A 12-Gene Pharmacogenetic Panel to Prevent Adverse Drug Reactions

Study Questions:

Does pre-emptive pharmacogenetic testing prior to initiating drug therapy reduce clinically relevant adverse drug reactions?


This study was an open-label, multicenter, cluster-randomized crossover study conducted in seven European countries. Participants were randomized to either genotype-guided drug prescribing (study group) or standard clinical care (control group). All study sites crossed over to the opposite treatment group during the study period. Patients aged ≥18 years who were receiving a first prescription for a drug (“index drug”) with an actionable recommendation in the Dutch Pharmacogenetics Working Group (DPWG) were eligible. Patients were excluded if they had received previous genetic testing for a gene relevant to the index drug, a planned treatment duration <7 days, or had severe renal or liver impairment. An actionable drug-gene interaction was defined as a result for which the DPWG recommended a change to standard treatment. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant were treated according to DPWG recommendations. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were conducted irrespective of adherence to DPWG treatment guidelines. The primary analysis was completed using a gatekeeping analysis, in which outcomes in people with an actionable gene-drug interaction in the study group were compared to the control group, and only statistically significant differences were further evaluated in an analysis including all patients.


A total of 6,944 (51.4% female, 48.6% male; 97.7% European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided treatment (n = 3,342) or standard care (n = 3,602). Fifty-two patients in the study group and 47 patients in the control group withdrew consent and 419 patients and 332 patients were lost to follow-up in the study group and control group, respectively. Of the 6,944 patients enrolled, 93.5% carried at least one actionable variant. The most common index drug was atorvastatin (n = 716), followed by clopidogrel (n = 619), and tacrolimus (n = 472). Overall, 69.9% of DPWG recommendations were accepted. A total of 3,096 adverse events reported by 1,563 participants met prespecified severity criteria.

Of patients with an actionable test result for the index drug, the incidence of a clinically relevant adverse drug reaction occurred in 152/725 (21%) study group participants versus 231/833 (27.7%) of control group participants (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.54-0.91; p = 0.0075). For all patients, the incidence was 628/2,923 (21.5%) in the study group compared to 934/3,270 (28.6%) in the control group (OR, 0.70; 95% CI, 0.61-0.79; p < 0.0001).


Use of a 12-gene pharmacogenetic test panel to provide genotype-guided treatment recommendations resulted in a 30% reduction in clinically relevant adverse drug reactions compared to standard treatment. The study provides evidence to support large-scale implementation of pre-emptive, panel-based pharmacogenomic testing to improve the safety of drug therapy.


Prior evidence has documented the benefit of pharmacogenetic testing for several single gene-drug pairs in specialized care settings; however, this study demonstrates the utility of a broader, pre-emptive testing strategy across diverse European health care organizations and settings. Together, these results support a personalized medicine approach using pharmacogenetics-guided drug prescribing to reduce the incidence of clinically relevant adverse drug reactions.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Dyslipidemia, Prevention, EP Basic Science, Genetic Arrhythmic Conditions, Lipid Metabolism, Statins

Keywords: Atorvastatin, Clopidogrel, Drug Interactions, Drug Prescriptions, Drug-Related Side Effects and Adverse Reactions, Ethnic Groups, Genetics, Medical, Genotype, Patient Care Team, Pharmacogenetics, Pharmacogenomic Testing, Secondary Prevention, Tacrolimus

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