11/13/24, 7\:43 PM Guide | Prescribing anticoagulants

Prescribing anticoagulants

Table of contents

Introduction

1
Venous thromboembolisms (VTEs) a
preventing and treating thromboembolisms, so understanding how these medications work and their potential side e
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 e

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 pro

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
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 2
UFH is indicated in the following\:
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
2
LMWHs exert their anticoagulant ecoagulation cascade. By inactivating
factor Xa, LMWHs impede the formation of thrombin, thereby preventing the conversion of
halting the clotting process.
3
Indications
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One of the de2
translates into less frequent dosing requirements, enhancing patient convenience and compliance.
This prolonged activity
LMWHs have a reduced risk of certain adverse e
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 re
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
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NSAIDs
These interactions can potentiate the anticoagulant e
Concurrent use of medications a
2

Key side e

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

Vitamin K antagonists

Vitamin K antagonists, such as warfarin, acenocoumarol, and phenindione, work by inhibiting the e
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 e
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
Patients with a history of recurrent VTE and not suitable for DOAC therapy or su
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 e
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 (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
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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 e
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 e

Bleeding
6
This may manifest in several ways, ranging from nose bleeds lasting less than 10 minutes, bleeding gums, or easy bruising to
signi
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
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
Blue toe syndrome
2
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 e
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
e
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 e
liver to become active. It acts by reversibly inhibiting free thrombin,
aggregation.
By impeding thrombin, a serine protease pivotal in converting , 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 ecoagulation 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 e
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

DOACs vs warfarin

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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
12
DOACs need less monitoring
DOACs typically have
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 signi12
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
Switching from warfarin to DOACs
Transitioning from warfarin to DOACs may be warranted under certain circumstances, such as poor INR control or drug
interactions. The switch involves stopping warfarin and initiating the DOAC once the INR reaches a suitable level,
typically within three to
For dabigatran and apixaban, the suitable INR level is less than two, while for rivaroxaban, it is less than three.
14

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
administration is considered if the INR is above 1.5 before surgery.
2,6
Oral phytomenadione
In cases where immediate cessation of anticoagulation poses a high thrombotic risk, such as in patients with mechanical heart
valves or atrial
anticoagulant to maintain therapeutic anticoagulation during the peri-operative period. It is typically discontinued 24 hours
before surgery to minimise the bleeding risk.
15

Reviewer

Anna Wozniak-Pierozek
Anticoagulation independent pharmacist prescriber

References

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