Impact of Urate Level on Cardiovascular Risk in Allopurinol Treated Patients. A Nested Case-Control Study

BackgroundGout gives rise to increased risk of cardiovascular events. Gout attacks can be effectively prevented with urate lowering drugs, and allopurinol potentially reduces cardiovascular risk. What target level of urate is required to reduce cardiovascular risk is not known.ObjectivesTo 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.MethodsWe identified long-term users of allopurinol in Funen County, Denmark. Among these, we identified all cases of cardiovascular events 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 and in- and outpatient contacts.ResultsNo association between treatment-to-target urate level and cardiovascular events were found (adjusted odds ratio of 1.01, 95% confidence interval 0.79–1.28). No significant effect was seen in any subgroup defined 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/day).ConclusionWe were unable to demonstrate a link between achieved urate level in patients treated with allopurinol and risk of cardiovascular events. Possible explanations include that allopurinol doses higher than those used in this study are required to achieve cardiovascular risk reduction or that the cardiovascular effect of allopurinol is not mediated through low urate levels. It remains to be seen whether allopurinol has a dose-response relationship with cardiovascular events at higher doses.背景：痛风（Gout）可增加心血管不良事件的发生风险。降尿酸（urate）药物可有效预防痛风急性发作，而别嘌醇（allopurinol）或可降低心血管不良事件风险。目前尚不明确需将尿酸控制在何种靶标水平，方能降低心血管风险。 目的：在长期使用别嘌醇的人群中开展一项嵌套式病例对照研究，探讨别嘌醇治疗下达到血浆尿酸靶标水平对心血管结局的影响。 方法：在丹麦菲英郡筛选长期使用别嘌醇的人群。从中纳入所有发生心血管不良事件的病例，并从同一源人群中为每例病例匹配4名对照。对比病例组与对照组在别嘌醇治疗期间是否达到了低于0.36 mmol/l的尿酸靶标水平。基于处方数据、实验室检测指标以及门诊、住院就诊记录中可获取的潜在混杂因素，对计算得到的比值比进行校正。 结果：未发现尿酸达标治疗与心血管不良事件之间存在显著关联（校正后比值比为1.01，95%置信区间为0.79~1.28）。在按年龄、性别、肾功能、别嘌醇剂量或实际尿酸水平划分的所有亚组中，均未观察到显著效应。本研究中使用的别嘌醇总体剂量偏低，平均剂量约为140 mg/日。 结论：本研究未能证实别嘌醇治疗患者的实际尿酸水平与心血管不良事件风险之间存在关联。可能的解释包括：其一，需使用高于本研究剂量的别嘌醇，方可实现心血管风险的降低；其二，别嘌醇的心血管效应并非通过降低尿酸水平介导。更高剂量下，别嘌醇与心血管不良事件是否存在剂量-反应关系，仍有待进一步研究明确。