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

Abstract

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

Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice

“…This regulation is based on the recognition that PGx-guided clopidogrel therapy requires more than just a pharmacogenetic test. Indeed, a subanalysis of the GEMINI-ACS-1 multicenter trial reported that mere routine notification of CYP2C19 metabolizer status resulted in switching to another antiplatelet therapy in only 5.9% of patients with current clopidogrel therapy and intermediate or reduced metabolizer genotype [ 18 ]. In contrast, in a specialized pharmacogenetic program with integrated clinical decision support at the University of Florida, preemptive testing led to implementation of therapy changes in 70.0% of individuals with actionable genotypes [ 26 ].…”

“…However, the implementation of PGx-guided clopidogrel therapy in clinical practice remains a complex challenge [ 18 ]. Our specialized clinical pharmacology services therefore established a comprehensive PGx-guided pharmacotherapy program at two Swiss hospitals.…”

“…Furthermore, it is of interest that about one third of the patients also received an oral anticoagulant, which is relevant when benefits vs. risks of clopidogrel therapy are evaluated for individual patients with different CYP2C19 variants. The median number of prescribed drugs was 8 (range[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]…”

A meta‐analysis of efficacy and safety of genotype‐guided versus standard of care treatment strategies in selecting antiplatelet therapy in patients with acute coronary syndrome

“…Previous studies have shown that providers knowledge of patients' CYP2C19 status did not have a significant influence on P2Y12 inhibitor prescription patterns 28,29 . In addition, in the recently published single center ADAPT‐PCI trial, almost half (47%) of patients continued to receive clopidogrel in the genotype group despite loss of function allele in CYP2C19 18 .…”

Logistical Challenges Associated With Implementing Precision Medicine

“…To the Editor We read with interest the article by Povsic et al showing the reluctance of physicians to use CYP2C19 genotyping results to guide antiplatelet therapy within 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) study. Their data point out a large knowledge gap in that approximately 50% of investigators did not have a plan to alter therapy in genotype-determined nonresponders despite the study being conducted more than 5 years after the US Food and Drug Administration issued a boxed warning about using clopidogrel in poor metabolizers (PMs) homozygous for CYP2C19 nonfunctional alleles.…”