Pharmacogenetics-Guided De-Escalation of Dual Antiplatelet Therapy Based on CYP2C19 Testing in Patients After Acute Coronary Syndrome: Clinical Outcomes and Cost-Consequence Analysis.

CYP2C19

In carriers of a loss-of-function CYP2C19 allele, switching from ticagrelor to clopidogrel after PCI may leave platelet inhibition insufficient; here the genotype decides whether to de-escalate.

De-escalating dual antiplatelet therapy from ticagrelor to clopidogrel after PCI for acute coronary syndrome reduces bleeding risk, but may leave platelet inhibition insufficient in carriers of a loss-of-function CYP2C19 allele. This prospective, randomised, open-label, parallel-group trial compared, over 12 months, de-escalation decided by CYP2C19 genotype (n = 75) with standard practice left to the treating physician's discretion (n = 75); the primary safety endpoint was the cumulative incidence of clinically relevant bleeding (BARC ≥ 2) and the secondary efficacy endpoint a composite of ischaemic events. In the intention-to-treat population (n = 150), BARC ≥ 2 bleeding was 10.7% versus 12.0% (HR 0.88; 95% CI 0.34-2.28; p = 0.79) and the ischaemic composite 13.3% versus 14.7% (HR 0.91; 95% CI 0.38-2.13; p = 0.82), with no significant difference. The per-protocol analysis, excluding eight patients who required non-protocol anticoagulant therapy, gave similar bleeding rates (9.7% vs 11.4%; HR 0.84) and a numerically larger but non-significant effect on the ischaemic composite (11.1% vs 15.7%; HR 0.69). The genotype-guided strategy was associated with savings in drug and testing costs of RUB 1,036,340.21 for the cohort (RUB 15,278.16 per patient), which stayed positive across the full range of observed drug prices, the break-even price for testing being RUB 19,748.16 per patient.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This neutral result should not be read as equivalence: in 150 open-label patients, the confidence intervals for bleeding (HR 0.88; 0.34-2.28) and for the ischaemic endpoint (HR 0.91; 0.38-2.13) are wide enough to remain compatible with a benefit as well as with an excess of events, so the trial establishes neither a reduction in bleeding nor ischaemic safety of genotype-guided de-escalation. The per-protocol sensitivity analysis, which points towards fewer ischaemic events (HR 0.69), is non-significant and cannot be read as a benefit, and the control strategy, left to the physician's discretion, is by construction not standardised. The only advantage reported is a saving on drug and testing costs alone, to be confirmed, as the authors say, in larger cohorts before this trial is used as an argument to de-escalate by genotype.

Analysis by Dr Thibaut Benquey