Anticoagulation

Question 1

What is haemostasis?

Answer 1

Process by which the body limits blood loss after vascular damage. The formation of a thrombus or clot is one element of the process and involves the interaction of:
* The blood vessel wall, which restricts blood flow
* Circulating platelets, which form a mechanical plug
* Blood coagulation factors- which eventually form fibrin and the resulting thrombus through the clotting cascade

Question 2

The coagulation cascade

Answer 2

Platelets are activated by contact with the site of endothelial damage and the exposure of blood components to subendothelial proteins causes initiation of the coagulation cascade. This cascade leads to the production and deposition of fibrin at the site of tissue damage and the formation of a thrombus via platelet aggregation and fibrin formation. Venous thrombi can be described as consisting of platelets in a fibrin web, whereas in the faster flowing arterial circulation, thrombi are composed mainly of platelets with little fibrin.
Coagulation may also lead to the development of a thrombus that can block blood vessels, e.g. venous thrombosis or the development of arterial thrombotic disease. Thrombosis can be considered to be “haemostasis in the wrong place, at the wrong time”1.
Venous thrombosis and arterial thrombotic diseases have traditionally been considered separate processes but they share many similarities in pathophysiology and risk factors2.
Activation of the coagulation cascade underlies venous thrombosis and platelet activation underlies arterial thrombosis. Thus antithrombotic therapy can be directed towards both fibrin formation (anticoagulants e.g. warfarin) and platelet aggregation (antiplatelets e.g. aspirin).

Question 3

Main factors for thrombus formation

Answer 3

• Abnormalities of blood flow e.g. AF, DVT
  
  • Abnormalities of the surfaces in contact with the blood
    Abnormalities in clotting components as seen in patients with cancer, elevated fibrinogen, raised platelets, lupus anticoagulant

Question 4

What is a VTE

Answer 4

Formation of a thrombus within a vein is known as a venous thrombosis and if the thrombus breaks loose and travels through the blood vessels it is an embolus.
VTE can occur as DVT or PE.

Question 5

Cardioembolic stroke in AF

Answer 5

AF is a risk factor for the formation of ‘venous-type’ thrombi as a result of pooling of blood in the heart.
These thrombi can break free and the resulting emboli can block a cerebral artery, causing ischaemic injury.

Question 6

Assessing stroke risk in AF

Answer 6

Abnormal beating of the heart can cause blood pooling and embolus formation in the small chambers of the heart (atria). Anticoagulants are used for stroke prevention in patients with AF and the long-term risk of stroke in AF depends on additional risk factors (such as hypertension). Several scoring systems are available to help clinicians estimate the stroke risk in AF, such as CHA2DS2-VASc score7. The European Cardiology Society 2020 guidelines for the management of AF recommend the use of the HAS BLED score to assess the risk of bleeding in patients with AF. The overall incidence of AF in the UK has been stated as 1.7 per 1000 person-years

Question 7

How long do people with mechanical heart valves need to be anticoagulated for?

Answer 7

People with artificial valves require lifelong anticoagulation to prevent valve thrombosis and thromboembolic stroke.

Question 8

parenteral anticoagulants

Answer 8

• unfractionated heparin
• LMWH e.g. clexane, tinzaparin, dalteparin

Question 9

UFH MOA

Answer 9

The anticoagulant effects of UFH is due to the inactivation of thrombin (through activation of antithrombin) and by potentiating the naturally occurring inhibitors of activated Factor X (Xa)1. The anticoagulant effect of UFH can be reversed with protamine; however, protamine’s effect on LMWH is limited.

Question 10

LMWH MOA

Answer 10

LMWHs inactivate several coagulation enzymes (like UFH) and primarily act by selectively inhibiting Factor Xa. They are associated with a predictable dose response and fewer non-haemorrhagic side-effects

Question 11

complications of heparins

Answer 11

• heparin induced hyperkalaemia
• heparin induced thrombocytopenia

Question 12

LMWH indications

Answer 12

LMWHs are indicated for the prevention and treatment of DVT and are preferred over heparin as they have equivalent efficacy but lower risk of heparin-induced thrombocytopenia. They are also used in the treatment of PE, MI, unstable coronary artery disease and for the prevention of clotting in extracorporeal circuits.
LMWHs are more effective than warfarin in patients with cancer-associated VTE7 and have been used as a first-line treatment in patients with active cancer who require VTE prevention or treatment for many years.
LMWHs are the treatment of choice for venous thromboembolism in pregnancy; this is an unlicensed indication.
LMWHs are indicated for the prevention and treatment of DVT and are preferred over heparin as they have equivalent efficacy but lower risk of heparin induced thrombocytopenia

Question 13

Warfarin MOA

Answer 13

Step 1
Vitamin K enters the body in the diet and is reduced to hydroquinone form
Step 2
Vitamin K hydroquinone is converted to vitamin K epoxide via Vitamin K dependent carboxylase and produces biologically active coagulation proteins
Step 3
To regenerate the reduced vitamin K, the enzyme vitamin K epoxide reductase is required – warfarin blocks this action. To a lesser extent, warfarin blocks the action of vitamin K reductase.
Therefore, warfarin competitively inhibits the formation of vit K-dependent clotting factors so the blood clotting process is slowed down – therapeutic doses of warfarin decrease the total amount of each vit K-dependent coagulation factor by between 30 and 50%.

Question 14

Warfarin PK

Answer 14

Warfarin has 100% bioavailability when administered orally and has a low volume of distribution. Therefore it can be taken at any time of the day, with or without food, although it is normally recommended that warfarin is taken in the evening time – teatime or bedtime. This means that if patients have their bloods checked in the morning, their dose of warfarin can be changed in the evening if necessary.
However, if a patient has a problem with adherence, it may be more appropriate for them to take warfarin in the morning than not take it at all.
Warfarin is eliminated almost entirely by hepatic metabolism and is metabolised by the cytochrome P450 system, which explains some of its drug interactions. Its half-life is approximately 35 hours so it is given once daily

Question 15

Warfarin indications

Answer 15

The following are a list of indications for warfarin:
* prophylaxis of systemic embolisation in rheumatic heart disease and AF
* prophylaxis after insertion of prosthetic heart valve
* prophylaxis and treatment of venous thromboembolism (DVT and/or PE).
Warfarin should not be commenced in the acute phase of ischaemic stroke- antiplatelets are more appropriate. For the long term management of stroke associated with atrial fibrillation, treatment with warfarin is an option3.

Question 16

Warfarin Contraindications

Answer 16

Contra-indications to warfarin use are:
* known hypersensitivity to warfarin or to any of the excipients
* haemorrhagic stroke
* clinically significant bleeding
* within 72 hours of major surgery with risk of severe bleeding (those on long term therapy, warfarin is usually started on evening of surgery at maintenance dose, clinical decision is based on the bleeding risk of surgery)
* Within 48 hours postpartum- the administration of vitamin K to all neonates at birth which is routine practice minimises the risk of coumarin anticoagulant-induced neonatal haemorrhage
* pregnancy
* drugs where interactions may lead to a significantly increased risk of bleeding, however, if alternative drug cannot be given, warfarin may be indicated despite drugs which interact being given e.g. amiodarone, but additional INR’s will be needed +/or dose adjustment in anticipation

Question 17

Warfarin cautions

Answer 17

The following should be considered when prescribing warfarin:
* thrombocytopenia
* hepatic impairment (avoid if severe)
* previous intracranial or retinal bleed
* peptic ulceration
* severe hypertension
* alcohol consumption
* risk/severity of falls
* unwilling/inability to comply with treatment or monitoring4.

Question 18

Advantages of warfarin in comparison to DOACs

Answer 18

• is cheaper
• has been used since the 1950’s so there is a wealth of experience with it
• allows the practitioner to check adherence, through INR tests
• continuous monitoring provides an opportunity for the practitioner to discuss other issues
• allows once daily dosing and if a dose is missed it is less critical; the influence on coagulation can be detected
  has the licensed antidote, Vitamin K.

Question 19

Warfarin disadvantages

Answer 19

• slow onset of action
• narrow therapeutic window
• audits demonstrate only 55% to 60% of patients regularly achieve their therapeutic target INR
• adherence is difficult - variable doses, regular blood test monitoring
• patient inconvenience
• dose adjustments required
• interactions with other drugs and foods
• genetic variations between individual patients
• side-effects:
• bleeding (potentially life-threatening)
• skin necrosis
  contra-indicated in pregnancy as it is teratogenic

Question 20

DOACs factor Xa inhibitors

Answer 20

• Apixaban
• Edoxaban
• Rivaroxaban

Question 21

DOACs oral direct thrombin inhibitors

Answer 21

Dabigatran

Question 22

Dabigatran licensed indications

Answer 22

Primary prevention of venous thromboembolism (VTE) following hip or knee replacement (NICE TA157).
NICE TA249 (which provides cost-effective recommendations) states that dabigatran can be used for the prevention of stroke and systemic embolism in patients with non-valvular AF who have ≥ 1 of the following risk factors:
* previous stroke, transient ischaemic attack or systemic embolism
* left ventricular ejection fraction < 40%
* symptomatic heart failure (NYHA class II or above)
* age ≥ 75 years
* age ≥ 65 years with one of the following: diabetes, coronary artery disease or hypertension.
Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (NICE TA327).

Question 23

Dabigatran pharmacology

Answer 23

Dabigatran etexilate is a direct inhibitor of the enzyme thrombin. Thrombin is a key enzyme in blood clot (thrombus) formation because it enables the conversion of fibrinogen to fibrin during the coagulation cascade. Inhibition of thrombin prevents further development of clot formation.
Dabigatran etexilate is a small molecule prodrug, which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in the plasma and in the liver.
Food does not affect the bioavailability, which is approximately 6.5%.
Plasma levels of the drug peak in 2 hours. It has a short T1/2 of 12 to 14 hours.
Elimination (after hepatic activation) is via the kidney (80% of the given dose).

Question 24

Dabigatran contra indications

Answer 24

Hypersensitivity to the active substance or to any of the excipients.
Patients with severe renal impairment (CrCl < 30 ml/min).
Active clinically significant bleeding.
Organic lesion at risk of bleeding.
Spontaneous or pharmacological impairment of haemostasis.
Hepatic impairment or liver disease expected to have an impact on survival.
Systemic ketoconazole, ciclosporin, itraconazole, tacrolimus and dronedarone.
Prosthetic heart valves requiring anticoagulant treatment.
Concomitant treatment with any other anticoagulants, except when switching therapy.
Pregnancy and breast-feeding (there is no safe and effective data for use in pregnancy - adequate contraception is imperative in women of childbearing age).

Question 25

Dabigatran dose

Answer 25

VTE prevention: Dose is 110 mg (1 to 4 hrs) after surgery, then 220 mg once daily. Dose in elderly (>75 yrs) is 75 mg (1 to 4 hrs) after surgery then 150 mg once daily. Dose reduction to 150 mg once daily for patients taking amiodarone or verapamil. Dose is reduced in moderate renal impairment (Creatinine Clearance (CrCl) 30-50 ml/min) to 75 mg initial dose then 150 mg OD (or 75 mg OD if on verapamil). Treatment duration is 10 days for knee replacement and 28 to 35 days for hip replacement.
AF: Dose is 150 mg twice daily. Dose reduction to 110 mg twice daily for elderly (>80 yrs) or high risk of bleeding or taking verapamil.
Treatment of DVT and PE and prevention of recurrent DVT and PE in adults: Dose is 150 mg twice daily following a parenteral anticoagulant for at least 5 days. Duration should be individualised, see SPC.
Renal impairment: Dabigatran is contra-indicated in severe renal impairment (CrCl < 30 ml/min) for any indication. Monitor renal function at least annually.
Hepatic impairment: Not recommended with elevated liver enzymes (>2 upper limit of normal).

Question 26

dabigatran drug interactions

Answer 26

Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), LMWHs, heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban etc) except when switching therapy to or from dabigatran or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
NSAIDs, antiplatelets, glucocorticoids, SSRIs and SNRIs increase the risk of bleeding when co-administered with dabigatran.
P-glycoprotein inhibitors – amiodarone, verapamil, clarithromycin, quinidine, verapamil etc. In patients who receive verapamil, the dabigatran dose should be reduced to 220mg taken as one 110mg capsule twice daily; in this situation dabigatran and verapamil should be taken at the same time.
P-glycoprotein inducers including rifampicin, St. John’s wort, carbamazepine, phenytoin, etc.
In addition, if the patient has received an epidural, administration of the first dose of dabigatran should occur a minimum of two hours after the catheter is removed as per the SPC, following approval from the anaesthetist. These patients require frequent observation for neurological signs and symptoms.

Question 27

Dabigatran side effects

Answer 27

Nausea
Dyspepsia
Diarrhoea
Bleeding, see recent controversy surrounding this.
Anaemia
Less common side-effects
* Thrombocytopenia
* Hepatobiliary disorders
Gastro-intestinal ulcer

Question 28

rivaroxaban licensed indications

Answer 28

NICE TA256 (which provides cost-effective recommendations) states that rivaroxaban can be used for the prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors, such as:congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or TIA.
Rivaroxaban can also be used for the treatment of DVT and PE and the prevention of recurrent DVT and PE in adults (NICE TA261). It is licensed for the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery (NICE TA170).
Rivaroxaban is the only NOAC licensed for the prevention of artherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated biomarkers (2.5mg twice daily in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine).
Rivaroxaban is also licensed for the prophylaxis of atherothrombotic events in patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events (in combination with aspirin) (NICE TA607)

Question 29

rivaroxaban pharmacology

Answer 29

Highly selective direct factor Xa inhibitor: inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi.
Does not directly inhibit thrombin (activated Factor II).
No direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.
15 mg and 20 mg must be taken with food to ensure sufficient absorption of the drug.
The 2.5 mg and 10 mg dose can be taken with or without food

Question 30

rivaroxaban contraindications

Answer 30

Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
Patients with CrCl < 15 ml/min, but if using in patients with CrCl < 29 ml/min, care is needed.
Organic lesion or condition at risk of bleeding.
Concomitant treatment with any other anticoagulants, except when switching therapy.
Patients with a prosthetic heart valve requiring anticoagulation.
Pregnancy and breast-feeding (there is no safe and effective data for use in pregnancy - adequate contraception is imperative in women of childbearing age).

Question 31

rivaroxaban dose

Answer 31

AF: Recommended dose is 20 mg once daily.
VTE prevention: Recommended dose is 10 mg once daily (6 to 10 hours after surgery). For patients undergoing major hip surgery, 5 weeks treatment is recommended. For patients undergoing major knee surgery, 2 weeks treatment is recommended.
DVT treatment and prevention: Initially 15 mg bd for the first three weeks, followed by 20 mg od for the continued treatment period. When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. The duration of therapy and dose selection should be individualised after careful assessment of the treatment benefit against the risk for bleeding.
Prophylaxis of atherothombotic events: Recommended dose is 2.5mg twice daily. See SPC for specific indications and anti-platelet combinations.
Renal impairment: AF: Moderate (CrCl 30 - 49 ml/min) or severe (15 - 29 ml/min) renal impairment, recommended dose is 15 mg once daily. Not recommended in patients with CrCl < 15 ml/min.
DVT Treatment & Prevention: Moderate or severe renal impairment, patients should be treated with 15 mg bd for the first three weeks. Thereafter, the recommended dose is 20 mg once daily. Use is not recommended in patients with CrCl < 15 ml/min.

Question 32

rivaroxaban interactions

Answer 32

Rivaroxaban is not recommended to be taken with:
* azole-antimycotics, e.g. ketoconazole, itraconazole, voriconazole and posaconazole
* HIV protease inhibitors, e.g. ritonavir
* other anticoagulants due to an increased bleeding risk
* antiplatelets due to a lack of clinical data
* CYP3A4 inducers, e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort.
NSAIDs, use with care

Question 33

Rivaroxaban side effects

Answer 33

Nausea
Vomiting
Diarrhoea
Bleeding, see recent controversy surrounding this
Anaemia
Increased GGT
Increase in transaminases

Question 34

Apixaban licensed indications

Answer 34

NICE TA275 (which provides cost-effective recommendations) states that apixaban can be used for the prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors, such as:
* prior stroke or transient ischaemic attack
* age ≥ 75 years
* hypertension
* diabetes mellitus
* symptomatic heart failure (NYHA Class ≥ II).
Apixaban is also licensed for the treatment of DVT and PE , the prevention of recurrent DVT and PE in adults (NICE TA341) and for VTE prophylaxis post hip replacement and knee replacement surgery (NICE TA245)

Question 35

Apixaban pharmacology

Answer 35

Potent selective factor Xa inhibitor thus inhibiting thrombin formation and the development of thrombi.
Does not need antithrombin III to exhibit antithrombin activity.
No direct antiplatelet activity.
Half-life 12 hours.
Hepatically metabolised.
Renal function does not affect peak plasma concentrations but plasma apixaban concentrations are increased in patients with renal impairment

Question 36

apixaban contraindications

Answer 36

Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
Patients with CrCl < 15 ml/min, but if using in patients with CrCl < 30 ml/min, care is needed.
Organic lesion or condition at risk of bleeding.
Concomitant treatment with any other anticoagulant, except when switching therapy.
Patients with a prosthetic heart valve requiring anticoagulation.
Pregnancy and breast-feeding (there is no safe and effective data for use in pregnancy - adequate contraception is imperative in women of childbearing age).

Question 37

apixaban dose

Answer 37

VTE prevention: Dose is 2.5 mg twice daily (initial dose 12-24 hrs after surgery). Duration of treatment is 10-14 days for knee replacement, 32-38 days for hip replacement.
Treatment of acute DVT and PE: 10 mg twice daily for the first 7 days followed by 5 mg twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation).
Prevention of recurrent DVT and PE: 2.5 mg twice daily following completion of 6 months of treatment with apixaban 5 mg twice daily or with another anticoagulant. For more information consult SPC.
AF: 5 mg twice daily. Reduce to 2.5 mg twice daily in patients with AF and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dl (133 micromol/l); or if creatinine clearance is 15-29ml/min.
Renal impairment: No dose adjustment is necessary in patients with mild or moderate renal impairment. With severe (15-29 ml/min) renal impairment the recommended dose for AF is 2.5 mg twice daily. For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, the dose is not reduced but apixaban is to be used with caution if creatinine clearance is 15-29 ml/min. It is not recommended in patients with CrCl < 15 ml/min.

Question 38

apixaban interactions

Answer 38

Apixaban is not recommended to be taken with:
* azole-antimycotics, e.g. ketoconazole, itraconazole, voriconazole and posaconazole
* HIV protease inhibitors, e.g. ritonavir
* any other anticoagulants due to an increased bleeding risk
* antiplatelets due to a lack of clinical data
* CYP3A4 inducers, e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort.
NSAIDs, use with care

Question 39

apixaban side effects

Answer 39

Nausea
Haemorrhage
Bruising
Anaemia

Question 40

edoxaban licensed indications

Answer 40

NICE TA355 states that edoxaban (Lixiana®) is an option for preventing stroke and systemic embolism in people with non-valvular AF who have one or more risk factors, such as:
* heart failure, high blood pressure or diabetes
* had a stroke or transient ischaemic attack before
* aged 75 years or older.
Furthermore NICE TA354 states that edoxaban (Lixiana®) is recommended as an option for treating and preventing recurrent DVT or PE

Question 41

pharmacology edoxaban

Answer 41

Edoxaban is a highly selective, direct and reversible inhibitor of factor Xa, the serine protease located in the final common pathway of the coagulation cascade; therefore it prolongs clotting time and reduces the risk of thrombus formation.
Edoxaban is absorbed with peak plasma concentrations within 1 to 2 hours. The absolute bioavailability is approximately 62%. Food increases peak exposure to a varying extent, but has minimal effect on total exposure. The half-life for oral administration is 10 to 14 hours.
Unchanged edoxaban is the predominant form in plasma; < 10% is metabolised. Renal clearance accounts for approximately 35% of the administered dose. Biliary/intestinal excretion account for the remaining clearance.

Question 42

edoxaban contraindications

Answer 42

Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
Lesion or condition, if considered to be a significant risk for major bleeding.
Uncontrolled severe hypertension.
Concomitant treatment with any other anticoagulants except under specific circumstances of switching oral anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
Pregnancy and breast-feeding (there is no safe and effective data for use in pregnancy - adequate contraception is imperative in women of childbearing age).

Question 43

edoxaban dose

Answer 43

AF: The recommended dose is 60 mg edoxaban once daily.
Treatment of DVT and PE and prevention of recurrent DVT and PE in adults: The recommended dose is 60 mg edoxaban once daily following initial use of a parenteral anticoagulant for at least 5 days. Edoxaban and an initial parenteral anticoagulant should not be administered simultaneously.
Renal impairment: Exclude patients with end stage renal disease (i.e. CrCL < 15 mL/min). In patients with CrCL 15 – 50 mL/min use 30 mg once daily and in patients with CrCL > 50 mL/min use 60 mg once daily.
Hepatic impairment: edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. In patients with severe hepatic impairment edoxaban is not recommended. In patients with mild to moderate hepatic impairment the recommended dose is 60 mg once daily; caution is required.
Low body weight: Patients with a body weight ≤ 60 kg should be prescribed 30 mg edoxaban once daily.
Interactions: For patients concurrently taking ciclosporin, dronedarone, erythromycin or ketoconazole,

Question 44

edoxaban interactions

Answer 44

Edoxaban is not recommended to be taken with:
* quinidine, verapamil, amiodarone
* other medicines to reduce blood clotting, e.g. heparin, clopidogrel, warfarin, dabigatran, rivaroxaban, apixaban
* phenytoin, carbamazepine, phenobarbital
* St John’s Wort
* anti-inflammatory and pain-relieving medicines, e.g. naproxen or aspirin.
Patients concurrently taking ciclosporin, dronedarone, erythromycin or ketoconazole should have their dose of edoxaban reduced to 30mg once daily.

Question 45

edoxaban side effects

Answer 45

The most common adverse reactions relate to bleeding with edoxaban 60 mg, e.g. cutaneous soft tissue haemorrhage, epistaxis and vaginal haemorrhage. Bleeding can occur at any site and may be severe and even fatal.
Other common adverse reactions include anaemia, rash and abnormal liver function tests.