Influence of Genetic Variants and Drug Interactions on the Response to Antiplatelet Drugs


Dr. A.M. Harmsze, Antonius Ziekenhuis, Nieuwegein
Promotor: Prof. dr. A. de Boer. Co-promotoren: Dr. V.H.M. Deneer, Dr. O.H. Klungel
  Antiplatelet therapy plays an important role in the treatment of cardiovascular disease. The combination of acetylsalicylic acid (ASA) and clopidogrel (“dual antiplatelet therapy”) is routine care in patients with acute coronary syndromes (ACS) or undergoing percutaneous coronary interventions (PCI). Although the efficacy of ASA and clopidogrel is well established, several studies have shown interindividual variability in the response to these antiplatelet drugs. In this thesis, studies are presented in which the impact of genetic variants and co-medication on the response to these antiplatelet agents was investigated.

CONTENTS CHAPTER 1 General introduction
  • 1.1 Introduction
  • 1.2 The use of the VerifyNow system to monitor antiplatelet therapy: a review of the current evidence
CHAPTER 2 Factors influencing on-treatment platelet reactivity and clopidogrel’s active metabolite plasma concentrations
  • 2.1 Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation
  • 2.2 The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response
  • 2.3 The influence of omeprazole on on-treatment platelet reactivity might be dependent on clopidogrel’s dosing regimen
  • 2.4 Sulfonylureas and on-treatment platelet reactivity in type 2 diabetes mellitus patients
  • 2.5 Esomeprazole but not pantoprazole is associated with lower plasma concentrations of clopidogrel’s active metabolite
CHAPTER 3 Factors influencing clinical outcome in patients receiving antiplatelet therapy
  • 3.1 CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis – a case-control study
  • 3.2 Combined influence of proton pomp inhibitors, calcium channel blockers and CYP2C19*2 on on-treatment platelet reactivity and on the occurrence of atherothrombotic events in patients undergoing coronary stent implantation
  • 3.3 Interactions between CES2, CYP2C9, UGT1A6 and COX1 genetic variants and acetylsalicylic acid modify the risk of myocardial infarction
  • 3.4 The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting
CHAPTER 4 General discussion
CHAPTER 5 Summary
CHAPTER 6 Samenvatting