Editorial
Comparative Effects of Genetic and Nongenetic Factors in Antithrombotic Strategy
2023 Volume 30 Issue 12 Pages 1763-1765
Details
2023 Volume 30 Issue 12 Pages 1763-1765
See article vol. 30: 1791-1802
A recent randomized trial showed that a CYP2C19 genotype-guided strategy for oral P2Y12 inhibitor therapy was noninferior to standard treatment at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding among patients undergoing primary percutaneous coronary intervention (PCI)1). In addition, recent studies showed that integrating CYP2C19 loss-of-function genotypes with clinical factors that influence P2Y12 inhibitor response may enhance the ability to identify patients at risk of high platelet reactivity (HPR)2, 3), and thus, appropriate selection of P2Y12 inhibitor therapy is necessary.
In this issue of the Journal of Atherosclerosis and Thrombosis, Goto et al. investigated whether clinical factors listed in novel composite scoring system that developed to identify patients with HPR on P2Y12 inhibitor could be predictive for future cardiovascular events4). Briefly, the study showed the increase in the number of clinical factors in HHD-GENE (hypertension, hemodialysis, and diabetes) score was associated with an increased risk of major adverse cardiovascular event in patients on a P2Y12 inhibitor; however, the number of clinical factors of ABCD-GENE (age ≥ 75 years, body mass index ＞30 kg/m2, chronic kidney disease, and diabetes) score was not predictive for ischemic events in patients with myocardial infarction.
This study is worthy and admirable because genetic and platelet function testing are still not widely available in daily practice.
Recent meta-analysis demonstrated the potential usefulness of guided P2Y12 inhibitor therapy, using either platelet function or genetic testing, as compared with the routine selection of antiplatelet agents in patients with acute coronary syndrome5). While platelet function testing provides a direct measure of individual response to P2Y12 inhibitors, it is characterized by an assay-dependent variability in results and requires the patient to be on treatment with P2Y12 inhibitors that may represent a limitation in the setting of acute coronary syndrome6). Moreover, CYP2C19 genotypes contribute to only a fraction of the variability in the effect of antithrombotic therapy, and other clinical variables have contributing roles7). Thus, a strategy of combined assessment with clinical and genetic variables may be relevant (Fig.1). As demonstrated by the recently published ABCD-GENE score, genetic factors can be incorporated with clinical variables in the form of a composite scoring system that could be helpful in identifying high-risk patients and selecting appropriate oral P2Y12 inhibitor therapy2). Despite this, genetic testing cannot be performed in daily clinical practice. Thus, simple risk model stratifying ischemic risk in patients with acute myocardial infarction undergoing PCI and treatment with clopidogrel or prasugrel is warranted.
Incorporation of genetic and non-genetic factors into treatment plan
The original HHD-GENE score, comprising hypertension, hemodialysis, diabetes, and CYP2C19 loss-of-function alleles, was developed to evaluate patients at a high risk for HPR on prasugrel3). On a practical level, in this issue of Journal of Atherosclerosis and Thrombosis, the authors have shown the prognostic ability of clinical factors listed in the HHD-GENE score, without information on the genetic variant associated with ischemic events4). In contrast, clinical factors alone in ABCD-GENE score were insufficiently predictive for subsequent ischemic outcomes. There were several reasons for the prognostic superiority of clinical factors listed in the HHD-GENE score as demonstrated in the present study. First, the distribution of CYP2C19 genotypes varies by race, and the prevalence of a loss-of-function allele is more frequent in Asians than in Caucasians8), and the greater impact of genetic factor in the ABCD-GENE score than in the HHD-GENE score might be attributed to the study results. Second, although the ABCD-GENE score included chronic kidney disease as a clinical factor, including hemodialysis, are known to have extremely higher risk of cardiovascular disease9), potentially resulting in differential impact of clinical factors between the ABCD-GENE and HHD-GENE scores on ischemic outcomes.
Against this background, what types of patients are expected to derive therapeutic benefit from testing genotypes? Study population with clustering clinical factors predisposed to HPR may reduce the ability to detect a clinical benefit with tailored antiplatelet therapy solely based on the results of genetic testing. Careful selection of patient population with adequately powered clinical trials should be investigated in the future.
These results suggest that the clinical factors listed in the HHD-GENE score were useful for risk stratification in patients with acute myocardial infarction undergoing PCI and treated with P2Y12 inhibitors. Besides, this study provides one step forward to appropriate selection of study population in genotype-guided antithrombotic strategy.
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