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Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y12 Inhibitor Therapy: A Meta-AnalysisFree Access

Focus on Coronary Pharmacotherapy

J Am Coll Cardiol Intv, 14 (7) 739–750
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Central Illustration

Abstract

Objectives

The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel.

Background

The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear.

Methods

Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype.

Results

Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction <0.001).

Conclusions

The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y12 inhibitor therapy.

Introduction

Clopidogrel is a prodrug and is metabolized primarily by the cytochrome P450 enzyme CYP2C19, resulting in an active metabolite that blocks the platelet P2Y12 receptor, inhibiting platelet aggregation (1). Patients with CYP2C19 loss-of-function (LOF) genotype are unable to metabolize clopidogrel effectively and hence are at an increased risk for cardiovascular (CV) ischemic events (2). The U.S. Food and Drug Administration (FDA) therefore advises medical practitioners to prescribe alternative antiplatelet therapies that are not predominantly metabolized by CYP2C19, such as ticagrelor or prasugrel, for patients who are CYP2C19 poor metabolizers (3). Ticagrelor and prasugrel have both been demonstrated in randomized controlled trials (RCTs) to be superior to clopidogrel in reducing ischemic outcomes in patients with acute coronary syndromes (ACS) (4,5). However, it is not clear whether the presence of CYP2C19 LOF genotype influenced outcomes in these RCTs. It remains uncertain whether the benefit of alternative P2Y12 inhibitors occurs primarily in patients who are CYP2C19 LOF carriers and not in noncarriers. Treatment with alternative P2Y12 inhibitors compared with clopidogrel is more expensive and results in increased bleeding complications and adverse effects such as dyspnea in the case of ticagrelor; therefore, it may be advantageous to individualize antiplatelet therapy on the basis of CYP2C19 genotype (4). A recent study of CYP2C19 genotype–guided P2Y12 inhibitor therapy strategy demonstrated noninferiority in reducing a composite of ischemic and bleeding events compared with treating all patients with ticagrelor after percutaneous coronary intervention (PCI) for myocardial infarction (6). In this study, patients in the genotype-guided group who were CYP2C19 LOF carriers received ticagrelor, and noncarriers received clopidogrel, so the results were suggestive that treating noncarriers with clopidogrel was as efficacious as treating them with ticagrelor. However, CYP2C19 genotyping information was not available for patients receiving ticagrelor in the standard-of-care arm that if available would have allowed evaluation of the test of interaction on the basis of CYP2C19 genotype status in our study described herein. In the recently completed TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) trial, the point estimate suggests a 34% reduction in ischemic events in CYP2C19 LOF carriers receiving ticagrelor compared with clopidogrel, with a 95% confidence interval (CI) of 0.43 to 1.02 (7). The upper boundary may be due to a lack of power given that the sample size calculation for the trial was based on a 50% treatment effect.

Considering that these RCTs may not have been conclusive, largely because of a lack of power, we conducted a systematic review and meta-analysis to examine the association of CYP2C19 genotype and clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent PCI with CYP2C19 genotyping information available and compared outcomes of those treated with ticagrelor or prasugrel versus clopidogrel.

Methods

The study was considered exempt by the Mayo Clinic Institutional Review Board. The inclusion and exclusion criteria of this systematic review (Table 1) and statistical analysis plan were defined a priori. The reporting of this systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement ( http://www.prisma-statement.org).

Table 1 Inclusion and Exclusion Criteria Applied for Review of All Studies Extracted Using Initial Search Strategy

Inclusion criteria
 Original research published in English language
 Patients >18 yrs of age
CYP2C19 genotyping available
 Presentation with ACS or stable CAD
 At least 50% of patients underwent PCI
 One or more components of MACE should be reported
 Two-arm design: clopidogrel vs. alternative (prasugrel or ticagrelor)
 Outcomes by genotype groups: CYP2C19 loss of function vs. wild-type
Exclusion criteria
 Studies published in languages other than English
 Study population containing patients <18 yrs of age
 Nonoriginal research papers
 Studies containing duplicate analyses of previously reported datasets
CYP2C19 genotyping data not available
 Study population without ACS or stable CAD
 Less than 50% of study population underwent PCI
 Cardiovascular outcomes not reported
 No two-arm design
 Outcomes not reported by genotyping groups

ACS = acute coronary syndrome(s); CAD = coronary artery disease; MACE = major adverse cardiovascular event(s); PCI = percutaneous coronary intervention.

Search strategy

A systematic search for published studies was conducted in several databases, including Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid Cochrane Central Register of Controlled Trials, and Scopus from inception to February 19, 2020. Controlled vocabulary supplemented with keywords “CYP2C19” and “clopidogrel,“ “ticagrelor,” or “prasugrel” was used to search for studies in human adults. The detailed search strategy is outlined in the Supplemental Appendix.

Study selection and data extraction

The citations identified by the initial search were evaluated in 2 rounds by 2 investigators (G.M., S.S.) independently for inclusion. The first round of evaluation consisted of title and abstract review, and the second round consisted of full-text review. Any discrepancies were adjudicated by a third investigator (R.L.). The inclusion and exclusion criteria used are described in Table 1.

Data were extracted in duplicate (G.M., S.S.) to a standardized data collection file with pre-specified fields, including study identifiers, genotyping information, baseline characteristics, study design parameters, and clinical outcomes. The target primary efficacy endpoint was defined as the composite CV death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Similarly, the safety endpoint was defined as rate of major or minor bleeding on the basis of TIMI (Thrombolysis In Myocardial Infarction) criteria. If a study did not report these endpoints, the available endpoint most similar in definition was abstracted. Disagreements in data abstraction were resolved by consensus or by a third evaluator (R.L.) if consensus was not reached.

Risk for bias and certainty in the evidence

The risk for bias was assessed using the Cochrane tool for assessing risk for bias in RCTs (8). The certainty in the evidence for an outcome was evaluated using the GRADE approach (9). In this approach, RCTs provide high-certainty evidence that could be rated down for risk for bias, imprecision (wide CIs), inconsistency (i.e., heterogeneity), indirectness (surrogate outcomes or extrapolation from other populations), or publication bias (10).

Statistical analysis

For each study, the most adjusted effect size was extracted. If unavailable, we extracted an unadjusted effect (i.e., a 2 × 2 table). Effect sizes were pooled across studies using the random-effects model (11) because of heterogeneity of study populations and settings. The pooled effect was expressed as relative risk (RR) with 95% CIs. Analysis was conducted separately for CYP2C19 LOF carriers and noncarriers to explore the interaction between genotype and treatment effect, as well as a combined analysis that pooled both genotypes together to compare the 2 different drug regimens. The primary analysis included only RCTs. A secondary analysis was conducted by adding non-RCTs to the analysis. Heterogeneity was assessed using the I2 statistic, which represents the percentage of heterogeneity not attributable to chance. An interaction test was conducted as described by Altman and Bland (12), with 2-tailed p values <0.05 considered to indicate statistical significance. Analysis was done using Stata version 16 (StataCorp LLC, College Station, Texas).

Results

The initial search identified 1,335 potential citations, of which 1,303 (97.6%) were excluded during the initial screening, most commonly because they were not original studies (n = 599), failed to report CV outcomes (n = 274), or did not report genotyping information (n = 186). The remaining 32 publications underwent full-text review and data extraction. Of these, 21 were further excluded, most commonly because the study design did not allow assessment of outcomes on the basis of CYP2C19 LOF carrier and noncarrier status. Figure 1 shows the details of the search. Finally, data from the recently presented TAILOR-PCI trial were added to the systematic review, resulting in 12 studies from 7 RCTs and 4 non-RCTs (7,13–23). Two publications by Mega et al. (13,22) were subanalyses from a single RCT, as each compared CYP2C19 LOF carriers with noncarriers within a given P2Y12 receptor inhibitor regimen (Figure 1). The characteristics of studies included are summarized in Table 2.

Figure 1
Figure 1

Flowchart Summary of Study Selection for Meta-Analysis According to Inclusion and Exclusion Criteria

ACS = acute coronary syndrome(s); CAD = coronary artery disease; CV = cardiovascular; PCI = percutaneous coronary intervention; RCT = randomized controlled trial; TAILOR-PCI = Tailored Antiplatelet Therapy Following PCI.

Table 2 Characteristics of Studies Included in the Meta-Analysis

First Author(Year) (Ref. #)TypeSubgroups ReportedIschemic OutcomeBleeding OutcomeAlleles GenotypedMaximum FU (months)Clopidogrel Loading/Maintenance Doses (mg)Alternative TherapyAlternative Loading/Maintenance Doses (mg)Mean Age (yrs)% Men
Mega et al. (2009) (13)
Mega et al. (2009) (22)
RCTLOF and non-LOFCVD, MI, CVAMajor or minorCYP2C19, CYP2C9, CYP2B6, CYP1A2, CYP3A5, CYP1A1215300/75Prasugrel60/106072
Wallentin et al. (2010) (14)RCTLOF and non-LOFCVD, MI, CVAMajorCYP2C19 (∗2, ∗3, ∗4, ∗5, ∗6, ∗7, ∗8)12300–600/75Ticagrelor180/906370
Deiman et al. (2016) (15)Non-RCTLOF onlyCVD, MI, CVA, ST, re-PCICYP2C19 (∗2, ∗3)18300/75Prasugrel—/106774
Dong et al. (2016) (16)RCTLOF onlyDeath, MI, CVA, revascCYP2C19 (∗2, ∗3)1600/75Ticagrelor180/906780
Ogawa et al. (2016) (17)RCTLOF and non-LOFCVD, MI, CVAMajor or minorCYP2C19 (∗2, ∗3)6300/75Prasugrel20/3.756481
Zhang et al. (2016) (18)RCTLOF onlyDeath, MI, CVAMajor or minorCYP2C19 (∗2, ∗3)6600/75Ticagrelor180/907050
Chen et al. (2017) (19)Non-RCTLOF onlyCVD, MI, CVAAny bleeding eventCYP2C19 (∗2)12300/75Ticagrelor—/9060
Cavallari et al. (2018) (20)Non-RCTLOF and non-LOFDeath, MI, CVACYP2C19 (∗2, ∗3)12300/75Prasugrel, ticagrelor, high-dose clopidogrel—/—6367
Lee et al. 2018 (21)Non-RCTLOF and non-LOFDeath, MI, CVA, TIA, ST, UA-hospClinically significantCYP2C19 (∗2, ∗3)12Prasugrel or ticagrelor—/—
Xiong et al. (2015) (23)RCTLOF onlyMACEMajor or minorCYP2C19 (∗2)1600/150Ticagrelor180/906771
Pereira et al. (2020) (7)RCTLOF onlyCVD, MI, CVA, ST, SRIMajor or minorCYP2C19 (∗2, ∗3)12300–600/75Ticagrelor180/906276

CVA = cerebrovascular accident; CVD = cardiovascular-related death; FU = follow-up; LOF = loss-of-function; MACE = major adverse cardiovascular event(s); MI = myocardial infarction; re-PCI = repeat percutaneous coronary intervention; RCT = randomized controlled trial; revasc = revascularization (percutaneous coronary intervention or coronary artery bypass graft); SRI = severe recurrent ischemia; ST = stent thrombosis; TIA = transient ischemic attack; UA-hosp = hospitalization for unstable angina.

The studies reported on a total of 15,949 patients who were enrolled in RCTs (the mean age was 62 years, 71% were men, 77% underwent PCI, 98% had ACS, 25% had diabetes, and 34% were smokers) and 18,808 patients in both RCTs and non-RCTs (the mean age was 62 years, 71% were men, 80% underwent PCI, 94% had ACS, 26% had diabetes, and 34% were smokers).

Risk for bias

The details of risk for bias assessment are summarized in Table 3 for RCTs and Table 4 for non-RCTs, and definitions of indicators of risk for bias are outlined in Supplemental Table 1. Most RCTs had adequate randomization approaches and concealment of allocation, while degree of blinding varied. Most non-RCTs had appropriate selection and ascertainment approaches, while adjustment for confounding and blinded assessments were typically lacking. Overall, the global risk for bias for both ischemic and bleeding outcomes in the RCTs was low and in the non-RCTs was high.

Table 3 Assessments of the Risk for Bias in Randomized Clinical Trials Included in the Meta-Analysis

First Author(Year) (Ref. #)Randomization SequenceAllocation ConcealmentBlinding of PatientsBlinding of CaregiversBlinding of Outcome AssessorsBlinding of AnalystsPercentage Lost to Follow-Up
Mega et al. (2009) (13)AdequateAdequateAdequateAdequateAdequateInadequate1.2
Mega et al. (2009) (22)AdequateAdequateAdequateAdequateAdequateInadequate0.75
Wallentin et al. (2010) (14)AdequateAdequateAdequateAdequateAdequateInadequate0
Dong et al. (2016) (16)AdequateInadequateInadequateInadequateInadequateInadequate0
Ogawa et al. (2016) (17)AdequateAdequateAdequateInadequateAdequateInadequate0
Zhang et al. (2016) (18)AdequateInadequateInadequateInadequateInadequateInadequate0
Xiong et al. (2015) (23)AdequateInadequateInadequateInadequateInadequateInadequate0
Pereira et al. (2020) (7)AdequateAdequateInadequateInadequateAdequateInadequate2.9

Table 4 Assessments of the Risk for Bias in Non-RCT Studies Included in the Meta-Analysis

First Author(Year) (Ref. #)Exposed Cohort SelectionControl Cohort SelectionAscertainment of ExposureAscertainment of OutcomeGroups Comparable in CharacteristicsAnalysis Adjusted for Important ConfoundersAssessment of Outcome BlindedFollow-Up Sufficient for Outcome to OccurPercentage Lost to Follow-Up
Deiman et al. (2016) (15)InadequateInadequateAdequateAdequateAdequateInadequateInadequateAdequateUnknown
Chen et al. (2017) (19)AdequateAdequateAdequateAdequateAdequateInadequateInadequateAdequateUnknown
Cavallari et al. (2018) (20)AdequateAdequateAdequateAdequateAdequateAdequateInadequateAdequateUnknown
Lee et al. (2018) (21)AdequateAdequateAdequateAdequateInadequateInadequateInadequateAdequateUnknown

Meta-analysis

Ischemic outcomes

Meta-analysis of 7 RCTs enrolling 6,409 CYP2C19 LOF carriers demonstrated a statistically significant reduction in the risk for ischemic events (RR: 0.70; 95% CI: 0.59 to 0.83) (Figure 2A) with the use of ticagrelor or prasugrel (7.0%; 223 events in 3,172 patients) compared with clopidogrel (10.3%; 335 events in 3,237 patients). There was no similar significant reduction observed in meta-analysis of 4 studies enrolling 9,540 noncarriers (RR: 1.00; 95% CI: 0.80 to 1.25; alternative therapy 8.8% [419 of 4,781], clopidogrel 9.2% [439 of 4,759]) (Figure 2A). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modifies the effect. In a secondary analysis, all studies (RCTs and non-RCTs) were analyzed (Figure 2B). The results were consistent with the main analysis, demonstrating a significant reduction in the risk for ischemic events in CYP2C19 LOF carriers treated with ticagrelor and prasugrel (11 studies) compared with clopidogrel and no difference in noncarriers (6 studies) (p value of the test of interaction <0.001).

Figure 2
Figure 2

Effect of CYP2C19 Genotype on Ischemic Outcomes in Patients Treated With Ticagrelor or Prasugrel Versus Clopidogrel

(A) Analysis of ischemic events in RCTs comparing alternative P2Y12 inhibitors with clopidogrel treatment according to CYP2C19 genotype status. Meta-analysis of ischemic event risk in patients with CAD predominantly after PCI treated with alternative P2Y12 inhibitors or clopidogrel. The top panel analyzes patients identified as CYP2C19 loss-of-function (LOF) carriers, and the bottom panel analyzes those identified as noncarriers. Risk ratios < 1 indicate better outcomes for alternative therapy, and risk ratios > 1 indicate better outcomes for clopidogrel. The test for interaction between genotype status and treatment effect was significant (p = 0.013), indicating a statistically significant difference in effect on the basis of genotype. (B) Analysis of ischemic events in RCTs and non-RCTs comparing alternative P2Y12 inhibitors with clopidogrel treatment according to CYP2C19 genotype status. Meta-analysis of ischemic event risk in patients with CAD predominantly after PCI treated with alternative P2Y12 inhibitors or clopidogrel. The top panel analyzes patients identified as CYP2C19 LOF carriers, and the bottom panel analyzes those identified as noncarriers. Risk ratios < 1 indicate better outcomes for alternative therapy; risk ratios > 1 indicate better outcomes for clopidogrel. The test for interaction between CYP2C19 genotype status and treatment effect was significant (p < 0.001), indicating a statistically significant difference in effect on the basis of genotype. CI = confidence interval; ES = effect size; other abbreviations as in Figure 1.

Bleeding outcome

Meta-analysis of 6 RCTs enrolling 6,309 CYP2C19 LOF carriers showed no significant difference in the risk for major and minor bleeding (RR: 0.91; 95% CI: 0.64 to 1.30) with the use of ticagrelor or prasugrel (6.7%; 210 events in 3,132 patients) compared with clopidogrel (6.8%; 215 events in 3,177 patients) (Figure 3A). The difference was also not significant in the meta-analysis of 3 RCTs enrolling 9,466 CYP2C19 LOF noncarriers (RR: 0.99; 95% CI: 0.86 to 1.14; alternative therapy 7.9% [376 of 4,754], clopidogrel 8.0% [375 of 4,712]) (Figure 3A). The results were also consistent with the secondary analysis that included non-RCTs (Figure 3B); that is, the reduction in the risk for the bleeding outcome was not statistically significant in meta-analysis of 9 studies with CYP2C19 LOF carriers and in 4 studies with noncarriers. Tests of interaction on the basis of CYP2C19 genetic status were nonsignificant in both analyses (p = 0.67 in RCTs, p = 0.92 in all studies).

Figure 3
Figure 3

Effect of CYP2C19 Genotype on Bleeding Outcomes in Patients Treated With Ticagrelor or Prasugrel Versus Clopidogrel

(A) Analysis of bleeding events in RCTs comparing alternative P2Y12 inhibitors with clopidogrel treatment according to CYP2C19 genotype. Meta-analysis of bleeding event risk in patients with CAD predominantly after PCI treated with alternative P2Y12 inhibitor or clopidogrel. The top panel analyzes patients identified as CYP2C19 LOF carriers, and the bottom panel analyzes those identified as noncarriers. Risk ratios < 1 indicate better outcomes for alternative therapy, risk ratios > 1 indicate better outcomes for clopidogrel. The test for interaction between metabolizer type and treatment effect was nonsignificant (p = 0.67), indicating no statistically significant evidence for a differential effect of alternative therapies on the basis of genotype. (B) Analysis of bleeding events in RCTs and non-RCTs comparing alternative P2Y12 inhibitors with clopidogrel treatment according to CYP2C19 genotype. Meta-analysis of bleeding event risk in patients with CAD predominantly after PCI treated with alternative P2Y12 inhibitors or clopidogrel. The top panel analyzes subjects identified as CYP2C19 LOF carriers, and the bottom panel analyzes those identified as noncarriers. Risk ratios < 1 indicate better outcomes for alternative therapy, and risk ratios > 1 indicate better outcomes for clopidogrel. The test for interaction between metabolizer type and treatment effect was nonsignificant (p = 0.92), indicating no statistically significant evidence for a differential effect of alternative therapies based on genotype. Abbreviations as in Figures 1 and 2.

Heterogeneity, publication bias and certainty in the evidence

Statistical heterogeneity of treatment effect was overall minimal (I2 < 50% in all analyses when stratified by CYP2C19 genotype). Publication bias could not be statistically assessed, because of the small number of studies per each stratified analysis. The certainty in the estimates of the ischemic outcome was high. The certainty in the estimates of the bleeding outcome was low, likely because of lack of power due to the smaller number of bleeding events in each genotype category, as reflected by the wide CIs.

Discussion

Main findings

In the present meta-analysis, CYP2C19 LOF carriers with CAD who predominantly had ACS and underwent PCI had improved ischemic outcomes when treated with ticagrelor or prasugrel compared with those receiving clopidogrel. This beneficial effect was not observed in CYP2C19 LOF noncarriers (Central Illustration). Our findings suggest that the reduction in ischemic events observed with alternative P2Y12 inhibitors compared with clopidogrel in clinical trials is likely due to substantially reduced events in CYP2C19 LOF carriers and not in noncarriers. This meta-analysis supports genetic testing for selection of P2Y12 inhibitors in this patient population, validates the model of personalized medicine, and is proof of concept for a precision-medicine approach to adopting optimal and safe therapies for patients with CV disease (24). The increasing acceptance of genetic testing is reflected in the 2020 European Society of Cardiology guidelines for ACS that recommend as Class 2b, consideration of de-escalation of P2Y12 receptor inhibitor treatment (e.g., with a switch from prasugrel or ticagrelor to clopidogrel) for patients with ACS deemed unsuitable for potent platelet inhibition using CYP2C19 genotyping (25). This perspective is also reflected in a state-of-the-art expert consensus statement that advocates either de-escalation or escalation of dual-antiplatelet therapy on the basis of clinical and procedural characteristics and results of platelet function and CYP2C19 genetic testing (26).

Central Illustration
Central Illustration

A Proposed Algorithm Using CYP2C19 Pharmacogenetic Testing to Individualize Oral P2Y12 Inhibitor Therapy in Patients With Coronary Artery Disease on the Basis of the Meta-Analysis Results

The use of ticagrelor compared with clopidogrel without a genotyping strategy in the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial decreased ischemic events (hazard ratio [HR]: 0.84; 95% CI: 0.77 to 0.92) in 18,624 patients with ACS with an overall ischemic event rate that was 9.8% in the ticagrelor group and 11.7% in the clopidogrel group (5). The PLATO genetic substudy, which included 10,285 patients from the original trial, suggested a reduction in ischemic events in CYP2C19 LOF carriers receiving ticagrelor compared with clopidogrel (HR: 0.77; 95% CI: 0.60 to 0.99) but not in noncarriers (HR: 0.86; 95% CI: 0.74 to 1.01) (14). Because of a nonsignificant interaction test (p = 0.46), the investigators concluded that ticagrelor was more efficacious than clopidogrel irrespective of CYP2C19 genotype status. The investigators acknowledged that this genetic “sub-study was not prospectively powered.” No similar study examining the effect of CYP2C19 with the use of prasugrel had been performed to date.

Despite an FDA black-box warning in the drug-labeling information for clopidogrel, American Heart Association and American College of Cardiology clinical expert consensus guidelines do not support the routine practice of CYP2C19 genotyping prior to prescribing clopidogrel (3). It was unknown whether identifying CYP2C19 LOF carriers and prescribing alternative P2Y12 inhibitors such as ticagrelor or prasugrel on the basis of CYP2C19 genotype reduced ischemic outcomes. The randomized trials and observational studies that followed the FDA warning were underpowered to address the question of whether to genotype and, therefore, lacked statistical significance to definitively demonstrate a role for genotyping. In the recently reported TAILOR-PCI trial, treatment with ticagrelor compared with clopidogrel in CYP2C19 LOF carriers did not result in a significant reduction of ischemic events at 12 months on the basis of the pre-specified analysis plan and the 50% treatment effect that the study had been powered to detect (7). Despite the occurrence of 89 ischemic events observed in this trial, which exceeded the 76 events anticipated to provide adequate power, the observed RR reduction was 34% instead of the estimated 50%, hence a borderline p value of 0.056 was observed. This meta-analysis of 7 RCTs enrolling 6,409 patients overcomes this limitation and demonstrates an overall risk reduction of 30% with alternative P2Y12 inhibitors compared with clopidogrel, consistent with the treatment effect observed in TAILOR-PCI.

Practical implications

These results suggest that genetic testing for identifying CYP2C19 LOF carriers and noncarriers could be beneficial prior to prescribing antiplatelet therapy, resulting in the selection of an alternative P2Y12 inhibitor for the former and clopidogrel for the latter patients (Central Illustration). If alternative P2Y12 inhibitor therapy had reduced ischemic outcomes in noncarriers, then a ticagrelor or prasugrel for all approach, irrespective of CYP2C19 genotype, might have been preferred to clopidogrel. On the contrary, our meta-analysis results demonstrate that there was no difference in the rates of ischemic events when noncarriers were treated either with clopidogrel or alternative P2Y12 inhibitors. These results support the findings of the POPular Genetics trial, in which all patients in one randomized group received ticagrelor and were compared with patients receiving genotype-guided P2Y12 inhibitors (i.e., noncarriers receiving clopidogrel and LOF carriers receiving ticagrelor). This study demonstrated that such a targeted genotyping strategy was noninferior to a ticagrelor-for-all approach, with ischemic event rates of 4.6% and 4.7%, respectively, at 12 months (6). These studies imply that a large proportion of patients could safely receive clopidogrel given that CYP2C19 LOF noncarriers constitute approximately 50% to 70% of the population (1). CYP2C19 genotype can be incorporated with clinical variables in the form of a composite scoring system that could be helpful in identifying high-risk patients and selecting appropriate oral P2Y12 inhibitor therapy, as demonstrated by the recently published ABCD-GENE score (27).

In the PLATO trial, no significant difference was observed in the rates of major bleeding between ticagrelor- and clopidogrel-treated patients, although there was a higher risk for non–coronary artery bypass graft major bleeding in the ticagrelor group (HR: 1.19; 95% CI: 1.02 to 1.38) (5). In the PLATO genetic substudy, CYP2C19 genotype was shown to have no effect on major bleeding with P2Y12 inhibitor therapy (14), a finding that was similar to that observed in the TAILOR-PCI clinical trial (7) and our meta-analysis. It is important to note that the PLATO genetic substudy did not report TIMI minor bleeding episodes by CYP2C19 genotype, which may have attenuated the bleeding outcomes reported in this meta-analysis. Patients treated with prasugrel have a higher risk for major bleeding compared with clopidogrel, as demonstrated in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–TIMI 38) study (4) (HR: 1.32; 95% CI: 1.03 to 1.68). This increased risk for major bleeding was not observed in the CYP2C19 genetic substudies of TRITON–TIMI 38 or in other studies comparing prasugrel with clopidogrel included in our meta-analysis. Although the risk for major bleeding may not be affected by CYP2C19 genotype, multiple prior studies have demonstrated a lower incidence of minor bleeding with clopidogrel than with prasugrel or ticagrelor. For example, although Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding was reported to be lower in the genotype-guided group (9.9%) compared with ticagrelor for all (12.8%) in POPular Genetics, this effect was driven primarily by a reduction in BARC type 2 bleeding (HR: 0.69; 95% CI: 0.53 to 0.89) rather than BARC type 3 or 5 bleeding (HR: 1.23; 95% CI: 0.71 to 2.13) (6). A similar increased risk for bleeding was observed in the TAILOR-PCI trial when bleeding was assessed by the BARC classification in the CYP2C19 LOF per-protocol genotype-guided group that primarily received ticagrelor compared with those who received clopidogrel (7). One of the potential advantages of genotype-guided P2Y12 inhibitor therapy in which a large number of patients receive clopidogrel (given an approximate 50% to 70% prevalence of CYP2C19 noncarriers) and the remainder receive more potent alternative P2Y12 inhibitors is a lower risk for bleeding for this group of patients compared with all patients receiving either ticagrelor or prasugrel. This beneficial effect was observed in POPular Genetics. Similar to prior studies, our meta-analysis did not demonstrate an effect of CYP2C19 genotype on bleeding outcomes, likely because of reporting of bleeding complications by TIMI major or minor bleeding classification, which does not result in reporting of actionable minor bleeding episodes that do not meet the drop in hemoglobin or hematocrit criteria of the TIMI classification but would be captured by BARC2 bleeding criteria, for example. Furthermore, the bleeding results of the meta-analysis need to be interpreted with caution, as the certainty in the estimates of the bleeding outcome was low.

The CYP2C19∗17 allele is considered a gain-of-function allele and has been shown, in some studies, to lead to enhanced response to clopidogrel (via platelet function testing) and perhaps a higher rate of bleeding events (28,29). However other studies have not demonstrated increased platelet inhibition or altered clinical outcomes in clopidogrel-treated patients with the CYP2C19∗17 allele (30–33). Therefore, its role in attenuating response to clopidogrel is controversial, and guidelines do not recommending altering P2Y12 inhibitor therapy on the basis of CYP2C19∗17 genotype (34).

Study strengths

The strengths of this meta-analysis relate to the comprehensive search for published studies, selecting and appraising studies by independent pairs of reviewers, and evaluating the whole body of evidence of randomized and nonrandomized studies with stratified analyses on the basis of study design.

Study limitations

First, there was incomplete reporting across studies. Not all studies reported results in CYP2C19 LOF noncarriers, and the ischemic endpoints varied, but most consisted of CV death, myocardial infarction, and stroke. Most studies categorized subjects on the basis of CYP2C19∗2/∗3 alleles, but some had broader criteria. Nevertheless, despite such variation, we did not observe substantial statistical heterogeneity (the I2 measure did not exceed 50% for any analysis stratified by genetic status).

Second, we were unable to evaluate publication bias, which would have affected only the nonrandomized studies, considering that they are not required to be registered in trial registries such as ClinicalTrials.gov.

Third, combining the use of ticagrelor and prasugrel in the alternative P2Y12 inhibitor therapy group included in this meta-analysis may have attenuated the results of the ischemic outcomes, given findings of a recent study that demonstrated a lower incidence of death, myocardial infarction, or stroke in patients who received prasugrel compared with ticagrelor (35). However, the differences in ischemic outcomes would have been similar in both CYP2C19 LOF patients and CYP2C19 noncarriers without altering the overall results observed. Furthermore, CYP2C19 LOF patients who received either ticagrelor or prasugrel have a similar degree of platelet inhibition (36).

Finally, bleeding outcomes according to the BARC definition were not reported in the RCTs included in this meta-analysis, other than TAILOR-PCI, which may limit the interpretation of bleeding risk with the use of the various P2Y12 inhibitors according to CYP2C19 genotype.

Conclusions

The findings of the present meta-analysis confirm the beneficial trends observed in individual studies and support the use of genotyping to guide P2Y12 inhibitor therapy in patients with CAD, especially with ACS and after PCI. The findings also support the concept of personalized medicine and justify the need for such studies in CV disease.

Perspectives

WHAT IS KNOWN? Whether the benefit of alternative P2Y12 inhibitors such as ticagrelor or prasugrel compared with clopidogrel occurs primarily in patients who are CYP2C19 LOF carriers and not in noncarriers is unknown.

WHAT IS NEW? This meta-analysis demonstrates that ticagrelor or prasugrel compared with clopidogrel significantly reduced ischemic events in CYP2C19 LOF carriers but not in noncarrier patients with CAD after PCI.

WHAT IS NEXT? Clopidogrel therefore can be safely used in the majority of patients, and genetic testing prior to prescribing P2Y12 inhibitor therapy would be useful to guide selection of these agents for use after PCI.

Funding Support and Author Disclosures

Funding for this research was provided by National Institutes of Health grants U01HL128606 and 3U01HL128606-03S1. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

ACS

acute coronary syndrome(s)

BARC

Bleeding Academic Research Consortium

CAD

coronary artery disease

CI

confidence interval

CV

cardiovascular

FDA

U.S. Food and Drug Administration

HR

hazard ratio

LOF

loss-of-function

PCI

percutaneous coronary intervention

RCT

randomized controlled trial

RR

relative risk

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Footnotes

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