Bristol TAG, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Patient representative.
Health Technol Assess. 2024 Sep;28(57):1-194. doi: 10.3310/PWCB4016.
Stroke or transient ischaemic attack patients are at increased risk of secondary vascular events. Antiplatelet medications, most commonly clopidogrel, are prescribed to reduce this risk. Factors including genetic variants can hinder clopidogrel metabolism. Laboratory-based or point-of-care tests can detect these variants, enabling targeted treatment.
To assess the effectiveness of genetic testing to identify clopidogrel resistance in people with ischaemic stroke or transient ischaemic attack. Specific objectives: Do people tested for clopidogrel resistance, and treated accordingly, have a reduced risk of secondary vascular events? Do people with loss-of-function alleles associated with clopidogrel resistance have a reduced risk of secondary vascular events if treated with alternative interventions compared to clopidogrel? Do people with loss-of-function alleles associated with clopidogrel resistance have an increased risk of secondary vascular events when treated with clopidogrel? What is the accuracy of point-of-care tests for detecting variants associated with clopidogrel resistance? What is the technical performance and cost of genetic tests? Is genetic testing for clopidogrel resistance cost-effective compared with no testing?
Systematic review and economic model.
Objective 1: Two studies assessed secondary vascular events in patients tested for loss-of-function alleles and treated accordingly. They found a reduced risk, but confidence intervals were wide (hazard ratio 0.50, 95% confidence interval 0.09 to 2.74 and hazard ratio 0.53, 95% confidence interval 0.24 to 1.18). Objective 2: Seven randomised controlled trials compared clopidogrel with alternative treatment in people with genetic variants. Ticagrelor was associated with a lower risk of secondary vascular events than clopidogrel (summary hazard ratio 0.76, 95% confidence interval 0.65 to 0.90; two studies). Objective 3: Twenty-five studies compared outcomes in people with and without genetic variants treated with clopidogrel. People with genetic variants were at an increased risk of secondary vascular events (hazard ratio 1.72, 95% confidence interval 1.43 to 2.08; 18 studies). There was no difference in bleeding risk (hazard ratio 0.98, 95% confidence interval 0.68 to 1.40; five studies). Objective 4: Eleven studies evaluated Genomadix Cube accuracy; no studies evaluated Genedrive. Summary sensitivity and specificity against laboratory reference standards were both 100% (95% confidence interval 94% to 100% and 99% to 100%). Objective 5: Seventeen studies evaluated technical performance of point-of-care tests. Test failure rate ranged from 0.4% to 19% for Genomadix Cube. A survey of 8/10 genomic laboratory hubs revealed variation in preferred technologies for testing, and cost per test ranging from £15 to £250. Most laboratories expected test failure rate to be < 1%. Additional resources could enhance testing capacity and expedite turnaround times. Objective 6: Laboratory and point-of-care testing strategies were cost-saving and increase quality-adjusted life-years compared with no testing. Both strategies gave similar costs, quality-adjusted life-years and expected net monetary benefit.
Our results suggest that testing followed by tailored treatment is likely to be effective and cost-effective in both populations.
Accuracy and technical performance of Genedrive. Test failure rate of Genomadix Cube in a National Health Service setting. Value of testing additional loss-of-function alleles. Appropriateness of treatment dichotomy based on loss-of-function alleles.
Lack of data on Genedrive. No randomised 'test-and-treat' studies of dipyramidole plus aspirin.
This study is registered as PROSPERO CRD42022357661.
This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135620) and is published in full in ; Vol. 28, No. 57. See the NIHR Funding and Awards website for further award information.
中风或短暂性脑缺血发作患者发生二次血管事件的风险增加。抗血小板药物（最常用的是氯吡格雷）常用于降低这种风险。包括遗传变异在内的多种因素会阻碍氯吡格雷的代谢。基于实验室或即时检测的测试可以检测到这些变异，从而实现针对性治疗。
评估基因检测识别缺血性中风或短暂性脑缺血发作患者氯吡格雷抵抗的有效性。具体目标：检测氯吡格雷抵抗的患者，并进行相应治疗，是否会降低二次血管事件的风险？与氯吡格雷相比，携带氯吡格雷抵抗相关失活等位基因的患者接受替代干预治疗，是否会降低二次血管事件的风险？携带氯吡格雷抵抗相关失活等位基因的患者使用氯吡格雷治疗，是否会增加二次血管事件的风险？即时检测与氯吡格雷抵抗相关的变异的准确性如何？基因检测的技术性能和成本是多少？与不进行检测相比，检测氯吡格雷抵抗是否具有成本效益？
系统评价和经济模型。
目标 1：两项研究评估了检测失活等位基因并进行相应治疗的患者的二次血管事件。他们发现风险降低，但置信区间较宽（风险比 0.50，95%置信区间 0.09 至 2.74 和风险比 0.53，95%置信区间 0.24 至 1.18）。目标 2：七项随机对照试验比较了携带遗传变异的患者使用氯吡格雷与替代治疗的效果。替格瑞洛与氯吡格雷相比，二次血管事件的风险较低（汇总风险比 0.76，95%置信区间 0.65 至 0.90；两项研究）。目标 3：二十五项研究比较了携带和不携带遗传变异并接受氯吡格雷治疗的患者的结局。携带遗传变异的患者发生二次血管事件的风险增加（风险比 1.72，95%置信区间 1.43 至 2.08；18 项研究）。出血风险无差异（风险比 0.98，95%置信区间 0.68 至 1.40；五项研究）。目标 4：十一项研究评估了 Genomadix Cube 的准确性；没有研究评估 Genedrive。与实验室参考标准相比，Genomadix Cube 的综合敏感性和特异性均为 100%（95%置信区间 94%至 100%和 99%至 100%）。目标 5：十七项研究评估了即时检测的技术性能。Genomadix Cube 的检测失败率范围为 0.4%至 19%。对 10 个基因组学实验室中心的调查显示，检测技术偏好存在差异，检测费用为 15 英镑至 250 英镑不等。大多数实验室预计检测失败率将低于 1%。增加额外资源可以提高检测能力并加快周转时间。目标 6：实验室和即时检测策略与不进行检测相比，具有成本效益，并增加了质量调整生命年。两种策略的成本、质量调整生命年和预期净货币收益都相似。
我们的研究结果表明，在这两种人群中，检测后进行针对性治疗可能是有效且具有成本效益的。
Genedrive 的准确性和技术性能。Genomadix Cube 在国家卫生服务（NHS）环境中的检测失败率。检测其他失活等位基因的价值。基于失活等位基因的治疗二分法的适当性。
缺乏关于 Genedrive 的数据。没有随机“检测和治疗”二磷酸腺苷加阿司匹林的研究。
本研究已在 PROSPERO（注册号：CRD42022357661）上注册。
本研究由英国国家卫生与保健优化研究所（NIHR）证据合成计划资助（NIHR 项目编号：NIHR135620），全文发表于；第 28 卷，第 57 期。欲了解更多有关该奖项的信息，请访问 NIHR 资助和奖项网站。
