Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients

Highlights

• This subgroup analysis included acute coronary syndrome patients aged 70 and older.

• Clopidogrel in noncarriers of CYP2C19 LoF was compared to ticagrelor.

• In this small subgroup, no differences in bleeding and ischemic outcomes were found.

• Overall, results were comparable to the POPular Genetics main trial results.

Abstract

Background

Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y₁₂ inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically.

Methods

Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding).

Results

A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77–1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66–1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62–1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively.

Conclusion

In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

Introduction

In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) plays an essential role in preventing recurrent atherothrombotic events [1]. Although clopidogrel is still widely used in combination with aspirin, The Platelet Inhibition and Patient Outcomes (PLATO) [2] and Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction (TRITON TIMI) 38³ trials demonstrated superiority of ticagrelor and prasugrel, respectively, over clopidogrel in preventing atherothrombotic events in patients with ACS. Therefore, current guidelines favor these more potent platelet inhibitors over clopidogrel [4,5]. However, patients treated with ticagrelor or prasugrel are at a higher bleeding risk compared to patients treated with clopidogrel [2,3], which is even more pronounced in elderly patients [6]. The Clopidogrel versus Ticagrelor or Prasugrel in Patients Aged 70 years or older with non-ST-elevation Acute Coronary Syndrome (POPular Age) trial showed that in elderly patients, DAPT with clopidogrel has similar results as DAPT with the more potent platelet inhibitors in terms of ischemic events, while bleeding events were lower [7].

Clopidogrel is a prodrug which is converted to its active metabolite by CYP P450 hepatic enzymes [8]. Approximately 30% of the Caucasian population show an inadequate response to clopidogrel when measured with platelet function tests, which is associated with a worse clinical outcome [9]. At least part of this variation in drug efficacy can be explained by genetic variations, of which the CYP2C19*2 and *3 loss-of-function alleles are the most important [10]. For ticagrelor and prasugrel no relevant gene-drug interaction have been found [11,12]. Although the correlation of CYP2C19 genotype and clinical outcome was not assessed in the POPular Age trial so far, it can be hypothesized that also in elderly patients CYP2C19 genotype influences the balance between benefit and harm when the more potent P2Y₁₂ inhibitors are prescribed in comparison to clopidogrel.

A strategy in which the antiplatelet treatment was chosen based on CYP2C19 genotype, although in a cohort of patients with ST-segment elevation myocardial infarction (STEMI), was evaluated in the The Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome after Primary Percutaneous Coronary Intervention (POPular Genetics) trial [13]. In this trial, a genotype-guided strategy was found to be non-inferior compared to standard treatment with ticagrelor or prasugrel for a net clinical benefit outcome and ischemic events, while bleeding events were lower. While both atherothrombotic and bleeding event rates are higher in elderly patients, and bleeding events have shown to be strongly correlated to a worse clinical outcome [14], the use of genetic testing may improve clinical decision making in selecting patients who benefit most from clopidogrel versus prasugrel or ticagrelor treatment.

In the present analysis, containing ACS patients aged 70 years and older derived from the POPular Age and POPular Genetics trial cohorts, we compare the use of clopidogrel in noncarriers of CYP2C19 loss-of-function alleles with ticagrelor, irrespective of CYP2C19 genotype and we assess the effect of CYP2C19 loss-of-function alleles in clopidogrel treated elderly patients.