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

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.

Keywords: CYP2C19 genotype; clopidogrel; ischemic outcomes; meta-analysis; prasugrel; systematic review; ticagrelor.

Figure 1.

Flowchart Summary of Study Selection for Meta-Analysis According to Inclusion/Exclusion Criteria. RCT, Randomized Controlled Trial; ACS, Acute Coronary Syndrome; CAD, Coronary Artery Disease; CV, Cardiovascular; PCI, Percutaneous Coronary Intervention.

Figure 2a.

Analysis of Ischemic Events in RCTs Comparing Alternate P2Y12 Inhibitors to Clopidogrel Treatment According to CYP2C19 Genotype Status. Meta-analysis of ischemic event risk in CAD patients predominantly after PCI treated with an alternate P2Y12 inhibitor or clopidogrel. The top panel analyzes patients identified as CYP2C19 LOF carriers; the bottom panel analyzes those identified as non-carriers. Risk ratios less than 1 indicate better outcomes for alternative therapy; risk ratios greater than 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 based on genotype. ES, Effect Size; LOF, Loss-of-Function; RCT, Randomized Controlled Trial; CAD, Coronary Artery Disease; PCI, Percutaneous Coronary Intervention.

Figure 2b.

Analysis of Ischemic Events in RCTs and Non-RCTs Comparing Alternate P2Y12 Inhibitors to Clopidogrel Treatment According to CYP2C19 Genotype Status. Meta-analysis of ischemic event risk in CAD patients predominantly after PCI treated with an alternate P2Y12 inhibitor or clopidogrel. The top panel analyzes patients identified as CYP2C19 LOF carriers; the bottom panel analyzes those identified as non-carriers. Risk ratios less than 1 indicate better outcomes for alternative therapy; risk ratios greater than 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 based on genotype. ES, Effect Size; LOF, Loss-of-Function; RCT, Randomized Controlled Trial; CAD, Coronary Artery Disease; PCI, Percutaneous Coronary Intervention.

Figure 3a.

Analysis of Bleeding Events in RCTs Comparing Alternate P2Y12 Inhibitors to Clopidogrel Treatment According to CYP2C19 Genotype. Meta-analysis of bleeding event risk in CAD patients predominantly after PCI treated with an alternate P2Y12 inhibitor or clopidogrel. The top panel analyzes patients identified as CYP2C19 LOF carriers; the bottom panel analyzes those identified as non-carriers. Risk ratios less than 1 indicate better outcomes for alternative therapy; risk ratios greater than 1 indicate better outcomes for clopidogrel. The test for interaction between metabolizer type and treatment effect was non-significant (p=0.67) indicating no statistically significant evidence for a differential effect of alternative therapies based on genotype. ES, Effect Size; LOF, Loss-of-Function; RCT, Randomized Controlled Trial; CAD, Coronary Artery Disease; PCI, Percutaneous Coronary Intervention.

Figure 3b.

Analysis of Bleeding Events in RCTs and Non-RCTs Comparing Alternate P2Y12 Inhibitors to Clopidogrel Treatment According to CYP2C19 Genotype. Meta-analysis of bleeding event risk in CAD patients predominantly after PCI treated with an alternate P2Y12 inhibitor or clopidogrel. The top panel analyzes subjects identified as CYP2C19 LOF carriers; the bottom panel analyzes those identified as non-carriers. Risk ratios less than 1 indicate better outcomes for alternative therapy; risk ratios greater than 1 indicate better outcomes for clopidogrel. The test for interaction between metabolizer type and treatment effect was non-significant (p=0.92) indicating no statistically significant evidence for a differential effect of alternative therapies based on genotype. ES, Effect Size; LOF, Loss-of-Function; RCT, Randomized Controlled Trial; CAD, Coronary Artery Disease; PCI, Percutaneous Coronary Intervention.

Central Illustration.

A Proposed Algorithm Utilizing CYP2C19 Pharmacogenetic Testing to Individualize Oral P2Y12 Inhibitor Therapy in Patients with Coronary Artery Disease (CAD) based on the Meta-Analysis Results. ACS, Acute Coronary Syndromes; PCI, Percutaneous Coronary Intervention; RCT, Randomized Controlled Trial; LOF, Loss-of-Function; RR, Relative Risk.