CYP2C19 genotype–guided antiplatelet therapy in ST-segment elevation myocardial infarction patients—Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study

Bergmeijer, Thomas O.; Janssen, Paul W.A.; Schipper, J.C.; Qaderdan, Khalid; Ishak, Maycel; Ruitenbeek, Rianne S.; Asselbergs, Folkert W.; Hof, Arnoud W J van ‘t; Dewilde, Willem; Spanó, Fabrizio; Herrman, Jean‐Paul R.; Kelder, Johannes C.; Postma, Maarten J.; Boer, Anthonius de; Deneer, Vera H.M.; Berg, Jürrien M. ten

doi:10.1016/j.ahj.2014.03.006

Cited by 69 publications

(44 citation statements)

References 25 publications

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“…Two ongoing randomized studies compare CYP2C19 genotype-guided antiplatelet therapy to a nontailored strategy in PCI patients. 24,25 In this regard, we believe that the findings of the present observational study could supply additional evidence regarding the clinical appropriateness of the current genetic testing to assess clopidogrel metabolism. In addition, our results also reemphasize that the traditional risk factors are still strong predictors of a broad cardiovascular end point.…”

Section: Original Research Articlementioning

confidence: 69%

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Park

Her

Kim

et al. 2016

Genetics in Medicine

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Original research article INTRODUCTIONThe identification of individuals at risk of future adverse cardiovascular outcomes is important after percutaneous coronary intervention (PCI). Thus, the use of novel risk markers such as genetic polymorphisms to augment standard risk algorithms, including conventional clinical risk factors, has attracted increasing attention in recent years.Dual antiplatelet therapy with aspirin and clopidogrel is the current standard of treatment after PCI with drug-eluting stent to reduce the rate of recurrent ischemic events. 1,2 However, considerable interindividual variability exists in response to clopidogrel, and those with high on-clopidogrel platelet reactivity are at increased risk of cardiovascular events. 3,4 Several clinical, genetic, and cellular factors have been suggested as mechanisms for clopidogrel response variability. 5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene. Purpose: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. Methods:We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. Results:A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). Conclusions:In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors. Genet Med

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Section: Original Research Articlementioning

confidence: 69%

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Park

Her

Kim

et al. 2016

Genetics in Medicine

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“…This is done in other ongoing trials, that are based on personalised treatment approaches implementing either (CYP2C19) genotyping (POPULAR Genetics, TAILOR-PCI) (84) or phenotyping (TROPICAL-ACS) (85) by means of platelet function testing. Both POPULAR Genetics and TROPI-CAL-ACS share a common idea of treatment de-escalation.…”

Section: The Futurementioning

confidence: 99%

Antithrombotic therapy for acute coronary syndrome: Past, present and future

Sibbing

Angiolillo²,

Huber³

2017

Thromb Haemost

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SummaryPlaque erosions and ruptures are the histopathological hallmarks of arterial thrombus formation in the coronary arteries. The clinical condition associated with this process is usually referred to as acute coronary syndrome (ACS). Importantly, both blood platelets and the coagulation cascade are key players for initiation, amplification and perpetuation of ACS. There has been great progress in ACS treatment in recent decades, both at the technical level of (percutaneous) revascularisation and at the level of antithrombotic treatment. Numerous trials have led to significant advancements in the development of effective anticoagulant and antiplatelet drugs. The large number of randomised controlled clinical trials (RCTs) and the huge number of patients enrolled in these RCTs, with mega trials including >10,000 patients, is unique in the history of medical research and also reflects the exceptional efforts associated with these huge research activities. The crucial issue, however, with respect to optimising treatment, relates to finding the delicate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Interestingly, there is a gap in modern days between current guideline recommendations favouring potent platelet inhibition in ACS and the utilization of the respective drugs in clinical practice. In this review, we will summarise and discuss the past, present and future antithrombotic treatment for ACS patients with a focus on the development of optimised antiplatelet treatment strategies and their utilisation in the real world.

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“…[59][60][61][62] In an ongoing prospective post-PCI study assessing CYP2C19 genotype, antiplatelet therapy was changed from clopidogrel to ticagrelor or prasugrel in those with a loss of function polymorphism. 63 These data will clarify the role of CYP2C19 genotype in selecting the type of antiplatelet therapy and will either confirm or refute the smaller studies suggesting an improvement in cardiovascular outcome with this strategy.…”

Section: Aspirin and Clopidogrel Resistancementioning

confidence: 89%

Current State and Novel Approaches of Antiplatelet Therapy

Metharom

Berndt

Baker

et al. 2015

ATVB

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Abstract-An unresolved problem with clinical use of antiplatelet therapy is that a significant number of individuals either still get thrombosis or run the risk of life-threatening bleeding. Antiplatelet drugs are widely used clinically, either chronically for people at risk of athero/thrombotic disease or to prevent thrombus formation during surgery. However, a subpopulation may be resistant to standard doses, while the platelet targets of these drugs are also critical for the normal hemostatic function of platelets. In this review, we will briefly examine current antiplatelet therapy and existing targets while focusing on new potential approaches for antiplatelet therapy and improved monitoring of effects on platelet reactivity in individuals, ultimately to improve antithrombosis with minimal bleeding. Primary platelet adhesion-signaling receptors, glycoprotein (

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CYP2C19 genotype–guided antiplatelet therapy in ST-segment elevation myocardial infarction patients—Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study

Cited by 69 publications

References 25 publications

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Antithrombotic therapy for acute coronary syndrome: Past, present and future

Current State and Novel Approaches of Antiplatelet Therapy

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