Implementation of NICE TA 249, NICE TA 256 and NICE TA 275

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-1-Implementation of NICE TA 249, NICE TA 256 and NICE TA 275

Dabigatran, rivaroxaban and apixaban for the prevention of stroke and systemic

embolism in non-valvular atrial fibrillation

(version 3, 08/13)

-2-1. Summary

NICE has issued Technology Appraisals (TA) for dabigatran (Pradaxa®), rivaroxaban (Xarelto®) and for apixaban (Eliquis®▼) for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (TA249, TA256 and TA275).

This guidance has been produced to:-

Help identify those patients who are most likely to benefit from dabigatran, rivaroxaban or apixaban Provide advice on using these new drugs in the safest possible manner.

Dabigatran, rivaroxaban and apixaban are orally active antithrombotic agents. Dabigatran is a direct thrombin inhibitor

Rivaroxaban is an oral direct factor Xa inhibitor Apixaban is an oral direct factor Xa inhibitor.

All three drugs have the potential advantage over warfarin of not requiring INR blood monitoring, but other factors about these drugs need to be taken into consideration when deciding whether any of the drugs are appropriate for an individual patient.

These factors include

Unknown long term safety profile of the new agents Lack of reversibility of the new agents

Consideration of the patient’s current INR control on warfarin Renal function

Bleeding risk, especially gastro-intestinal bleeding risk Drug interactions

Compliance.

The choice of agent is the decision of the prescriber and there are pros and cons to each agent.

Guidance is provided both for patients newly diagnosed with non-valvular atrial fibrillation and for existing patients currently taking warfarin.

Warfarin remains a suitable first-line oral anticoagulant for most patients.

The guidance does not and should not over-ride the NICE TA’s. A clinician may initiate dabigatran, rivaroxaban or apixaban for any patient within the Technology Appraisals’ criteria.

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-3-2. What does NICE say?

NICE issued a Technology Appraisal (TA249) “Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation” in March 2012.

http://guidance.nice.org.uk/TA249

1.1 Dabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with non-valvular atrial fibrillation with one or more of the following risk factors:

Previous stroke, transient ischaemic attack (TIA) or systemic embolism Left ventricular ejection fraction below 40%

Symptomatic heart failure of New York Heart Association (NYHA) class 2 or above Age 75 years or older

Age 65 years or older with one of the following: diabetes mellitus, coronary artery disease or hypertension.

1.2 The decision about whether to start treatment with dabigatran etexilate should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran etexilate compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to dabigatran etexilate should be considered in light of their level of international normalised ratio (INR) control.

NICE issued a Technology Appraisal (TA256) “Rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation” in May 2012.

1.1 Rivaroxaban is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more risk factors such as:

Congestive heart failure Hypertension

Age 75 years or older Diabetes mellitus,

Prior stroke or transient ischaemic attack.

1.2 The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control.

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-4-NICE issued a Technology Appraisal (TA275) “Apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation” in February 2013.

1.1 Apixaban is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation, that is, in people with non-valvular atrial fibrillation with one or more risk factors such as:

 Prior stroke or transient ischaemic attack

 Age 75 years or older

 Hypertension

 Diabetes mellitus

 Symptomatic heart failure.

1.2 The decision about whether to start treatment with apixaban should be made after an informed discussion between the clinician and the person about the risks and benefits of apixaban compared with warfarin, dabigatran etexilate and rivaroxaban. For people who are taking warfarin, the potential risks and benefits of switching to apixaban should be considered in light of their level of international normalised ratio (INR) control.

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-5-3 . Summary table for new oral anticoagulants for the prevention of stroke and systemic

embolism in non-valvular atrial fibrillation

Dabigatran

(Note that the trials compared different levels of INR rates – time in therapeutic range (TTR) was 64% in RE-LY

Rivaroxaban

(Note that the trials compared different levels of INR rates – time in therapeutic range (TTR) was 55% in ROCKET AF)

Apixaban

(Note that the trials compared different levels of INR rates – time in therapeutic range (TTR) was 66% in

ARISTOTLE) Efficacy in stroke prevention compared to warfarin Overall no difference

Superior (150mg twice daily dose) Non-inferior (110mg bd dose)

Overall no difference Non inferior

Overall superior

Superior for haemorrhagic stroke No difference for ischaemic and uncertain type stroke

Reduced risk of bleeding compared to warfarin

Evidence for reduced bleeding risk at lower dose.

NB Increased risk of GI bleed compared to warfarin at higher dose (which is the usual dose).

Overall reduced intra cranial haemorrhage (ICH)

Equivalent to warfarin (except reduced ICH)

Evidence for reduced risk of bleeding

Reversibility

Uncertain. Uncertain (possible data supports use of prothrombin complex concentrate which may reverse the laboratory

abnormalities of clotting but this may not translate into stopping the actual bleeding event)

Uncertain

Dialysable

Yes, but will need to be carried out for at least 6 hours in order to ensure adequate drug clearance

No No

Renal Function

Cannot be used if eGFR <30ml/min Manufacturer states cannot be used if eGFR<15ml/min, however locally we are advising not to use if eGFR <30ml/min (If eGFR 15-49 a reduced dose of 15mg once daily should be used.)

Manufacturer states cannot be used if eGFR<15ml/min, however locally we are advising not to use if eGFR <30ml/min (If eGFR 15-29 a reduced dose of 2.5mg twice daily should be used.)

Dosing Twice daily Once daily Twice daily

Drug interactions

P- glycoprotein substrates – inhibitors and inducers etc, refer to summary of product characteristics for full list Anticoagulants

See appendix 8 for full details

Simultaneous P-glycoprotein & CYP-3A4 inhibitors, refer to summary of product characteristics for full list Anticoagulants

See appendix 8 for full details

Simultaneous P-glycoprotein & CYP-3A4 inhibitors, agents associated with serious bleeding (e.g. thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and

sulfinpyrazone) refer to summary of product characteristics for full list Anticoagulants

See appendix 8 for full details Drug cautions

(increased bleeding risk)

Anticoagulants, antiplatelet agents, NSAIDs, SSRIs or SNRIs

Anticoagulants, antiplatelet agents, NSAIDs

Use in patients with swallowing difficulties

Capsule should not be opened May be crushed and put through naso-gastric tubebut this is outside of license

May be crushed and put through naso-gastric tube but this is outside of license

Suitability for monitored dosage systems (MDS)

Not suitable Suitable Not suitable

Cost / year (Costs may vary in different settings because of negotiated procurement discounts) £803 £767 £802

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-6-Possibility of using

in other conditions

NICE approved for orthopaedic prophylaxis.

Phase III data shows efficacy in DVT but no NICE appraisal currently planned

NICE approved for orthopaedic prophylaxis. NICE approved for treatment of DVT, and the prevention of recurrent DVT and PE.

NICE TA in development for use in acute coronary syndrome, expected September 2013.

NICE approved for orthopaedic prophylaxis.

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-7-4. Selection of appropriate patients

4.1 Newly diagnosed non valvular AF patients

Warfarin remains a suitable first-line oral anticoagulant for most patients. Patients who are well controlled and tolerant of warfarin are not recommended to change. The effectiveness of warfarin for the prevention of stroke in patients with AF is well established.

Oral anticoagulation is indicated for patients with a CHADS2 or a CHA2DS2-VASc score ≥2. When CHADS2 score is 0 or 1, further assessment of risk with CHA2DS2-VASc is essential to ensure all high risk patients are identified.

A new oral anticoagulant (NOAC) may be considered for patients where;

There are insurmountable difficulties with safe compliance of INR monitoring and dose adjustments i.e. significant difficulty in gaining venous access to take blood

Allergic to vitamin K antagonists

All patients considered for a NOAC must meet NICE criteria (page 3). Warfarin remains a suitable first choice anticoagulant for most patients especially in thosewith:

eGFR <30

Patients with a baseline eGFR of 30-40 are at risk of progressive/acute renal dysfunction and the potential risks of bleeding with dabigatran, rivaroxaban or apixaban should be weighed on an individual basis

Prescribers should also be alert to the risks associated with using the NOACs in the event of an acute decline in renal function due to an acute co-morbidity (e.g. dehydration, shock, initiation of nephrotoxic medicines such as NSAIDs, ACE inhibitors, aminoglycosides)

History of significant peptic ulcer disease

Significant ischaemic heart disease in absence of other determining considerations.

4.2 Existing patients currently taking vitamin K antagonists

Oral anticoagulation is indicated for patients with a CHADS2 or a CHA2DS2-VASc score ≥2. When CHADS2 score is 0 or 1, further assessment of risk with CHA2DS2-VASc is essential to ensure all high risk patients are identified.

Warfarin remains a suitable first-line oral anticoagulant for most patients. Patients who are well controlled and tolerant of warfarin are not recommended to change. The effectiveness of warfarin for the prevention of stroke in patients with AF is well established.

4.2.1 Conversion to NOAC will be recommended for patients:

Allergic to vitamin K antagonists

TTR < 60% after > 6 months (providing no evidence of non-compliance).

4.2.2 Conversion to NOAC may be considered for patients:

With history of stroke or TIA (not haemorrhagic) while taking warfarin (providing no evidence of non-compliance)

There are insurmountable difficulties with safe compliance of INR monitoring and dose adjustments.

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-8-All patients considered for a NOAC must meet NICE criteria (page 3).

Other patients who are well controlled and tolerant of warfarin are not recommended to change.

5. Pathway for initiation

5.1 Newly diagnosed non-valvular AF patients not already on an anticoagulant GP or other initiating clinician including secondary care clinician to;

Ensure no history of non-compliance with previous medication

Ensure criteria has been met and relevant blood tests have been carried out prior to initiation (appendix 3/4/5)

Ensure the patient has been counselled on the risks and benefits of the new oral anticoagulant and understands the importance of compliance

Ensure patient is clear when they will next need their renal function to be checked (see monitoring, page 10)

Ensure the patient has been given a patient alert card and this has been completed (appendix 10).

5.2 Patients currently taking vitamin K antagonists

GP or other initiating clinician to;

Ensure no history of non-compliance with medication

Ensure criteria has been met and relevant blood tests have been carried out prior to initiation (appendix 3/4/5)

Ensure the patient has been counselled on the risks and benefits of the new oral anticoagulant and understands the importance of compliance

Counsel patient on stopping vitamin K antagonist and starting the NOAC i) Stop vitamin K antagonist

ii) Wait 3 days

iii) Check INR before starting NOAC. Dabigatran, rivaroxaban and apixaban can be given as soon as INR <2

Ensure the patient has been given a patient alert card and this has been completed (appendix 10)

Send letter to anticoagulant clinic informing them that your patient has been switched to a NOAC, state reason for switch

If initiated by secondary care a letter must be sent to GP informing them of this and the reasons why a NOAC was chosen (appendix 12).

5.3 Where the GP would like to refer a patient into secondary care for initiation, the referral checklist needs to be completed and sent to the relevant department.

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-9-5.4 Dabigatran dose

Normal adult dose is 150mg twice a day.

Elderly (≥ 80 years) or receiving concomitant treatment with verapamil, 110mg twice a day.

For the following groups, the daily dose of dabigatran of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding:

o Patients between 75-80 years

o Patients with moderate renal impairment

o Patients with gastritis, esophagitis or gastroesophageal reflux

o Other patients at increased risk of bleeding.

No dose adjustment is necessary in patients with mild renal impairment (eGFR 50 - ≤ 80 ml/min). For patients with moderate renal impairment (eGFR 30-50 ml/min) the recommended dose of dabigatran is also 300 mg taken as one 150 mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of dabigatran to 220 mg taken as one 110 mg capsule twice daily should be considered. Dabigatran is contraindicated in patients with severe renal impairment (eGFR < 30 ml/min).

Dabigatran should be swallowed whole with water, with or without food.

A forgotten dabigatran dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.

5.5 Rivaroxaban dose

Normal adult dose is 20mg once daily.

In patients with moderate (eGFR 30 - 49 ml/min) or severe (eGFR 15 - 29 ml/min) renal impairment the recommended dose is 15mg once daily. Please note that locally we do not recommend rivaroxaban is used in patients with an eGFR of <30ml/min.

If a dose is missed the patient should take rivaroxaban immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

5.6 Apixaban dose

Normal adult dose is 5mg twice daily.

Patients with non-valvular AF and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 micromole/l), the recommended dose of apixaban is 2.5 mg taken orally twice daily.

Patients with exclusive criteria of severe renal impairment (eGFR 15-29 ml/min) should also receive the lower dose of apixaban 2.5 mg twice daily. Please note that locally we do not recommend apixaban is used in patients with an eGFR of <30ml/min.

Patients with serum creatinine ≥ 1.5 mg/dL (133 micromole/l) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lower dose of apixaban 2.5 mg twice daily.

Apixaban should be swallowed with water, with or without food.

If a dose is missed, the patient should take apixaban immediately and then continue with twice daily intake as before.

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-10-6. Monitoring

6.1 Recommended monitoring

It is essential to monitor renal function; if renal function declines exposure to dabigatran, rivaroxaban and apixaban will increase. There have been MHRA warnings on dabigatran relating to the risk of haemorrhage if renal function is not closely monitored.

For all patients prior to initiation, check;

o HASBLED, CHADS2 and/ or CHA2DS2-VASc, eGFR, U+Es, FBC’s, clotting screen and

LFTs

After initiation check renal function at 1, 3, and 6 months for all patients.

Then after 6 months;

If eGFR ≥60ml/min continue to check renal function every 6 months If eGFR 30-59ml/min continue to check renal function every 3 months

If patient is on dabigatran and eGFR drops below 30ml/min stop dabigatran, recheck HASBLED. If patient still requires anticoagulation seek advice from the anticoagulant clinic. If patient is on rivaroxaban and eGFR drops below 15ml/min stop rivaroxaban, recheck HASBLED. If patient still requires anticoagulation seek advice from the anticoagulant clinic. If patient is on apixaban and eGFR drops below 15ml/min stop apixaban, recheck HASBLED. If

patient still requires anticoagulation seek advice from the anticoagulant clinic. At least one annual clinical review

 check HAS-BLED (appendix 2)

 CHAD2 or CHA2DS2VaSc check patient still has a score of ≥2 (appendix 1)

 Check patient compliance

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-11-7. Patient Pathway

Appendix 1

Yes Yes

Warfarin is the preferred oral anticoagulant for the vast majority of patients. Is patient allergic to warfarin or are there insurmountable difficulties

to taking warfarin i.e. difficulties obtaining blood?

Patient is well controlled on warfarin?

Consider a NOAC Appendix 3/4/5 Consider warfarin 1st line Continue warfarin Consider conversion to NOAC. Appendix 3/4/5 No No

Anticoagulation indicated for patient with non-valvular AF

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-12-Calculation of CHADS2 or CHA2DS2-VASc score.

CHADS2

The acronym CHADS2 is derived from individual stroke risk factors. Adding together the points allocated to each risk factor yields the total CHADS2 score

Risk factor Score if present

C Congestive heart failure 1 H Hypertension (or treated hypertension) 1

A Age ≥ 75 years 1

D Diabetes mellitus 1

S Previous stroke or TIA 2

Score Risk Anticoagulation

Therapy

Considerations

0 Low Aspirin Aspirin daily

1 Moderate Aspirin

Warfarin

Aspirin daily or raise INR to 2-3 depending on factors such as patient preference

2 or more Moderate or high risk Warfarin Dabigatran Rivaroxaban Apixaban

Raise INR to 2.0-3.0, unless contraindicated (e.g. clinically significant GI bleeding, inability to obtain regular INR screening)

CHA2DS2-VASc

This scoring system is deemed to be better at refining stroke risk than the CHADS2 system. Many patients at low risk according to CHADS2 are not truly low risk and treatment guidelines are not conclusive for those at intermediate risk.

Risk factor Score if present

Congestive heart failure 1

Hypertension (or treated hypertension) 1

Age ≥ 75 years 2

Diabetes mellitus 1

Previous stroke, TIA or thromboembolism 2

Vascular disease (MI, PAD, aortic plaque) 1

Age 65-74 years 1

Female sex 1

According to latest ESC guidelines (update 2012, link below): Females with lone AF (without other risk factors) under the age of 65 are not at increased risk compared with men and are considered to score 0. http://www.escardio.org/guidelines-surveys/esc-

guidelines/GuidelinesDocuments/Guidelines_Focused_Update_Atrial_Fib_FT.pdf

Appendix 2

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-13-Calculation of HAS-BLED score

Source: European Society of Cardiology guidelines for the management of atrial fibrillation

Letter Clinical characteristic Points awarded

H Hypertension 1

A Abnormal renal and liver function (1 point each) 1 or 2

S Stroke 1

B Bleeding 1

L Labile INRs 1

E Elderly (e.g. age >65 years) 1 D Drugs or alcohol (1 point each) 1 or 2

Maximum 9 points Clinical characteristic Definition Hypertension Systolic BP >160mmHg Abnormal renal function

Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 micromol/l

Abnormal liver function

Chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin >2 x upper limit of normal, in association with aspartate aminotransferase/alanine

aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.) Bleeding Previous bleeding history and/or predisposition to bleeding, e.g.

bleeding diathesis, anaemia, etc.

Labile INR Unstable/high INRs or poor time in therapeutic range (e.g. 60%) Drugs or

alcohol (1 point each)

Concomitant use of drugs such as antiplatelet agents, NSAIDs or alcohol abuse

Maximum 9 points

A score of 3 or more indicates increased one year bleed risk on anticoagulation sufficient to justify caution or more regular review.

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-14-Dabigatran Checklist

Clinicians should check that patient meets the desired criteria i.e. answer is yes to all sections. Patient must meet NICE criteria and it is recommended that the local criteria is also met.

Yes No

NICE criteria (essential)

Patient has non-valvular AF

Patient has one or more risk factors

i) Previous stroke, transient ischaemic attack or systemic embolism ii) Left ventricular ejection fraction below 40%

iii) Symptomatic heart failure (NYHA Class 2 or above) iv) Age ≥ 75years

v) Age ≥65 years with one of the following:

Diabetes mellitus, coronary artery disease, hypertension

Other local criteria

1. Patient is considered for dabigatran because (one of the following should apply)

i) Patient is allergic to warfarin

ii) There are insurmountable difficulties with safe compliance of INR monitoring and dose adjustments

iii) History of stroke or TIA while taking warfarin (providing no evidence of non- compliance)

iv) TTR < 60% after > 6 months (providing no evidence non-compliance) 2. eGFR >30ml/min

Dabigatran is contraindicated if eGFR <30ml/min.

Caution is advised if eGFR <50ml/min. Dabigatran is principally renally excreted. 3. Patient is not taking any contraindicated medicines

Systemic ketoconazole, ciclosporin, itraconazole, tacrolimus, dronedarone, or any other anticoagulants

4. Patient has ability to comply with the twice daily medication dosing

5. Patient has no other contraindications to dabigatran

o Hypersensitivity to the active substance or to any of the excipients

o Active clinically significant bleeding

o Lesion or condition at significant risk of major bleeding such as, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

o Current or recent gastrointestinal ulceration

o Concomitant treatment with any other anticoagulant agent

o Hepatic impairment or liver disease expected to have any impact on survival

o Impaired haemostasis

o Prosthetic heart valves.

6. Baseline bloods satisfactory:

eGFR, U+Es, FBCs, clotting screen, LFTs

7. Explain purpose of anticoagulation to patient

8. Explain risks/benefits and side effects to patient

9. Give the patient a patient alert card, get patient to fill in (appendix 9)

10. Tell patient they will need to have a blood test in 1, 3 and 6 months time (eGFR)

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-15-Rivaroxaban Checklist

Clinicians should check that patient meets the desired criteria i.e answer is yes to all sections. Patient must meet NICE criteria and it is recommended that the local criteria is also met.

Yes No

i) Previous stroke or transient ischaemic attack ii) Congestive heart failure

iii) Hypertension iv) Age ≥ 75years v) Diabetes mellitus

1. Patient is considered for rivaroxaban because (one of the following should apply)

Rivaroxaban is contraindicated if eGFR <15ml/min however locally we are recommending not to use if eGFR<30ml/min

A lower dose of 15mg once daily should be prescribed if eGFR <50ml/min.

3. Patient is not taking any contraindicated medicines

Other anticoagulant e.g. unfractionated heparin (UFH), low molecular weight heparins, oral anticoagulants.

4. Patient has ability to comply with the once daily medication dosing

5. Patient has no other contraindications to rivaroxaban

o Clinically significant active bleeding

o Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

o Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C

o Pregnancy and breast feeding. 6. Baseline bloods satisfactory:

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-16-Appendix 5

Apixaban Checklist

Clinicians should check that patient meets the desired criteria i.e answer is yes to all sections. Patient must meet NICE criteria and it is recommended that the local criteria is also met.

Yes No

i) Prior stroke or transient ischaemic attack

ii) Age 75 years or older

iii) Hypertension

iv) Diabetes mellitus

v) Symptomatic heart failure.

1. Patient is considered for apixaban because (one of the following should apply)

Apixaban is not recommended if eGFR<15ml/min however locally we are recommending not to use if eGFR<30ml/min.

5. Patient has no other contraindications to apixaban

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 at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

Concomitant treatment with any other anticoagulant agent. 6. Baseline bloods satisfactory:

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-17-Patient frequently asked questions

Q: What is Atrial Fibrillation?

A: Atrial Fibrillation (known as AF) is a condition that affects the heart, causing it to beat irregularly. People with AF may be at an increased risk of blood clots because their heart does not pump blood round the body as efficiently as usual. This means they may be more likely to have a stroke, which can happen if a clot blocks an artery in the brain.

Q: What are dabigatran, rivaroxaban and apixaban and what are they used for?

A: These drugs are new types of oral anticoagulants. They are used to lower the risk of blood clots in people with atrial fibrillation and other factors for stroke. Dabigatran does this by interfering with a substance in the body (thrombin) that is involved in the development of blood clots. Rivaroxaban and apixaban help by stopping a substance called Factor Xa from working which aids in the binding together of a clot. These agents work by only stopping one blood clotting formation, warfarin works by interfering with a wide range of substances.

Q: Which of the new agents is better?

A: These new agents have not been directly compared with each other in a clinical trial therefore it is not possible to say if one is better than the other. They share some of the same advantages and disadvantages compared to warfarin, however because they work slightly differently, they also have some unique characteristics. These characteristics may help the doctor decide which drug is most appropriate.

Q: For patients with AF, is it worth changing from warfarin?

A: Warfarin has been prescribed for more than 50 years and therefore there is plenty of experience of its clinical use. Trials have shown that when warfarin is used well, it is probably as effective as any of the newer agents currently available and, if anticoagulant control is very good (as measured by blood tests), warfarin may be better overall.

Q: Do the new agents cause less bleeding than warfarin?

A: As dabigatran, rivaroxaban, apixaban and warfarin all affect blood clotting, patients may experience side effects such as bruising and bleeding. Rivaroxaban also caused more nose-bleeds and haematuria (blood in urine) than warfarin in a clinical trial. In clinical trials, dabigatran and rivaroxaban both caused less intracranial bleeding than warfarin. Gastrointestinal (stomach and bowel) bleeding is also a concern as it varies widely in terms of severity and is more common. Severe gastrointestinal bleeds occurred more often in the new agents that warfarin in clinical trials.

Q: If bleeding occurs with the new agents can it be reversed?

A: There is currently no antidote for dabigatran, rivaroxaban or apixaban. However, if urgent treatment is required the drugs will be discontinued and supportive measures will be started. It is more difficult to manage major bleeding in patients on a new agent.

Q: Are the new agents associated with any side effects?

A: All anticoagulants are associated with side effects. In the clinical trials, more patients stopped taking dabigatran and rivaroxaban than warfarin because of side effects. Dabigatran caused more gastrointestinal symptoms than warfarin (e.g. indigestion and stomach ache) and rivaroxaban caused more nose-bleeds and haematuria (blood in urine) than warfarin.

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-18-Rivaroxaban

If a dose is missed the patient should take rivaroxaban immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

Dabigatran

A forgotten dabigatran dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.

Apixaban

If a dose is missed, the patient should take apixaban immediately and then continue with twice daily intake as before.

It is very important that all anticoagulants (warfarin, dabigatran, rivaroxaban and apixaban) are taken exactly as they are prescribed by your doctor otherwise they will not be of benefit.

Q: Do the new agents interact with other medicines, food or alcohol?

A: Dabigatran, rivaroxaban and apixaban have fewer potential interactions with other medicines compared with warfarin, and at present there are no known interactions with specific foods or alcohol. There are some medicines that dabigatran, rivaroxaban and apixaban do interact with, so patients should inform their prescriber and pharmacist of the names of all medicines they are taking (including over the counter medicines), vitamins and herbal supplements such as St Johns Wort.

Q: Are regular blood tests needed to monitor the new agents?

A: There is no need for regular blood tests to measure dabigatran, rivaroxaban or apixaban. However, a regular blood test is needed to measure how well the kidneys are working before starting treatment with dabigatran, rivaroxaban and apixaban and at regular intervals after starting treatment. Your doctor will tell you when you will need to have a blood test next.

Q: Should patients stop taking dabigatran, rivaroxaban or apixaban if they are going to have a dental or medical procedure?

A: Patients should always tell their healthcare professional (doctor, dentist, nurse or pharmacist) that they are taking anticoagulants. Patients taking dabigatran, rivaroxaban or apixaban should be given a patient alert card which they can show to all relevant health professionals. Patients should NOT stop taking dabigatran, rivaroxaban or apixaban without first talking to their doctor or dentist. The new agents may need to be stopped before any planned surgery, dental or medical procedure – always check with your doctor for advice. Ask your doctor for a patient alert card if you do not have one.

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-19-Contraindications www.medicines.org.uk

Dabigatran

Hypersensitivity to the active substance or to any of the excipients

Patients with severe renal impairment CrCL < 30 ml/min (eGFR <30ml/min) Active clinically significant bleeding

Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

Concomitant treatment with any other anticoagulant agent e.g. *unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under the circumstances of switching therapy to or from dabigatran or when UFH is given at doses necessary to maintain an open central venous or arterial catheter

Hepatic impairment or liver disease expected to have any impact on survival

Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, tacrolimus and dronedarone

Prosthetic heart valves requiring anticoagulant treatment.

Rivaroxaban

Hypersensitivity to the active substance or to any of the excipients

Patients with severe renal impairment CrCL < 15ml/min (eGFR <15ml/min) Clinically significant active bleeding.

Concomitant treatment with any other anticoagulant agent*

Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C

Pregnancy and breast feeding.

Apixaban

(20)

Clinically significant active bleeding

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk

Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal

ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

Concomitant treatment with any other anticoagulant agent*.

Warfarin

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 Within 48 hours postpartum

Pregnancy (first and third trimesters )

Drugs where interactions may lead to a significantly increased risk of bleeding.

(21)

-21-Drug interactions for Dabigatran

The manufacturer of dabigatran (Pradaxa®) advises dabigatran:

is contra-indicated with: Any anticoagulant agent, e.g: Unfractionated heparin ◊

LMW H (e.g. enoxaparin, dalteparin) ◊ Heparin derivatives (e.g. fondaparinux) ◊

Oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban) ◊ Ciclosporin Ϯ

Dronedarone Ϯ◊ Itraconazole Ϯ◊

Systemic ketoconazole Ϯ_◊ Tacrolimus Ϯ◊

should be avoided with: Carbamazepine ◊ Phenytoin ◊ Rifampicin Ϯ◊ St John’s Wort ◊ should be used with caution with: Amiodarone Ϯ

Clarithromycin Verapamil Ϯ Quinidine is not recommended with: Posaconazole

Protease inhibitors increases the risk of bleeding with: Aspirin ◊

Clopidogrel ◊

NSAIDs Ϯ (BNF specifically advises to avoid ketorolac and intravenous diclofenac)

may increase the risk of bleeding with: Dextran

GPIIb/IIIa receptor antagonists ◊ Prasugrel ◊

SSRIs SNRIs Sulfinpyrazone Ϯ◊ Thrombolytic agents Ticagrelor ◊

Information compiled from the Summary of Product Characteristics: Pradaxa 150 mg hard capsules (Boehringer Ingelheim) DOR 08/2012

Ϯ BNF October 2012 advise potentially serious (‘black dot’) interaction – consult BNF for further information (accessed online 9/10/12 via MedicinesComplete.com)

◊ Stockley Interaction Alerts advise avoid – consult Stockley for further information (accessed online 9/10/12 via MedicinesComplete.com)

This list is not exhaustive always check the latest summary of product characteristics

www.medicines.org.uk

(22)

-22-The manufacturer of rivaroxaban (Xarelto®) advises rivaroxaban:

is contra-indicated with: Any anticoagulant agent, e.g: Unfractionated heparin ◊

LMW H (e.g. enoxaparin, dalteparin) ◊ Heparin derivatives (e.g. fondaparinux) ◊

Oral anticoagulants (e.g. warfarin, dabigatran, apixaban) ◊

should be avoided with: Dronedarone

should be used with caution with: Strong CYP3A4 inducers, e.g: Rifampicin

Phenytoin Carbamazepine Phenobarbital St John’s Wort

Potent inhibitors of CYP3A4 in patients with renal impairment, e.g: Clarithromycin

Telithromycin Erythromycin

NSAIDs (Ϯ BNF specifically advises to avoid ketorolac and intravenous diclofenac)

Aspirin

Platelet aggregation inhibitors Antithrombotic agents

Any other anticoagulant agent (Ϯ _{BNF specifically advises to avoid} dabigatran)

is not recommended with: Ketoconazole Ϯ_◊ Itraconazole ◊ Voriconazole ◊ Posaconazole ◊

HIV Protease inhibitors (e.g. ritonavir) ◊

Information compiled from the Summary of Product Characteristics: Xarelto 20mg film-coated tablets (Bayer) DOR 05/2012

Ϯ BNF October 2012 advise potentially serious (‘black dot’) interaction – consult BNF for further information (accessed online 9/10/12 via MedicinesComplete.com)

www.medicines.org.uk

(23)

-23-The manufacturer of apixaban (Eliquis®) advises apixaban:

is contra-indicated with: Any anticoagulant agent Ϯ e.g: Unfractionated heparin

LMW H (e.g. enoxaparin, dalteparin) Heparin derivatives (e.g. fondaparinux)

Oral anticoagulants (e.g. warfarin, dabigatran, rivaroxaban)

should be used with caution with: Aspirin

NSAIDS (Ϯ BNF specifically advises to avoid ketorolac and intravenous diclofenac)

Platelet aggregation inhibitors

Strong CYP3A4 and P-gp inducers e.g. Rifampicin,

Phenytoin, Carbamazepine, Phenobarbital St. John's Wort)

is not recommended with: Systemic treatment with strong inhibitors of both CYP3A4 and P-gp e.g. KetoconazoleϮ

Itraconazole Voriconazole Posaconazole

HIV protease inhibitors(e.g., ritonavir) Thrombolytic agents

GPIIb/IIIa receptor antagonists Thienopyridines (e.g., clopidogrel) Dipyridamole

Dextran Sulfinpyrazone

Information compiled from the Summary of Product Characteristics: Eliquis 2.5mg film-coated tablets (Bristol-Myers Squibb-Pfizer)

Appendix 9

Ϯ BNF March 2013 advise potentially serious (‘black dot’) interaction – consult BNF for further information (accessed online 09/04/13 via MedicinesComplete.com)

(24)

-24-Referral Checklist for referring a patient into secondary care for dabigatran

Patient name:

Patient NHS number:

Patient D.O.B:

Name and practice of referring GP:

Practice phone number:

Yes No

Patient has non-valvular AF Patient has one or more risk factors

i) Previous stroke, transient ischaemic attack or systemic embolism ii)Left ventricular ejection fraction below 40%

iii) Symptomatic heart failure (NYHA Class 2 or above) iv) Age ≥ 75years

v) Age ≥65 years with one of the following:

Diabetes, coronary artery disease, hypertension

Other criteria

1. Patient is considered for dabigatran because (one of the following should apply)

iii) History of stroke or TIA while taking warfarin (providing no evidence of non-compliance) iv) TTR < 60% after > 6 months (providing no evidence non-compliance)

2. eGFR >30ml/min

Dabigatran is contraindicated if eGFR <30.

Caution is advised if eGFR <50. Dabigatran is principally renally excreted. 3. Patient is not taking any contraindicated medicines

Systemic ketoconazole, ciclosporin, itraconazole, tacrolimus, dronedarone, or any other anticoagulants

5. Patient has no other contraindications to dabigatran

o Active clinically significant bleeding

o Lesion or condition at significant risk of major bleeding such as presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

o Current or recent gastrointestinal ulceration

o Hepatic impairment or liver disease expected to have any impact on survival

o Impaired haemostasis

o Prosthetic heart valves. 6. Baseline bloods satisfactory:

eGFR, U+Es, FBCs, LFTs, clotting screen

(25)

-25-Patient name:

Patient D.O.B:

Yes No

Patient has non-valvular AF

Patient has one or more risk factors

i) Previous stroke or transient ischaemic attack ii) Congestive heart failure

iii) Hypertension iv) Age ≥ 75years v) Diabetes mellitus

Other criteria

1. Patient is considered for rivaroxaban because (one of the following should apply)

iii) History of stroke or TIA while taking warfarin (providing no evidence of non-compliance) iv) TTR < 60% after > 6 months (providing no evidence non-compliance)

Rivaroxaban is contraindicated if eGFR <15 however locally we are recommending not to use if eGFR<30ml/min

Rivaroxaban should be used with caution if eGFR <50 and a lower dose of 15mg once daily should be prescribed.

4. Patient has ability to comply with the once daily medication dosing

5. Patient has no other contraindications to rivaroxaban

o Clinically significant active bleeding.

o Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

o Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C

o Pregnancy and breast feeding. 6. Baseline bloods satisfactory:

eGFR, U+Es, FBCs, LFTs, clotting screen

(26)

-26-Patient name:

Patient D.O.B:

Yes No

Patient has non-valvular AF

Patient has one or more risk factors

i) Prior stroke or transient ischaemic attack

ii) Age 75 years or older

iii) Hypertension

iv) Diabetes mellitus

v) Symptomatic heart failure.

1. Patient is considered for apixaban because (one of the following should apply)

iii) History of stroke or TIA while taking warfarin (providing no evidence of non- compliance) iv) TTR < 60% after > 6 months (providing no evidence non-compliance)

Apixaban is not recommended if eGFR<15ml/min however locally we are recommending not to use if eGFR<30ml/min

5. Patient has no other contraindications to apixaban

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 at significant risk of major bleeding such as current or recent

gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial

haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulant agent.

6. Baseline bloods satisfactory:

Appendix 10

Patient alert cards

(27)

-27-All patients started on a new oral anticoagulant should be given a patient alert card. This should be filled in when the patient is initiated on a new oral anticoagulant and should form part of the initial patient counselling.

These alert cards can be ordered free of charge from stores Tel 01473 329180

Email [email protected] Or can be printed from these websites:

http://www.pradaxa.co.uk/downloads/patient-alert-card.pdf

http://www.xarelto-info.co.uk/site-resources/pdfs/Patient_Alert_Card_15and20mg.pdf https://eliquis.co.uk/Images/5829_FINAL_Patient%20Alert%20Card_WEB_.pdf

Appendix 11

(28)

-28-http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON175429 http://www.clingov.eoe.nhs.uk/prescqipp/index.php/news/resources/view.download/82/502 http://www.medicines.org.uk/EMC/searchresults.aspx?term=dabigatran+etexilate+mesilate&search type=QuickSearch http://www.medicines.org.uk/EMC/searchresults.aspx?term=rivaroxaban&searchtype=QuickSearc h http://www.medicines.org.uk/emc/searchresults.aspx?term=apixaban&searchtype=QuickSearch http://www.nice.org.uk/

Appendix 12

(29)

-29-Dear Dr

Your patient has today been recommended to start dabigatran to prevent stroke associated with non-valvular atrial fibrillation.

Please can you prescribe this medication for your patient. If you have any queries please do not hesitate to phone me.

The decision to do so has been made on the basis of one or more of the following (please circle):

Insurmountable difficulties with safe compliance of INR monitoring and dose adjustments i.e. difficulty getting venous access

Patient allergic to warfarin

Previous poor control on warfarin

o Time in Treatment Range <60%

o h/o stroke or TIA on warfarin (providing no evidence of non compliance).

CHA2DS2-VASc HASBLED eGFR

Your patient should be prescribed (please circle):

Dabigatran 150mg bd

OR

Dabigatran 110mg bd (preferred because of identified high risk of bleeding)

Your patient

has been counselled on the risks, benefits and the safe use of dabigatran. The following monitoring is recommended* for patients on dabigatran

For all patients check renal function at 1, 3 and 6 months, then;

o If eGFR ≥60ml/min check renal function every 6 months

o If eGFR 30-59ml/min check renal function every 3 months. Annual review

o Check HAS-BLED, CHAD2 or CHA2DS2-VASc, patient compliance, eGFR, FBCs,

clotting and LFTs. *local recommendations

Letter to Primary Care following initiation of Rivaroxaban for Stroke Prevention in AF

(30)

-30-Your patient has today been recommended to start rivaroxaban to prevent stroke associated with non-valvular atrial fibrillation.

o Time in treatment range <60%

o H/o stroke or TIA on warfarin (providing no evidence of non-compliance).

Your patient should be prescribed (please circle): Rivaroxaban 20mg once daily

OR

Rivaroxaban 15mg once daily

Your patient:

Has been counselled on the risks, benefits and the safe use of rivaroxaban. The following monitoring is recommended* for patients on rivaroxaban

o Check HAS-BLED, CHAD2 or CHA2DS2-VASc, patient compliance, eGFR, FBCs, clotting

and LFTs.

*local recommendation

Letter to Primary Care following initiation of Apixaban for Stroke Prevention in AF

(31)

-31-Your patient has today been recommended to start apixaban to prevent stroke associated with non-valvular atrial fibrillation.

o Time in treatment range <60%

o H/o stroke or TIA on warfarin (providing no evidence of non-compliance).

Your patient should be prescribed (please circle): Apixaban 5mg twice daily

OR

Apixaban 2.5mg twice daily Your patient:

Has been counselled on the risks, benefits and the safe use of apixaban. The following monitoring is recommended* for patients on apixaban:

o Check HAS-BLED, CHAD2 or CHA2DS2-VASc, patient compliance, eGFR, FBCs, clotting

and LFTs.

Implementation of NICE TA 249, NICE TA 256 and NICE TA 275

-1-Implementation of NICE TA 249, NICE TA 256 and NICE TA 275

Dabigatran, rivaroxaban and apixaban for the prevention of stroke and systemic

embolism in non-valvular atrial fibrillation

Contents

-2-1. Summary

-3-2. What does NICE say?

-5-3 . Summary table for new oral anticoagulants for the prevention of stroke and systemic

embolism in non-valvular atrial fibrillation

-7-4. Selection of appropriate patients

5. Pathway for initiation

-10-6. Monitoring

-11-7. Patient Pathway

Appendix 1

Appendix 2

-16-Appendix 5

Appendix 9

Appendix 10

Appendix 11

Appendix 12