Direct oral anticoagulants

Key examples

• Apixaban
• Dabigatran
• Edoxaban
• Rivaroxaban

Common indications

1. Venous thromboembolism (VTE, the collective term for deep vein thrombosis and pulmonary embolism): Direct oral anticoagulants (DOACs) are an option for treatment and prevention of recurrence (secondary prevention) of VTE. Heparin and warfarin are alternatives. DOACs are also indicated for primary prevention of VTE in patients undergoing elective hip or knee replacement surgery.
2. Atrial fibrillation (AF): Anticoagulation with DOACs is indicated to prevent stroke and systemic embolism in patients with non-valvular AF who have at least one risk factor (including previous stroke, symptomatic heart failure, diabetes mellitus or hypertension). Warfarin is an alternative.

Mechanisms of action

• The coagulation cascade is a series of reactions triggered by vascular injury that generates a fibrin clot. 
• The DOACs act on the final common pathway of the coagulation cascade, comprising factor X, thrombin and fibrin. 
• Apixaban, edoxaban and rivaroxaban directly inhibit activated factor X (Xa), preventing conversion of prothrombin to thrombin. 
• Dabigatran directly inhibits thrombin, preventing the conversion of fibrinogen to fibrin. 
• All DOACs therefore inhibit fibrin formation, preventing clot formation or extension in the veins and heart. 
• They are less effective in the arterial circulation where clots are largely platelet driven, and are better prevented by antiplatelet agents.

Important adverse effects

• Bleeding is a common adverse effect, particularly epistaxis, GI and genitourinary haemorrhage. The risk of intracranial haemorrhage and major bleeding is less with DOACs than with warfarin. However, the risk of GI bleeding is greater, possibly due to intraluminal drug accumulation causing local anticoagulant effects. 
• Other adverse effects include anaemia, GI upset, dizziness and elevated liver enzymes.

Warnings

• DOACs should be avoided in people with active, clinically significant bleeding and in those with risk factors for major bleeding, such as peptic ulceration, cancer, and recent surgery or trauma, particularly of the brain, spine or eye. 
• As DOACs are excreted by multiple routes, including cytochrome P450 (CYP) enzyme metabolism and elimination in faeces and urine, dose reduction or an alternative agent may be required in hepatic or renal disease. 
• DOACs are contraindicated in pregnancy and breastfeeding, where the risk of harm to offspring is unknown.

Important interactions

• Risk of bleeding with DOACs is increased by concurrent therapy with other antithrombotic agents (e.g. heparin, antiplatelets and NSAIDs). 
• Other interactions can arise with drugs that affect the metabolism of DOACs (e.g. CYP inducers/inhibitors) or their excretion (through induction/inhibition of transport proteins). 
• For example, the anticoagulant effect can be increased by macrolides, protease inhibitors and fluconazole and decreased by rifampicin and phenytoin.