Introduction
P2Y12 Inhibitors
Overview of P2Y12 Inhibitors
Clopidogrel
Phenotype | Rapid metabolizer | Normal metabolizer | Intermediate metabolizer | Poor metabolizer |
---|---|---|---|---|
Genotype | *17/*17 *1/*17 | *1/*1 *2/*17 *3/*17 *4/*17 *6/*17 | *1/*2 *1/*3 *1/*4 *1/*6 | *2/*2 *2/*3 *2/*4 *2/*6 *3/*3 *3/*4 *3/*6 *4/*4 *4/*6 *6/*6 |
European | East Asian | African American/Afro-Caribbean | Latino | |
---|---|---|---|---|
*2 | 0.1469 | 0.2835 | 0.1815 | 0.1042 |
*3 | 0.0016 | 0.0725 | 0.0028 | 0.0008 |
*4 | 0.0024 | 0.0002 | 0 | 0.0005 |
*6 | 0.0003 | 0.0006 | 0 | 0 |
*17 | 0.2154 | 0.0205 | 0.2072 | 0.1666 |
Prasugrel
Ticagrelor
Current Status/Future Directions
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) |
Aspirin
Pseudo-resistance
Bodyweight and BMI
Inflammation
Pharmacogenomics
A Note on Aspirin in Primary Prevention
Is There a Need for Precision Medicine? Aspirin | |
The pharmacogenomics of aspirin non-response are poorly elucidated and appear to be of relatively minimal concern compared to other, non-genetic factors. Enteric aspirin has reduced bioavailability and does not have sufficient evidence to support its use in ASCVD; thus, it should be avoided in the cardiac patient, although guidelines do not always explicitly make this point [123]. With respect to personalization, the most useful application appears to be that of dosing according to bodyweight and/or BMI. The common low-dose aspirin strategy is aimed at achieving the minimum protective dose such that the risk of bleeding is lessened. However, this leaves minimal “buffer,” putting many non-average patients at risk of failing to reach the threshold concentration required to achieve benefit, which can be due to any number of factors, including body size and composition [124]. Moreover, the studies from which this approach is derived are decades old and took place when the prevalence of obesity was much lower. Recent evidence suggests that only patients of lower bodyweight benefit from the cardioprotective effects of low-dose aspirin. In contrast to patients on warfarin who receive functional testing to verify the adequate response, aspirin response is not routinely tested for and is simply presumed to be conferring a benefit. Considering the pervasiveness of ASCVD and the widespread use of aspirin in its treatment, this represents a considerable issue that could potentially be remedied through standardized dosing strategies. Furthermore, non-adherence appears to be especially relevant to aspirin, which may be a consequence of the patient belief that aspirin is less important than other medications, given its routine household use for minor indications and the ability to acquire it without a prescription. Whatever the reason, non-adherence is likely a sizeable contributor to treatment failure, necessitating appropriate intervention. Inflammation is another important consideration; common afflictions, including obesity and ASCVD, constitute chronic inflammatory states and have all been associated with increased platelet reactivity [125, 126]. Thus, many patients, including those receiving aspirin for secondary prevention, may be predisposed to HTPR, and yet continue to be prescribed the same low-dose regimens as those without preexisting disease. All these factors can impact the holistic efficacy of DAPT and should not be overlooked. However, with evidence that short DAPT followed by P2Y12 inhibitor monotherapy is as effective as conventional DAPT but with less bleeding, there may be a move away from using aspirin post-PCI [127] Finally, the avoidance of aspirin in the primary prevention of ASCVD is likely a missed opportunity for clinicians. RCTs of aspirin in primary prevention have demonstrated an excess risk of bleeding, negating any potential benefit; however, inappropriate patient selection in these studies might underpin the disappointing results. Increased personalization with PFTs, such as LTA, might be better able to identify high-risk patients who are more likely to achieve a net clinical benefit from primary prophylactic aspirin |