Clinical pharmacology of antiplatelet drugs

ABSTRACT

Introduction

Platelets play a key role in arterial thrombosis and antiplatelet therapy is pivotal in the treatment of cardiovascular disease. Current antiplatelet drugs target different pathways of platelet activation and show specific pharmacodynamic and pharmacokinetic characteristics, implicating clinically relevant drug–drug interactions.

Areas covered

This article reviews the role of platelets in hemostasis and cardiovascular thrombosis, and discusses the key pharmacodynamics, drug–drug interactions and reversal strategies of clinically used antiplatelet drugs.

Expert opinion

Antiplatelet therapies target distinct pathways of platelet activation: thromboxane A₂ synthesis, adenosine diphosphate-mediated signaling, integrin α_IIbβ₃ (GPIIb/IIIa), thrombin-mediated platelet activation via the PAR1 receptor and phosphodiesterases. Key clinical drug–drug interactions of antiplatelet agents involve acetylsalicylic acid – ibuprofen, clopidogrel – omeprazole, and morphine – oral P2Y₁₂ inhibitors, all of which lead to an attenuated antiplatelet effect. Platelet function and genetic testing and the use of scores (ARC-HBR, PRECISE-DAPT, ESC ischemic risk definition) may contribute to a more tailored antiplatelet therapy. High on-treatment platelet reactivity presents a key problem in the acute management of ST-elevation myocardial infarction (STEMI). A treatment strategy involving early initiation of an intravenous antiplatelet agent may be able to bridge the gap of insufficient platelet inhibition in high ischemic risk patients with STEMI.

KEYWORDS:

• Platelet
• antiplatelet
• pharmacodynamics
• acetylsalicylic acid
• aspirin
• clopidogrel
• prasugrel
• ticagrelor
• cangrelor
• P2Y12
• GPIIbIIIa
• PAR1
• bleeding
• thrombosis

Article highlights

• Key pathways of platelet activation targeted by clinically used antiplatelet agents: thromboxane A₂ synthesis, ADP-mediated signaling, integrin α_IIbβ₃ (GPIIb/IIIa), thrombin-mediated platelet activation via the PAR1 receptor and phosphodiesterases

• Non-steroidal anti-inflammatory drugs attenuate the antiplatelet effect of aspirin

• Omeprazole attenuates the antiplatelet effect of clopidogrel

• Morphine delays and decreases the antiplatelet effect of oral P2Y₁₂ inhibitors

• The antiplatelet effect of ticagrelor cannot be reversed with platelet transfusions; the monoclonal antibody bentracimab specifically binds ticagrelor reversing its effect

• Platelet function and genetic testing and the use of scores (ARC-HBR, PRECISE-DAPT, ESC ischemic risk definition) may help guide antiplatelet therapy in patients undergoing PCI with high bleeding and ischemic risk; high bleeding risk may outweigh high ischemic risk as it is associated with a higher mortality

• High on-treatment platelet reactivity is a clinical phenomenon encountered in critically ill patients and patients with STEMI

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

G Gelbenegger is supported by a grant from the Austrian Science Funds (FWF SFB54-P04).