Elsevier

The Lancet

Volume 386, Issue 9990, 18–24 July 2015, Pages 281-291
The Lancet

Series
Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments

https://doi.org/10.1016/S0140-6736(15)60243-4Get rights and content

Summary

Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies.

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

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.

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