Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes

Notarangelo, Francesca M.; Maglietta, Giuseppe; Bevilacqua, Paola; Cereda, Marco; Merlini, Piera Angelica; Villani, Giovanni; Moruzzi, P; Patrizi, Giampiero; Tagliazucchi, Guidantonio Malagoli; Crocamo, Antonio; Guidorossi, Angela; Pigazzani, Filippo; Nicosia, Elisa; Paoli, Giorgia De; Bianchessi, M; Comelli, Mario; Caminiti, Caterina; Ardissino, Diego

doi:10.1016/j.jacc.2018.02.029

Cited by 169 publications

(172 citation statements)

References 30 publications

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“…An analysis of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial showed bleeding events were significantly reduced in clopidogrel‐treated patients who are carriers of CYP2C19 LOF alleles. Additionally, in the prematurely stopped PHARMCLO (Pharmacogenetics of clopidogrel in patients with ACSs) trial ( n = 888), patients with ACS who underwent point‐of‐care genotyping of ABCB1 , CYP2C19*2 , and CYP2C19*17 had a significantly lower incidence of the composite of MI, stroke, and BARC (Bleeding Academic Research Consortium) three to five major bleeding (15.9 vs 25.9% control arm; P < 0.01). Our results demonstrated a lower trend of both ischemic and bleeding endpoints in the genotype‐guided group.…”

Section: Discussionmentioning

confidence: 99%

“…P2Y 12 receptor inhibitors are an important part of the management of patients undergoing coronary stenting, especially if they have acute coronary syndromes (ACS). Although ticagrelor and prasugrel are superior in preventing ischemic events, clopidogrel is the most utilized P2Y 12 receptor antagonist worldwide. This is likely due to its lower rate of bleeding and reduced cost.…”

Section: Introductionmentioning

confidence: 99%

“…Although ticagrelor and prasugrel are superior in preventing ischemic events, clopidogrel is the most utilized P2Y 12 receptor antagonist worldwide. This is likely due to its lower rate of bleeding and reduced cost. Unlike ticagrelor and prasugrel, genetic variations of clopidogrel‐treated patients, such as cytochrome P450 (CYP) 2C19 variations, are associated with substantial inter‐individual response variability.…”

Section: Introductionmentioning

confidence: 99%

“…This is likely due to its lower rate of bleeding and reduced cost. Unlike ticagrelor and prasugrel, genetic variations of clopidogrel‐treated patients, such as cytochrome P450 (CYP) 2C19 variations, are associated with substantial inter‐individual response variability. CYP2C19 is paramount in the biotransformation of the clopidogrel prodrug into its active metabolite.…”

Section: Introductionmentioning

confidence: 99%

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CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta‐analysis of randomized clinical trials

Kheiri

Osman

Abdalla

et al. 2018

Cathet Cardio Intervent

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Objectives This study aimed to evaluate the efficacy and safety of personalized genotype‐guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI). Background Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter‐individual response variability which could limit its efficacy. Methods Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype‐guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random‐effects model. Results We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype‐guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35–1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype‐guided group (RR 0.44; 95% CI: 0.28–0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27–1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23–1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13–1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43–1.06; P = 0.09). Conclusion In patients undergoing stent implantation, MACE with genotype‐guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta‐analysis of randomized clinical trials

Kheiri

Osman

Abdalla

et al. 2018

Cathet Cardio Intervent

View full text Add to dashboard Cite

show abstract

“…Therefore, personalized antiplatelet therapy with particular consideration of clopidogrel pharmacogenetic and pharmacodynamic characteristics has gained much attention. Unfortunately, large randomized clinical trials (RCTs) that incorporated either platelet function assays or genetic testing have failed to demonstrate any clinical benefit . Furthermore, previous meta‐analyses of such strategies showed conflicting results .…”

Section: Introductionmentioning

confidence: 99%

Personalized antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention: A network meta‐analysis of randomized clinical trials

Kheiri

Abdalla

Barbarawi

et al. 2019

Cathet Cardio Intervent

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Objectives This study aimed to evaluate the efficacy and safety of genotype‐ and phenotype‐guided intensified antiplatelet therapy compared with conventional therapy in patients undergoing stent implantation. Background Although potent P2Y12 receptor inhibitors are recommended for percutaneous coronary intervention (PCI)‐treated acute coronary syndrome, their usage is limited by a high bleeding risk. Therefore, personalized antiplatelet therapy could provide a valuable foundation for selection of antiplatelet therapy in this population. Methods We conducted a Bayesian network meta‐analysis for all randomized clinical trials (RCTs) that evaluated genotype‐ and/or phenotype‐guided therapy in PCI‐treated coronary artery disease. Results Thirteen RCTs were included with a total of 6,845 patients. The results showed no significant differences in major adverse cardiovascular events (MACE) between the treatment options ((genotype guided vs. standard of care; OR 0.64; 95% CI: 0.38–1.05) and (phenotype vs. standard of care; OR 0.93; 95% CI: 0.54–1.37)). In addition, no significant differences were demonstrated in bleeding events ((genotype guided vs. standard of care; OR 0.73; 95% CI: 0.45–1.25) and (phenotype vs. standard of care; OR 0.90; 95% CI: 0.62–1.39)). Conclusions In this mixed treatment meta‐analysis of RCTs, neither genotype‐ nor phenotype‐guided antiplatelet therapy in patients with PCI‐treated coronary artery disease was superior to conventional therapy.

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P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes

et al. 2019

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IMPORTANCE Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown.OBJECTIVE To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial. DESIGN, SETTING, AND PARTICIPANTSThe GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.INTERVENTIONS Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization. MAIN OUTCOMES AND MEASURESReasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected. RESULTS Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.CONCLUSIONS AND RELEVANCE Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02293395

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Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes

Abstract: A personalized approach to selecting antiplatelet therapy for patients with ACS may reduce ischemic and bleeding events. (Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes [PHARMCLO]; NCT03347435).

Cited by 169 publications

References 30 publications

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta‐analysis of randomized clinical trials

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta‐analysis of randomized clinical trials

Personalized antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention: A network meta‐analysis of randomized clinical trials

P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes

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