A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study
A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study
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DOI：
10.1016/s0140-6736(22)01841-4
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发表时间：
2023-02-02
期刊：
影响因子：
168.9
通讯作者：
Guchelaar, Henk-Jan
中科院分区：
文献类型：
--
作者：
Swen, Jesse J.;van der Wouden, Cathelijne H.;Guchelaar, Henk-Jan
背景：在开始药物治疗前进行药物遗传学测试的益处已经在几种单基因-药物组合中得到了很好的证明。然而，使用药物遗传学小组的先发制人基因分型策略的临床应用还没有得到严格的评估。方法我们在7个欧洲国家(奥地利、希腊、意大利、荷兰、斯洛文尼亚、西班牙和英国)的18家医院、9个社区卫生中心和28家社区药店进行了一项开放标签、多中心、对照、整群随机、交叉实施的12基因药物遗传学小组研究。18岁或18岁以上的患者获得荷兰药物遗传学工作组指南中临床推荐的药物(即索引药物)的第一处方，作为常规护理的一部分，有资格纳入。排除标准包括以前对与索引药物相关的基因进行基因测试，计划治疗持续时间少于连续7天，以及严重的肾或肝功能不全。所有患者在参与研究前均给予书面知情同意。参与者接受了12个基因的50个生殖系变异的基因分型，那些具有可操作变异(即，荷兰药物遗传学工作组[DPWG]建议改变为标准护理药物治疗的药物-基因相互作用测试结果)的人根据DPWG的建议进行治疗。对照组患者接受标准治疗。为了使临床医生为先发制人的药物遗传学测试做好准备，在现场启动访问期间对当地团队进行了培训，并提供了在线教育材料。主要结果是在12周的随访期内发生与临床相关的药物不良反应。分析与患者是否遵守DPWG指南无关。初步分析是使用把关分析进行的，在这种分析中，将研究组中具有可操作的药物-基因相互作用的人的结果与对照组进行比较，只有在差异具有统计学意义的情况下，才会进行包括研究中所有患者的分析。比较了研究组和对照组之间的结果，包括具有可操作的药物-基因相互作用测试结果的患者(即DPWG建议改变为标准护理药物治疗的结果)和所有接受至少一剂索引药物治疗的患者。安全性分析包括所有接受至少一剂研究药物的参与者。这项研究已在ClinicalTrials.gov注册，NCT03093818，并对新参与者关闭。结果在2017年3月7日至2020年6月30日期间，41 696名患者接受了资格评估，6944名患者(51.4%女性，48.6%男性；97.7%自我报告的欧洲、地中海或中东种族)进入并分配接受基因指导药物治疗(n=3342)或标准护理(n=3602)。99例患者(研究组52例(1.6%)和对照组47例(1.3%))在分组后撤回同意。652名参与者(研究组367名(11.0%)和对照组285名(7.9%))失去了随访。在指标药物试验结果可操作的患者(n=1558)中，研究组725例患者中152例(21个中心点0%)发生临床相关不良反应，对照组833例患者中231例(27.7%)发生临床相关不良反应(优势比[OR]0中心点70[95%CI 0中心点54-0中心点91]；P=0.0075)，而研究组2923例中628例(21.5%)，对照组3270例中934例(28.6%)(OR0.70[95%CI0.61-0.79]；P
Background The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Findings Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51.4 % female, 48.6% male; 97.7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1.6%] of the study group and 47 [1.3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11.0%] in the study group and 285 [7.9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21 center dot 0%) of 725 patients in the study group and 231 (27.7%) of 833 patients in the control group (odds ratio [OR] 0 center dot 70 [95% CI 0 center dot 54-0 center dot 91]; p=0.0075), whereas for all patients, the incidence was 628 (21.5%) of 2923 patients in the study group and 934 (28.6%) of 3270 patients in the control group (OR 0.70 [95% CI 0.61-0.79]; p