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

Daniel M.F Claassens,Clemens Von Birgelen,Emanuele Barbato,Pim Van Der Harst,Reinier A Waalewijn,Willem Dewilde,Sjoerd H Hofma,Frank R Den Hartog,Michiel Voskuil,Carmine Morisco,Vera H.M Deneer,Folkert W Asselbergs,Thomas O Bergmeijer,Bakhtawar K Mahmoodi,Marieke E Gimbel,J Wouter Jukema,Evelyn A De Vrey,Ton Heestermans ,Arnoud W J Van 'T Hof ,Arend Mosterd ,R Melvyn Tjon Joe Gin ,Renicus S Hermanides ,Gerrit J.A Vos,Jean‐Paul R Herrman ,Jurriën Ten Berg

doi:10.1016/j.ijcard.2021.04.029

Abstract

BackgroundPatients 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. MethodsPatients 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). ResultsA 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. ConclusionIn 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.

Highlights

In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) plays an essential role in preventing recurrent atherothrombotic events [1]
In noncarriers of loss-of-function alleles treated with clopidogrel, more female patients and a lower baseline hemoglobin level were observed, compared to patients treated with ticagrelor
After adjustment for differences in baseline characteristics between the groups, there was no statistically significant difference in the net clinical benefit outcome (17.2% vs. 15.1%, adjusted hazard ratio 1.05, 95%confidence intervals (CI), 0.77–1.44, p = 0.76) (Fig. 2A), thrombotic outcome (9.7% vs. 9.2%, adjHR 1.00, 95%CI, 0.66–1.50, p = 0.98) (Fig. 2B), and bleeding outcome (17.7% vs. 19.8%, adjHR 0.83, 95%CI, 0.62–1.12, p = 0.23) (Fig. 2C), in noncarriers of loss-of-function alleles treated with clopidogrel compared to patients treated with ticagrelor irrespective of CYP2C19 genotype

Summary

Introduction

In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) plays an essential role in preventing recurrent atherothrombotic events [1]. 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]. The correlation of CYP2C19 genotype and clinical outcome was not assessed in the POPular Age trial so far, it can be hypothesized that in elderly patients CYP2C19 genotype influences the balance between benefit and harm when the more potent P2Y12 inhibitors are prescribed in comparison to clopidogrel. Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes

Methods

Results

Discussion

Conclusion