The following are 10 key points from this review of the pharmacology of antithrombotic medications:

1. Antithrombotic agents, including anticoagulant and antiplatelet medications, are frequently used for a variety of cardiovascular diseases. Careful consideration of the efficacy to safety ratio is needed when selecting antithrombotic agents for patients.
2. Oral antiplatelet agents target the adhesion, activation, or aggregation of platelets to prevent thrombus formation. Aspirin selectively inhibits cyclooxygenase (COX)-1 at a lower dose to provide antiplatelet effects while it inhibits both COX-1 and COX-2 at higher doses to provide additional anti-inflammatory and analgesic effects. Aspirin leads to permanent and irreversible inactivation of platelets for their 7- to 10-day lifespan. Aspirin is rapidly absorbed through the gastrointestinal membrane with peak plasma concentrations obtained within 30 minutes (regular aspirin) to 4 hours (enteric-coated formulations). For this reason, patients presenting with acute coronary syndromes are recommended to chew 150-325 mg of regular aspirin to expedite the clinical effect.
3. P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor provide additional antiplatelet effects beyond that of aspirin. Clopidogrel and prasugrel are both prodrugs that require biotransformation to become active. Loading doses of clopidogrel (600 mg) are associated with antiplatelet action within 2 hours compared to 30 minutes with prasugrel (loading dose of 60 mg). Both medications have a slow offset duration of 7-10 days. No clinical studies have demonstrated efficacy of personalizing clopidogrel dosing based on genetic testing or consistent adverse outcomes associated with concurrent proton pump inhibitor use. Prasugrel use is contraindicated in patients with a prior stroke or transient ischemic attack (TIA), and is not advised in patients ages >75 years because of an increased risk of bleeding.
4. Ticagrelor inhibits P2Y12 through a unique mechanism that allows for quicker offset of action than either clopidogrel or prasugrel. Ticagrelor should be given as a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. While ticagrelor inhibits 40% of platelets within 30 minutes of dosing, at least 4 hours are needed to achieve effective inhibition in most ST-elevation myocardial infarction patients. Use of ticagrelor along with potent CYP3A4 inhibitors and inducers, CYP3CA4 substrates (e.g., simvastatin and lovastatin), and grapefruit juice should be avoided.
5. Vorapaxar and atopaxar are thrombin receptor antagonists that inhibit platelet aggregation. Vorapaxar is Food and Drug Administration approved for use in patients with myocardial infarction or peripheral vascular disease, but should not be used in patients with a prior stroke, TIA, or intracranial hemorrhage.
6. Vitamin K antagonists, such as warfarin, are the most commonly used oral anticoagulants. Warfarin disrupts the formation of vitamin K-dependent clotting factors (II, VII, IX, X, protein C, and protein S). Warfarin’s half-life of 40 hours correlates to a delayed clinic effect of 48-72 hours due to the indirect action through vitamin K factor inhibition. Warfarin’s effect can be reversed with vitamin K administration or the infusion of clotting factors. Warfarin’s narrow therapeutic window and its many drug-drug and drug-food interactions necessitate frequent blood laboratory testing.
7. Nonvitamin K oral anticoagulants (NOACs) include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. These medications have a fast onset of action. All are at least partially excreted through the kidneys and have dose adjustments based on the degree of renal dysfunction. They each have important drug-drug interactions, including P-glycoprotein substrates (e.g., verapamil, dronedarone, and amiodarone).
8. NOAC dosing is unique to the specific indication. For patients with venous thromboembolism, the initial therapy includes either parenteral heparin (for dabigatran and edoxaban) or higher-intensity NOACs (for rivaroxaban and apixaban). After the initial treatment, usual doses of NOACs are used for venous thromboembolism treatment, but lower doses are sometimes indicated for the extended secondary prevention phase (e.g., apixaban).
9. Collectively, all four NOAC agents have demonstrated reduction in the risk of intracranial hemorrhage as compared to warfarin therapy in trials of stroke prevention in atrial fibrillation. However, many NOACs (dabigatran, rivaroxaban, and edoxaban) demonstrated increased risks of gastrointestinal bleeding in those same studies, which might relate to the varying levels of active NOAC medication that is not absorbed through the gastrointestinal tract.
10. Routine monitoring of NOAC agents is not advised. However, when necessary, the prothrombin time can be used to make a qualitative assessment of the factor Xa inhibitors, and the activated partial thromboplastin time can be used for the direct thrombin inhibitors. Direct antidotes to these agents are not yet available.

Keywords: Acute Coronary Syndrome, Anticoagulants, Antithrombins, Biotransformation, Blood Platelets, Fibrinolytic Agents, Intracranial Hemorrhages, Ischemic Attack, Transient, Peripheral Vascular Diseases, Platelet Aggregation, Prothrombin Time, Secondary Prevention, Stroke, Venous Thromboembolism, Amiodarone, Aspirin, Cyclooxygenase 1, Factor Xa Inhibitors, Food-Drug Interactions, Heparin, Lovastatin, ATP Binding Cassette Transporter, Subfamily B, Member 1, Purinergic P2Y Receptor Antagonists, Verapamil, Vitamin K, Warfarin

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