Is There a Need for Precision Medicine? P2Y12 Inhibitors

The newer, more potent P2Y12 inhibitors, prasugrel and ticagrelor, exhibit minimal inter-subject variability and achieve higher rates of therapeutic response in the general population; hence, there is a minimal clinical need to personalize their dosing regimens. Nevertheless, some research groups have identified certain alleles associated with an increased bleeding risk that should be investigated further. However, the most useful application of personalization appears to be that of DAPT de-escalation in ACS patients treated with PCI, the specific approach of which might be chosen according to clinical risk profile. Induction of DAPT with the newer agents is the most practical approach to preventing early post-procedural thrombosis, especially given that guided therapy cannot feasibly be implemented emergently, but long-term maintenance therapy with conventional DAPT is associated with excess bleeding. The two most promising strategies for combating this are de-escalation by the eventual downgrading of P2Y12 inhibition to clopidogrel and shortening the duration of DAPT via early discontinuation of aspirin. The latter appears to provide superior bleeding protection while the former appears to provide superior ischemic protection, findings which are unsurprising given their inherent differences. Nevertheless, both approaches reduce bleeding and their relative differences in reducing ischemic vs. hemorrhagic endpoints might be strategically utilized according to clinical context. For instance, in those with a high (e.g., previous ACS, bifurcation stent) or normal risk of ischemia, guided de-escalation to clopidogrel may be favorable, especially given its cost-effectiveness. Of course, this necessitates that the patient be sensitive to clopidogrel (i.e., devoid of major CYP2C19 LoF alleles); otherwise, the continuation of standard DAPT might be necessary. Alternatively, short DAPT with eventual transition to ticagrelor monotherapy may be favorable in those with high bleeding risk (e.g., prior bleeding, low bodyweight)