Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting

Martin, Jessica R.; Williams, Alexis K.; Klein, Melissa; Sriramoju, Vindhya; Madan, Shivanshu; Rossi, Joseph S.; Clarke, Megan M.; Cicci, Jonathan D.; Cavallari, Larisa H.; Weck, Karen E.; Stouffer, George A.; Lee, Craig

doi:10.1038/s41436-019-0611-1

Cited by 49 publications

(41 citation statements)

References 42 publications

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“… 15 A line of evidence shows that CYP2C19 genotyping to guide this de-escalation is effective in optimizing the clinical outcomes in patients undergoing PCI. 16 , 17 , 18 The present study aimed to evaluate the efficiency of genotype test-guided antiplatelet therapy (de-escalating ticagrelor to clopidogrel) on major adverse cardiac outcomes (MACE) in patients undergoing PCI.…”

Section: Introductionmentioning

confidence: 99%

Incidence of major adverse cardiovascular events with genotype test guided antiplatelet treatment strategy after percutaneous coronary intervention

Ramesh

Socrates

Rajasekaran

et al. 2020

Indian Heart Journal

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Objective To estimate the incidence of major adverse cardiovascular events (MACE) with genotype test-guided antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome. Methods Patients who had undergone PCI for acute coronary syndrome as well as stable coronary artery disease were recruited. Salivary samples were obtained from these patients and genotyped for CYP2C19∗2, CYP2C19∗3 variations by sequencing method (GAAP x method). Patients were categorized as normal (GG, GG) (29%), intermediate (AG) (52%) or poor metabolizes (homozygous variant AA) (19%). Dual antiplatelets were given based on the genotyping data. Poor metabolizes received newer agent (ticagrelor), intermediate metabolizes received double-dose of clopidogrel and normal metabolizes received therapeutic doses of clopidogrel. All subjects were followed-up for six months. Results Based on the genotyping data of CYP2C19∗2 and CYP2C19∗3 variations, it was found that most patients were categorized as ‘intermediate’ (78, 51.65%), followed by ‘normal’ (43, 28.48%) and ‘poor’ metabolizes (30, 19.87%). Only 3 (1.5%) of 151 patients reported MACE at follow-up. Conclusions Genotyping for CYP2C19 variations to assess clopidogrel resistance in patients undergoing PCI and subsequent drug selection helps reduce MACE after coronary intervention.

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Section: Introductionmentioning

confidence: 99%

Incidence of major adverse cardiovascular events with genotype test guided antiplatelet treatment strategy after percutaneous coronary intervention

Ramesh

Socrates

Rajasekaran

et al. 2020

Indian Heart Journal

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“…Event rates were reported as the number of events per 100 patient‐years of follow‐up. The relationship between P2Y 12 receptor inhibitor therapy, CYP2C19 metabolizer phenotype, and time to occurrence of the primary and secondary clinical outcomes was evaluated by Cox proportional hazards regression, as described 10,33 . Kaplan‐Meier curves were generated, and the log‐rank test was used to compare the cumulative risk of an event across groups.…”

Section: Methodsmentioning

confidence: 99%

“…During a median follow-up of 6.3 (1.0-11.0) months after PCI, 353 patients (10.6%) experienced a major atherothrombotic event. The risk of the primary outcome by CYP2C19 metabolizer status (29) 176 (19) 252 (31) 378 (34) 151 (32) < 0.001 0.466 Female 1,075 (32) 250 (27) 289 (36) 368 (33) 168 (35 (19) 247 (26) 129 (16) 192 1760 13Non-STEMI 939 (28) 275 (29) 230 (28) 297 (26) 137 29Unstable angina 723 (22) 167 (18) 182 (23) 253 23121 26Non-ACS 1,052 (31) 244 (26) 269 (33) 381 (34) 158 ( 83 (10) 118 (11) 67 (14) < 0.001…”

Section: Clinical Outcomesmentioning

confidence: 99%

Impact of the CYP2C1917* Allele on Outcomes in Patients Receiving Genotype‐Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Lee

Thomas

Beitelshees

et al. 2020

Clin Pharma and Therapeutics

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Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19‐guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel‐treated normal metabolizers (20.4 events/100 patient‐years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75–1.33, P = 0.993) and clopidogrel‐treated rapid or ultrarapid metabolizers (19.1 events/100 patient‐years; adjusted HR 0.95, 95% CI, 0.69–1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient‐years). In contrast, clopidogrel‐treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor‐treated patients (adjusted HR 1.56, 95% CI, 1.12–2.16, P = 0.008). When comparing clopidogrel‐treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73–1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83–2.17, P = 0.224) were observed. In a real‐world setting of genotype‐guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post‐PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

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“…[31][32][33][34] A recent pragmatic, randomized trial of CYP2C19 genotyping implementation demonstrated that return of genetic test results influenced antiplatelet therapy prescribing after PCI. 35 In addition, multiple nonrandomized 36,38 and randomized trials 39,41 have examined the impact of genotype-guided-antiplatelet therapy on clinical outcomes. Collectively, these studies demonstrate that a genotypeguided strategy, whereby prasugrel or ticagrelor are prescribed in CYP2C19 IM and PMs, lowers the risk for high on-treatment platelet reactivity and MACE compared to conventional treatment strategies, without significantly increasing bleeding risk.…”

Section: Clinical Outcomes Of Genotype-guided Antiplatelet Therapy Afmentioning

confidence: 99%

“…In contrast, patients without a no function allele de-escalated to clopidogrel had no difference in risk compared to patients initiated and continued on prasugrel or ticagrelor (21 vs 19 events/100 patient-years; adjusted HR: 1.13; 95% CI: 0.51-2.34; p=0.751). 38…”

Section: Unc-chapel Hillmentioning

confidence: 99%

<p>Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence</p>

Gower

Ratner

Williams

et al. 2020

PGPM

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In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y 12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y 12 inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y 12 inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotypeguided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotypeguided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.

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Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting

Cited by 49 publications

References 42 publications

Incidence of major adverse cardiovascular events with genotype test guided antiplatelet treatment strategy after percutaneous coronary intervention

Incidence of major adverse cardiovascular events with genotype test guided antiplatelet treatment strategy after percutaneous coronary intervention

Impact of the CYP2C1917* Allele on Outcomes in Patients Receiving Genotype‐Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

<p>Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence</p>

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Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting

Cited by 49 publications

References 42 publications

Incidence of major adverse cardiovascular events with genotype test guided antiplatelet treatment strategy after percutaneous coronary intervention

Incidence of major adverse cardiovascular events with genotype test guided antiplatelet treatment strategy after percutaneous coronary intervention

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype‐Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

<p>Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence</p>

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Impact of the CYP2C1917* Allele on Outcomes in Patients Receiving Genotype‐Guided Antiplatelet Therapy After Percutaneous Coronary Intervention