Prescribing Anticoagulants

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Introduction

Venous thromboembolisms (VTEs) affect approximately 1 in 1,000 people annually in the UK.¹ Anticoagulants are crucial for preventing and treating thromboembolisms, so understanding how these medications work and their potential side effects is essential.

In this article, we will focus on three main types of anticoagulants: heparins, vitamin K antagonists, and direct oral anticoagulants (DOACs) and discuss their roles, side effects, monitoring, and key points for safe use.

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Heparins

Due to their rapid onset of action and reversibility, heparins, including unfractionated heparin (UFH) and low molecular weight heparins (LMWHs), are usually preferred over oral anticoagulants in situations requiring rapid anticoagulation (e.g. acute thromboembolic events and peri-operative settings).

Additionally, heparins (LMWH) are commonly used during pregnancy due to their established safety profile.

Unfractionated heparin (UFH)

Mechanism of action

UFH enhances the activity of antithrombin, leading to the inhibition of coagulation factors IIa (thrombin) and Xa.^2,3 The inhibition of those coagulation factors prevents the conversion of fibrinogen to fibrin, thereby impeding clot formation.^2,3

Indications 

UFH is preferred over LMWHs in patients with a higher risk of bleeding or renal impairment due to its shorter half-life and reversibility.^2,3 UFH is indicated in the following:²

• Acute treatment of VTEs, including deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Prophylaxis of VTE in hospitalised patients undergoing surgery or medical patients

Dosing 

Dosing of UFHs depends on the indication. For the treatment of DVT, initial administration is typically an intravenous loading dose of either 5000 units or 75 units/kg followed by 18 units/kg/hour as a continuous intravenous infusion or 15000 units subcutaneously twice daily.²

For thromboprophylaxis in medical patients, the dose is usually a subcutaneous injection every 8-12 hours at a dosage of 5000 units.

For surgical patients, a single pre-operative dose of 5000 units is usually administered subcutaneously, followed by 5000 units every 8-12 hours postoperatively.²

Low molecular weight heparins (LMWHs)

Examples: dalteparin, enoxaparin, tinzeparin

Mechanism of action

LMWHs exert their anticoagulant effect by targeting factor Xa², a pivotal player in the coagulation cascade. By inactivating factor Xa, LMWHs impede the formation of thrombin, thereby preventing the conversion of fibrinogen to fibrin and ultimately halting the clotting process.³

Indications

One of the defining characteristics of LMWHs is their extended duration of action compared to UFHs.² This prolonged activity translates into less frequent dosing requirements, enhancing patient convenience and compliance.

LMWHs have a reduced risk of certain adverse effects, such as osteoporosis and heparin-induced thrombocytopenia (HIT), making them more appropriate than UFHs in certain patient groups such as in pregnant women.²

LMWH may be preferred in certain scenarios, such as:²

• Acute treatment of venous VTEs including deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Prophylaxis of VTE in hospitalised patients undergoing surgery or with medical illnesses
• Treatment and prevention of VTE in pregnant people or individuals with cancer.

Dosing 

The dosing of LMWHs varies based on the indication and patient factors such as weight, renal function, and concomitant medications.²

For the treatment of DVT and PE in uncomplicated patients, LMWHs are often used to bridge the gap until oral anticoagulation can be established or long-term, depending on the patient’s circumstances. Common dosing for treatment is:²

• 1.5mg/kg enoxaparin SC
• 200 units/kg dalteparin SC 

For thromboprophylaxis in hospitalised patients a lower dose is typically used and will vary slightly depending on the reason for admission. In medical patients typical doses are:²

• 40mg enoxaparin SC once daily
• 5000 units dalteparin SC once daily

The exact dosing and timing of doses around surgical procedures will vary, depending on the procedure being carried out and the patient’s individual risk factors, local guidelines should exist for these scenarios and practice will vary.²

Monitoring heparins

Platelet count

Platelet counts should be assessed before initiating treatment with a heparin due to the risk of HIT. Regular monitoring of platelet counts may be necessary for treatments lasting longer than 4 days.²

Potassium levels

In patients at risk of hyperkalaemia, it is advisable to measure plasma potassium levels before commencing heparin therapy and to continue regular monitoring after that, especially for treatments exceeding 7 days.²

Activated partial thromboplastin time (aPTT)

For patients receiving UFH, regular monitoring of a coagulation screen, including activated partial thromboplastin time (aPTT) levels, is recommended.³ The aPTT reflects the time taken for the blood to clot and is used to adjust UFH dosage to maintain therapeutic levels.

Target aPTT ranges vary based on the clinical indication and patient factors, but generally aim for 1.5 to 2.5 times the control value.³

Duration of treatment

The duration of anticoagulation will depend on the indication. Heparins are more likely to be used short-term while patients are in hospital or as part of a bridging plan. However, they can still be used long-term in some patients:

• Isolated calf DVT: typically six weeks
• Provoked VTE (induced by factors like oral contraceptives or pregnancy): three months
• Unprovoked VTE or PE: at least six months
• Recurrent PE, DVT and AF: long term therapy

Key interactions of heparins 

Heparins may interact with several medications:²

• Other anticoagulants
• Antiplatelet agents
• NSAIDs

These interactions can potentiate the anticoagulant effects of heparins, increasing the risk of bleeding complications. Concurrent use of medications affecting platelet function such as SSRIs can further exacerbate this risk.²

Key side effects of heparins 

Haemorrhage

In the event of haemorrhage, heparins are usually withdrawn. However, in situations necessitating urgent reversal of anticoagulation, the use of the antidote, protamine, may be warranted.²

Hyperkalaemia

Heparins can induce hyperkalaemia, particularly in individuals with underlying conditions such as diabetes mellitus and chronic kidney disease. This electrolyte disturbance arises from heparin-mediated inhibition of aldosterone secretion, thereby impairing potassium excretion.²

Heparin-induced thrombocytopenia (HIT)

HIT is a potentially life-threatening immune-mediated complication associated with heparin exposure, characterised by a 30% reduction in platelet count, skin allergies, and an increased risk of thrombosis.²

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Vitamin K antagonists

Vitamin K antagonists, such as warfarin, acenocoumarol, and phenindione, work by inhibiting the effects of vitamin K.²

As it is the most used vitamin K antagonist, warfarin will be the main subject of discussion in this section.

Mechanism of action

Vitamin K antagonists, including warfarin, exert their therapeutic effect by inhibiting the synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) as well as coagulation regulatory factors, proteins C and S.⁴ This inhibition occurs through the blockade of vitamin K epoxide reductase, a pivotal enzyme in the vitamin K cycle.⁴

Indications

Warfarin may be indicated in the following situations:²     

• Long-term anticoagulation for patients with mechanical heart valves or valvular atrial fibrillation
• Patients with a history of recurrent VTE and not suitable for DOAC therapy or suffered a clot whilst on a DOAC
• Individuals requiring anticoagulation with close monitoring of international normalised ratio (INR) levels.

Onset of action and dosage

Warfarin takes 48 to 72 hours for its anticoagulant effect to manifest fully.²

It is available in various strengths, including 0.5mg (white), 1mg (brown), 3mg (blue), and 5mg (pink). The initiation dose typically ranges from 5-10mg, with subsequent monitoring every one to two days initially.

Maintenance doses usually fall within the range of 3-9mg.²

Monitoring

Baseline prothrombin levels are assessed before initiating treatment.² Subsequently, monitoring encompasses:

• Time in therapeutic range (TTR) over a maintenance period of at least six months and
• International normalised ratio (INR) measurements. INR, representing the ratio of patient prothrombin times to control samples, guides dosage adjustments.

The target INR varies depending on the indication, with a standard target of 2.5 for conditions like VTE, atrial fibrillation (AF), and myocardial infarction (MI). Recurrent VTEs whilst on warfarin treatment mandate a higher target of 3.5.⁵ 

Once stability is achieved, monitoring intervals can extend to every three months.⁶

Duration of treatment

As with other anticoagulants, the duration of therapy depends on the indication:⁶

• Isolated calf DVT: typically six weeks
• Provoked VTE (induced by factors like oral contraceptives or pregnancy): three months
• Unprovoked VTE or PE: at least six months
• Recurrent PE, DVT and AF: long term therapy

Key interactions

Warfarin is metabolised by CYP450 enzymes and so can have many potential interactions:

• CYP450 inducers such as carbamazepine and primidone reduce the efficacy of warfarin
• CYP450 inhibitors such as the macrolides and metronidazole increase the INR levels

Therefore, patients on these medications require more frequent monitoring.

^{Warfarin also interacts with drugs that increase bleeding risk, such as NSAIDs and SSRIs.2}

Key side effects

Bleeding⁶

This may manifest in several ways, ranging from nose bleeds lasting less than 10 minutes, bleeding gums, or easy bruising to significant haemorrhage.

In cases of major bleeding, immediate cessation of warfarin is advised, accompanied by administering intravenous phytomenadione (vitamin K) and dried prothrombin complex or fresh frozen plasma. Minor bleeding incidents may require the administration of IV phytomenadione.

Management of bleeding risk in the acute setting depends on the INR:

• If the INR is between five and eight without bleeding, one to two doses of warfarin should be withheld, the maintenance dose reduced, and INR rechecked after two to three days.
• For INR levels above eight without bleeding, warfarin should be omitted, oral phytomenadione administered, and warfarin restarted when the INR is less than five.

Blue toe syndrome²

This is a rare complication at the beginning of warfarin therapy that some healthcare professionals may not be aware of. It manifests as sudden painful discolouration of the toes due to micro-embolisms.

Key points for patients on warfarin

Patients on warfarin should be informed about the importance of maintaining a yellow treatment booklet and carrying an anticoagulant alert card at all times for quick reference in emergencies.⁶ Additionally, they should be educated about the strength and colour of their tablets and their prescribed dose.⁶ 

In cases of missed doses or taking the wrong dose, patients should:⁶

• Document the incident
• Resume their normal dosage the following day.
• If the normal dose is greatly exceeded, they should promptly contact their anticoagulation clinic.

Regular INR tests are crucial, and patients should be advised to keep records of treatment and blood results from the preceding six months.⁷

Patients should also be educated about bleeding side effects:⁶

• Prolonged nosebleeds
• Blood in bodily secretions
• Severe bruising
• Unusual headaches

They should seek advice before undergoing dental or medical procedures and exercise caution when purchasing other medications, especially those containing aspirin or NSAIDs.⁶

Adherence to alcohol consumption guidelines as well as maintaining a consistent diet, particularly in green leafy vegetables, chickpeas, liver, egg yolk, and dairy products, is recommended as these foods are high in vitamin K and can antagonise the effects of warfarin, so significant variation in their consumption can impact the time in the therapeutic range.⁷

For more information, see our comprehensive guide to warfarin counselling.

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Direct oral anticoagulants (DOACs)

Examples: dabigatran, apixaban, edoxaban, and rivaroxaban.

Mechanism of action

Dabigatran

Dabigatran is an inactive prodrug that exerts its anticoagulant effect after being hydrolysed by esterases in plasma and the liver to become active. It acts by reversibly inhibiting free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.

By impeding thrombin, a serine protease pivotal in converting fibrinogen to insoluble fibrin strands, dabigatran prevents the formation of blood clots, preventing thrombus development.⁸

Apixaban, edoxaban and rivaroxaban

These DOACs competitively inhibit both free and clot-bound factor Xa, a crucial enzyme in the coagulation cascade responsible for converting prothrombin to thrombin.

By targeting factor Xa, these agents effectively impede the amplification of the coagulation cascade, as a single molecule of factor Xa can generate over a thousand molecules of thrombin.⁹

Indications

DOACs are increasingly used and may be preferred in the following circumstances:²          

• Non-valvular AF for stroke prevention.
• Treatment of acute VTE, including DVT and PE.

Monitoring

Baseline assessments should include:

• Clotting screen
• Full blood count (FBC)  
• Liver function tests (LFTs)
• Urea and electrolytes (U&Es)

Subsequently, annual monitoring of FBCs, renal and liver function tests is advised.

Initial review of treatment should occur after one month, followed by regular assessments every three months. It is essential to note contraindications based on renal function:²

• Dabigatran should be avoided in patients with creatinine clearance (CrCl) under 30
• Rivaroxaban and apixaban should be avoided in patients with creatinine clearance (CrCl) under 15

Key points for patients on DOACs

Patients should be provided with a DOAC patient booklet and an alert card to be always carried and the necessity of undergoing monitoring tests periodically should be reinforced.¹⁰

Adherence should be emphasised, ensuring patients understand the prescribed dose and timing and ideally remain consistent daily. The anticoagulant effect reduces after six to 12 hours from the last dose, so there is a risk of thromboembolic events.

Guidance should be given on missed dose management:¹⁰

• For rivaroxaban once daily (OD), the forgotten dose can be taken up to 12 hours after
• For dabigatran or apixaban twice daily (BD), the forgotten dose can be taken six hours after the scheduled intake
• Otherwise, the dose should be skipped, and the next dose taken as scheduled

Patients should be encouraged to consult healthcare professionals before purchasing other medications, especially those containing aspirin or NSAIDs.

Education on adherence to alcohol guidelines should be provided, along with counselling on bleeding risks, emphasising the need to seek medical advice before dental or medical procedures.¹⁰

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DOACs vs warfarin

Warfarin has been historically widely used in the UK for many years as a standard oral anticoagulant. In recent years, trials like ROCKET AF, RE-LY, and ARISTOTLE have shown DOACs are non-inferior or superior to warfarin in preventing stroke and VTE with similar or lower bleeding risks.¹¹

These findings, coupled with other benefits to DOACs, prompted a notable rise in DOAC prescribing:¹²

• DOACs need less monitoring
• DOACs typically have fixed dosing regimens
• Onset of anticoagulation is faster in DOACs
• Discontinuation is faster on cessation of treatment
• DOACs have fewer food and medication interactions

However, DOACs also come with limitations. Patients with severe renal disease may not be suitable candidates for DOAC therapy, as a significant portion of DOACs are renally cleared.¹² Similarly, DOACs are contraindicated in hepatic disease associated with coagulopathy.² 

Furthermore, DOACs have not been as extensively studied as warfarin, lacking data in certain patient populations such as pregnant women, children, those with malignant disease, mechanical heart valve issues, or antiphospholipid syndrome.¹³

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Anticoagulation and surgery

Anticoagulation management in surgery involves assessing the type of surgery, the underlying indication for anticoagulation, and the type of anticoagulant in question. Careful planning is required to balance the risk of thrombotic events with the risk of bleeding.

DOACs are typically stopped at least 24 hours preoperatively in procedures with lower bleed risk and at least 48 hours preoperatively in procedures with higher bleed risk.¹⁰

Warfarin may require cessation up to 5 days before surgery to allow for INR normalisation.⁶ Oral phytomenadione administration is considered if the INR is above 1.5 before surgery.^2,6

In cases where immediate cessation of anticoagulation poses a high thrombotic risk, such as in patients with mechanical heart valves or atrial fibrillation, bridging therapy with a heparin may be considered. A heparin is temporarily substituted for the oral anticoagulant to maintain therapeutic anticoagulation during the peri-operative period. It is typically discontinued 24 hours before surgery to minimise the bleeding risk.¹⁵

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Reviewer

Anna Wozniak-Pierozek

Anticoagulation independent pharmacist prescriber 

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Editor

Dr Jess Speller

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References

1. The Clatterbridge Cancer Centre. Venous Thromboembolism (VTE). 2017. Available from: [LINK] 
2. Joint Formulary Committee. BNF 86. 2023.
3. Nutescu E et al. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. 2016. Available from: [LINK] 
4. Patel S et al. Warfarin. 2023. Available from: [LINK] 
5. British Society for Haematology. Oral Anticoagulation with Warfarin- fourth Edition. 2011. Available from: [LINK] 
6. NICE CKS. Warfarin. 2024. Available from: [LINK] 
7. NHS. Warfarin Anticoagulant therapy. 2022. Available from: [LINK] 
8. Comin J et al. Dabigatran (Pradaxa). 2012. Available from: [LINK] 
9. Kim J H et al. New Anticoagulants for the Prevention and Treatment of Venous Thromboembolism. 2017. Available from: [LINK] 
10. NICE CKS. Anticoagulation- oral. 2024. Available from: [LINK] 
11. Ruff C T et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. 2014. Available from: [LINK] 
12. Elfar S. Direct Oral Anticoagulants vs. Warfarin in Hemodialysis Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis. 2022. Available from: [LINK] 
13. Aronis K N et al. Evidence Gaps in the Era of Non–Vitamin K Oral Anticoagulants. 2018. Available from: [LINK] 
14. Williams H et al. Guidance for the safe switching of warfarin to direct oral anticoagulants (DOACs) for patients with non-valvular AF and venous thromboembolism (DVT / PE) during the coronavirus pandemic. 2020. Available from: [LINK] 
15. Oxford University Hospitals. Oxford haemophilia and thrombosis centre protocols for outpatient oral anticoagulation with vitamin k antagonists. 2017. Available from: [LINK] 

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