Genotype-Guided Antiplatelet Therapy After Coronary Intervention in Patients With High Bleeding Risk　― Never Judge a Book by Its Cover ―

Risk stratification of major bleeding is established in the Japan Circulation Society guideline, in which 14 factors defined as high bleeding risks (HBR) are to be considered.¹ One key factor for preventing any bleeding complications is a shortened duration of dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). Several clinical trials with a 1- or 3-month duration of DAPT have succeeded in reducing major bleeding without the risk of ischemic events.² On the other hand, the guideline does not adequately clarify which P2Y12 receptor inhibitor (i.e., either clopidogrel or prasugrel) to use for DAPT in HBR patients. Clopidogrel is a pro-drug with a two-step metabolism process through cytochrome P-450 (CYP)-dependent oxidation, leading to a gradual onset of effect. Conversely, prasugrel, which is not predominantly metabolized by CYP2C19, promptly and potently confers its antiplatelet effects even among poor metabolizers of CYP2C19.² This difference in metabolic action can explain why prasugrel is preferred in patients with acute myocardial infarction. However, a cohort study reported that the incidence of TIMI major bleeding tended to be higher in patients receiving prasugrel than in those receiving clopidogrel (3.6% vs. 2.0%, P=0.06).³

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Here, just think for a moment. In daily practice, which P2Y12 receptor inhibitor would be selected if a patient undergoing PCI has several HBR factors (e.g., elderly, use of anticoagulant, and lower body weight)? A physician might select clopidogrel, expecting a gradual antiplatelet effect. Indeed, the European Society of Cardiology guideline recommends clopidogrel and aspirin but not prasugrel in HBR patients treated using drug-eluting stents (DES) for chronic and even acute coronary syndromes.² One approach to resolving this discrepancy is to tailor P2Y12 receptor inhibitors based on the identification of genetic polymorphisms and measurement of platelet function according to the clinical presentation of individual patients. Genotype-guided strategies involve escalating or de-escalating antiplatelet agents based on whether or not the patient is a CYP2C19 loss-of-function (LOF) carrier. The TAILOR-PCI trial evaluated the efficacy of genotype-guided antiplatelet therapy in patients carrying a CYP2C19 LOF genotype, but it failed to demonstrate the statistical superiority of genotype-guided antiplatelet therapy in terms of reducing adverse cardiovascular events.⁴ In contrast, a recent meta-analysis supported the utility of genotype-guided strategy of P2Y12 receptor inhibitor especially in patients with acute coronary syndrome.⁵

Given the controversy surrounding the usefulness of genotype-guided antiplatelet therapy in real-world clinical practice, in this issue of the Journal, Sawayama et al⁶ report important findings that fill in the gaps. Among the 618 patients treated with 2nd-generation DES, 319 patients with HBR and available CYP2C19 polymorphism information were evaluated. These patients were then divided into 2 groups, namely the decreased P2Y12 inhibitor action group (i.e., clopidogrel use in CYP2C19 LOF carriers) and retained P2Y12 inhibitor action group (i.e., clopidogrel use in CYP2C19 LOF non-carriers or prasugrel use, regardless of CYP2C19 polymorphism), and clinical outcomes were compared after 1 year. The major findings of this study can be summarized as follows. The first point is that, surprisingly, among patients with HBR, 66% were CYP2C19 LOF carriers. Thus, even among HBR patients, close attention should be given to the routine use of clopidogrel. This finding is consistent with a subanalysis of the PENDULUM registry, although it was based on platelet reactivity tests.⁷ Figure 1 shows the cumulative incidence of thrombotic/ischemic events in patients with HBR in the PENDULUM registry. The 2 curves indicate differences in platelet reactivity that might be caused by CYP2C19 LOF. Moreover, thrombotic/ischemic events were significantly higher in patients with HBR with hyper platelet reactivity (high residual platelet function) than in those with non-hyper platelet reactivity. In other words, hyper platelet reactivity exists in even patients with HBR and is associated with an increased risk of thrombotic/ischemic events. These findings suggest that even patients at high risk for bleeding complications should be administered potent P2Y12 receptor inhibitors that are less affected by genetic polymorphisms. Figure 2 details the findings of a meta-analysis of 6 studies enrolling 2,462 CYP2C19 LOF carriers, which demonstrated that the use of mainly prasugrel (6.6%; 90 events in 1,362 patients) promoted a significantly lower risk for ischemic events (odds ratio: 0.52; 95% confidence interval: 0.39–0.69) that did the use of clopidogrel (12.1%; 133 events in 1,100 patients).^5,8 Hence, it would be acceptable to use prasugrel as short DAPT for patients with HBR, at least in the acute phase.

Figure 1.

Cumulative incidences of thrombotic/ischemic events according to platelet reactivity status in patients with high bleeding risk (HBR). CI, confidence interval; HR, hazard ratio.

Figure 2.

Meta-analysis of ischemic events in CYP2C19 loss-of-function carriers receiving prasugrel vs. clopidogrel. *Study includes Ticagrelor. CI, confidence interval; LOF, loss-of-function; OR, odds ratio.

Secondly, Sawayama et al suggest that P2Y12 receptor inhibitors as single-antiplatelet therapy (SAPT) would be better based on the presence or absence of CYP2C19 LOF carriers. The guideline recommends the use of P2Y12 receptor inhibitors after very short DAPT in HBR patients treated with DES.¹ The present study demonstrated that clopidogrel use may be a better choice for patients with HBR if they have been confirmed as a CYP2C19 non-LOF carrier. The reason for this is that prasugrel treatment promoted more instances of bleeding complications than did clopidogrel treatment (8.4% vs. 1.9%) among the retained P2Y12-I action group with HBR status.⁶ Although theoretically correct, the present study was underpowered to provide meaningful data on clinical events. Recently, the PENDULUM-MONO registry⁹ reported the 24-month clinical outcomes in 1,107 HBR patients treated with prasugrel SAPT following short DAPT. Notably, clinically relevant bleeding and major adverse cardiac and cerebrovascular events were observed in 4.6% and 7.7% of the patients, respectively, which seems acceptable for patients with HBR considering that major bleeding and ischemic events had been observed in 4.5% and 9.5% of patients, respectively, receiving the outdated long DAPT strategy. Therefore, long-term prasugrel SAPT could be a better option for patients with HBR.

Future Direction

Genotyping-guided antiplatelet therapy is the ideal approach because it has the potential to reduce both bleeding and ischemic events based on genetic analysis of individual patients, regardless of HBR factors. However, performing genetic analysis for all patients is unrealistic. As the authors mention, the identification of CYP2C19 LOF non-carriers in patients with HBR would provide robust information necessary for making decisions regarding de-escalation to clopidogrel. However, well-designed randomized trials will be needed for the establishment of precision medicine in the form of genotype-guided antiplatelet therapy.

As the saying goes, “Never judge a book by its cover,” so there are things that cannot be known without genetic analysis. This study is a valuable reminder of the need to keep in mind that approximately two-thirds of patients with HBR based on clinical HBR criteria may not respond well to clopidogrel due to being CYP2C19 poor metabolizers.

Disclosures

R.I. has received honoraria and lecture fees from Abbott Medical Japan LLC and Daiichi Sankyo Co., Ltd.

References

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