Genotype-guided antiplatelet therapy in patients receiving PCI

In a prespecified analysis of the TAILOR-PCI trial, genotype-guided therapy with clopidogrel showed to be associated with a significantly lower risk of cumulative ischaemic events in patients undergoing percutaneous coronary intervention (PCI). A strategy to prevent recurrent events could dramatically impact a patient's clinical course.

Clopidogrel is a prodrug that has to be converted in the liver to its active metabolite. “Loss-of-function carriers of the CYP2C19*2 or*3 carriers have 40% less antiplatelet activity then non-carriers,” Dr Brenden Ingraham (Mayo Clinic, MN, USA) explained [1]. Therefore, the TAILOR-PCI (NCT01742117) research question was whether identifying loss-of-function CYP2C19 allele carriers and altering P2Y12 inhibitor therapy based on CYP2C19 genotype can reduce ischaemic outcomes.

TAILOR-PCI was a 2 arm, parallel, open-label, international, multicentre, randomised clinical trial including 5,302 adults who underwent PCI and were prescribed at least 12 months of dual antiplatelet therapy. Participants were randomised into 2 groups, a conventional therapy group that received clopidogrel (75 mg daily), or the point-of-care genotype-guided therapy group. In this group, genotype was assessed and CYP2C19*2/e* loss-of-function carriers were treated with 90 mg ticagrelor twice daily; only non-carriers received 75 mg clopidogrel daily. The primary study endpoint was the time-to-first event for a composite of cardiovascular death, myocardial infarction (MI), severe recurrent ischaemia, definite or probable stent thrombosis, and stroke at 122 months.

The trial did not meet its primary endpoint with results for genotype-guided therapy versus standard therapy (P=0.056). However, in a post-hoc, hypothesis-generating, secondary analysis of cumulative endpoints was conducted where all ischaemic and bleeding endpoint within the 12 months were assessed, including recurrent events. A total of 5,276 patients were eligible for this analysis; 1,849 CYP2C19 loss-of-function carriers were analysed. 903 of them were assigned to genotype-guided therapy, another 946 to conventional therapy.

The cumulative incidence of ischaemic events in CYP2C19 loss-of-function carriers was 7% in the conventional therapy compared with 4.5% in the genotype-guided therapy, which translates in a statistically significant 40% reduction in cumulative ischaemic events (HR 0.61; 95% CI 0.41–0.89; P<0.01). Moreover, there was no significant difference in major or minor bleedings between the 2 groups. “Our findings demonstrate the potential clinical utility of a precision medicine approach,” Dr Ingraham concluded.

1. Ingraham BS. Genotype-guided oral P1Y12 inhibitor therapy reduces cumulative ischemic events following percutaneous coronary intervention. ESC Congress 2022, Barcelona, Spain, 26–29 August.

 

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Posted on 27 October 202226 October 2022