University of Connecticut School of Medicine, Farmington, 06030-3940, USA.
Am Heart J. 2012 Jul;164(1):14-20. doi: 10.1016/j.ahj.2012.04.011. Epub 2012 Jun 13.
Comprehensive safety evaluation of new drugs for noncardiac indications is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk such as gout. Febuxostat is a potent nonpurine selective inhibitor of xanthine oxidase approved for the treatment of gout. Long-term CV safety of febuxostat is being established in a randomized, allopurinol-controlled clinical study in patients with gout who have increased CV risk using an analytical approach that provides 90% power to meet a noninferiority margin of 1.3 for the hazard ratio (HR) (febuxostat relative to allopurinol). The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina requiring urgent coronary revascularization. Approximately 7,500 men and women with gout and CV disease are being recruited and will be followed up for up to 5 years postrandomization. The statistical plan for the trial uses a design that evaluates the HR of febuxostat to allopurinol based on the primary CV composite end point when there are a maximum of 624 CV events. Interim analyses will be conducted when approximately 25%, 50%, and 75% of events have occurred. At each analysis, if the upper 1-sided confidence limit of the HR is <1.3, the study will be stopped, and the noninferiority of febuxostat relative to allopurinol with regard to CV risk will be declared. The CARES trial will define the CV safety profile of febuxostat and allopurinol in gout patients at high risk for CV events.
需要对非心脏适应证的新药进行全面的安全性评估，特别是在心血管（CV）风险较高的人群中，如痛风。非布司他是一种强效的黄嘌呤氧化酶非嘌呤选择性抑制剂，已被批准用于治疗痛风。在一项针对具有较高 CV 风险的痛风患者的随机、别嘌醇对照临床试验中，正在通过一种分析方法确定非布司他的长期 CV 安全性，该方法提供了 90%的功效，以满足风险比（HR）（非布司他与别嘌醇相比）的非劣效性边界 1.3。该试验的主要 CV 终点是 CV 死亡、非致死性心肌梗死、非致死性卒中和需要紧急冠状动脉血运重建的不稳定型心绞痛的复合终点。大约 7500 名患有痛风和 CV 疾病的男性和女性正在被招募，并将在随机分组后随访长达 5 年。该试验的统计计划使用一种设计，根据主要 CV 复合终点评估非布司他与别嘌醇的 HR，当最多发生 624 例 CV 事件时。当大约发生 25%、50%和 75%的事件时，将进行中期分析。在每次分析中，如果 HR 的上单侧置信限<1.3，则研究将停止，并宣布非布司他相对于别嘌醇在 CV 风险方面的非劣效性。CARES 试验将确定高 CV 事件风险的痛风患者中非布司他和别嘌醇的 CV 安全性特征。
