Objectives

The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes.

Background

Clopidogrel is the most broadly used platelet P2Y₁₂ inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles.

Methods

Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel.

Results

A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m², chronic kidney disease [glomerular filtration rate <60 ml/min], and diabetes mellitus) and 1 genetic (cytochrome P450 2C19 loss-of-function alleles). The C-statistics for the score as an integer variable were 0.71 (95% confidence interval [CI]: 0.68 to 0.75) and 0.64 (95% CI: 0.60 to 0.67) in the pharmacodynamic derivation and validation cohorts, respectively. A cutoff score ≥10 was associated with the best sensitivity and specificity to identify HPR status. The C-statistics for the score were 0.67 (95% CI: 0.64 to 0.71) for all-cause death and 0.66 (95% CI: 0.63 to 0.69) for the composite of all-cause death, stroke, or myocardial infarction at 1 year. Using multiple models for adjustment, the ABCD-GENE score consistently and independently correlated with all-cause death, as well as with the composite of all-cause death, stroke, or myocardial infarction, both as a continuous variable and by using the cutoff of ≥10. The score did not predict bleeding.

Conclusions

The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y₁₂ inhibitors other than clopidogrel should be considered.

中文翻译：

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对氯吡格雷无反应的预测规则的推导，验证和预测效用：ABCD-GENE得分。

目标

这项研究的目的是开发一个风险评分，将细胞色素P450 2C19功能丧失基因型与影响氯吡格雷反应的临床危险因素相结合，从而可以更准确地鉴定高血小板反应性（HPR）和临床不良反应风险中的受试者结果。

背景

氯吡格雷是使用最广泛的血小板P2Y ₁₂抑制剂。但是，相当多的患者由于持续的HPR（血栓风险增加的确定标志）而无法充分抑制血小板，因此需要使用工具来识别这些受试者。尽管细胞色素P450 2C19酶功能丧失等位基因的携带者减少了氯吡格雷的代谢，从而导致HPR和血栓并发症的发生率增加，但这仅解释了对氯吡格雷的药效学反应的一小部分，并且许多临床因素也已被证实被证明具有贡献作用。

方法

进行了三项前瞻性和独立研究：1）建立综合遗传和临床因素的风险评分，以识别接受氯吡格雷治疗的HPR患者；2）调查风险评分的外部有效性；和3）定义与氯吡格雷治疗的心肌梗死患者队列中与风险评分相关的临床结局。

结果

制定了风险评分ABCD-GENE（年龄，体重指数，慢性肾脏病，糖尿病和基因分型），纳入了5种独立的HPR预测因子：4种临床（年龄> 75岁，体重指数> 30 kg / m ^2），慢性肾脏疾病（肾小球滤过率<60 ml / min）和糖尿病）和1种遗传基因（细胞色素P450 2C19功能丧失等位基因）。在药代动力学推导和验证队列中，作为整数变量的分数的C统计量分别为0.71（95％置信区间[CI]：0.68至0.75）和0.64（95％CI：0.60至0.67）。临界分值≥10与确定HPR状态的最佳敏感性和特异性相关。对于全因死亡，该得分的C统计量为0.67（95％CI：0.64至0.71），对于全因死亡，中风或心肌梗死的综合评分为0.66（95％CI：0.63至0.69）年。使用多种模型进行调整，ABCD-GENE得分与全因死亡以及全因死亡，中风，或心肌梗塞，作为连续变量并使用≥10的临界值。该分数不能预测出血。

结论

ABCD-GENE评分是一种简单的工具，可用于识别氯吡格雷的HPR患者以及急性心肌梗死后发生不良缺血事件（包括死亡）的风险增加。对于ABCD-GENE评分较高的患者，应考虑使用氯吡格雷以外的长期口服P2Y ₁₂抑制剂。