Effect of Gender on Clinical Outcomes in Patients Receiving CYP2C19 Genotype-guided Antiplatelet Therapy after Percutaneous Coronary Intervention

The use of CYP2C19 genotyping to guide dual anti-platelet therapy (DAPT) has been associated with reduced rates of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention (PCI) with stent placement.^1,2,3 However, it is uncertain how use of CYP2C19 genotype guided DAPT affects clinical outcomes, both ischemic and bleeding, in women compared to men. It is also unknown whether there are gender-based differences in the use of genotyping results to guide anti-platelet therapy selection.

The University of North Carolina-Chapel Hill (UNC) instituted an algorithm in 2012 that recommended, but did not mandate, the use of prasugrel or ticagrelor in PCI patients with a CYP2C19 loss-of-function (LOF) allele (*2 or *3).⁴ This single-center retrospective cohort study included 1260 patients who underwent PCI at the UNC Hospitals from 2012–2015, had CYP2C19 genetic testing at the time of PCI and for whom there was follow-up data available in the electronic medical record. This study was approved by the Biomedical Institutional Review Board. The study data are available on reasonable request. The primary endpoint was MACCE (composite of death, acute coronary syndrome (ACS), stent thrombosis or cerebrovascular event) over 12 months following PCI. Clinically significant bleeding (defined as Global Use of Strategies to Open Occluded Arteries (GUSTO) moderate or severe/life-threatening bleeding) events was a secondary outcome. Data collection and analysis were performed as previously described.⁴ Time-to-event analyses were compared across CYP2C19-antiplatelet therapy groups, following stratification by gender, by Cox proportional hazards regression. The analysis adjusted for covariates that differed across groups and/or associated with clinical outcomes. The adjusted hazard ratio (HR) and 95% confidence intervals (CIs) for each comparison were calculated.

Women comprised 31.3% of the study population. Women were older, more likely to be African American, and had a higher prevalence of multiple comorbidities such as diabetes and hypertension compared to men (Figure A). Overall, 61.9% of men and 62.8% of women had an ACS indication for PCI. CYP2C19 genotyping identified 265 (30.7%) men and 92 (23.3%) women with one LOF allele and 22 (2.5%) men and 7 (1.8%) women with two LOF alleles. In accordance with genotype-guided prescribing recommendations, prasugrel or ticagrelor were prescribed more frequently in CYP2C19 LOF allele carriers compared to patients without a LOF allele in both men (64.8% vs 30.6%; p<0.001) and women (61.6% vs 21.6%; p<0.001). The use of prasugrel or ticagrelor was slightly higher in men versus women with one (64.2% vs 60.9%; p=0.578), two (72.7% vs 71.4%; p=1.00) or any LOF allele (64.8% vs 61.6%, p=0.570) but the differences were not statistically significant. However, men without a LOF allele were significantly more likely than women without a LOF allele to be prescribed prasugrel or ticagrelor (30.6% vs 21.6%, p=0.004).

Figure.

Baseline characteristics and cardiovascular outcomes by gender, CYP2C19 genotype, and antiplatelet therapy. A. Baseline characteristics for men and women. P-value calculated using Chi-square or Fisher’s exact test. B. Summary of the clinically significant bleeding events for men and women stratified by CYP2C19 genotype and antiplatelet therapy: LOF allele carriers prescribed clopidogrel (Clop-LOF), patients without a LOF allele prescribed clopidogrel (Clop - Non LOF), and any patient prescribed prasugrel or ticagrelor (Pras/Ticag). [*LOF and non-LOF allele carrier’s prescribed prasugrel or ticagrelor therapy were combined into a single referent group for comparison]. The number (percentage) that experienced a bleeding event, the event rate per 100 patient-years, and the unadjusted log-rank P-value across the three groups is provided. Kaplan-Meier curve illustrating cumulative risk of MACCE over 12 months in men (C) and women (D) stratified by CYP2C19 genotype and antiplatelet therapy. The unadjusted log-rank P-value across the three groups is provided. The number (percentage) in each group that experienced MACCE, the event rate per 100 patient-years in each group, and the adjusted HR, 95% CI and P-value for the Cox proportional hazards regression analysis, is provided. The primary outcome analyses stratified the cohort by gender and evaluated the associations separately in men and women. A secondary analysis in the entire cohort, with men and women combined, evaluated the gender*treatment interaction on MACCE and found no interaction between gender and CYP2C19-antiplatelet therapy groups (p = 0.796).

There was no difference between men and women in the occurrence of either MACCE (10.8% versus 10.6%; p=0.662) or clinically significant bleeding (3.4% versus 4.6%; p=0.407). The risk of MACCE was significantly higher in patients with a LOF allele treated with clopidogrel, compared to prasugrel or ticagrelor, in both men (Figure C: adjusted HR 2.24, 95% CI 1.21–4.01, p=0.010) and women (Figure D: adjusted HR 3.26, 95% CI 1.07–9.60, p=0.038). In contrast, MACCE rates were not significantly different in clopidogrel-treated patients without a LOF allele compared to prasugrel or ticagrelor in both men (adjusted HR 1.07, CI 0.68–1.71, p=0.760) and women (adjusted HR 1.57, CI 0.73–3.66, p=0.255). No association between CYP2C19 genotype, anti-platelet therapy and risk of clinically significant bleeding events was observed in either men or women (Figure B).

This study was limited by the observational design and sample size. The low number of bleeding events in clopidogrel-treated LOF carriers made it difficult to determine if genotype-guided anti-platelet therapy impacted bleeding risk differently in men versus women. The impact of the increased function *17 allele on gender differences in bleeding outcomes was not considered due to limitations in sample size. Covariate-adjusted analyses were conducted but residual confounding may remain. Additionally, our single-center results may not be generalizable to other settings. Validation in larger, multi-center populations is warranted.

In summary, this study found that the frequency of prescribing alternative antiplatelet therapy in PCI patients with one or two CYP2C19 LOF alleles, and its impact on clinical outcomes, was similar between men and women following implementation of CYP2C19 genotype-guided antiplatelet therapy after PCI in a real-world clinical setting. This finding is consistent with a recent randomized clinical trial showing that the impact of genotype-guided therapy on ischemic and bleeding outcomes is not influenced by gender², and that gender has no significant influence on relative risk of ischemic or bleeding outcomes when comparing clopidogrel and prasugrel or ticagrelor in post-PCI patients.⁵ Taken together, our results suggest that CYP2C19 genotype guided DAPT is equally effective in men and women and may be used in both genders to reduce the risk of adverse outcomes following PCI.

Nonstandard Abbreviations and Acronyms

ACS

acute coronary syndrome

DAPT

dual anti-platelet therapy

GUSTO

Global Use of Strategies to Open Occluded Arteries

LOF

loss-of-function

MACCE

major adverse cardiovascular and cerebrovascular events

PCI

percutaneous coronary intervention