We searched PubMed for relevant articles using the terms “antithrombotic”, “antiplatelet”, and “anticoagulant” in conjunction with the terms “pharmacology”, “oral”, “medications”, “agents”, and “therapies.” Relevant articles were selected and we reviewed their references. We did not apply any date restrictions to our search.
SeriesPharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments
Introduction
Haemostasis consists of a complex interplay of the vascular endothelium, platelets, and coagulation factors. This process can lead to clot formation in the arteries or veins, which ultimately manifests as an acute coronary syndrome (ACS) or venous thromboembolism. As such, antithrombotic drugs, including antiplatelet therapies and anticoagulants, are frequently used in patients with cardiovascular disease. This Series paper focuses on the pharmacological properties of the most commonly used oral antithrombotic drugs.
Careful consideration of the efficacy to safety ratio is needed in design and selection of antithrombotic drugs. Additionally, several pharmacological factors can affect a drug's success: a high rate of absorption, an active parent drug rather than a prodrug that needs to be metabolised, minimum interactions, rapid action, linear pharmacokinetics with a dose-dependent drug effect, many modes of elimination, and a direct target. These features restrict drug resistance and reduce interpatient variability in the antithrombotic effect. The aim is now to develop antithrombotic drugs with these more favourable pharmacological properties, thereby reducing thrombotic events without generation of unacceptably high bleeding rates.
Section snippets
Targeting of platelets
Platelets are integral to the development of the pathological thrombus responsible for cardiovascular disease.1 Disruption of the endothelium exposes platelets to the adhesive proteins of the subendothelial matrix. Platelet adhesion is dependent on the interactions between the matrix proteins and platelet-receptor glycoproteins (figure 1). Activation of intracellular signalling pathways in the platelet results in the release of activators such as ADP, adrenaline, serotonin, thrombin, and
Targeting of the coagulation system
In 1964, the concept of the coagulation cascade of enzymatic steps was introduced.87 Since then, there has been a change in the notion of the process, whereby complexes of vitamin K-dependent enzymes and non-enzyme cofactors interact. These complexes include extrinsic tenase, intrinsic tenase, and prothrombinase. Their interaction leads to the formation of thrombin (factor IIa) that further amplifies the coagulation system, converts soluble fibrinogen to insoluble fibrin, and activates platelets
Conclusions
Antithrombotic drugs have been developed to inhibit platelets or coagulation factors that can cause ACS or venous thromboembolism, and the initial oral antiplatelet and anticoagulant treatments successfully reduce thrombotic events. However, over time some limitations to these treatments were noted. As a result, clopidogrel has been joined by the next generation of P2Y12 inhibitors, prasugrel and ticagrelor. In terms of anticoagulants, options now include warfarin and the direct factor
Search strategy and selection criteria
References (118)
- et al.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines
J Am Coll Cardiol
(2013) - et al.
Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control
Thromb Res
(2004) - et al.
The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes
J Thromb Haemost
(2012) The story of clopidogrel and its predecessor, ticlopidine: Could these major antiplatelet and antithrombotic drugs be discovered and developed today?
C R Chim
(2012)- et al.
Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects
Blood
(2006) - et al.
Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study
Lancet
(2009) - et al.
Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial
Lancet
(2012) - et al.
A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (assessment of the best loading dose of clopidogrel to blunt platelet activation, inflammation and ongoing necrosis) trial
J Am Coll Cardiol
(2006) - et al.
High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (clopidogrel and response variability investigation study 2)
JACC Cardiovasc Interv
(2011) - et al.
Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials
Lancet
(2009)
The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study
J Am Coll Cardiol
Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives
J Am Coll Cardiol
Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study
Lancet
Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel
J Thromb Haemost
Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial
J Am Coll Cardiol
Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients
J Am Coll Cardiol
A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study
J Am Coll Cardiol
A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study
JACC Cardiovasc Interv
Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding
J Am Coll Cardiol
Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study
J Am Coll Cardiol
Normalization of platelet reactivity in clopidogrel-treated subjects
J Thromb Haemost
Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance
J Am Coll Cardiol
Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation
J Thromb Haemost
Pharmacogenetics
Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial
Lancet
Mechanisms of thrombus formation
N Engl J Med
Novel antiplatelet agents in acute coronary syndrome
Nat Rev Cardiol
Antiplatelet drugs
Br J Pharmacol
Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides
Proc Natl Acad Sci USA
The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase
Nat Struct Biol
Low-dose aspirin for the prevention of atherothrombosis
N Engl J Med
Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers
J Clin Pharmacol
ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation
Eur Heart J
Dose comparisons of clopidogrel and aspirin in acute coronary syndromes
N Engl J Med
Aspirin
Circulation
Drug insight: aspirin resistance—fact or fashion?
Nat Clin Pract Cardiovasc Med
Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease
Circ Cardiovasc Interv
Ticlopidine and subcutaneous heparin as an alternative regimen following coronary stenting
Cathet Cardiovasc Diagn
Combined antiplatelet therapy with ticlopidine and aspirin. A simplified approach to intracoronary stent management
Eur Heart J
Intracoronary stent implantation without ultrasound guidance and with replacement of conventional anticoagulation by antiplatelet therapy. 30-day clinical outcome of the French Multicenter Registry
Circulation
Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study
Circulation
[Antiplatelet therapy during coronary endoprosthesis placement]
Arch Mal Coeur Vaiss
Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS)
Circulation
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation
N Engl J Med
Prasugrel versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
Ticagrelor versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes
N Engl J Med
Prehospital ticagrelor in ST-segment elevation myocardial infarction
N Engl J Med
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events
N Engl J Med
Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents
N Engl J Med
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