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Sharma R, Aggarwal G, Kumar A, Thakur AK, Pandit M, Sharma V, Singh M, Majeed J, Ajmera P. Effect of loss-of-function CYP2C19 variants on clinical outcomes in coronary artery disease patients treated with clopidogrel: A systematic meta-analysis approach. Int J Cardiol 2024; 414:132418. [PMID: 39121919 DOI: 10.1016/j.ijcard.2024.132418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024]
Abstract
For many years, clopidogrel has been a commonly utilised antiplatelet drug in the management of coronary artery disease (CAD). It's thought that the CYP2C19 loss of function (LoF) polymorphism causes clopidogrel's poor metabolism, which eventually leads to resistance. Previous research produced extremely divergent and inconsistent results, making it impossible to draw definitive conclusions. Therefore, current, investigation was carried out to obtain definitive evidence from an updated meta-analysis on the connection between CYP2C19 LoF polymorphism and coronary artery event in patients treated with clopidogrel. 52,542 individuals with coronary artery disease who were receiving clopidogrel treatment were included in 87 carefully chosen trials from reliable databases that we used for our meta-analysis. According to our data, those who carry one or more CYP2C19 LoF alleles worldwide are much more likely to experience composite events and coronary artery events than people who do not carry these alleles, especially in Asian populations. Our meta-analysis observed that the global population, particularly Asians receiving clopidogrel treatment, is at risk of recurrent coronary artery events and composite events if they carry the CYP2C19 LoF alleles. Additional research is essential on alternative antiplatelet therapies for individuals who exhibit poor or intermediate metabolic activity. OBJECTIVES: 1.To systematically analyze the current evidence regarding the association of CYP2C19 variants with coronary artery disease (CAD). 2.To conduct a meta-analysis to investigate the association between loss of function (LoF) CYP2C19 modifications and CAD.
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Affiliation(s)
- Ruchika Sharma
- Centre for Precision Medicine and Pharmacy, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Geeta Aggarwal
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Anoop Kumar
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Ajit K Thakur
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | | | | | | | - Jaseela Majeed
- School of Allied Health Sciences and Management, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India.
| | - Puneeta Ajmera
- School of Allied Health Sciences and Management, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India.
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van den Broek WWA, Ingraham BS, Pereira NL, Lee CR, Cavallari LH, Swen JJ, Angiolillo DJ, Ten Berg JM. Genotype-Guided Antiplatelet Therapy: JACC Review Topic of the Week. J Am Coll Cardiol 2024; 84:1107-1118. [PMID: 39260933 PMCID: PMC11495226 DOI: 10.1016/j.jacc.2024.06.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 06/21/2024] [Indexed: 09/13/2024]
Abstract
The clinical efficacy and safety of antiplatelet agents vary among patients. Consequently, some patients are at increased risk of recurrent ischemic events during treatment. This interindividual variability can be a result of genetic variants in enzymes that play a role in drug metabolism. The field of pharmacogenomics explores the influence of these genetic variants on an individual's drug response. Tailoring antiplatelet treatment based on genetic variants can potentially result in optimized dosing or a change in drug selection. Most evidence supports guiding therapy based on the CYP2C19 allelic variants in patients with an indication for dual antiplatelet therapy. In ticagrelor-treated or prasugrel-treated patients, a genotype-guided de-escalation strategy can reduce bleeding risk, whereas in patients treated with clopidogrel, an escalation strategy may prevent ischemic events. Although the clinical results are promising, few hospitals have implemented these strategies. New results, technological advancements, and growing experience may potentially overcome current barriers for implementation in the future.
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Affiliation(s)
| | - Brenden S Ingraham
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Naveen L Pereira
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Craig R Lee
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Larisa H Cavallari
- Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA
| | - Jesse J Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
| | - Jurriën M Ten Berg
- Department of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands; Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
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Wang Z, Ma R, Li X, Li X, Xu Q, Yao Y, Wang C, Lv Q. Clinical efficacy of clopidogrel and ticagrelor in patients undergoing off-pump coronary artery bypass grafting: a retrospective cohort study. Int J Surg 2024; 110:3450-3460. [PMID: 38445500 PMCID: PMC11175730 DOI: 10.1097/js9.0000000000001246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/21/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND Ticagrelor is reportedly more effective than clopidogrel in preventing atherothrombotic events in patients with percutaneous coronary intervention. However, the optimal antiplatelet therapy strategy after off-pump coronary artery bypass grafting (OPCABG) is yet to be established. MATERIALS AND METHODS This study was performed using the prospectively-maintained database at our institution. Patients who underwent OPCABG were divided into the clopidogrel and the ticagrelor groups. Propensity score matching analysis was performed between the two groups. The clinical outcome was the occurrence of major adverse cardiovascular event (MACE), defined as a composite of vascular death, myocardial infarction, or stroke 1-year after surgery. RESULTS In total, 545 patients completed the entire follow-up assessment. After propensity score matching, 232 patients each were included in the clopidogrel and ticagrelor groups. The primary outcome occurred in 7.8 and 4.3% of patients in the clopidogrel and ticagrelor groups, respectively ( P =0.113). CYP2C19 variants (*2, *3, and *17) did not impact the clinical outcomes, regardless of the use of clopidogrel or ticagrelor. The rates of MACE were significantly lower in patients carrying the ABCB1 C3435T CT/TT genotypes in the ticagrelor group than in those carrying the ABCB1 C3435T CC genotype in the clopidogrel group (1.4 vs. 9.1%, adjusted P =0.030), as well as those carrying the ABCB1 C3435T CC genotype in the ticagrelor group (1.4 vs. 8.9%, adjusted P =0.036). The ABCB1 C3435T CC genotype was significantly associated with the incidence of 1-year MACE (HR=1.558, 95% CI: 1.109-2.188, P =0.011). Patients who experienced severe perioperative bleeding exhibited a significantly higher incidence of MACE than those who did not experience severe perioperative bleeding (14.0 vs. 4.9%, adjusted P =0.007). CONCLUSION There was no significant difference in the 1-year MACE between patients receiving clopidogrel and those receiving ticagrelor after OPCABG. Notably, The ABCB1 C3435T CC genotype was related to a higher risk of MACE.
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Affiliation(s)
- Zi Wang
- Department of Pharmacy, Zhongshan Hospital, Fudan University
| | - Runhua Ma
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xiaoyu Li
- Department of Pharmacy, Zhongshan Hospital, Fudan University
| | - Xiaoye Li
- Department of Pharmacy, Zhongshan Hospital, Fudan University
| | - Qing Xu
- Department of Pharmacy, Zhongshan Hospital, Fudan University
| | - Yao Yao
- Department of Pharmacy, Zhongshan Hospital, Fudan University
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Qianzhou Lv
- Department of Pharmacy, Zhongshan Hospital, Fudan University
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Mauriello A, Ascrizzi A, Molinari R, Falco L, Caturano A, D’Andrea A, Russo V. Pharmacogenomics of Cardiovascular Drugs for Atherothrombotic, Thromboembolic and Atherosclerotic Risk. Genes (Basel) 2023; 14:2057. [PMID: 38003001 PMCID: PMC10671139 DOI: 10.3390/genes14112057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/25/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
PURPOSE OF REVIEW Advances in pharmacogenomics have paved the way for personalized medicine. Cardiovascular diseases still represent the leading cause of mortality in the world. The aim of this review is to summarize the background, rationale, and evidence of pharmacogenomics in cardiovascular medicine, in particular, the use of antiplatelet drugs, anticoagulants, and drugs used for the treatment of dyslipidemia. RECENT FINDINGS Randomized clinical trials have supported the role of a genotype-guided approach for antiplatelet therapy in patients with coronary heart disease undergoing percutaneous coronary interventions. Numerous studies demonstrate how the risk of ineffectiveness of new oral anticoagulants and vitamin K anticoagulants is linked to various genetic polymorphisms. Furthermore, there is growing evidence to support the association of some genetic variants and poor adherence to statin therapy, for example, due to the appearance of muscular symptoms. There is evidence for resistance to some drugs for the treatment of dyslipidemia, such as anti-PCSK9. SUMMARY Pharmacogenomics has the potential to improve patient care by providing the right drug to the right patient and could guide the identification of new drug therapies for cardiovascular disease. This is very important in cardiovascular diseases, which have high morbidity and mortality. The improvement in therapy could be reflected in the reduction of healthcare costs and patient mortality.
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Affiliation(s)
- Alfredo Mauriello
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Antonia Ascrizzi
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Riccardo Molinari
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Luigi Falco
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Alfredo Caturano
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80100 Naples, Italy;
| | - Antonello D’Andrea
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
- Unit of Cardiology, “Umberto I” Hospital, Nocera Inferiore, 84014 Salerno, Italy
| | - Vincenzo Russo
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
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Baturina O, Chashkina M, Andreev D, Mirzaev K, Bykova A, Suvorov A, Yeryshova D, Suchkova S, Sychev D, Syrkin A. Pharmacokinetic and Pharmacogenetic Predictors of Major Bleeding Events in Patients with an Acute Coronary Syndrome and Atrial Fibrillation Receiving Combined Antithrombotic Therapy. J Pers Med 2023; 13:1371. [PMID: 37763139 PMCID: PMC10532904 DOI: 10.3390/jpm13091371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/30/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Objective: This study's objective was to evaluate the effects of pharmacokinetic and pharmacogenetic factors on major bleeding in patients with ACS and non-valvular AF receiving combined antithrombotic therapy consisting of rivaroxaban, clopidogrel, and aspirin as part of dual or triple therapy. Methods: A prospective observational study was conducted in two PCI centers in Moscow, the Russian Federation, from 2017 to 2018. One hundred patients with ACS and AF were enrolled. Prospective follow-ups continued for 12 months. Results: A total of 36 patients experienced bleeding events, with 10 experiencing major bleeding based on the BARC scale and 17 experiencing major bleeding based on the ISTH scale. The following predictors associated with an increased number of major bleeding events were identified: for the ISTH scale, a Css min. of rivaroxaban of >137 pg/mL (5.94 OR, (95% CI, 3.13-12.99; p < 0.004)) and carriage of the T allelic variant polymorphism ABCB1 rs4148738 (8.97 OR (95% CI, 1.48-14.49; p < 0.017)), as well as for the BARC scale (5.76 OR (95% CI, 2.36-9.87; p < 0.018)). Conclusions: Measuring residual steady-state rivaroxaban concentrations and determining the carriage of the T allelic variant polymorphism ABCB1 rs4148738 may be applicable to high-risk patients for subsequent antithrombotic therapy modification.
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Affiliation(s)
- Olga Baturina
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
| | - Maria Chashkina
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
| | - Denis Andreev
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
| | - Karin Mirzaev
- Clinical Pharmacology and Therapy Department B.E. Votchal, Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow 125993, Russia; (K.M.); (D.S.)
| | - Alexandra Bykova
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
| | - Alexandr Suvorov
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia;
| | - Daria Yeryshova
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
| | - Svetlana Suchkova
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
| | - Dmitry Sychev
- Clinical Pharmacology and Therapy Department B.E. Votchal, Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow 125993, Russia; (K.M.); (D.S.)
| | - Abram Syrkin
- Cardiology, Functional and Ultrasound Diagnostics Department, N.V. Sklifosovskiy Institute of Clinical Medicine, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow 119048, Russia; (O.B.); (D.A.); (A.B.); (D.Y.); (S.S.); (A.S.)
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Tsujimura T, Iida O, Ishihara T, Asai M, Masuda M, Okamoto S, Nanto K, Matsuda Y, Hata Y, Uematsu H, Toyoshima T, Higashino N, Nakao S, Mano T. Angioscopic Evaluation of Vascular Response After Fluoropolymer-Based Drug-Eluting Stent Implantation for Femoropopliteal Artery Lesions. Circ J 2023; 87:432-429. [PMID: 36624062 DOI: 10.1253/circj.cj-22-0635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Although favorable clinical outcomes have been demonstrated for fluoropolymer-based paclitaxel-eluting stents (FP-DES) in the treatment of femoropopliteal lesions, the vascular response after implantation has not been systematically studied through intravascular imaging. METHODS AND RESULTS We angioscopically compared FP-DES: 24 in the early phase (mean [±SD] 3±1 months), 26 in the middle phase (12±3 months), and 20 in the late phase (≥18 months) after implantation. The dominant neointimal coverage grade, heterogeneity of neointimal coverage grade, and thrombus adhesion in the stent segment were evaluated. Neointimal coverage was graded as follows: Grade 0, stent struts exposed; Grade 1, struts bulging into the lumen, although covered; Grade 2, struts embedded in the neointima, but visible; Grade 3, struts fully embedded and invisible. Dominant neointimal coverage and heterogeneity grades were significantly higher in the middle and late phases than in the early phase (all P<0.05), but did not differ significantly between the middle and late phases. The incidence of thrombus adhesion was recorded for all stents in each of the 3 different phases. CONCLUSIONS The middle and late phases after FP-DES implantation were associated with significantly higher dominant neointimal coverage and heterogeneity grades than the early phase. However, thrombus adhesion was observed in all phases after FP-DES implantation. Arterial healing may not be completed even in the late phase after FP-DES implantation.
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Affiliation(s)
| | - Osamu Iida
- Kansai Rosai Hospital Cardiovascular Center
| | | | | | | | | | | | | | | | | | | | | | - Sho Nakao
- Kansai Rosai Hospital Cardiovascular Center
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Kranendonk J, Willems LH, Vijver-Coppen RVD, Coenen M, Adang E, Donders R, Zeebregts CJ, Deneer V, Reijnen M, Kramers C, Warlé MC. CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD). Am Heart J 2022; 254:141-148. [PMID: 35988587 DOI: 10.1016/j.ahj.2022.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 07/04/2022] [Accepted: 08/04/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients. METHODS GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications. CONCLUSION The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients.
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Affiliation(s)
- J Kranendonk
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - L H Willems
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - M Coenen
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - E Adang
- Department of Epidemiology and Biostatistics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - R Donders
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - C J Zeebregts
- Department of Surgery, Division of Vascular Surgery, University Medical Center Groningen, University Of Groningen, Groningen, The Netherlands
| | - Vhm Deneer
- Department of Clinical Pharmacy, Division of Laboratories, Pharmacy and Biomedical Genetics University Medical Center Utrecht, Utrecht, The Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht university, Utrecht, The Netherlands
| | - Mmpj Reijnen
- Department of Surgery, Rijnstate Hospital, Arnhem, The Netherlands; Multimodality Medical Imaging Group, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - C Kramers
- Department of Internal Medicine and Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Pharmacy, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
| | - M C Warlé
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
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Antiplatelet response to clopidogrel is associated with a haplotype in CYP2C19 gene in Pakistani patients. Sci Rep 2022; 12:6171. [PMID: 35418564 PMCID: PMC9007971 DOI: 10.1038/s41598-022-09679-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 02/15/2022] [Indexed: 11/09/2022] Open
Abstract
Clopidogrel, an antiplatelet drug, is frequently prescribed to patients diagnosed with ischemic diseases such as those suffering from acute coronary syndromes or ischemic stroke. Despite the drug being effective in majority of the patients, some still experience ischemic events early in the treatment which might be due to poor platelet inhibition. This study aims to investigate the association of cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms, haplotypes as well as a wide range of clinical and demographic variables with platelet aggregation phenotypes to clopidogrel in a Pakistani cohort. The study comprised of a total of 120 patients diagnosed with cardiovascular diseases and were treated with clopidogrel. Antiplatelet response to clopidogrel was monitored by Helena AggRAM (HL-2-1785P) and patients with maximal platelet aggregation more than 50% were categorized as low responders and those with less than 50% as high responders. Our results show that 56.6% of patients were homozygous for the CYP2C19 wild-type allele, 38.3% of patients possessed one copy of the CYP2C19*2 allele and 5% of patients possessed both CYP2C19*2 alleles. No CYP2C19*3 allele was found in our patient cohort. There was no statistically significant difference between the high and low responder groups to clopidogrel in terms of extensive, intermediate and poor metabolizer genotypes. However, haplotype (H1), leukocyte count, random blood glucose, and history of diabetes mellitus was associated with the antiplatelet response to clopidogrel. The prevalence of clopidogrel resistance in our population was in line with that reported for other regional and global populations.
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Xie Q, Xiang Q, Liu Z, Mu G, Zhou S, Zhang Z, Ma L, Gong Y, Jiang J, Cui Y. Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis. BMC Cardiovasc Disord 2022; 22:111. [PMID: 35300607 PMCID: PMC8928616 DOI: 10.1186/s12872-022-02547-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/04/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Studies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying. METHODS This systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes. RESULTS Eight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22-0.75; P = 0.004). Furthermore, any LOF allele carriers didn't yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76-1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99-2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17-4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27-1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30-2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33-2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required. CONCLUSIONS This qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included.
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Affiliation(s)
- Qiufen Xie
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Qian Xiang
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Zhiyan Liu
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Guangyan Mu
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Shuang Zhou
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Zhuo Zhang
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Lingyue Ma
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China
| | - Yanjun Gong
- Department of Cardiology, Peking University First Hospital, No. 8, Xi Shi Ku Street, Beijing, 100034, China
| | - Jie Jiang
- Department of Cardiology, Peking University First Hospital, No. 8, Xi Shi Ku Street, Beijing, 100034, China.
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China.
- Institue of Clinical Pharmacology, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, 100191, China.
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10
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Beitelshees AL, Thomas CD, Empey PE, Stouffer GA, Angiolillo DJ, Franchi F, Tuteja S, Limdi NA, Lee JC, Duarte JD, Kreutz RP, Skaar TC, Coons JC, Giri J, McDonough CW, Rowland R, Stevenson JM, Thai T, Vesely MR, Wellen JT, Johnson JA, Winterstein AG, Cavallari LH, Lee CR, Implementing Genomics in Practice (IGNITE) Network Pharmacogenetics Working Group. CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings. J Am Heart Assoc 2022; 11:e024159. [PMID: 35156424 PMCID: PMC9245803 DOI: 10.1161/jaha.121.024159] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.
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Affiliation(s)
- Amber L. Beitelshees
- Department of Medicine and Program for Personalized and Genomic MedicineUniversity of Maryland School of MedicineBaltimoreMD
| | - Cameron D. Thomas
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision MedicineUniversity of Florida College of PharmacyGainesvilleFL
| | - Philip E. Empey
- Department of Pharmacy and TherapeuticsUniversity of Pittsburgh School of PharmacyPittsburghPA
| | - George A. Stouffer
- Division of Cardiology and McAllister Heart InstituteUniversity of North Carolina, Chapel HillNC
| | | | - Francesco Franchi
- University of Florida College of Medicine‐JacksonvilleJacksonvilleFL
| | - Sony Tuteja
- University of Pennsylvania Perelman School of MedicinePhiladelphiaPA
| | - Nita A. Limdi
- Department of NeurologyProgram for Translational Pharmacogenomics and Hugh Kaul Personalized Medicine InstituteSchool of MedicineUniversity of Alabama at BirminghamAL
| | - James C. Lee
- Department of Pharmacy PracticeUniversity of Illinois at ChicagoIL
| | - Julio D. Duarte
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision MedicineUniversity of Florida College of PharmacyGainesvilleFL
| | | | | | - James C. Coons
- Department of Pharmacy and TherapeuticsUniversity of Pittsburgh School of PharmacyPittsburghPA
| | - Jay Giri
- Cardiovascular Medicine DivisionUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPA
| | - Caitrin W. McDonough
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision MedicineUniversity of Florida College of PharmacyGainesvilleFL
| | - Rachel Rowland
- Department of Medicine and Program for Personalized and Genomic MedicineUniversity of Maryland School of MedicineBaltimoreMD
| | - James M. Stevenson
- Department of Pharmacy and TherapeuticsUniversity of Pittsburgh School of PharmacyPittsburghPA,Division of Clinical PharmacologyJohns Hopkins University School of MedicineBaltimoreMD
| | - Thuy Thai
- Department of Pharmaceutical Outcomes & Policy and Center for Drug Evaluation and SafetyUniversity of FloridaGainesvilleFL
| | - Mark R. Vesely
- Department of Medicine and Program for Personalized and Genomic MedicineUniversity of Maryland School of MedicineBaltimoreMD
| | - Jacob T. Wellen
- Department of Medicine and Program for Personalized and Genomic MedicineUniversity of Maryland School of MedicineBaltimoreMD
| | - Julie A. Johnson
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision MedicineUniversity of Florida College of PharmacyGainesvilleFL
| | - Almut G. Winterstein
- Department of Pharmaceutical Outcomes & Policy and Center for Drug Evaluation and SafetyUniversity of FloridaGainesvilleFL
| | - Larisa H. Cavallari
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision MedicineUniversity of Florida College of PharmacyGainesvilleFL
| | - Craig R. Lee
- Division of Cardiology and McAllister Heart InstituteUniversity of North Carolina, Chapel HillNC,Division of Pharmacotherapy and Experimental TherapeuticsUNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillNC
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11
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V Aswathy SP, Chandra KR, Jyothikrishna P, Arun KP. Dosage optimization of clopidogrel via a precision medicine approach: the way forward. Pharmacogenomics 2022; 23:195-206. [PMID: 35112572 DOI: 10.2217/pgs-2020-0198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Clopidogrel is a prodrug chiefly metabolized by the hepatic isoenzyme CYP2C19 to its active metabolite that inhibits the platelet aggregation. It has been proven in many populations that the genetic polymorphism of CYP2C19 has influence on the pharmacokinetic and or pharmacodynamics of this drug and resulting in high inter-individual variability in the treatment outcomes. As CYP2C19 genetic polymorphism is highly prevalent among the Asian population, the influence of the same on the pharmacokinetics and; thereby, the pharmacodynamics of clopidogrel needs more attention. Using the pharmacogenetic information for drug therapy could help overcome these issues and to optimize the dosage regimen of clopidogrel, this review advocates the precision medicine approach for reducing the clopidogrel resistance and adverse cardiovascular events.
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Affiliation(s)
- Sasidharan Pillai V Aswathy
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty, Tamil Nadu, 643001, India
| | - Kotha Rohith Chandra
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty, Tamil Nadu, 643001, India
| | - Pakkath Jyothikrishna
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty, Tamil Nadu, 643001, India
| | - Kanniappan Parthasarathy Arun
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty, Tamil Nadu, 643001, India
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12
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Bass DI, Young CC, Park MS, Cruz MJ, Carroll KT, Vanent KN, Lee C, Sen RD, Angiolillo DJ, Cattaneo M, Kim LJ, Levitt MR. Severe, Intolerable Fatigue Associated with Hyperresponse to Clopidogrel. World Neurosurg 2021; 156:e374-e380. [PMID: 34563718 DOI: 10.1016/j.wneu.2021.09.075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Clopidogrel is a commonly used antiplatelet agent for the prevention of thromboembolic complications following neuroendovascular procedures, but anecdotal data have raised concern for the possibility that clopidogrel may induce severe, intolerable fatigue. The purpose of this study is to systematically investigate this phenomenon. METHODS We performed a dual-institution, 9-year, retrospective study of patients undergoing clopidogrel therapy for neuroendovascular procedures. Patients were included only if their response to clopidogrel was assessed by platelet function testing using the VerifyNow P2Y12 (VNP) assay. Hyperresponse to clopidogrel was defined as P2Y12 reaction units ≤60. Patients were considered to have had clopidogrel-induced severe fatigue if the onset of symptoms followed the initiation of clopidogrel therapy; symptoms improved following a reduction in the dose of clopidogrel; and symptoms could not be attributed to any other medical explanation. RESULTS Data were collected on 349 patients. Five patients (1.4%) met criteria for clopidogrel-induced severe fatigue. All 5 patients were female, ages 39-68. VNP assessments obtained while patients were symptomatic revealed hyperresponse to clopidogrel (0-22 P2Y12 reaction units). Symptoms improved in all 5 patients when the dose of clopidogrel was reduced by half. Notably, 30% of patients (n = 103) demonstrated a hyperresponse to clopidogrel on at least 1 VNP assessment, but 98 of these patients did not suffer from severe fatigue. CONCLUSIONS A syndrome of severe fatigue and other constitutional symptoms is a rare but clinically significant side effect of hyperresponse to clopidogrel in patients undergoing neuroendovasular intervention.
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Affiliation(s)
- David I Bass
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
| | - Christopher C Young
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
| | - Min S Park
- Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Michael J Cruz
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
| | - Kate T Carroll
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
| | - Kevin N Vanent
- School of Medicine, University of Washington, Seattle, Washington, USA
| | - Chungeun Lee
- School of Medicine, Washington State University, Spokane, Washington, USA
| | - Rajeev D Sen
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
| | - Dominick J Angiolillo
- Division of Cardiology, Department of Medicine, University of Florida, Jacksonville, Florida, USA
| | - Marco Cattaneo
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Louis J Kim
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA; Stroke & Applied Neurosciences Center, University of Washington, Seattle, Washington, USA; Department of Radiology, University of Washington, Seattle, Washington, USA
| | - Michael R Levitt
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA; Stroke & Applied Neurosciences Center, University of Washington, Seattle, Washington, USA; Department of Radiology, University of Washington, Seattle, Washington, USA; Department of Mechanical Engineering, University of Washington, Seattle, Washington, USA.
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13
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Abstract
Over the past decade, pharmacogenetic testing has emerged in clinical practice to guide selected cardiovascular therapies. The most common implementation in practice is CYP2C19 genotyping to predict clopidogrel response and assist in selecting antiplatelet therapy after percutaneous coronary intervention. Additional examples include genotyping to guide warfarin dosing and statin prescribing. Increasing evidence exists on outcomes with genotype-guided cardiovascular therapies from multiple randomized controlled trials and observational studies. Pharmacogenetic evidence is accumulating for additional cardiovascular medications. However, data for many of these medications are not yet sufficient to support the use of genotyping for drug prescribing. Ultimately, pharmacogenetics might provide a means to individualize drug regimens for complex diseases such as heart failure, in which the treatment armamentarium includes a growing list of medications shown to reduce morbidity and mortality. However, sophisticated analytical approaches are likely to be necessary to dissect the genetic underpinnings of responses to drug combinations. In this Review, we examine the evidence supporting pharmacogenetic testing in cardiovascular medicine, including that available from several clinical trials. In addition, we describe guidelines that support the use of cardiovascular pharmacogenetics, provide examples of clinical implementation of genotype-guided cardiovascular therapies and discuss opportunities for future growth of the field.
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Affiliation(s)
- Julio D Duarte
- Center for Pharmacogenomics and Precision Medicine and Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA
| | - Larisa H Cavallari
- Center for Pharmacogenomics and Precision Medicine and Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.
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14
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Wang W, Shao C, Xu B, Wang J, Yang M, Chen J, Zhang K, Wang S, Li P, Tang YD. CYP2C19 genotype has prognostic value in specific populations following coronary stenting. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1066. [PMID: 34422978 PMCID: PMC8339845 DOI: 10.21037/atm-20-7724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 03/28/2021] [Indexed: 11/06/2022]
Abstract
Background The prognostic value of the CYP2C19 genotype in post-percutaneous coronary intervention (PCI) patients remains controversial. The recently-published, limited-sample PHARMCLO trial indicates a personalized pharmacogenomic approach may reduce adverse events. This study aimed to determine the prognostic value of CYP2C19 genotypes. Methods The original cohort consisted of 10,724 PCI patients in 2013. 756 patients with genotyped CYP2C19 were included in our analysis. The CYP2C19 genotype prognostic value was tested based on different clinical factors. The primary endpoint was major adverse cardio- and cerebro-vascular event (MACCE). Results MACCE 2-years post-PCI occurred in 19 patients (17.4%) in poor metabolizers (PM, CYP2C19 *2/*2, *2/*3, *3/*3), 43 patients (12.2%) in intermediate metabolizers (IM, CYP2C19 *1/*2 or *1/*3) and 27 patients (9.2%) in extensive metabolizers (EM, CYP2C19 *1/*1). PM was an independent MACCE predictor compared with EM (HR: 1.960, 95% CI: 1.139–3.372), but the difference between IM and PM was not significant (HR: 1.314, 95% CI: 0.843–2.048). Major bleeding (BARC grade ≥3) was not significantly different between the three groups (2.5% vs. 2.1% vs. 0.8%, P=0.133). Subgroup analysis showed that the CYP2C19 genotype prognostic value was present in the following subgroups: male, age >60 years, body mass index (BMI) >24 kg/m2, SYNTAX score >15, current smokers, and patients without chronic kidney disease. Conclusions Utilizing CYP2C19 genotype to guide post-PCI antiplatelet therapy might be appropriate in patients with the following characteristics: male, age >60 years, BMI >24 kg/m2, SYNTAX score >15, current smokers, and non-chronic kidney disease (CKD) patients.
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Affiliation(s)
- Wenyao Wang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunli Shao
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Xu
- Catheterization Laboratory, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingjia Wang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Yang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Chen
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kuo Zhang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Siyuan Wang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ping Li
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi-Da Tang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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15
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Jafrin S, Naznin NE, Reza MS, Aziz MA, Islam MS. Risk of stroke in CYP2C19 LoF polymorphism carrier coronary artery disease patients undergoing clopidogrel therapy: An ethnicity-based updated meta-analysis. Eur J Intern Med 2021; 90:49-65. [PMID: 34092486 DOI: 10.1016/j.ejim.2021.05.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/20/2021] [Accepted: 05/16/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND Antiplatelet agent clopidogrel has been widely used for stroke management for many years, although resistance to clopidogrel may increase the chance of stroke recurrence. CYP2C19 loss-of-function (LoF) polymorphism is assumed to be responsible for the poor metabolism of clopidogrel that ultimately turns to resistance. Previous publications could not provide firm evidence due to highly conflicting and heterogeneous outcomes. AIM To get clear evidence from an updated meta-analysis on CYP2C19 LoF polymorphism association with stroke risk in clopidogrel treated patients, this study has been performed. METHODS We conducted a meta-analysis with 72 selected studies from authentic databases, including 40,035 coronary artery disease patients treated with clopidogrel. RESULTS This analysis showed that the worldwide carrier of one or more CYP2C19 LoF alleles had a significantly higher risk of stroke and composite events than the non-LoF carriers (RR=1.78, 95% CI=1.52-2.07, p<0.00001 and RR=1.39, 95% CI=1.26-1.54, p<0.00001, respectively). Besides, subgroup analysis showed that Asian CYP2C19 LoF carriers had a significantly increased risk of stroke (RR=1.91, 95% CI=1.60-2.28, p<0.00001) while the risk of composite events was significantly higher in all ethnic populations (Asian: RR=1.58, 95% CI=1.32-1.89, p<0.00001; Caucasian: RR=1.27, 95% CI=1.08-1.50, p=0.003; Hispanic and others: RR=1.21, 95% CI=1.09-1.34, p=0.0003). CONCLUSION Our meta-analysis confirmed that the presence of CYP2C19 LoF alleles increases the risk of stroke and composite events recurrence in the worldwide population, especially in Asians undergoing clopidogrel treatment. Alternative antiplatelet therapy should be investigated thoroughly for the intermediate and poor metabolizers.
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Affiliation(s)
- Sarah Jafrin
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur 3814, Noakhali, Bangladesh
| | - Nura Ershad Naznin
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur 3814, Noakhali, Bangladesh
| | - Md Sharif Reza
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur 3814, Noakhali, Bangladesh
| | - Md Abdul Aziz
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur 3814, Noakhali, Bangladesh
| | - Mohammad Safiqul Islam
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur 3814, Noakhali, Bangladesh.
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16
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Biswas M, Kali SK. Association of CYP2C19 Loss-of-Function Alleles with Major Adverse Cardiovascular Events of Clopidogrel in Stable Coronary Artery Disease Patients Undergoing Percutaneous Coronary Intervention: Meta-analysis. Cardiovasc Drugs Ther 2021; 35:1147-1159. [PMID: 33523336 DOI: 10.1007/s10557-021-07142-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE It was aimed to determine the aggregated risk of MACE (major adverse cardiovascular events) in stable CAD patients carrying CYP2C19 LoF alleles taking clopidogrel. METHODS Literature was searched in different databases for relevant studies. Aggregated risk was estimated using a fixed/random effect model where p-value<0.05 was considered statistically significant. RESULTS In total, 21 studies with 16,194 stable CAD patients were assessed. It was found that patients treated with clopidogrel carrying either one or two CYP2C19 LoF alleles who underwent PCI were associated with significantly increased risk of MACE compared to non-carriers (OR: 1.71, 95% CI: 1.51-1.94, p<0.00001) that was driven from cardiovascular death (OR: 1.43, 95% CI: 1.02-1.99, p=0.04), myocardial infarction (OR: 1.75, 95% CI: 1.42-2.16, p<0.00001), stroke (OR: 2.30, 95% CI: 1.52-3.47, p<0.0001), and stent thrombosis (OR: 4.08, 95% CI: 2.52-6.61, p<0.00001). It was also found that carriers of two CYP2C19 LoF alleles were associated with a significantly marked risk of MACE than non-carriers (OR: 2.22, 95% CI: 1.60-3.09, p<0.00001). Furthermore, the increased risk of MACE remained markedly significant in Asian patients (OR: 2.03, 95% CI: 1.72-2.40, p<0.00001) and was less significant in western patients (OR: 1.35, 95% CI: 1.11-1.63, p=0.002). Bleeding events were not significantly different in carriers of CYP2C19 LoF alleles compared to non-carriers (OR: 1.11, 95% CI: 0.85-1.45, p=0.43). CONCLUSION Stable CAD patients treated with clopidogrel and carried CYP2C19 LoF alleles undergoing PCI were associated with significantly increased risk of MACE compared to non-carriers, even markedly significant for Asian patients.
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Affiliation(s)
- Mohitosh Biswas
- Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh.
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17
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Khan H, Gallant RC, Zamzam A, Jain S, Afxentiou S, Syed M, Kroezen Z, Shanmuganathan M, Britz-McKibbin P, Rand ML, Ni H, Al-Omran M, Qadura M. Personalization of Aspirin Therapy Ex Vivo in Patients with Atherosclerosis Using Light Transmission Aggregometry. Diagnostics (Basel) 2020; 10:diagnostics10110871. [PMID: 33114560 PMCID: PMC7693608 DOI: 10.3390/diagnostics10110871] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/23/2022] Open
Abstract
Acetylsalicylic acid (ASA), also known as aspirin, appears to be ineffective in inhibiting platelet aggregation in 20-30% of patients. Light transmission aggregometry (LTA) is a gold standard platelet function assay. In this pilot study, we used LTA to personalize ASA therapy ex vivo in atherosclerotic patients. Patients were recruited who were on 81 mg ASA, presenting to ambulatory clinics at St. Michael's Hospital (n = 64), with evidence of atherosclerotic disease defined as clinical symptoms and diagnostic findings indicative of symptomatic peripheral arterial disease (PAD), with an ankle brachial index (ABI) of <0.9 (n = 52) or had diagnostic features of asymptomatic carotid arterial stenosis (CAS), with >50% stenosis of internal carotid artery on duplex ultrasound (n = 12). ASA compliance was assessed via multisegmented injection-capillary electrophoresis-mass spectrometry based on measuring the predominant urinary ASA metabolite, salicyluric acid. LTA with arachidonic acid was used to test for ASA sensitivity. Escalating ASA dosages of 162 mg and 325 mg were investigated ex vivo for ASA dose personalization. Of the 64 atherosclerotic patients recruited, 8 patients (13%) were non-compliant with ASA. Of ASA compliant patients (n = 56), 9 patients (14%) were non-sensitive to their 81 mg ASA dosage. Personalizing ASA therapy in 81 mg ASA non-sensitive patients with escalating dosages of ASA demonstrated that 6 patients became sensitive to a dosage equivalent to 162 mg ASA and 3 patients became sensitive to a dosage equivalent to 325 mg ASA. We were able to personalize ASA dosage ex vivo in all ASA non-sensitive patients with escalating dosages of ASA within 1 h of testing.
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Affiliation(s)
- Hamzah Khan
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
| | - Reid C. Gallant
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (R.C.G.); (H.N.)
| | - Abdelrahman Zamzam
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
| | - Shubha Jain
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
| | - Sherri Afxentiou
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
| | - Muzammil Syed
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
| | - Zachary Kroezen
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4M1, Canada; (Z.K.); (M.S.); (P.B.-M.)
| | - Meera Shanmuganathan
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4M1, Canada; (Z.K.); (M.S.); (P.B.-M.)
| | - Philip Britz-McKibbin
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4M1, Canada; (Z.K.); (M.S.); (P.B.-M.)
| | - Margaret L. Rand
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M4B 1B3, Canada;
- Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, ON M4B 1B3, Canada
- Translational Medicine, Research Institute, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON M4B 1B3, Canada
| | - Heyu Ni
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (R.C.G.); (H.N.)
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M4B 1B3, Canada;
| | - Mohammed Al-Omran
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (R.C.G.); (H.N.)
- Department of Surgery, University of Toronto, Toronto, ON M4B 1B3, Canada
| | - Mohammad Qadura
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (H.K.); (A.Z.); (S.J.); (S.A.); (M.S.); (M.A.-O.)
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON M4B 1B3, Canada; (R.C.G.); (H.N.)
- Department of Surgery, University of Toronto, Toronto, ON M4B 1B3, Canada
- Correspondence: ; Tel.: +1-416-864-6047
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Wang Z, Xia L, Li X, Shen J, Xu Q, Ji Q, Lv Q. Genetic Polymorphisms and Perioperative Bleeding in Off-Pump Coronary Artery Bypass Grafting Surgery. Ann Thorac Surg 2020; 112:116-123. [PMID: 33075321 DOI: 10.1016/j.athoracsur.2020.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 08/07/2020] [Accepted: 08/13/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Clopidogrel use before coronary artery bypass graft surgery may increase risk for perioperative hemorrhage. The effect of genetic polymorphisms related to clopidogrel responses on bleeding during or after off-pump coronary artery bypass graft surgery is unknown. METHODS This prospective study included 206 coronary artery disease patients scheduled for off-pump coronary artery bypass graft surgery. Genotypes were determined using Sequenom MassARRAY system. Severe bleeding was defined by the universal definition of perioperative bleeding in cardiac surgery. RESULTS Patients carrying the ABCB1 3435 wild-type genotype (CC) had a higher risk of severe perioperative bleeding compared with patients carrying the variant genotype (CT or TT; 33.9% vs 16.5%, P = .009). Low baseline hemoglobin level (odds ratio 0.944; 95% confidence interval, 0.917 to 0.972; P < .001), low baseline estimated glomerular filtration rate (odds ratio 0.977; 95% confidence interval, 0.956 to 0.999; P = .041), discontinuing clopidogrel 5 days or less before surgery (odds ratio 2.458; 95% confidence interval, 1.044 to 5.786; P = .039), and the ABCB1 wild-type genotype (CC; odds ratio 2.941; 95% confidence interval, 1.250 to 6.944; P = .014) were independent risk factors for severe perioperative bleeding. CONCLUSIONS Patients carrying the ABCB1 wild-type genotype (CC) had a higher rate of severe perioperative bleeding compared with patients carrying the variant genotype (CT or TT). Discontinuation of clopidogrel 5 days or less before surgery and the ABCB1 wild-type genotype (CC) were independent risk factors for severe perioperative bleeding.
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Affiliation(s)
- Zi Wang
- Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Limin Xia
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoye Li
- Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinqiang Shen
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qing Xu
- Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiuyi Ji
- Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qianzhou Lv
- Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.
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Hernandez-Suarez DF, Melin K, Marin-Maldonado F, Nunez HJ, Gonzalez AF, Gonzalez-Sepulveda L, Rivas-Tumanyan S, Naik H, Ruaño G, Scott SA, Duconge J. Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial. BMJ Open 2020; 10:e038936. [PMID: 32764090 PMCID: PMC7412606 DOI: 10.1136/bmjopen-2020-038936] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Minority populations in the USA are disproportionately affected by cardiovascular conditions. Reduced responsiveness to clopidogrel among carriers of CYP2C19 variants has been reported in patients with either coronary artery disease (CAD) or acute coronary syndrome (ACS) after the percutaneous coronary intervention (PCI). Previous studies have evaluated CYP2C19 genotyping-guided antiplatelet therapy in selected populations; however, this has yet to be tested among Hispanics. Given the paucity of clinical research on CYP2C19 and antiplatelet clinical outcomes in Hispanics, our study will test the safety and efficacy of a genetic-driven treatment algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics. METHODS AND ANALYSIS This is a multicentre, prospective, non-randomised clinical trial that proposes an assessment of pharmacogenomic-guided DAPT in post-PCI Caribbean Hispanic patients with ACS or CAD. We will recruit 250 patients to be compared with a matched non-concurrent cohort of 250 clopidogrel-treated patients (standard-of-care). Major adverse cardiovascular events (MACEs) such as all-cause death, myocardial infarction (MI), stroke, coronary revascularisation, stent thrombosis and bleedings over 6 months will be the study endpoints. Among the recruited, high-risk patients will be escalated to ticagrelor and low-risk patients will remain on clopidogrel. The primary objective is to determine whether genetic-guided therapy is superior to standard of care. The secondary objective will determine if clopidogrel treatment in low-risk patients is not associated with a higher rate of MACEs compared with escalated antiplatelet therapy in high-risk patients. Patients will be enrolled up to the group's completion. ETHICS AND DISSEMINATION Approval was obtained from the Institutional Review Board of the University of Puerto Rico Medical Sciences Campus (protocol # A4070417). The study will be carried out in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. Findings will be published in a peer-reviewed journal and controlled access to experimental data will be available. TRIAL REGISTRATION NUMBER NCT03419325; Pre-results.
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Affiliation(s)
- Dagmar F Hernandez-Suarez
- Division of Cardiovascular Medicine, University of Puerto Rico School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Kyle Melin
- Department of Pharmacy Practice, University of Puerto Rico School of Pharmacy, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Frances Marin-Maldonado
- RCMI Program, Academic Affairs Deanship, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Hector J Nunez
- Division of Cardiovascular Medicine, University of Puerto Rico School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Ariel F Gonzalez
- Division of Cardiovascular Medicine, University of Puerto Rico School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Lorena Gonzalez-Sepulveda
- Research Design and Biostatistics Core, Puerto Rico Clinical and Translational Research Consortium (PRCTRC), Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Sona Rivas-Tumanyan
- Research Design and Biostatistics Core, Puerto Rico Clinical and Translational Research Consortium (PRCTRC), Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Hetanshi Naik
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Gualberto Ruaño
- Hartford Hospital Institute of Living, Hartford, Connecticut, USA
| | - Stuart A Scott
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Jorge Duconge
- Department of Pharmaceutical Sciences, University of Puerto Rico School of Pharmacy, Medical Sciences Campus, San Juan, Puerto Rico, USA
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20
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Pereira NL, Rihal CS, So DYF, Rosenberg Y, Lennon RJ, Mathew V, Goodman SG, Weinshilboum RM, Wang L, Baudhuin LM, Lerman A, Hasan A, Iturriaga E, Fu YP, Geller N, Bailey K, Farkouh ME. Clopidogrel Pharmacogenetics. Circ Cardiovasc Interv 2020; 12:e007811. [PMID: 30998396 DOI: 10.1161/circinterventions.119.007811] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.
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Affiliation(s)
- Naveen L Pereira
- Department of Cardiovascular Medicine (N.L.P., C.S.R., A.L.), Mayo Clinic, Rochester, MN.,Department of Molecular Pharmacology and Experimental Therapeutics (N.L.P., R.M.W., L.W.), Mayo Clinic, Rochester, MN
| | - Charanjit S Rihal
- Department of Cardiovascular Medicine (N.L.P., C.S.R., A.L.), Mayo Clinic, Rochester, MN
| | - Derek Y F So
- University of Ottawa Heart Institute, Ontario, Canada (D.Y.F.S.)
| | - Yves Rosenberg
- National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R., A.H., E.I., Y.-P.F., N.G.)
| | - Ryan J Lennon
- Department of Health Sciences Research (R.J.L., K.B.), Mayo Clinic, Rochester, MN
| | - Verghese Mathew
- Division of Cardiology, Loyola University Health System, Loyola University Chicago Stritch School of Medicine, Maywood, IL (V.M.)
| | - Shaun G Goodman
- St. Michael's Hospital, University of Toronto, Ontario, Canada (S.G.G.)
| | - Richard M Weinshilboum
- Department of Molecular Pharmacology and Experimental Therapeutics (N.L.P., R.M.W., L.W.), Mayo Clinic, Rochester, MN
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics (N.L.P., R.M.W., L.W.), Mayo Clinic, Rochester, MN
| | - Linnea M Baudhuin
- Department of Laboratory Medicine and Pathology (L.M.B.), Mayo Clinic, Rochester, MN
| | - Amir Lerman
- Department of Cardiovascular Medicine (N.L.P., C.S.R., A.L.), Mayo Clinic, Rochester, MN
| | - Ahmed Hasan
- National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R., A.H., E.I., Y.-P.F., N.G.)
| | - Erin Iturriaga
- National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R., A.H., E.I., Y.-P.F., N.G.)
| | - Yi-Ping Fu
- National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R., A.H., E.I., Y.-P.F., N.G.)
| | - Nancy Geller
- National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R., A.H., E.I., Y.-P.F., N.G.)
| | - Kent Bailey
- Department of Health Sciences Research (R.J.L., K.B.), Mayo Clinic, Rochester, MN
| | - Michael E Farkouh
- Peter Munk Cardiac Centre, Heart and Stroke Richard Lewar Centre, University of Toronto, Canada (M.E.F.)
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21
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Zhang M, Wang J, Zhang Y, Zhang P, Jia Z, Ren M, Jia X, Ma L, Gao M, Hou Y. Impacts of CYP2C19 Polymorphism and Clopidogrel Dosing on in-Stent Restenosis: A Retrospective Cohort Study in Chinese Patients. Drug Des Devel Ther 2020; 14:669-676. [PMID: 32109992 PMCID: PMC7038774 DOI: 10.2147/dddt.s242167] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/29/2020] [Indexed: 11/23/2022] Open
Abstract
Objective This retrospective cohort study is to analyze the impacts of CYP2C19 polymorphism and clopidogrel dosing on in-stent restenosis (ISR) after coronary stenting. Methods Totally, 111 patients were included, who underwent percutaneous coronary intervention (PCI) with drug-eluting stent. Patients received clopidogrel treatment after the intervention on the background treatment with aspirin, based on the genotypes: 75 mg clopidogrel once each day for subjects without CYP2C19 loss-of-function (LOF) alleles (n=51; EM), 75 mg clopidogrel once each day (n=27; IM75) or twice each day (n=33; IM150) for subjects with one CYP2C19 LOF allele. ISR at 3-18 months after coronary stenting was assessed. Results ISR rate was significantly higher in the IM75 group (40.7%) than the EM group (11.8%). ISR rate in the IM150 group was lower than the IM75 group (6.1% vs 40.7%), and comparable to that in the EM group. Multivariate logistic regression showed that both CYP2C19 genotype and clopidogrel dosing were associated with the risk of ISR after adjusting the relevant confounding factors. ISR risk was higher in the IM patients than the EM patients. Patients with clopidogrel dose of 75 mg once each day had significantly higher risk of ISR than those with the dose of 75 mg twice each day. Conclusion Increased dose of clopidogrel may reduce the risk of ISR after PCI in CYP2C19 LOF allele(s) carriers. The presence of CYP2C19 LOF allele(s) increases the risk of ISR after stenting, which could be counteracted by the increased dose of clopidogrel.
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Affiliation(s)
- Min Zhang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China.,Department of Cardiology, The Fifth People's Hospital of Jinan, Jinan 250022, Shandong, People's Republic of China
| | - Jiangrong Wang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Yong Zhang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Pei Zhang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Zhisheng Jia
- Department of Cardiology, The Fifth People's Hospital of Jinan, Jinan 250022, Shandong, People's Republic of China
| | - Manyi Ren
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Xiaomeng Jia
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Liping Ma
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Mei Gao
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
| | - Yinglong Hou
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, People's Republic of China
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22
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Zhang Z, Chen M, Zhang L, Zhao Q. The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention. BMC Pharmacol Toxicol 2020; 21:1. [PMID: 31900240 PMCID: PMC6942367 DOI: 10.1186/s40360-019-0378-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 12/20/2019] [Indexed: 12/28/2022] Open
Abstract
Background Clopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China. Methods One hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected. Results The frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77–25.04; p = 0.005); 22.74(95% CI, 3.11–166.27; p = 0.002); 5.69 (95% CI,1.06–30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE. Conclusion Our study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up. Trial registration ChiCTR, ChiCTR1800018316. Registered 11 September 2018 – prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4.
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Affiliation(s)
- Zhaowei Zhang
- Department of Pharmacy, Jin Hua Municipal Central Hospital, Jin Hua, 32100, China.
| | - Mingxiao Chen
- Department of Pharmacy, Jin Hua Municipal Central Hospital, Jin Hua, 32100, China
| | - Long Zhang
- Department of Medical laboratory, Jin Hua Municipal Central Hospital, Jin Hua, 32100, China
| | - Qiang Zhao
- Department of Vascularcardiology, Jin Hua Municipal Central Hospital, Jin Hua, 32100, China
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23
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Cohen MV, Downey JM. What Are Optimal P2Y12 Inhibitor and Schedule of Administration in Patients With Acute Coronary Syndrome? J Cardiovasc Pharmacol Ther 2019; 25:121-130. [DOI: 10.1177/1074248419882923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Guidelines recommend treatment with a P2Y12 platelet adenosine diphosphate receptor inhibitor in patients undergoing elective or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified. The P2Y12 inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for upstream-administered oral agents to achieve a therapeutic P2Y12 level of inhibition by the time of balloon inflation. However, optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish postinfarction heart failure.
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Affiliation(s)
- Michael V. Cohen
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Mobile, AL, USA
- Department of Medicine, University of South Alabama College of Medicine, Mobile, AL, USA
| | - James M. Downey
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Mobile, AL, USA
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24
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Guzauskas GF, Basu A, Carlson JJ, Veenstra DL. Are There Different Evidence Thresholds for Genomic Versus Clinical Precision Medicine? A Value of Information-Based Framework Applied to Antiplatelet Drug Therapy. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2019; 22:988-994. [PMID: 31511188 PMCID: PMC6746330 DOI: 10.1016/j.jval.2019.03.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 02/14/2019] [Accepted: 03/23/2019] [Indexed: 05/12/2023]
Abstract
BACKGROUND The threshold of sufficient evidence for adoption of clinically- and genomically-guided precision medicine (PM) has been unclear. OBJECTIVE To evaluate evidence thresholds for clinically guided PM versus genomically guided PM. METHODS We develop an "evidence threshold criterion" (ETC), which is the time-weighted difference between expected value of perfect information and incremental net health benefit minus the cost of research, and use it as a measure of evidence threshold that is proportional to the upper bound of disutility to a risk-averse decision maker for adopting a new intervention under decision uncertainty. A larger (more negative) ETC value indicates that only decision makers with low risk aversion would adopt new intervention. We evaluated the ETC plus cost of research (ETCc), assuming the same cost of research for both interventions, over time for a pharmacogenomic (PGx) testing intervention and avoidance of a drug-drug interaction (aDDI) intervention for acute coronary syndrome patients indicated for antiplatelet therapy. We then examined how the ETC may explain incongruous decision making across different national decision-making bodies. RESULTS The ETCc for PGx increased over time, whereas the ETCc for aDDI decreased to a negative value over time, indicating that decision makers with even low risk aversion will have doubts in adopting PGx, whereas decision makers who are highly risk-averse will continue to have doubts about adopting aDDI. National recommendation bodies appear to be consistent over time within their own decision making, but had different levels of risk aversion. CONCLUSION The ETC may be a useful metric for assessing policy makers' risk preferences and, in particular, understanding differences in policy recommendations for genomic versus clinical PM.
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Affiliation(s)
- Gregory F Guzauskas
- The Comparative Health Outcomes, Policy & Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA, USA
| | - Anirban Basu
- The Comparative Health Outcomes, Policy & Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA, USA
| | - Josh J Carlson
- The Comparative Health Outcomes, Policy & Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA, USA
| | - David L Veenstra
- The Comparative Health Outcomes, Policy & Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA, USA.
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25
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Impaired adenylate cyclase signaling in acute myocardial ischemia: Impact on effectiveness of P2Y12 receptor antagonists. Thromb Res 2019; 181:92-98. [DOI: 10.1016/j.thromres.2019.07.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/21/2019] [Accepted: 07/19/2019] [Indexed: 01/14/2023]
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26
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Yun KH, Cho JY, Rhee SJ, Oh SK. Temporal Variability of Platelet Reactivity in Patients Treated with Clopidogrel or Ticagrelor. Korean Circ J 2019; 49:1052-1061. [PMID: 31347319 PMCID: PMC6813163 DOI: 10.4070/kcj.2019.0098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 05/02/2019] [Accepted: 06/19/2019] [Indexed: 01/15/2023] Open
Abstract
Background and Objectives The degree of antiplatelet response to P2Y12 inhibitors has been associated with clinical outcomes. The aim of this study was to test the variability of platelet reactivity over time among patients treated with clopidogrel or ticagrelor. Methods A single-center cohort of acute coronary syndrome patients that underwent percutaneous coronary intervention (PCI) was analyzed. Platelet reactivity was measured at baseline, 48 hours after PCI, 1 month, and 6 months after clopidogrel (n=79) or ticagrelor (n=93) treatment. High on-treatment platelet reactivity (HPR) was defined as ≥47 U, assessed by multiple electrode platelet aggregometry. Results Platelet reactivity in the clopidogrel group increased over time, 38.2±21.7 U at 48 hours, 41.4±22.3 U at 1 month, and 44.7±25.5 U at 6 months (p=0.018, 48 hours to 6 months). However, platelet reactivity in the ticagrelor group was not significantly changed, 21.4±12.6 U at 48 hours, 20.0±12.2 U at 1 month, and 22.8±13.8 U at 6 months (p=0.392). A platelet reactivity change over time of more than 20U was found in 67.1% of the patients with clopidogrel group and 34.4% of ticagrelor group (p<0.001). Between 48 hours and 6 months, 43% of patients changed their responder status in the clopidogrel group, and 13% in the ticagrelor group (p<0.001). Conclusions Although ticagrelor treatment resulted in less temporal variability of platelet reactivity than clopidogrel treatment in terms of HPR, platelet reactivity varied over time in a significant proportion of patients.
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Affiliation(s)
- Kyeong Ho Yun
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, Korea
| | - Jae Young Cho
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, Korea
| | - Sang Jae Rhee
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, Korea.
| | - Seok Kyu Oh
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, Korea
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27
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Yang D, Peng C, Liao Z, Wang X, Guo W, Li J. The effect of the CYP2C19*2 allele on cardiovascular outcomes in patients with coronary artery stenting: a prospective study. Arch Med Sci 2019; 15:837-844. [PMID: 31360178 PMCID: PMC6657238 DOI: 10.5114/aoms.2018.75349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 03/22/2018] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION The aim of the study was to evaluate the effects of cytochrome P450 2C19*2 (CYP2C19*2) on ischemic and bleeding events in the Chinese Han population. MATERIAL AND METHODS Patients after coronary artery stenting were enrolled for genotyping CYP2C19*2. Platelet reactivity 4 weeks after stent implantation was compared between different genotype groups. Ischemic and bleeding events were compared after 6 months' follow-up. RESULTS A total of 255 patients were enrolled and 57.7% and 42.3% of patients presented with stable angina and acute coronary syndrome, respectively. The prevalence of homozygous (AA) and heterozygous (GA) CYP2C19*2 variants was 3.5% and 24.7% respectively, and the prevalence of wild type (GG) was 71.8%. Compared to GG and GA genotype groups, the absolute platelet activity reduction was significantly lower in AA genotype (GG 43.6 ±7.8%, GA 31.9 ±6.5%, and AA 24.8 ±5.3%, p < 0.01 for trend). After 6 months' follow-up, 3.3%, 4.8% and 11.1% of patients experienced ischemic events in GG, GA and AA genotype groups, respectively (p = 0.003 for trend). After adjusting for traditional risk factors, AA genotype was significantly associated with ischemic events, with hazard ratio 1.19 and 95% confidence interval 1.08-1.30 (p = 0.013). Also, 2.2%, 1.6% and 0% of patients experienced bleeding events in GG, GA and AA genotype groups (p = 0.153 for trend). No independent association of CYP2C19*2 genotype and bleeding events was observed. CONCLUSIONS Genotyping of CYP2C19*2 may be useful to guide antiplatelet treatment in the Chinese Han population. Randomized controlled trials are warranted to investigate whether genotype-guided antiplatelet treatment could reduce ischemic events.
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Affiliation(s)
- Dahao Yang
- Department of Cardiology, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzen, China
| | - Changnong Peng
- Department of Cardiology, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzen, China
| | - Zhiyong Liao
- Department of Cardiology, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzen, China
| | - Xiaoqing Wang
- Department of Cardiology, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzen, China
| | - Wenyu Guo
- Department of Cardiology, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzen, China
| | - Jun Li
- Department of Cardiology, The Second Clinical Medical College of Jinan University, Shenzen, China
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Association between CYP2C19*2/*3 Polymorphisms and Coronary Heart Disease. Curr Med Sci 2019; 39:44-51. [PMID: 30868490 DOI: 10.1007/s11596-019-1998-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 12/19/2018] [Indexed: 12/12/2022]
Abstract
This study sought to explore the relationship between cytochrome P450 2C19 (CYP2C19) *2/*3 polymorphisms and the development of coronary heart disease (CHD), and to evaluate the influence of the single nucleotide polymorphisms (SNPs) on the occurrence of adverse clinical events in CHD patients. A total of 231 consecutive patients candidate for percutaneous coronary intervention genotyped for CYP2C19*2 (681G>A) and *3 (636G>A) polymorphisms were enrolled. The adverse clinical events were recorded during a follow-up period of 14 months. The incidence of CHD, according to coronary angiography, was significantly higher (P=0.025) in CYP2C19*2 carriers group. Stepwise binary logistic regression analysis revealed that among factors that potentially influenced the presence of CHD (age>60 years, gender, BMI, etc.), CYP2C19*2 carriers (OR 1.94, 95% CI: 1.08-3.50, P=0.028) and male gender (OR 2.74, 95% CI: 1.58-4.76, P=0.001) were independent predictors, which were associated with the presence of CHD. The follow-up results showed that the incidence of adverse cardiovascular events within 14 months of discharge was significantly higher in the CYP2C19*2 carriers than in the non-carriers (21.6% vs. 6.3%, P=0.019). The results of the multivariate Cox proportional hazards model showed that CYP2C19*2 loss-of-function was the only independent factor which predicted the coronary events during the follow-up period of 14 months (OR=3.65, 95% CI 1.09-12.25, P=0.036). The adverse impact of CYP2C19*2 polymorphisms was found not only in the risk of the presence of CHD, but also in the adverse cardiovascular events in CHD patients during the follow-up period of 14 months. However the same influence was not found in CYP2C19*3 mutation in Chinese Han population.
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Laboratory Monitoring of Antiplatelet Therapy. Platelets 2019. [DOI: 10.1016/b978-0-12-813456-6.00036-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Reiner AP, Johnson AD. Platelet Genomics. Platelets 2019. [DOI: 10.1016/b978-0-12-813456-6.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Wang JY, Zhang YJ, Li H, Hu XL, Li MP, Song PY, Ma QL, Peng LM, Chen XP. CRISPLD1 rs12115090 polymorphisms alters antiplatelet potency of clopidogrel in coronary artery disease patients in Chinese Han. Gene 2018; 678:226-232. [DOI: 10.1016/j.gene.2018.08.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 07/29/2018] [Accepted: 08/06/2018] [Indexed: 11/28/2022]
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Cavallari LH, Obeng AO. Genetic Determinants of P2Y 12 Inhibitors and Clinical Implications. Interv Cardiol Clin 2018; 6:141-149. [PMID: 27886818 DOI: 10.1016/j.iccl.2016.08.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
There is significant interpatient variability in clopidogrel effectiveness, which is due in part to cytochrome P450 (CYP) 2C19 genotype. Approximately 30% of individuals carry CYP2C19 loss-of-function alleles, which have been consistently shown to reduce clopidogrel effectiveness after an acute coronary syndrome and percutaneous coronary intervention. Guidelines recommend consideration of prasugrel or ticagrelor in these patients. A clinical trial examining outcomes with CYP2C19 genotype-guided antiplatelet therapy is ongoing. In the meantime, based on the evidence available to date, several institutions have started clinically implementing CYP2C19 genotyping to assist with antiplatelet selection after percutaneous coronary intervention.
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Affiliation(s)
- Larisa H Cavallari
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida, 1333 Center Drive, PO Box 100486, Gainesville, FL 32610, USA.
| | - Aniwaa Owusu Obeng
- Division of General Internal Medicine, Department of Medicine, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA; Department of Pharmacy, The Mount Sinai Hospital, New York, NY, USA
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Chung CJ, Kirtane AJ, Zhang Y, Witzenbichler B, Weisz G, Stuckey TD, Brodie BR, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri EL, Mehran R, Stone GW. Impact of high on-aspirin platelet reactivity on outcomes following successful percutaneous coronary intervention with drug-eluting stents. Am Heart J 2018; 205:77-86. [PMID: 30196181 DOI: 10.1016/j.ahj.2018.07.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 07/25/2018] [Indexed: 11/16/2022]
Abstract
BACKGROUND Whether high on-aspirin platelet reactivity (HAPR) confers an increased risk of adverse outcomes after percutaneous coronary intervention (PCI) remains unclear. We sought to examine the specific relationship between HAPR and clinical outcomes in ADAPT-DES. METHODS A total of 8,526 "all-comer" patients in the ADAPT-DES registry who underwent placement of drug-eluting stents (DES) and were treated with aspirin and clopidogrel were assessed to measure platelet reactivity. HAPR was characterized as ≥550 aspirin reaction units and high on-clopidogrel platelet reactivity as >208 P2Y12 reaction units. Univariable and propensity-adjusted multivariable analyses were used to assess the relationship between HAPR and clinical outcomes. RESULTS HAPR was present in 478 (5.6%) patients. Patients with HAPR were older and had more comorbid illnesses and more complex coronary anatomy. During 2-year follow-up, HAPR was not associated with increased rates of major adverse cardiac events (MACE), stent thrombosis, myocardial infarction, or all-cause mortality. In propensity-adjusted multivariable analyses, HAPR was not an independent predictor of MACE after successful PCI (multivariable adjusted hazard ratio: 1.04; 95% CI 0.64-1.69, P = .87). Nor was HAPR associated with reduced bleeding. Even among patients with concomitant high on-clopidogrel platelet reactivity, HAPR was not associated with worse ischemic outcomes (adjusted hazard ratio for 2-year MACE: 1.06; 95% CI 0.55-2.00, P = .87). CONCLUSIONS HAPR was infrequently present in a large registry of patients undergoing PCI. There was no clear relationship between HAPR and 2-year clinical outcomes. Investigations of antiplatelet regimens without aspirin after DES implantation are ongoing and should inform future management of patients undergoing PCI.
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Affiliation(s)
- Christine J Chung
- New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY
| | - Ajay J Kirtane
- New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY; Clinical Trials Center, Cardiovascular Research Foundation, New York, NY
| | - Yiran Zhang
- Clinical Trials Center, Cardiovascular Research Foundation, New York, NY
| | | | - Giora Weisz
- Clinical Trials Center, Cardiovascular Research Foundation, New York, NY; Montefiore Medical Center, Bronx, NY
| | - Thomas D Stuckey
- LeBauer-Brodie Center for Cardiovascular Research and Education/Cone Health, Greensboro, NC
| | - Bruce R Brodie
- LeBauer-Brodie Center for Cardiovascular Research and Education/Cone Health, Greensboro, NC
| | | | - Franz-Josef Neumann
- Division of Cardiology and Angiology II, Heart Center University of Freiburg, Bad Krozingen, Germany
| | | | - Timothy D Henry
- Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, MN; Cedars-Sinai Heart Institute, Los Angeles, CA
| | - David A Cox
- CVA Brookwood Baptist Hospital, Birmingham, AL
| | - Peter L Duffy
- Reid Heart Center, FirstHealth of the Carolinas, Pinehurst, NC
| | | | - Roxana Mehran
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gregg W Stone
- New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY; Clinical Trials Center, Cardiovascular Research Foundation, New York, NY.
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Bai XF, Zhang YP, Zhou J, Wu Y, Li RF, Sun LZ, Ma QQ, Lou BW, Zhai BW, Liu MP, Cheng LL, Tong XN, Yuan ZY. Combination of the CYP2C19 metabolizer and the GRACE risk score better predicts the long-term major adverse cardiac events in acute coronary syndrome undergoing percutaneous coronary intervention. Thromb Res 2018; 170:142-147. [DOI: 10.1016/j.thromres.2018.08.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 07/14/2018] [Accepted: 08/22/2018] [Indexed: 10/28/2022]
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Lim HH, Li S, An GD, Woo KS, Kim KH, Kim JM, Kim MH, Han JY. Platelet Function Analyzer-200 P2Y Results Are Predictive of the Risk of Major Adverse Cardiac Events in Korean Patients Receiving Clopidogrel Therapy Following Acute Coronary Syndrome. Ann Lab Med 2018; 38:413-419. [PMID: 29797810 PMCID: PMC5973914 DOI: 10.3343/alm.2018.38.5.413] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 01/10/2018] [Accepted: 05/03/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Clopidogrel is one of the most commonly used anti-platelet agents in cardiovascular diseases. We analyzed the relationship between the platelet function analyzer (PFA)-200 P2Y (INNOVANCE PFA-200 System, Siemens Healthcare, Germany) results and occurrence of major adverse cardiac events (MACEs) in Korean patients with recent-onset acute coronary syndrome (ACS) taking clopidogrel. METHODS Between August 2013 and June 2016, we prospectively enrolled 106 patients with recent-onset ACS who had been treated with clopidogrel. We obtained blood samples and measured closure time (CT) using the PFA-200 P2Y test. Patients were divided into two groups on the basis of a CT cut-off value of 106 seconds. We compared patient characteristics and various MACEs that occurred during the follow-up period. RESULTS The CTs for 78 patients exceeded the cut-off value. At the time of these analyses, 11 patients had been diagnosed with MACEs. In the time-to-event analysis, there was a difference between the two groups (P<0.001). After adjusting other variables associated with MACE occurrence, CT value was the strongest predictor of MACEs, with a 7.30-fold occurrence risk (P=0.002). CONCLUSIONS We found a strong relationship between CT and MACE risk in Korean patients with recent-onset ACS taking clopidogrel. Accordingly, PFA-200 P2Y results could be used as a predictive marker for MACE risk in such patients.
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Affiliation(s)
- Hyeon Ho Lim
- Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Shuhua Li
- Department of Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Gyu Dae An
- Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Kwang Sook Woo
- Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Kyeong Hee Kim
- Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Jeong Man Kim
- Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Moo Hyun Kim
- Department of Cardiology, Dong-A University College of Medicine, Busan, Korea
| | - Jin Yeong Han
- Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea.
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Chouchene S, Dabboubi R, Raddaoui H, Abroug H, Ben Hamda K, Hadj Fredj S, Abderrazak F, Gaaloul M, Rezek M, Neffeti F, Hellara I, Sassi M, Khefacha L, Sriha A, Nouira S, Najjar MF, Maatouk F, Messaoud T, Hassine M. Clopidogrel utilization in patients with coronary artery disease and diabetes mellitus: should we determine CYP2C19*2 genotype? Eur J Clin Pharmacol 2018; 74:1567-1574. [PMID: 30073432 DOI: 10.1007/s00228-018-2530-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 07/26/2018] [Indexed: 11/30/2022]
Abstract
PURPOSE Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM). METHODS We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75 mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP. RESULTS We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p = 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759). CONCLUSIONS Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals. TRIAL REGISTRATION Clinical Trials.gov NCT03373552 (Registered 13 December 2017).
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Affiliation(s)
- Saoussen Chouchene
- Hematology Department, Fattouma Bourguiba University Hospital, TN 5000, Monastir, Tunisia.
| | - Rym Dabboubi
- Biochemistry and Molecular Biology Laboratory (LR00SP03), Children's Hospital Bechir Hamza, 1006, Tunis, Tunisia
| | - Haythem Raddaoui
- Cardiology Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Hela Abroug
- Epidemiology and Preventive Medicine Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Khaldoun Ben Hamda
- Cardiology Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Sondess Hadj Fredj
- Biochemistry and Molecular Biology Laboratory (LR00SP03), Children's Hospital Bechir Hamza, 1006, Tunis, Tunisia
| | - Fatma Abderrazak
- Hematology Department, Fattouma Bourguiba University Hospital, TN 5000, Monastir, Tunisia
| | - Mayssa Gaaloul
- Hematology Department, Fattouma Bourguiba University Hospital, TN 5000, Monastir, Tunisia
| | - Marwa Rezek
- Hematology Department, Fattouma Bourguiba University Hospital, TN 5000, Monastir, Tunisia
| | - Fadoua Neffeti
- Biochemistry Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Ilhem Hellara
- Biochemistry Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Mouna Sassi
- Biology Department, Maternity and Neonatal Medicine Center, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Linda Khefacha
- Biology Department, Maternity and Neonatal Medicine Center, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Asma Sriha
- Epidemiology and Preventive Medicine Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Semir Nouira
- Research Laboratory (LR12SP18), University of Monastir, 5000, Monastir, Tunisia
| | - Mohamed Fadhel Najjar
- Biochemistry Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Faouzi Maatouk
- Cardiology Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Taieb Messaoud
- Biochemistry and Molecular Biology Laboratory (LR00SP03), Children's Hospital Bechir Hamza, 1006, Tunis, Tunisia
| | - Mohsen Hassine
- Hematology Department, Fattouma Bourguiba University Hospital, TN 5000, Monastir, Tunisia
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Fedorinov DS, Mirzaev KB, Ivashchenko DV, Temirbulatov II, Sychev DA, Maksimova NR, Chertovskih JV, Popova NV, Tayurskaya KS, Rudykh ZA. Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia). Drug Metab Pers Ther 2018; 33:91-98. [PMID: 29738309 DOI: 10.1515/dmpt-2018-0004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 04/10/2018] [Indexed: 11/15/2022]
Abstract
BACKGROUND The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups. METHODS The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction. RESULTS In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency. CONCLUSIONS The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.
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Affiliation(s)
- Denis S Fedorinov
- Department of Clinical Pharmacology and Pharmacotherapy, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya str., Moscow 119991, Russian Federation.,Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation, Phone: +79169553950
| | - Karin B Mirzaev
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation
| | - Dmitriy V Ivashchenko
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation
| | - Ilyas I Temirbulatov
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Dmitriy A Sychev
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation
| | | | | | | | | | - Zoya A Rudykh
- Republican Hospital No. 3, Yakutsk, Russian Federation
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Ko YM, Kim JK, Kim JH, Park SH, Choi RK. Comparison of antiplatelet treatment in patients with clopidogrel nonresponders with or without carriage of CYP2C19 polymorphism. Korean J Intern Med 2018:kjim.2017.363. [PMID: 29843492 DOI: 10.3904/kjim.2017.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/08/2018] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND/AIMS Several interventions exist for overcoming high platelet reactivity (HPR) on clopidogrel therapy. The goal of this study was to identify strategies that improve inhibition of platelet reactivity in clopidogrel nonresponders with or without loss of function CYP2C19 genotypes, resulting in platelet reactivity similar to that in responders. METHODS A total of 376 patients with stenting for coronary artery disease underwent platelet function testing in three centers. Blinded platelet function tests were performed after 75 mg daily clopidogrel treatment for 28 days. In total, 183 nonresponders were genotyped, were randomized to four treatment groups with each treatment lasting approximately 28 days, and underwent repeated measurements of platelet reactivity after treatment. RESULTS With 75 mg of daily clopidogrel, nonresponders had significantly higher HPR than did responders (multiple electrode aggregometry [MEA, arbitrary platelet aggregation unit]: mean, 71.4; 95% confidence intervals [CI], 68.6 to 74.3; and mean, 27.5; 95% CI, 26.0 to 28.9, respectively; p < 0.001). Ticagrelor or ticlopidine treatment in nonresponders resulted in platelet reactivity similar to that in responders in intermediate metabolizers (mean, 24.0; 95% CI, 19.6 to 28.4; p > 0.05; and mean, 30.0; 95% CI, 24.7 to 37.5; p > 0.05, respectively) and poor metabolizers (mean, 23.2; 95% CI, 18.0 to 28.3; p > 0.05; and mean, 30.3; 95% CI, 24.5 to 6.0; p > 0.05, respectively). However, in extensive metabolizers, only ticagrelor treatment showed platelet reactivity similar to that in responders (mean, 26.1; 95% CI, 24.1 to 28.0; p > 0.05). CONCLUSIONS Among clopidogrel nonresponders with cardiovascular disease on 75 mg daily clopidogrel, ticagrelor resulted in a comparable degree of platelet inhibition in all nonresponders compared with 150 mg daily clopidogrel or triple therapy with clopidogrel and cilostazol, irrespective of phenotype.
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Affiliation(s)
- Yun Myoung Ko
- Department of Internal Medicine, Sun Hospital, Daejeon, Korea
| | - Jeong Kyung Kim
- Cardiovascular Center, Department of Internal Medicine, Sun Hospital, Daejeon, Korea
| | - Jeong Hee Kim
- Cardiovascular Center, Department of Internal Medicine, Sun Hospital, Daejeon, Korea
| | - Sang-Ho Park
- Department of Internal Medicine, Soonchunhyang University Hospital Cheonan, Cheonan, Korea
| | - Rak Kyeong Choi
- Division of Cardiovascular, Department of Internal Medicine, Mediplex Sejong Hospital, Incheon, Korea
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Abstract
Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit-risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient. To date, a multitude of studies has tried to delineate the effects of gene-drug interactions for drugs commonly used to treat cardiovascular-related disease. The focus of this review is on how genetic variability may modify drug responsiveness and patient outcomes following therapy with commonly used cardiovascular drugs including clopidogrel, warfarin, statins, and β-blockers. Also included are examples of how genetic studies can be used to guide drug discovery and examples of how genetic information may be deployed in clinical decision making.
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Affiliation(s)
- Peter E Weeke
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark.
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Kaikita K, Yoshimura H, Ishii M, Kudoh T, Yamada Y, Yamamoto E, Izumiya Y, Kojima S, Shimomura H, Tsunoda R, Matsui K, Ogawa H, Tsujita K. Tailored Adjunctive Cilostazol Therapy Based on CYP2C19 Genotyping in Patients With Acute Myocardial Infarction - The CALDERA-GENE Study. Circ J 2018; 82:1517-1525. [PMID: 29743380 DOI: 10.1253/circj.cj-18-0197] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Patients with reduced-function CYP2C19 genotypes on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel show higher clinical risk for acute myocardial infarction (AMI). We investigated the effect of CYP2C19 genotype-tailored adjunctive cilostazol therapy on treatment of AMI. METHODS AND RESULTS The study group of 138 patients with suspected AMI were screened for CYP2C19 genotype immediately after percutaneous coronary intervention (PCI) using a SPARTAN RX point-of-care device. Carriers of the CYP2C19 reduced-function allele were randomized into DAPT (Carrier/DAPT) and DAPT plus 14-day cilostazol (Carrier/DAPT+Cilostazol) groups, while noncarriers were treated with DAPT (Noncarrier/DAPT). After exclusion of 10 patients, the remaining 128 patients were analyzed for P2Y12 reaction unit (PRU) using VerifyNow®P2Y12 system, and levels of biomarkers immediately after, and 1, 14, and 28 days after PCI. DAPT+Cilostazol reduced PRU levels in carriers (n=46) to those found in the Noncarrier/DAPT group (n=40), and significantly lower than those of the Carrier/DAPT group (n=42) at 14 days post-PCI. Discontinuation of cilostazol for 14 days was associated with a significant rise in PRU levels to those of the Carrier/DAPT group at 28 days post-PCI. Plasma B-type natriuretic peptide levels at 14 days post-PCI were lower in Carrier/DAPT+Cilostazol than in the other 2 groups, and the levels increased to those of the other groups at 28 days post-PCI after withdrawal of cilostazol. CONCLUSIONS Adjunctive cilostazol therapy tailored to CYP2C19 genotype seemed useful in AMI patients with the CYP2C19 reduced-function allele.
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Affiliation(s)
- Koichi Kaikita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Hiromi Yoshimura
- Department of Cardiovascular Medicine, Japanese Red Cross Kumamoto Hospital
| | - Masanobu Ishii
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Takashi Kudoh
- Department of Cardiovascular Medicine, Fukuoka Tokushukai Medical Center
| | - Yoshihiro Yamada
- Department of Cardiovascular Medicine, Fukuoka Tokushukai Medical Center
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Yasuhiro Izumiya
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Sunao Kojima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Hideki Shimomura
- Department of Cardiovascular Medicine, Fukuoka Tokushukai Medical Center
| | - Ryusuke Tsunoda
- Department of Cardiovascular Medicine, Japanese Red Cross Kumamoto Hospital
| | - Kunihiko Matsui
- Department of Community Medicine, Kumamoto University Hospital
| | | | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
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Tang YD, Wang W, Yang M, Zhang K, Chen J, Qiao S, Yan H, Wu Y, Huang X, Xu B, Gao R, Yang Y, Yuan X, Ji H, Zhou Z, Liu Z, Chen J, Yuan J, Liu H, Qian J, Hu F, Shao C, Zhao H, Hua Y, Lu J. Randomized Comparisons of Double-Dose Clopidogrel or Adjunctive Cilostazol Versus Standard Dual Antiplatelet in Patients With High Posttreatment Platelet Reactivity. Circulation 2018; 137:2231-2245. [DOI: 10.1161/circulationaha.117.030190] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 01/17/2018] [Indexed: 11/16/2022]
Affiliation(s)
- Yi-Da Tang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Wenyao Wang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Min Yang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Kuo Zhang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Jing Chen
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Shubin Qiao
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Hongbing Yan
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Yongjian Wu
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Xiaohong Huang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Bo Xu
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Runlin Gao
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
| | - Yuejin Yang
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Cardiology (X.Y., J.C., J.Y., H.L., J.Q., F.H., C.S., H.Z., Y.H., J.L.), Department of Anesthesiology (H.J.), State Key Laboratory of Cardiovascular Disease; and Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service
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Zeb I, Krim N, Bella J. Role of CYP2C19 genotype testing in clinical use of clopidogrel: is it really useful? Expert Rev Cardiovasc Ther 2018; 16:369-377. [PMID: 29589775 DOI: 10.1080/14779072.2018.1459186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION P2Y12 inhibitors, including clopidogrel have become an integral part of treatment for patients receiving coronary stent placement as a result of stable coronary artery disease or acute coronary syndromes (ACS) and also for medically managed ACS patients. Areas covered: Clopidogrel efficacy can be significantly modified by polymorphism of CYP2C19 genotype (more than 25 allelic variants) involved in its metabolism that can adversely affect its anti-platelet activity. As a result, a substantial number of patients (20-30%) with ACS show an inadequate response to clopidogrel despite a standardized dosing regimen. Experts commentary: Currently, there is conflicting evidence in regards to the use of CYP2C19 genotyping to identify poor responders to clopidogrel in clinical practice. ACC/AHA guidelines do not recommend routine use of CYP2C19 in clinical practice, whereas Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend its use to identify poor/intermediate metabolizers of Clopidogrel and suggest alternative P2Y12 inhibitors among ACS patients undergoing percutaneous coronary intervention. This review article will look at the literature evidence for the use of CYP2C19 genotyping in clinical practice.
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Affiliation(s)
- Irfan Zeb
- a Division of Cardiology, Department of Medicine , Bronxcare Health System , Bronx , NY , USA.,b Division of Cardiology, Department of Medicine , Icahn School of Medicine at Mount Sinai , New York , NY , USA
| | - Nassim Krim
- a Division of Cardiology, Department of Medicine , Bronxcare Health System , Bronx , NY , USA.,b Division of Cardiology, Department of Medicine , Icahn School of Medicine at Mount Sinai , New York , NY , USA
| | - Jonathan Bella
- a Division of Cardiology, Department of Medicine , Bronxcare Health System , Bronx , NY , USA.,b Division of Cardiology, Department of Medicine , Icahn School of Medicine at Mount Sinai , New York , NY , USA.,c Division of Cardiology, Department of Medicine , Weill Cornell Medicine , New York , NY , USA
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Bergmeijer TO, Reny JL, Pakyz RE, Gong L, Lewis JP, Kim EY, Aradi D, Fernandez-Cadenas I, Horenstein RB, Lee MTM, Whaley RM, Montaner J, Gensini GF, Cleator JH, Chang K, Holmvang L, Hochholzer W, Roden DM, Winter S, Altman RB, Alexopoulos D, Kim HS, Déry JP, Gawaz M, Bliden K, Valgimigli M, Marcucci R, Campo G, Schaeffeler E, Dridi NP, Wen MS, Shin JG, Simon T, Fontana P, Giusti B, Geisler T, Kubo M, Trenk D, Siller-Matula JM, Ten Berg JM, Gurbel PA, Hulot JS, Mitchell BD, Schwab M, Ritchie MD, Klein TE, Shuldiner AR. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J 2018; 198:152-159. [PMID: 29653637 PMCID: PMC5903579 DOI: 10.1016/j.ahj.2017.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/10/2017] [Indexed: 02/07/2023]
Abstract
RATIONALE The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies. RESULTS In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40). CONCLUSION The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.
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Affiliation(s)
- Thomas O Bergmeijer
- St Antonius Center for Platelet Function Research, Department of Cardiology, St Antonius Hospital Nieuwegein, the Netherlands
| | - Jean-Luc Reny
- Internal Medicine, Béziers Hospital, France, Geneva Platelet Group, University of Geneva School of Medicine, Department of Internal Medicine, Rehabilitation and Geriatrics, University Hospitals of Geneva, Geneva, Switzerland
| | - Ruth E Pakyz
- Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Li Gong
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | - Joshua P Lewis
- Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eun-Young Kim
- Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, South Korea
| | - Daniel Aradi
- Heart Center Balatonfüred and Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Israel Fernandez-Cadenas
- Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca Mútua Terrassa, Neurovascular Research Laboratory, Valle d'Hebron Hebron Institute of Research, Barcelona, Spain
| | - Richard B Horenstein
- Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Ryan M Whaley
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | - Joan Montaner
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Barcelona, Spain
| | - Gian Franco Gensini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - John H Cleator
- Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kiyuk Chang
- Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Lene Holmvang
- Department of Cardiology and Cardiac Catheterization Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Willibald Hochholzer
- University Heart Center Freiburg, Bad Krozingen, Department of Cardiology and Angiology II, Bad Krozingen, Germany
| | - Dan M Roden
- Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Stefan Winter
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany
| | - Russ B Altman
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA; Departments of Bioengineering and Genetics, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA
| | | | - Ho-Sook Kim
- Department of Pharmacology and Pharmacogenomics Research Center, College of Medicine, Inje University, Busan, South Korea
| | | | - Meinrad Gawaz
- Department of Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Kevin Bliden
- Inova Center for Thrombosis Research and Drug Development. Inova Heart and Vascular Institute, Falls Church, VA, USA
| | - Marco Valgimigli
- Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland
| | - Rossella Marcucci
- Department of Experimental and Clinical Medicine, University of Florence, Atherothrombotic Diseases Center, Careggi Hospital, Florence, Italy
| | - Gianluca Campo
- Cardiology Unit, Azienda Ospedaliera Universitria di Ferrara, Cona (FE) and Maria Cecilia Hospital, GVM Care and Research, Cotignola, (RA), Italy
| | - Elke Schaeffeler
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany
| | - Nadia P Dridi
- Department of Cardiology and Cardiac Catheterization Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ming-Shien Wen
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou and School of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Jae Gook Shin
- Department of Pharmacology and Pharmacogenomics Research Center, College of Medicine, Inje University, Busan, South Korea
| | | | - Pierre Fontana
- Geneva Platelet Group, University of Geneva School of Medicine, Division of Angiology and Haemostasis, University Hospitals of Geneva, Geneva, Switzerland
| | - Betti Giusti
- Department of Experimental and Clinical Medicine, University of Florence, Atherothrombotic Diseases Center, Careggi Hospital, Florence, Italy
| | - Tobias Geisler
- Department of Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Michiaki Kubo
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
| | - Dietmar Trenk
- Department of Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany
| | | | - Jurriën M Ten Berg
- St Antonius Center for Platelet Function Research, Department of Cardiology, St Antonius Hospital Nieuwegein, the Netherlands
| | - Paul A Gurbel
- Inova Center for Thrombosis Research and Drug Development. Inova Heart and Vascular Institute, Falls Church, VA, USA
| | - Jean-Sebastien Hulot
- Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013 Paris, France
| | - Braxton D Mitchell
- Department of Medicine, University of Maryland, Baltimore, MD, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, MD
| | - Matthias Schwab
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacology, University Hospital, Tübingen, Germany
| | - Marylyn DeRiggi Ritchie
- Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA
| | - Teri E Klein
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA
| | - Alan R Shuldiner
- Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
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CYP2C19 Genotype is an Independent Predictor of Adverse Cardiovascular Outcome in Iraqi Patients on Clopidogrel After Percutaneous Coronary Intervention. J Cardiovasc Pharmacol 2018; 71:347-351. [PMID: 29554005 DOI: 10.1097/fjc.0000000000000577] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
To determine the impact of CYP2C19 genotyping on the occurrence of major adverse cardiovascular events (MACE), in cohort of Iraqi patients on clopidogrel after percutaneous coronary intervention (PCI), a total of 201 Iraqi patients undergoing the latter procedure were enrolled. All enrollees had their CYP2C19 genotyped using polymerase chain reaction and reverse hybridization. Genotyping revealed that CYP2C19 *1, *17, *2, and *8 allele frequencies were, respectively, 0.604, 0.276, 0.117, and 0.0026. After the exclusion of those with 2 loss of function alleles, 186 patients were available for follow-up as long as they were on clopidogrel, or until MACE occurred, which was encountered in 8.6% after a median of 12 months. Among predictors associated with MACE was the carriage of one CYP2C19 loss of function allele {hazard ratio (HR) 8.6 [confidence interval (CI) 3.15-23.4]; P < 0.0005}, hypertension [HR 3.74 (CI 1.06-13.16); P = 0.04], reduced ventricular function [HR 3.88 (1.43-10.54); P = 0.008], and history of previous myocardial infarction [HR 4.9 (CI 1.48-11.33); P = 0.007] by univariate analysis, although only CYP2C19 genotype remained significant by multivariate analysis [HR 11.88 (CI 3.25-43.44); P < 0.0005]. The latter observation favors CYP2C19 genotype-guided antiplatelet therapy and extending the use of alternative antiplatelet drugs to those with single loss of function allele after percutaneous coronary intervention.
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Moon JY, Franchi F, Rollini F, Rios JRR, Kureti M, Cavallari LH, Angiolillo DJ. Role of genetic testing in patients undergoing percutaneous coronary intervention. Expert Rev Clin Pharmacol 2018; 11:151-164. [PMID: 28689434 PMCID: PMC5771818 DOI: 10.1080/17512433.2017.1353909] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.
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Affiliation(s)
- Jae Youn Moon
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Francesco Franchi
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Fabiana Rollini
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Jose R. Rivas Rios
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Megha Kureti
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Larisa H. Cavallari
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
- Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA
- Clinical & Translational Science Institute, University of Florida, Gainesville, FL, USA
| | - Dominick J. Angiolillo
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
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Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine. J Pers Med 2018; 8:jpm8010008. [PMID: 29385765 PMCID: PMC5872082 DOI: 10.3390/jpm8010008] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 01/20/2018] [Accepted: 01/22/2018] [Indexed: 12/21/2022] Open
Abstract
Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel. Individuals may be classified as poor, intermediate, extensive, or ultrarapid metabolizers, based on whether they carry wild type or polymorphic CYP2C19 alleles. Variant alleles differentially impact platelet reactivity, concentration of plasma clopidogrel metabolites, and clinical outcomes. Interestingly, response to clopidogrel appears to be modulated by additional factors, such as sociodemographic characteristics, risk factors for ischemic heart disease, and drug-drug interactions. Furthermore, systems medicine studies suggest that a broader approach may be required to adequately assess, predict, preempt, and manage variation in antiplatelet response. Transcriptomics, epigenomics, exposomics, miRNAomics, proteomics, metabolomics, microbiomics, and mathematical, computational, and molecular modeling should be integrated with pharmacogenomics for enhanced prediction and individualized care. In this review of pharmacogenomic variation of CYP450, a systems medicine approach is described for tailoring antiplatelet therapy in clinical practice of precision cardiovascular medicine.
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Risk of discontinuation of clopidogrel after 1 month following bare-metal stents: a propensity-score adjusted comparison with continued administration of clopidogrel after drug-eluting stents. J Thromb Thrombolysis 2018; 45:432-439. [PMID: 29349545 DOI: 10.1007/s11239-018-1613-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
In patients at high risk for bleeding undergoing percutaneous coronary intervention (PCI) the use of bare-metal-stent (BMS) is considered an option that allows discontinuation of clopidogrel after 4 weeks. We sought to investigate the risk of early discontinuation of clopidogrel in patients with BMS as compared with a 6-month course of clopidogrel after DES in patients with or without high on-treatment platelet reactivity (HTPR). In 765 consecutive patients undergoing PCI after loading with clopidogrel 600 mg, HTPR was tested by optical aggregometry and defined as residual platelet reactivity > 14%. On top of aspirin 100 mg, patients received clopidogrel 75 mg for 4 weeks after BMS or 6 months after DES. The primary endpoint was all-cause mortality or myocardial infarction (MI) during 1 year. The 1-year incidence of death or MI was 3.5% with BMS (n = 484), 0.9% with DES and no HTPR (n = 211), and 7.1% with DES and HTPR (n = 70; p = 0.03). Landmark analyses for the first 6 months demonstrated that the risk of patients receiving BMS was similar as in patients receiving a DES with HTPR during this period (2.3 vs. 2.9%) but lowest in patients receiving a DES without HTPR (0.5%). The incidence of bleeding was similar in all three groups. These findings did not change after propensity score adjustment for stent type. After discontinuation of clopidogrel at 1 month, patients treated with BMS are at higher risk for death or MI than patients treated with a DES and sufficiently responding to clopidogrel planned for 6 months.ClinicalTrials.gov number NCT00457236.
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Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China. Eur J Clin Pharmacol 2017; 74:423-431. [DOI: 10.1007/s00228-017-2393-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 11/28/2017] [Indexed: 10/18/2022]
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