Oral anticoagulants

The main use of anticoagulants is to prevent thrombus formation or extension of an existing thrombus in the slower-moving venous side of the circulation, where the thrombus consists of a fibrin web enmeshed with platelets and red cells. Anticoagulants are of less use in preventing thrombus formation in arteries, for in faster-flowing vessels thrombi are composed mainly of platelets with little fibrin.

This article provides an overview of the use of oral anticoagulants. For detailed information about doses, indications, side-effects and interactions, always consult the British National Formulary (in the UK) or other relevant prescribing guidance.

The oral anticoagulants available in the UK are:^{1 2}

• Vitamin K antagonists:

  • Take at least 48 to 72 hours for the anticoagulant effect to develop fully. Warfarin is the vitamin K antagonist of choice. If an immediate effect is required, unfractionated or low molecular weight heparin must be given concomitantly.

  • Should not be used in cerebral artery thrombosis or peripheral artery occlusion as first-line therapy.

  • Aspirin is more appropriate for reduction of risk in transient ischaemic attacks.

  • Unfractionated or a low molecular weight heparin is usually preferred for the prophylaxis of venous thromboembolism in patients undergoing surgery. However, warfarin sodium can be continued in selected patients currently taking long-term warfarin sodium and who are at high risk of thromboembolism (seek expert advice).

• Direct-acting oral anticoagulants:

  • Direct-acting oral anticoagulants (DOACs) include apixaban, dabigatran etexilate, edoxaban, and rivaroxaban.

  • Dabigatran etexilate is a reversible inhibitor of free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.

  • Apixaban, edoxaban, and rivaroxaban are reversible inhibitors of activated factor X (factor Xa) which prevents thrombin generation and thrombus development.

  • Dabigatran etexilate, rivaroxaban, edoxaban and apixaban do not require monitoring of the INR.

  • Apixaban, dabigatran etexilate, edoxaban, and rivaroxaban are used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in specific circumstances, and for the treatment and secondary prevention of deep-vein thrombosis and/or pulmonary embolism.

  • Apixaban, dabigatran etexilate, and rivaroxaban are also used for the prevention of venous thromboembolism after elective hip or knee replacement surgery.

  • Rivaroxaban is also used for the prevention of atherothrombotic events in patients with coronary or peripheral artery disease, and following an acute coronary syndrome with raised biomarkers in specific circumstances.

  • Unlike warfarin, DOACs do not require regular international normalised ratio (INR) monitoring. However, regular follow up is required to review the treatment, assess for adverse effects (such as bleeding), assess for thromboembolic events, and provide appropriate information and advice.

  • The anticoagulant effects of DOACs diminish 12 to 24 hours after the last dose is taken, therefore omitted or delayed doses could lead to a reduction in anticoagulant effect.

Warfarin INR targets¹

The base-line prothrombin time should be determined but the initial dose should not be delayed whilst awaiting the result.

An INR which is within 0.5 units of the target value is generally satisfactory. Larger deviations require dosage adjustment. Target values (rather than ranges) are now recommended.

INR 2.5 for:

• Deep vein thrombosis or pulmonary embolism (including those associated with antiphospholipid syndrome or for recurrence in patients no longer receiving warfarin sodium).

• Atrial fibrillation.

• Cardioversion: target INR should be achieved at least 3 weeks before cardioversion and anticoagulation should continue for at least 4 weeks after the procedure (higher target values, such as an INR of 3, can be used for up to 4 weeks before the procedure to avoid cancellations due to low INR).

• Dilated cardiomyopathy.

• Mitral stenosis or mitral regurgitation in patients with either atrial fibrillation, a history of systemic embolism, a left atrial thrombus, or an enlarged left atrium.

• Bioprosthetic heart valves in the mitral position (treat for 3 months), or in patients with a history of systemic embolism (treat for at least 3 months), or with a left atrial thrombus at surgery (treat until clot resolves), or with other risk factors (for example, atrial fibrillation or a low ventricular ejection fraction). The NICE guideline for heart valve disease presenting in adults does not recommend anticoagulation after surgical biological heart valve replacement unless there is another indication for anticoagulation.³

• Acute arterial embolism requiring embolectomy (consider long-term treatment).

• Myocardial infarction.

INR 3.5 for:

• Recurrent deep vein thrombosis or pulmonary embolism in patients currently receiving anticoagulation and with an INR above 2.

• Mechanical prosthetic heart valves: the recommended target INR depends on the type and location of the valve, and patient-related risk factors. Consider increasing the INR target or adding an antiplatelet drug, if an embolic event occurs whilst anticoagulated at the target INR.

Combined anticoagulant and antiplatelet therapy¹

• Existing antiplatelet therapy following an acute coronary syndrome or percutaneous coronary intervention should be continued for the necessary duration according to the indication being treated.

• The addition of warfarin sodium, when indicated (for example, for venous thromboembolism or atrial fibrillation) should be considered following an assessment of the patient’s risk of bleeding and discussion with a cardiologist.

• The duration of treatment with dual therapy (for example, aspirin and warfarin sodium) or triple therapy (for example, aspirin with clopidogrel and warfarin sodium) should be kept to a minimum where possible.

• The risk of bleeding with aspirin and warfarin sodium dual therapy is lower than with clopidogrel and warfarin sodium.

• Depending on the indications being treated and the patient’s risk of thromboembolism, it may be possible to withhold antiplatelet therapy until warfarin sodium therapy is complete, or vice versa (on specialist advice) in order to reduce the length of time on dual or triple therapy.

Peri-operative anticoagulation¹

Warfarin

• Warfarin sodium should usually be stopped 5 days before elective surgery. Phytomenadione (vitamin K1) by mouth (using the intravenous preparation orally [unlicensed use]) should be given the day before surgery if the INR is 1.5 or higher. If haemostasis is adequate, warfarin sodium can be resumed at the normal maintenance dose on the evening of surgery or the next day.

• Patients stopping warfarin sodium prior to surgery who are considered to be at high risk of thromboembolism (for example, those with a venous thromboembolic event within the last 3 months, atrial fibrillation with previous stroke or transient ischaemic attack, or mitral mechanical heart valve) may require interim therapy (‘bridging’) with a low molecular weight heparin (using treatment dose). The low molecular weight heparin should be stopped at least 24 hours before surgery. If the surgery carries a high risk of bleeding, the low molecular weight heparin should not be restarted until at least 48 hours after surgery.

• Patients on warfarin sodium who require emergency surgery that can be delayed for 6–12 hours can be given intravenous phytomenadione (vitamin K1) to reverse the anticoagulant effect. If surgery cannot be delayed, dried prothrombin complex can be given in addition to intravenous phytomenadione (vitamin K1) and the INR checked before surgery.

Managing haemorrhage and/or a high INR^{1 4}

The main adverse effect of all oral anticoagulants is haemorrhage.

Warfarin

• Checking the INR and omitting doses when appropriate is essential. If the anticoagulant is stopped but not reversed, the INR should be measured 2–3 days later to ensure that it is falling. The cause of an elevated INR should be investigated.

• Major bleeding: stop warfarin sodium; give phytomenadione (vitamin K1) by slow intravenous injection; give dried prothrombin complex (factors II, VII, IX, and X). If dried prothrombin complex unavailable, fresh frozen plasma can be given but is less effective; recombinant factor VIIa is not recommended for emergency anticoagulation reversal.

• INR above 8.0, minor bleeding: stop warfarin sodium; give phytomenadione (vitamin K1) by slow intravenous injection. Repeat dose of phytomenadione if INR still too high after 24 hours; restart warfarin sodium when INR below 5.0.

• INR above 8.0, no bleeding: stop warfarin sodium; give phytomenadione (vitamin K1) by mouth using the intravenous preparation orally [unlicensed use]. Repeat dose of phytomenadione if INR still too high after 24 hours; restart warfarin when INR below 5.0.

• INR 5.0–8.0, minor bleeding: stop warfarin sodium; give phytomenadione (vitamin K1) by slow intravenous injection; restart warfarin sodium when INR below 5.0.

• INR 5.0–8.0, no bleeding: withhold 1 or 2 doses of warfarin sodium and reduce subsequent maintenance dose.

• Unexpected bleeding at therapeutic levels: always investigate possibility of underlying cause, for example, unsuspected renal or gastrointestinal tract pathology.

Direct-acting oral anticoagulants

• Reversal agents are available for dabigatran etexilate, apixaban, and rivaroxaban.

• Idarucizumab is licensed for the rapid reversal of dabigatran etexilate in life-threatening or uncontrolled bleeding, or for emergency surgery or urgent procedures.

• Andexanet alfa is licensed for the reversal of apixaban or rivaroxaban in life-threatening or uncontrolled bleeding.