Author + information
- Received December 9, 2019
- Revision received January 17, 2020
- Accepted January 22, 2020
- Published online March 2, 2020.
- Dominick J. Angiolillo, MD, PhDa,∗∗ (, )
- Davide Capodanno, MD, PhDb,∗,
- Nicolas Danchin, MDc,d,
- Tabassome Simon, MD, PhDe,f,
- Thomas O. Bergmeijer, MDg,
- Jurrien M. ten Berg, MDg,
- Dirk Sibbing, MDh,i,j and
- Matthew J. Price, MDk
- aDivision of Cardiology, Department of Medicine, University of Florida College of Medicine, Jacksonville, Florida
- bDivision of Cardiology, A.O.U. “Policlinico G. Rodolico-San Marco” University of Catania, Catania, Italy
- cHôpital Européen Georges Pompidou, Department of Cardiology, Assistance Publique–Hôpitaux de Paris, Paris, France
- dUniversité Paris Descartes, Paris, France
- eAssistance Publique–Hôpitaux de Paris, Hôpital Saint Antoine, Department of Clinical Pharmacology, Clinical Research Platform (URCEST-CRB-CRCEST), Paris, France
- fSorbonne-Université, Faculté de Médecine, site St. Antoine, Service de Pharmacologie, Paris, France
- gSt. Antonius Center for Platelet Function Research, Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
- hDepartment of Cardiology, LMU München, Munich, Germany
- iDZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
- jPrivatklinik Lauterbacher Mühle am Ostersee, Seeshaupt, Germany
- kDivision of Cardiovascular Diseases, Scripps Clinic, La Jolla, California
- ↵∗Address for correspondence:
Dr. Dominick J. Angiolillo, University of Florida College of Medicine, 655 West 8th Street, Jacksonville, Florida 32209.
Objectives The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes.
Background Clopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles.
Methods Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel.
Results A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate <60 ml/min], and diabetes mellitus) and 1 genetic (cytochrome P450 2C19 loss-of-function alleles). The C-statistics for the score as an integer variable were 0.71 (95% confidence interval [CI]: 0.68 to 0.75) and 0.64 (95% CI: 0.60 to 0.67) in the pharmacodynamic derivation and validation cohorts, respectively. A cutoff score ≥10 was associated with the best sensitivity and specificity to identify HPR status. The C-statistics for the score were 0.67 (95% CI: 0.64 to 0.71) for all-cause death and 0.66 (95% CI: 0.63 to 0.69) for the composite of all-cause death, stroke, or myocardial infarction at 1 year. Using multiple models for adjustment, the ABCD-GENE score consistently and independently correlated with all-cause death, as well as with the composite of all-cause death, stroke, or myocardial infarction, both as a continuous variable and by using the cutoff of ≥10. The score did not predict bleeding.
Conclusions The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.
↵∗ Drs. Angiolillo and Capodanno equally contributed as first authors.
Dr. Angiolillo has received consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payments for participation in review activities from CeloNova and St. Jude Medical; and has received research grants to his institution from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, and Renal Guard Solutions. Dr. Capodanno has received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Daiichi-Sankyo, and Sanofi. Dr. Danchin has received grants, speaking fees, consulting fees, or nonfinancial support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Intercept, Novo-Nordisk, Pfizer, Sanofi and Servier. Dr. Simon has received grants to her institution from AstraZeneca, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Sanofi; and has received consulting fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Sanofi, and Novartis. Dr. ten Berg has received advisory, consulting, and speaker fees from Accumetrics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, The Medicines Company, Ferrer, Pfizer, and Merck; and has received research grants from AstraZeneca and ZonMw. Dr. Sibbing has received grants and personal fees from Roche Diagnostics and Daiichi-Sankyo; and has received personal fees from Bayer, Pfizer, Sanofi, and Haemonetics. Dr. Price has received consulting fees or honoraria from Abbott Vascular, ACIST Medical, AstraZeneca, Boston Scientific, Chiesi USA, Medtronic, St. Jude Medical, and W.L. Gore Medical; and has received research grants to his institution from Daiichi-Sankyo. Dr. Bergmeijer has reported that he has no relationships relevant to the contents of this paper to disclose.
- Received December 9, 2019.
- Revision received January 17, 2020.
- Accepted January 22, 2020.
- 2020 American College of Cardiology Foundation
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