Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, PQ, H1T1C8Canada.
Beaulieu-Saucier Pharmacogenomics Centre, Université de Montréal, Montreal, Canada.
Eur Heart J. 2022 Oct 14;43(39):3947-3956. doi: 10.1093/eurheartj/ehac374.
In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.
dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98).
Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.
Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.
在 dal-Outcomes 的回顾性分析中，达塞曲匹对心血管事件的影响受到腺嘌呤核苷酸环化酶 9（ADCY9）基因多态性的影响。dal-GenE 研究旨在检验这一药物遗传学假设。
dal-GenE 是一项在急性冠状动脉综合征发作后 1-3 个月内的患者中进行的双盲试验，ADCY9 基因中的变异 rs1967309 存在 AA 基因型。共有 6147 名患者被随机分配接受达塞曲匹 600mg 或每日安慰剂治疗。主要终点是从随机分组到首次发生心血管死亡、复苏性心脏骤停、非致死性心肌梗死或非致死性卒中的时间。中位随访 39.9 个月后，达塞曲匹组 3071 例患者中有 292 例（9.5%）和安慰剂组 3076 例患者中有 327 例（10.6%）发生主要终点事件[风险比 0.88；95%置信区间（CI）0.75-1.03；P=0.12]。主要终点各组成部分的风险比为心肌梗死 0.79（95%CI 0.65-0.96）、卒中 0.92（95%CI 0.64-1.33）、心血管原因死亡 1.21（95%CI 0.91-1.60）和复苏性心脏骤停 2.33（95%CI 0.60-9.02）。在预先指定的治疗敏感性分析中，达塞曲匹组的主要终点事件发生率为 7.8%（236/3015），安慰剂组为 9.3%（282/3031）（风险比 0.83；95%CI 0.70-0.98）。
达塞曲匹在研究结束时并未显著降低缺血性心血管事件主要终点的发生风险。需要进行新的试验来检验达塞曲匹改善 AA 基因型患者预后的药物遗传学假设。
dal-GenE ClinicalTrials.gov 标识符：NCT02525939。
