Wout Van Den Broek

Antithrombotic therapy is a rapidly evolving field, continuously shaped by emerging evidence and shifting paradigms. In the 1980s, aspirin became the cornerstone of treatment for acute coronary syndrome (ACS), and by the mid-1990s, the addition of a P2Y12-receptor inhibitor marked the beginning of the dual antiplatelet therapy (DAPT) era. The safer alternative clopidogrel, introduced shortly thereafter, became widely adopted and was incorporated into the guidelines nearly a decade later. In 2010, the U.S. Food and Drug Administration (FDA) issued a black box warning on clopidogrel, cautioning that patients carrying a CYP2C19 *2 or *3 loss-of-function allele may not derive full therapeutic benefit. Despite this warning, and the growing body of evidence linking impaired metabolism to adverse cardiovascular outcomes, clopidogrel remained on the most widely prescribed P2Y12-receptor inhibitors, with routine genetic testing rarely implemented in clinical practice. This misalignment underscores the persistence of a “one-size-fits-all” approach, overlooking the fact that clopidogrel—a prodrug requiring CYP2C19-mediated activation—may be significantly less effective in certain individuals.

Today, DAPT with aspirin and a potent P2Y12-receptor inhibitor (ticagrelor or prasugrel) remains the standard of care for ACS patients undergoing percutaneous coronary intervention (PCI). However, this standardized strategy overlooks important interpatient variability—differences in genetic profile, comorbidities, procedural characteristics, and bleeding risk—that can significantly affect treatment response. Growing evidence suggests that personalizing antithrombotic therapy may offer improved clinical outcomes by optimizing the balance between ischemic protection and bleeding risk. This thesis addresses the challenges of optimizing antithrombotic strategies through a three-part approach: first, by establishing the rationale for personalized antithrombotic therapy and reviewing current evidence and strategies (Part I); second, by evaluating the clinical impact of genetic polymorphisms on cardiovascular outcomes and treatment response using data from multiple large-scale clinical trials as well as smaller, mechanistic studies involving laboratory-based testing (Part II); and third, by examining the real-world implementation, clinical effectiveness, and cost-efficiency of a genotype-guided de-escalation strategy in patients with ACS (Part III).

Part I outlines the current landscape of personalized antiplatelet therapy. Chapter 2 explores the current state of personalized antithrombotic therapy by weighing the advantages and limitations of genotype-guided strategies. It provides an overview of available monitoring methods, including coagulation assays and platelet function tests. Chapter 3 provides a more detailed overview of genotype-guided antiplatelet therapy, emphasizing how genetic variation contributes to interindividual differences in treatment response. Building on this, Chapter 4 discusses the potential benefits and limitations of genotype-guided antithrombotic therapy specifically in elderly patients with ACS.

Part II presents studies evaluating the impact of different genetic polymorphisms on clinical outcomes in patients with ACS. In Chapter 5, the clinical relevance of CYP2C9 loss-of-function polymorphisms in patients with ACS treated with clopidogrel is examined. Chapter 6 investigates whether genetic variants in CYP3A4 and CYP3A5 affect clinical outcomes in STEMI patients treated with ticagrelor. Chapter 7 presents an individual patient data meta-analysis evaluating the efficacy and safety of de-escalation of dual antiplatelet therapy (DAPT). Chapter 8 presents an individual participant data meta-analysis comparing CYP2C19-guided antiplatelet therapy to conventional treatment in ACS patients undergoing PCI. Chapter 9 examines platelet reactivity in patients undergoing PCI who are treated with a novel oral anticoagulant (NOAC) and have a high ABCD-GENE score.

Part III of this thesis focuses on the real-world implementation of genotype-guided antiplatelet therapy. Chapter 10 evaluates the real-world feasibility of implementing CYP2C19 genotype-guided P2Y12 inhibitor de-escalation. Chapter 11 compares clinical outcomes of genotype-guided de-escalation with standard DAPT in a real-world cohort from the FORCE-ACS registry. Chapter 12 assesses the cost-effectiveness of a genotype-guided de-escalation strategy compared to standard DAPT from the perspective of the Dutch healthcare system. Chapter 13 presents the results of a large, prospective, multicentre implementation study evaluating the clinical safety and effectiveness of routine CYP2C19 genotype-guided antiplatelet therapy in patients with ACS.