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CYP2C19 Genotyping in Anticoagulated Patients After Percutaneous Coronary Intervention: Should It Be Routine?

2022; Lippincott Williams & Wilkins; Volume: 145; Issue: 10 Linguagem: Inglês

10.1161/circulationaha.121.057028

1524-4539

Dimitri J. Maamari, Farouc A. Jaffer, Amit V. Khera, Akl C. Fahed,

Venous Thromboembolism Diagnosis and Management

HomeCirculationVol. 145, No. 10CYP2C19 Genotyping in Anticoagulated Patients After Percutaneous Coronary Intervention: Should It Be Routine? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBCYP2C19 Genotyping in Anticoagulated Patients After Percutaneous Coronary Intervention: Should It Be Routine? Dimitri J. Maamari, Farouc A. Jaffer, Amit V. Khera and Akl C. Fahed Dimitri J. MaamariDimitri J. Maamari https://orcid.org/0000-0003-2797-9370 Center for Genomic Medicine (D.J.M., A.V.K., A.C.F.), Massachusetts General Hospital Cardiovascular Disease Initiative, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (D.J.M., A.V.K., A.C.F.). , Farouc A. JafferFarouc A. Jaffer https://orcid.org/0000-0001-7980-384X Division of Cardiology (F.A.J., A.V.K., A.C.F.), Department of Medicine, Massachusetts General Hospital Cardiovascular Research Center, Cardiology Division (F.A.J., A.C.F.), Massachusetts General Hospital Department of Medicine, Harvard Medical School (F.A.J., A.V.K., A.C.F.) Boston. , Amit V. KheraAmit V. Khera https://orcid.org/0000-0001-6535-5839 Center for Genomic Medicine (D.J.M., A.V.K., A.C.F.), Massachusetts General Hospital Division of Cardiology (F.A.J., A.V.K., A.C.F.), Department of Medicine, Massachusetts General Hospital Department of Medicine, Harvard Medical School (F.A.J., A.V.K., A.C.F.) Boston. Cardiovascular Disease Initiative, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (D.J.M., A.V.K., A.C.F.). and Akl C. FahedAkl C. Fahed Correspondence to: Akl C. Fahed, MD, MPH, Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.218, Boston, MA 02114. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4849-6389 Center for Genomic Medicine (D.J.M., A.V.K., A.C.F.), Massachusetts General Hospital Division of Cardiology (F.A.J., A.V.K., A.C.F.), Department of Medicine, Massachusetts General Hospital Cardiovascular Research Center, Cardiology Division (F.A.J., A.C.F.), Massachusetts General Hospital Department of Medicine, Harvard Medical School (F.A.J., A.V.K., A.C.F.) Boston. Cardiovascular Disease Initiative, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (D.J.M., A.V.K., A.C.F.). Originally published7 Mar 2022https://doi.org/10.1161/CIRCULATIONAHA.121.057028Circulation. 2022;145:721–723Balancing ischemic and bleeding risks in individuals on chronic oral anticoagulation (OAC) who undergo percutaneous coronary intervention (PCI) remains a key challenge in clinical practice. Approximately 10% of individuals who undergo PCI have a concurrent indication for long-term oral anticoagulation.1,2 Societal guidelines, as well as a recent North American perspective informed by several landmark trials, are leading to a shift in antiplatelet recommendations in the context of anticoagulation.1 After PCI, it is now recommended to prescribe a brief (up to 1 month, but as short as few days) period of triple therapy (aspirin, P2Y12 inhibitor, and OAC), followed by single antiplatelet P2Y12 inhibitor therapy with OAC for 6 to 12 months.1 Clopidogrel is the P2Y12 inhibitor of choice in patients taking OACs, although ticagrelor may be considered in select cases. This approach is considered a reasonable balance of ischemic and bleeding risks.However, single antiplatelet therapy with clopidogrel in patients on OAC may be problematic for those who are poor metabolizers of the drug. Clopidogrel is a prodrug that is activated by the hepatic CYP2C19 (cytochrome P450 family 2 subfamily C member 19). Genetic loss-of-function variation in 2 alleles of CYP2C19 is present in 2% to 15% of the population and leads to poor metabolism and reduced antiplatelet activity of clopidogrel.3 Despite the 2010 black-box warning from the US Food and Drug Administration regarding the reduced effectiveness of clopidogrel in poor metabolizers, incorporation of clopidogrel pharmacogenetic testing into routine clinical care is not established.4 In addition, most trials addressing the benefit of CYP2C19 genotyping were conducted to guide the choice of dual, not single, antiplatelet therapy after PCI. Therefore, a logical question appears: Could CYP2C19 pharmacogenetic assessment provide value for patients undergoing PCI and requiring anticoagulation? In particular, after aspirin is discontinued, as recommended in many guidelines, does clopidogrel resistance confer an increased risk for ischemic complications, despite concomitant anticoagulant therapy?CYP2C19 genotyping identifies alleles associated with the metabolizer status of clopidogrel and is routinely clinically available. A crucial result of this test is when poor metabolizers are identified because of the presence of 2 nonfunctional alleles in the gene ("clopidogrel nonresponders"). Decreased bioactivation of clopidogrel in those patients could lead to thrombotic complications following stent placement, particularly after stopping aspirin post-PCI, when clopidogrel serves as the sole antiplatelet agent. The CYP2C19 gene has around 35 (*) alleles cataloged, with CYP2C19*1 considered as wild-type, and the 2 most common nonfunctional alleles are CYP2C19*2 and CYP2C19*3.3 The frequency of carrying 2 nonfunctional alleles differs by ancestry and is estimated at 2% to 5% in individuals of European and African ancestry and up to 15% in individuals of Asian ancestry, where CYP2C19 testing may be of particularly higher value.3 On the opposite end of the spectrum, CYP2C19*17 is a common allele that associates with the ultrarapid metabolism of clopidogrel as well as higher bleeding rates. Thus, CYP2C19 genotyping can classify patients across a spectrum of metabolism/bioactivation status and antiplatelet activity: poor metabolizer (2 nonfunctional alleles); intermediate metabolizer (1 nonfunctional allele); normal metabolizer (no mutations); and rapid or ultrarapid metabolizer (1 or 2 hyperactive alleles; see Figure).Download figureDownload PowerPointFigure. CYP2C19 genotype testing and future studies in individuals on long-term OAC undergoing PCI.CYP2C19 (cytochrome P450 family 2 subfamily C member 19) genotyping may be of benefit for patients on OAC undergoing PCI, where the tentative post-PCI plan is for a triple therapy for up to 1 month followed by clopidogrel and OAC. CYP2C19 genotyping results indicate metabolizer status on a spectrum from "poor metabolizer" to "ultrarapid metabolizer." The metabolizer status of carriers of 1 nonfunctional and 1 hyperactive allele (eg, CYP2C19*2/CYP2C19*17) is not clear. In poor and intermediate metabolizers, future studies are needed to assess the safety and efficacy of replacing clopidogrel with aspirin or potent P2Y12 inhibitor to decrease the risk of serious ischemic outcomes. In rapid and ultrarapid metabolizers, further studies should explore the safety and efficacy of replacing clopidogrel with aspirin, with the aim of decreasing bleeding risks. CYP2C19 metabolizer status frequencies are based on average multiethnic frequencies.3 OAC indicates oral anticoagulation; and PCI, percutaneous coronary intervention.A review of CYP2C19 genotyping in post-PCI patients receiving OAC at our institution was consistent with the reported population prevalence of the genotype. Among 69 patients (87% of European ancestry) on OAC who underwent PCI with a single interventional cardiologist (F.A.J.) between January 1, 2018, and December 21, 2020, 15 (21.7%) were carriers of at least 1 nonfunctional CYP2C19 allele: 14 (20.3%) were intermediate metabolizers and 1 (1.5%) was a poor metabolizer.Despite the reduced platelet inhibition in poor metabolizers of clopidogrel,3 additional research is needed to demonstrate a benefit for pharmacogenetic testing in individuals planned for clopidogrel and OAC. Particularly, it remains unclear whether a genotype-guided approach in this population would truly result in improved ischemic and bleeding outcomes, compared to current standard of care, which consists of stopping aspirin after the triple therapy period, and continuing clopidogrel and OAC for 6 to 12 months. Among poor metabolizers, prospective studies should test whether stopping clopidogrel and continuing aspirin or a potent P2Y12 inhibitor with OAC results in reduced ischemic outcomes without significant increase in bleeding, compared with continuing clopidogrel with OAC. Among rapid or ultrarapid metabolizers, prospective studies should test whether stopping clopidogrel and continuing aspirin results in reduced bleeding without significant increase in ischemic outcomes, compared to continuing clopidogrel with OAC (Figure).Future design of clinical trials of genotype-guided approach to antiplatelet therapy among anticoagulated post-PCI patients will also need to consider several factors. First, although clopidogrel is activated to a lesser extent in poor or intermediate metabolizers, its active metabolite irreversibly inhibits P2Y12. As such, the initial triple therapy period may serve as a bridge to reach adequate concentrations of clopidogrel's active metabolite and provide sufficient maintenance antiplatelet therapy for the remainder of the treatment period. Second, with new second-generation drug-eluting stents, the risk of stent thrombosis is highest in the first month which coincides with the triple therapy period, and it is possible that afterward patients might tolerate lower levels of antiplatelet activity without a higher risk for ischemic outcomes.5 Third, there is heterogeneity in bleeding and ischemic risk which would need to be factored into any study. For example, if clopidogrel needs to be replaced after the triple therapy period in poor metabolizers, patients with high ischemic and low bleeding risk might benefit from potent P2Y12, as opposed to patients with low ischemic and high bleeding risk who might benefit from aspirin. The optimal duration of the triple therapy period would also need to be personalized.In conclusion, in individuals undergoing PCI on OAC for whom placement on clopidogrel as the sole antiplatelet agent is planned, we highlight an opportunity for further pharmacogenetic studies to explore the benefit of CYP2C19-guided antiplatelet therapy.Article InformationSources of FundingDr Khera reports funding support from an institutional grant from the Broad Institute of Massachusetts Institute of Technology and Harvard (BroadIgnite); the National Human Genome Research Institute (grant nos. 1K08HG010155 and 5UM1HG008895); a Hassenfeld Scholar Award from Massachusetts General Hospital; a Merkin Institute Fellowship from the Broad Institute of Massachusetts Institute of Technology and Harvard; and a sponsored research agreement from IBM Research. Dr Jaffer is supported by the National Institutes of Health (grant Nos. R01 HL150538 and R01 HL137913).Nonstandard Abbreviations and AcronymsCYP2C19cytochrome P450 family 2 subfamily C member 19OACoral anticoagulationPCIpercutaneous coronary interventionDisclosures Dr Fahed is a consultant and owns shares in Goodpath. Dr Khera has served as a scientific advisor to Sanofi, Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Novartis, Verve Therapeutics, Silence Therapeutics, Veritas International, Color Health, Third Rock Ventures, Foresite Labs, and Columbia University (National Institutes of Health); received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; and received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research. Dr Jaffer reports sponsored research from Canon USA, Siemens, Shockwave, Boston Scientific, and Teleflex; is a consultant for Boston Scientific, Siemens, Biotronik, Magenta Medical, Interventional Medical Device Solutions, and Asahi Intecc. Massachusetts General Hospital has a patent licensing arrangement with Canon, Terumo, and Spectrawave; Dr Jaffer has the right to receive licensing royalties.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 723.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Akl C. Fahed, MD, MPH, Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.218, Boston, MA 02114. Email [email protected]harvard.eduReferences1. Angiolillo DJ, Bhatt DL, Cannon CP, Eikelboom JW, Gibson CM, Goodman SG, Granger CB, Holmes DR, Lopes RD, Mehran R, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention: a North American perspective: 2021 update.Circulation. 2021; 143:583–596. doi: 10.1161/CIRCULATIONAHA.120.050438LinkGoogle Scholar2. Secemsky EA, Butala NM, Kartoun U, Mahmood S, Wasfy JH, Kennedy KF, Shaw SY, Yeh RW. Use of chronic oral anticoagulation and associated outcomes among patients undergoing percutaneous coronary intervention.J Am Heart Assoc. 2016; 5:e004310. doi: 10.1161/JAHA.116.004310LinkGoogle Scholar3. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy.Clin Pharmacol Ther. 2011; 90:328–332. doi: 10.1038/clpt.2011.132CrossrefMedlineGoogle Scholar4. Pereira NL, Farkouh ME, So D, Lennon R, Geller N, Mathew V, Bell M, Bae JH, Jeong MH, Chavez I, et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial.JAMA. 2020; 324:761–771. doi: 10.1001/jama.2020.12443CrossrefMedlineGoogle Scholar5. Kuramitsu S, Ohya M, Shinozaki T, Otake H, Horie K, Kawamoto H, Yamanaka F, Natsuaki M, Shiomi H, Nakazawa G, Ando K, Kadota K, Saito S, Kimura T. Risk factors and long-term clinical outcomes of second-generation drug-eluting stent thrombosis.Circ Cardiovasc Interv. 2019; 12:e007822. doi: 10.1161/CIRCINTERVENTIONS.119.007822LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bor W, de Veer A, Olie R, Rikken S, Chan Pin Yin D, Herrman J, Vrolix M, Meuwissen M, Vandendriessche T, van Mieghem C, Magro M, Bennaghmouch N, Hermanides R, Adriaenssens T, Dewilde W and ten Berg J (2022) Dual versus triple antithrombotic therapy after percutaneous coronary intervention: the prospective multicentre WOEST 2 Study, EuroIntervention, 10.4244/EIJ-D-21-00703, 18:4, (e303-e313) March 8, 2022Vol 145, Issue 10 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.057028PMID: 35254917 Originally publishedMarch 7, 2022 Keywordscytochrome P-450 CYP2C19precision medicineanticoagulantspharmacogeneticsPDF download Advertisement SubjectsCatheter-Based Coronary and Valvular InterventionsGeneticsPercutaneous Coronary InterventionPharmacologyPrecision Medicine