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CPD 54: NEW / NOVEL ORAL ANTI-COAGULANTS

New / Novel Oral Anti-Coagulants

60 Second SummaryCurrently there are three licensed new oral anti-coagulants, (NOAC) namely Dabigatran, Rivaroxaban

and Apixaban. These agents have been approved for the prevention of stroke and systemic

embolism, and also the prevention and treatment of deep vein thrombosis. Keys groups of patients

in whom NOAC s should be considered include patients who cannot take vitamin K agonists such as

warfarin, those who cannot be stabilised on warfarin and those taking aspirin for stroke prevention.

There are many benefits to treatment with NOAC, such as the lack of need for routine coagulation

monitoring and the compliance benefits of more straight-forward dosing. Although NOAC provide a

safe and effective alternative to warfarin, drawbacks can limit their use. Such drawbacks include the

lack of specific antidote for reversal of effects and the risk of gastrointestinal haemorrhage.

INTRODUCTION

Oral anticoagulants are a class of drug that work to prevent the coagulation or clotting of blood. The main use of anticoagulants is to prevent thrombus formation or an extension of an existing thrombus in the slower-moving venous side of the circulation. 1Here the thrombus consists of a fibrin enmeshed with platelets and red blood cells, whereas in the arteries the thrombi have little fibrin and anticoagulants are of less use. Many factors need to be considered before deciding to use anticoagulants and they are patient dependent. Some factors include: the risks of thrombosis and bleeding, age and drug interactions. Thromboembolic disorders are major causes of morbidity and mortality, and great advances have been made in understanding the basis of thrombus formation. Conventional anticoagulants such as unfractioned heparin, low molecular weight heparins and vitamin K antagonists (warfarin) act on several factors within the coagulation cascade. Although very effective, these traditional agents have various limitations and drawbacks. These include parenteral route of administration or routine coagulation monitoring and frequent dose adjustments. New approaches to anticoagulation therapy have focused on targeting specific enzymes within the coagulation cascade, such as thrombin and Factor Xa. The inhibition of either of these enzymes prevents fibrin formation. 2

TRADITIONAL ANTICOAGULANTS

Warfarin is a vitamin k antagonist and is indicated for:

• prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation

• Prophylaxis and treatment of venous thrombosis and pulmonary embolism

• Transient cerebral ischaemic attacks

Warfarin is an effective agent for stroke prevention, reducing the incidence by almost 50 per cent. Advantages of warfarin include its well-established efficacy, low cost, and an antidote is readily available. However, there are many limitations and contraindications to the use of warfarin. These include bleeding complications, a narrow therapeutic window, individual patient drug dose response, multiple drug and food interactions (especially alcohol) and finally the social and financial inconvenience of INR monitoring. Sudden changes in diet can potentially affect the control of anticoagulation. Certain food such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Changes in dosage are often required such as a dose reduction in cases of acute illness smoking cessation and weight loss, and a dose increase in cases of vomiting and diarrhoea, and weight gain. Warfarin is well absorbed following oral administration 3 however it takes 2-3 days for the full anticoagulant effect to develop. Warfarin also has a long half-life of about 40 hours and it can take up to five days for the prothrombin time to return to normal after stopping treatment. Warfarin treatment requires frequent monitoring to maintain INR within therapeutic range for the given indication. The dosage regiment is also complicated with no standardised dose. 4 There was therefore a

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Biography - Amy Louise Oates. I qualified from the Robert Gordon University Aberdeen with a Master in Phamacy in 2011. I then undertook my pre-registration year with Gordons Chemists in Edinburgh. After registration I moved back home, where I am now working for Johnstons Pharmacy in Longford Town, Lanesborough and Ballygar, Co. Galway. I also recently completed a Cardiology in Clinical Pharmacy Practice module with Trinity College Dublin.


need for an effective anticoagulant, which was as effective as warfarin, but with less of the above concerns.

NEW ORAL ANTICOAGULANTS

Three new oral anticoagulants (NOAC) have been licensed in Ireland since 2008: 2

• Dabigatran Etexilate – Pradaxa 75mg, 110mg, 150mg

• Rivaroxaban – Xarelto 10mg,15mg, 20mg

• Apixaban – Eliquis 2.5mg , 5mg

The NOACs are licensed in Ireland for the following indications:

• Prevention and treatment of stroke with non-valvular atrial fibrillation

• Primary prevention of venous thromboembolic events following total hip and knee replacement surgery

• Treatment and prevention of DVT and PE

However, warfarin remains the oral anticoagulant of choice 2 and treatment with NOAC should only be considered for:

• Patients with an allergy to warfarin

• Patients already on warfarin displaying poorly controlled INR despite adhering to monitoring and lifestyle requirements

• Patients who require treatment with medications that interact with warfarin

WHICH NOAC?

Firstly whether a patient needs anticoagulation or not needs to be decided. This is based on evaluation of their CHADS-VASC score, bleeding risk and patient or physician preference. Once the anticoagulation decision has been made, then a discussion about warfarin versus NOAC needs to take place. It is necessary that patients are actively involved in the decision making about anticoagulant treatment. Unlike with warfarin, there is no need for routine monitoring with NOAC and so patient compliance and adherence is vital. It is important that patients understand why they are taking anticoagulation, and understand the benefits and risks associated with the treatment. 5

WHEN IS ANTICOAGULATION RECOMMENDED?

The CHA2DS2- VASc score is a tool for estimating the risk of stroke in patients with non-valvular atrial fibrillation (NVAF). It is used to determine whether or not treatment is needed with anticoagulation therapy or antiplatelet therapy. In patients with a score of 0, who are at low risk with no risk factors, no anticoagulation is required. In patients with a score ≥ 2m therapy with VKA, Direct thrombin inhibitor, or an oral Factor Xa is recommended unless contraindicated. In patients with a score of 1, oral anticoagulant therapy should be considered. 5

Bleeding Risk should be assessed when prescribing any antithrombotic therapy, whether with VKA, NOAC aspirin or clopidogrel. The HAS-BLED score is used as a calculation to assess bleeding risk. A score of ≥ 3 indicated high risk. 5

DABIGATRAN

Dabigatran etexilate is an oral, reversible direct thrombin inhibitor. 1,2 Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-links monomers and augments further thrombin formation. Dabigatran is prodrug that has a bioavailability of approximately 6%. Once absorbed from the GI tract, Dabigatran is converted by esterases into its active metabolite. Maximum concentrations are observed within 2 hours of oral administration, with an estimated half-life of 14-17 hours.

Dabigatran is indicated for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation, with one or more of the following risk factors :

• Previous stroke, transient ischaemic attack, or systemic embolism

• Left ventricular ejection fraction <40%

• Symptomatic heart failure, ≥ New York Heart Association (NYHA) Class 2

• Age ≥ 75 years

• Age ≤ 65 years with one of the following diabetes mellitus, coronary artery disease or hypertension

It is also indicated for the primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. A further indication would be for the prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

The recommended daily dose of Dabigatran is 300mg, taken as Pradaxa 50mg twice daily. 5

For the following two groups the recommended daily dose of Dabigatran is 220mg taken as Pradaxa 110mg twice daily

1) Patients aged 80 years or above

2) Patients who receive concomitant verapamil

Dabigatran is contraindicated in patients with active bleeding or if they are at high risk of bleeding. Caution is also needed in patient receiving treatment with potent inhibitors of both CYP3A4 and P-glycoprotein, such as ketoconazole, macrolide antibiotics (e.g. Clarithromycin) or protease inhibitors. These drugs will increase the anticoagulant effect. Careful monitoring us also required with concomitant administration of P-glycoprotein inhibitors, such as amiodarone, quinidine and verapamil.

The most common side effect with Dabigatran is haemorrhage and patients should be monitored for signs of bleeding or anaemia. If bleeding is severe treatment should be stopped.

PHARMACIST COUNSELLING

A forgotten dose may still be taken up to 6 hours prior to the next scheduled dose. After this time, the missed dose should be omitted; no double dose should be taken to make up for the missed doses. Pradaxa capsules can be taken with or without food and should be swallowed whole with a glass of water to facilitate delivery to the stomach. Patients should be instructed not to open the capsule as this may increase the risk of GI bleeding, abdominal pain, diarrhoea, dyspepsia, nausea. 4

RIVAROXABAN

Rivaroxaban is a direct inhibitor of activated factor X (factor Xa). The onset of inhibition


Risk Factors

Risk Factors Score Congestive Heart Failure 1

Hypertension 1 Age ≥ 75 2

Age 65 - 74 1 Diabetes Mellitus 1

Stroke/ TIA/ Thromboembolism 2 Female 1

CHA2DS2- VASc

C Congestive Heart Failure 1 H Hypertension 1 A2 Age ≥ 75 2 D Diabetes 1 S2 Stroke / TIA / Thromboembolism 2 V Vascular Disease 1 A Age 65 - 74 1 Sc Sex Category (i.e. Female sex) 1

HAS- BLED Score

Clinical Characteristic Score Hypertension 1

Abnormal liver function 1 Abnormal renal function 1

Stroke 1 Labile INRs 1

Elderly (Age >65) 1 Drugs 1

Alcohol 1

Advantages of NOAC Treatment Disadvantages of NOAC Treatment No routine monitoring needed No antidote available Broader therapeutic index Costly Less drug interactions Lack of experience No food interactions Strict compliance needed due to short half

lives Fixed doses Not able to measure anticoagulation

RISK FACTORS


of Factor Xa activity is rapid with maximum concentrations appearing 2-4 hours after oral administration. 2 Rivaroxaban is indicated for the treatment of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery, Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and treatment and prevention of DVT and PE.

The recommended dose of Rivaroxaban depends of the indication: 5

• DVT Prophylaxis: Xarelto 10mg taken orally once daily. The initial dose should be taken 6-10 hours after surgery, provided that haemostasis has been established. For patients undergoing total hip replacement treatment duration of 5 weeks is recommended, and for total knee replacement treatment duration of 2 weeks is recommended.

• DVT / PE Treatment: initial treatment 15mg twice daily with food for 21 days

• Continued DVT/PE Treatment and prevention of recurrent DVT/PE: 20mg Once daily from Day 22 on for a minimum duration of 3 months.

Rivaroxaban is contraindicated in liver disease, active bleeding and patients at significant risk of bleeding. 1 Use with caution in cases of renal impairment. Caution is also needed in patient receiving treatment with potent inhibitors of both CYP3A4 and P-glycoprotein, such as ketoconazole, macrolide antibiotics (e.g. Clarithromycin) or protease inhibitors. These drugs will increase the anticoagulant effect. . If co-administered with CYP3A4 inducers such as carbamazepine, phenytoin or phenobarbital, Rivaroxaban plasma concentration is reduced. 4


If a dose of Xarelto is missed the patient should take the dose immediately and then continue the following day with once daily intake as before. Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope and dizziness have been reported to be common. 5 Patient experiencing these adverse reactions should not drive or use machinery.

APIXABAN

Apixaban is another direct inhibitor of Factor

Xa. It reversibly inhibits both free Factor Xa and prothrombinase activity. 2 Apixaban is associated with a high bioavailability and has a half-life of 8-15hours.

Apixaban is indicated for the prevention of stroke and systemic embolism with non-valvular atrial fibrillation in adult patients with one or more of the following risk factors:

• Previous stroke of transient ischaemic attack

• Age ≥ 75 years

• Hypertension

• Heart failure NYHA Class ≥ 11

• Diabetes mellitus

Another indication for Apixaban is for the prevention and treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE).11 Apixaban is also licensed for the prevention of venous thromboembolic events in adult patients who have undergone total hip or total knee replacement surgery.

The recommended dose for the prevention of stroke and systemic embolism is 5mg twice daily. A dose reduction is required in patients ages 80 years and over, patients weighing under 60kg and patients with a serum creatinine level of ≥133mmol/l. For the prevention of VTE following THR and TKR, a dose of 2.5mg twice daily is recommended. A duration of 10-14 days is required for TKR and a longer duration of 32-38 days for THR.


A missed dose of Apixaban should be taken immediately and then continue with twice daily dosing as normal the next day. 4

SWITCHING BETWEEN NOAC AND WARFARIN 4,5

Dabigatran to Warfarin

When changing treatment from warfarin to Dabigatran, warfarin is stopped when the INR <2, then Dabigatran can be commenced.

Warfarin to Dabigatran

The patients CrCl needs to be considered. If CrCl is ≥50mL/min start warfarin 3 days before stopping Dabigitran. If CrCl is ≥30 > 50ml/min start warfarin 2 days before stopping Dabigatran.

Rivaroxaban to Warfarin

Both warfarin and rivaroxaban should be given together until INR ≥ 2. This is due to the potential for inadequate anticoagulation during the transition. As INR is affected by rivaroxaban treatment , INR should not be tested until 24 hours after the previous dose but before the next dose of rivaroxaban.

Warfarin to Rivaroxaban

When changing from warfarin to Rivaroxaban the indication for treatment must be taken into


Risk Factors





CHA2DS2- VASc


HAS- BLED Score





Alcohol 1



CHA2DS2- VASC

Risk Factors





CHA2DS2- VASc


HAS- BLED Score





Alcohol 1



HAS- BLED SCORE



account. For prevention of systemic embolism, warfarin should be stopped and rivaroxaban commenced when INR ≤ 3. For the treatment of DVT, Pulmonary Embolism and prevention, warfarin should be stopped and rivaroxaban commenced when INR ≤ 2.5. INR is falsely elevated once Rivaroxaban is started so the measure of anticoagulation can’t be assessed with INR.

Apixaban to Warfarin

When changing patients from apixaban to warfarin, continue administration of apixaban for at least 2 days after beginning warfarin therapy. After 2 days of coadministration of apixaban and warfarin, obtain an INR before the next scheduled dose of apixaban. Continue coadministration of both apixaban and warfarin until the INR is ≥ 2. It normally takes at least 2 days to achieve an INR of ≥ 2.

Warfarin to Apixaban

Warfarin is stopped and Apixaban commenced when INR < 2.0

COMMENCING TREATMENT WITH NOACS

After the decision has been made to choose a NOAC :

• Patients should have Creatinine clearance (CrCl) assessed

• Liver Function Tests undertaken

• Patient education with regard to common side effects, missed dose procedure, warnings in relation to bleeding events

• Patients should be encouraged to carry an anticoagulant card for use in emergency situations.

BARRIERS TO USE OF NOACS AND RECOMMENDATIONS FOR MAINTENANCE TREATMENT

New oral anticoagulants offer a useful alternative to Warfarin treatment, however the inability to monitor the effect of anticoagulation with NOAC and the lack of a specific antidote to counteract the effects are considerable drawbacks to their use. 4 The greatest risk with all anticoagulants is haemorrhage and it is thought that gastrointestinal haemorrhage may be even greater with new oral anticoagulants when compared with warfarin. However, there has been evidence to support that there is a reduction in the rate of major bleeding with Apixaban and also a significant reduction in the rate of fatal bleeds when compared with warfarin.12 Pharmacists have a role to play in ensuring patients are not prescribed concomitant medication that interacts with their anticoagulant therapy. The Health Service Executive found that 28% of patients receiving treatment with Rivaroxaban also received medications that are expected to interact with the NOAC. 25% of patients also received medications such as NSAIDS and platelet aggregation inhibitors. The used of these medications are to be used with caution in combination with NOAC due to the increased risk of haemorrhage.10 Patients aged over 75 years and patients with impaired renal function treated with Dabigatran need to have renal function assessed at least once a year. All patients should be monitored for

signs of bleeding. When commencing new treatments, care must be taken that there is no contraindication to its use with NOAC. Continuous monitoring for signs of bleeding is necessary and reiteration to the patient regarding the need for strict compliance.

ROLE OF THE PHARMACIST

Pharmacists have a vital role to play in the area of anticoagulation. There are many pharmacist counselling points associated with the dispensing of NOAC, including dosage times, scheduling and administration recommendation. Pharmacists are ideally placed to monitor patients for signs of bleeding, including any unexplained bruising and bleeding. Pharmacists can also detect the prescribing of concomitant medication that may interact with the NOAC and place the patient at risk, and they can also give appropriate advice and offer alternatives in relation to over the counter sales of NSAIDS.

REFERENCES

1. BRITISH NATIONAL FORMULARY. No 68. September 2014. BNF online www.bnf.org.uk

2. Samama, M.M., The mechanism of action of rivaroxaban – an oral, direct Factor Xa inhibitor – compared with other anticoagulants, Thrombosis Research 127, 497-504, 2011

3. Neal, M.J., Medical Pharmacology at a Glance, Fifth Edition, 2005

4. Quality in Practice Committee, Anticoagulation in General Practice / Primary Care Part 2: New/ novel oral anticoagulants, 2014

5. Summary of Product Characteristics for each medication accessed on www.medicines.ie February 2015

6. NICE Implementation Collaborative Consensus

7. www.escardio.org/ guidelines

8. Cheng, J.W., Non-vitamin K antagonist oral anticoagulants in cardiovascular disease management: evidence and unanswered questions , J Clin Pharm Ther, 39(2): 118-35, 2014

9. National Medicines Information Centre, Update on oral anticoagulation therapy, 2012

10.HSE Clinicial Strategy and Programmes Division. Available from: http://www.hse.ie/eng/about/Who/clinical/natclinprog/medicinemanagementprogramme/NOACs.pdf

11. http://www.medicines.ie/medicine/15447/SPC/Eliquis+2.5+mg+film-coated+tablets/

12. Granger, C.B, et al, Apixaban versus Warfarin in Patients with Atrial Fibrillation, The New England Journal of Medicine, 365:981-992; 2011.

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