative effect of allopurinol on cardiovascular risk is not mediated through urate levels. It remains to be seen whether allopurinol has a dose-response relationship with cardiovascular events at higher doses.
Disclosure of Interest K. Søltoft Larsen Grant/research support from: Has participated in research projects funded by Menarini, with grants paid to institutions of employment and received personal fees, A. Pottegård: None declared, H. Lindegaard Grant/research support from: has received honoraria and/or participated in research projects funded by Berlin-Chemie/Menarini, Eli Lilly, MSD, Roche and Pfizer, J. Hallas Grant/research support from: has participated in research projects funded by Menarini and Nycomed/Takeda and received personal fees for teaching