anticoagulate campaign clinicians toolkit - booklet single page

www.weahsn.net

Declaration; The Programme is funded through a joint working project between Bayer Healthcare and West

of England AHSN

This document was funded with an unrestricted educational grant from Boehringer-Ingelheim

V2.0: (06/02/15)

Clinical guidance

Preventing

AF related stroke

What is this toolkit for?

It is intended to support clinicians in making decisions about AF-related stroke prevention and anticoagulation for people with AF. It has been produced as part of the ‘Don’t Wait to Anticoagulate’ project.

Declaration; The Programme is funded through a joint working project between Bayer Healthcare and West of England AHSN

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Contents

Section One Clinical Overview: The Case for Change 1

Section Two AF-related Stroke Prevention: Guides to Clinical Practice 9 1. West of England AF–related stroke prevention guidance

2. Key factors influencing anticoagulant choice in Non-Valvular AF

3. Oral anticoagulants: Frequently Asked Questions

4. Identifying stroke & bleed risk

5. Managing & predicting bleeding & switching between anticoagulants

6. Anticoagulating the frail and elderly

7. Managing patients with a labile INR

8. Shared decision making with patients

9. Local formulary guidance

References 38


Section One:

Clinical Overview: The Case for Change

Foreword

Dr Jim Moore, Stoke Road Surgery, Gloucestershire, Cardiology GPwSI and Clinical Lead for AF Stroke Prevention

Atrial fibrillation (AF) is a major cause of stroke. The 2014 National Institute for Health and Clinical Excellence (NICE) publication, Atrial Fibrillation: The Management of Atrial Fibrillation, resulted in a welcome focus on the risks of stroke associated with AF. Thousands of strokes in the UK are avoidable with both the timely identification of patients with AF and the appropriate management of their thromboembolic risk with anticoagulation. The risk of stroke is five times greater in a patient with AF and the associated disability and mortality are also significantly increased when compared to strokes in patients with a normal cardiac rhythm.

It is no coincidence that the guidelines published both nationally and internationally in the last few years emphasise the importance of addressing stroke risk early in the assessment and management of patients with newly diagnosed AF. Those same guidelines have additionally stressed that Aspirin should no longer be seen as a safe and effective drug for stroke prevention in AF patients, and most importantly should not be considered as an alternative to anticoagulation.

In recent years we have seen the introduction of several new oral anticoagulants (NOACs) available with NICE approval for use in AF patients. NOACs have been shown in clinical trials to be “non inferior” to warfarin in their ability to reduce stroke, and in addition to warfarin, they provide increased anticoagulant choice and flexibility in the management of stroke risk.

Lastly and most importantly, progress in this area will best be achieved through a balanced and honest dialogue with patients about the risks of stroke and the potential benefits of treatment. The recent NICE guidance supports this, highlighting “the need for a personalised package of care and information” as a key recommendation.

1Declaration; The Programme is funded through a joint working project between Bayer Healthcare and West of England AHSN

Foreword

Jo Jerrome Deputy CEO AF Association

Atrial fibrillation (AF) is a common heart arrhythmia. The number of patients with AF is rising and we expect this to continue, with GRASP-AF data for England showing a prevalence rate of 1.8%. Symptoms of AF can include breathlessness, palpitations, dizziness and chest discomfort. However, the condition can also remain silent and asymptomatic.

Either way, AF is the single most powerful independent risk factor for stroke.

As well as being more deadly and disabling, AF-related strokes are also more expensive. Every AF-related stroke costs the NHS almost £12,000 pounds in the first year - putting a disproportionately high burden both on healthcare budgets and on those providing care, either formally or informally.

Early diagnosis and appropriate management with an anticoagulant can prevent at least two thirds of AF-related strokes suffered annually. Consequently there is urgent need for the improved diagnosis and management of AF to prevent thousands suffering avoidable strokes, disability and premature death.

In order to improve health outcomes for people with AF and to achieve significant financial savings in the NHS, it is imperative that more AF patients in need of anticoagulation are identified. The tools included within this package provide extensive and significant support to facilitate accurate assessment and appropriate management of AF for patients and clinicians. The Don’t Wait to Anticoagulate resources reflect national guideline recommendations in practical, manageable and supportive tools.

Life with AF can be long and healthy when patients are able to appropriately manage and control this potentially devastating and debilitating condition. The power to do so is in a well-informed partnership between patient and clinician. This toolkit provides the inspiration and know-how to initiate and make a real difference to the lives of AF patients and those close to them.


Introduction

Dr Matthew Fay, GPwSI in Cardiology, Westcliffe Medical Practice, Bradford, and member of the NICE Guideline Development Group

We often hear that there is an epidemic of AF coming with the ageing population. The truth is that it is already upon us. In the UK there are a million or more patients suffering from the dysrhythmia, and as a result, shouldering the risk of stroke. With the development of better risk assessment tools and alternative anticoagulants emerging since the 2006 NICE Clinical Guideline, it has become clear that further guidance is needed to ensure that patients receive the best and most appropriate treatment.

The CG180 shows a simplified assessment of stroke, working from the view that all patients require intervention to minimise their risk of AF-related stroke apart from the small minority without risk features; that the risk factors for bleeding complications should be identified and where possible minimised and that the patient should choose the intervention best suited to their personal situation.

With only 1 in 2 of those at risk protected against stroke, the guideline is a ‘call to arms’ for every clinician to support our patients with AF to prevent at least 7,000 strokes per year which are devastating the lives of patients and their carers.

The assessment of stroke risk should be undertaken using the CHA2DS2-VASc risk score. Calculations using this assessment tool use a greater number of risk factors than the more commonly used CHADS tool, giving additional emphasis to the importance of older age, female gender and pre-existing vascular disease as risk factors for stroke. CHA2DS2-VASc identifies those at truly low risk who do not require treatment for their stroke risk. Changing the paradigm for seeking those at risk of AF related stroke to an attitude of wishing to treat all but those at very low risk of AF stroke

In those at high risk of stroke and eligible for anticoagulation we should routinely assess their bleeding risk using the HAS-BLED risk calculator identifying those risk factors which we can address and modify thereby reducing the risks of anticoagulation. Rarely will the bleeding risk be such that anticoagulation is not offered to a patient at high risk of stroke.


A stroke physician’s perspective

Dr Louise Shaw, Consultant Physician MB, ChB, FRCP, Royal United Hospital, Bath

I have seen a dramatic increase in the prevalence of AF and its consequences on the Acute Stroke Unit at the RUH in the past five years. Firstly, the incidence of AF rises rapidly with age and our population is living longer than ever before. Secondly, a person is 5 times more likely to have a stroke if they are in AF than if they are in sinus rhythm. It is predicted that the prevalence of AF will double over the next 30 years, although already in 2014 I find that almost half of the patients on my stroke unit have AF as a cause of their stroke.

Having a stroke in itself is devastating; however strokes caused by AF tend to be more severe than strokes from other causes. AF stroke patients are:

• Twice as likely to die as a patient in sinus rhythm.

• More likely to become seriously disabled.

• More likely to end up bedridden and in a nursing home.

It is important to be aware that the risk posed by AF is the same whether the AF is asymptomatic, paroxysmal or persistent. Patients with CHA2DS2-VASc 1 or higher should be anticoagulated. The default position should be ‘Opt Out, not Opt In’. Aspirin is ineffective at preventing AF strokes and is not an acceptable substitute.

A lot of stroke deaths and disability can be prevented by simple stroke prevention at all opportunities in all health settings. The most important aspect is a manual pulse check. If there is an irregular pulse, an ECG is needed. If AF is confirmed, always consider anticoagulation. This simple check can have a profound impact.

Key messages for GPs

The case for change needs to be actioned by us all. Everyone who is involved in the AF pathway needs to “think anticoagulation” and ask “Why should we not anticoagulate this patient?” We therefore need to embed a culture in our practice where:

• We use every opportunity to look for AF.

• CHA2DS2-VASc 1 or more means that anticoagulation is necessary.

• Antiplatelets are no longer an acceptable or appropriate treatment for AF.


Summary of NICE Clinical Guideline 180 on the

management of AF

Dr Matthew Fay

CG180 Background

Atrial fibrillation (AF) is the most common sustained arrhythmia, with a prevalence of 1.7% in the general practice population and over 10% in the practice population >65 years of age.

It is associated with significant morbidity and mortality both as a result of symptoms caused by rhythm disturbance, and from increased stroke risk. Although some patients present with cardiovascular symptoms of palpitations, and breathlessness/dyspnoea, AF may often be asymptomatic. It is commonly associated with other cardiovascular risk factors such as hypertension, diabetes, structural heart issues, occlusive vascular disease, and advancing age (≥75 years).

CG180 Patient-centred care summary

Support for people with AF should be centred on their needs and personal choices. With rhythm management in AF failing to reduce mortality or stroke risk, the need to intervene is based purely on the patient’s dysrhythmia symptoms, which can vary greatly between individuals. The benefits and risks of anticoagulants should be outlined to the patient.

Clinician concerns regarding haemorrhagic risk are misaligned with patient concerns as to the risk of stroke, often making it difficult to support clinical decision making. For this reason, an updated Patient Decision Aid was produced by NICE at the same time as Clinical Guideline (CG) 180.4 After initial management, on-going review of the patient is needed to: assess symptoms associated with AF progression, the risk/benefit of intervention with anticoagulants, and the quality of anticoagulation if a vitamin K antagonist (VKA) is used to ensure time in therapeutic range.

CG 180 Stroke risk reduction summary

Stroke related to AF is largely avoidable with appropriate assessment and intervention. There has been a paradigm shift in the attitude to stroke risk assessment meaning that all but those with no risk factors should be considered for intervention. The CHA2DS2-VASc is recommended for assessment of risk in AF.

Anticoagulation should be offered to those with a score of 2 or above, taking bleeding risk into account, and should be considered for those with a score of 1 (except if they are aged <65 years and the point is due to gender alone). The HAS-BLED tool should be used to assess bleeding risk in patients starting anticoagulation, to demonstrate how bleeding risk can be reduced by risk factor modification.

The type of anticoagulant, VKA or non-VKA oral anticoagulant, should be agreed with the patient, taking into account their clinical circumstances and personal preferences.

Individuals with no risk factors (or only gender as a risk factor) do not require anti-thrombotic intervention. Antiplatelet monotherapy with aspirin should not be offered to patients with AF solely for stroke prevention. If an anticoagulant is contraindicated or not tolerated should a left atrial appendage occlusion be considered.

The risks and benefits should be discussed with the patient.

The first consideration for symptom management should be rate control except in situations where:

• AF has a reversible cause.

• AF is thought to have caused heart failure.

• The patient has new onset AF.


3

www.eGuidelines.co.uk

Stroke prevention of people with non-valvular AF

Assess stroke risk strati� cationusing CHA2DS2-VASc

Discuss risks and bene� ts of anticoagulation

Identify low risk patients i.e. CHA2DS2-VASc = 0 (men) or 1 (women)

Left atrial appendage occlusion

Annual review for all patients

Assess bleeding risk strati� cationusing HAS-BLED

No antithrombotic therapy

CHA2DS2-VASc ≥2O� er oral anticoagulant

CHA2DS2-VASc = 1 (in men)Consider oral anticoagulant

Discuss the options for anticoagulation with the person and base the choice on their clinical features and preferences

Non-VKA oral anticoagulant

Vitamin K antagonists (VKA)

Assess anticoagulation control

Non-VKA oral anticoagulant[See TA numbers 249, 256, 275]

People who choose not to have treatment

Low risk

AnticoagulationcontraindicatedPoor control

Non-VKA contraindicated or not tolerated

References1. NICE. Atrial fibrillation: the management of

atrial fibrillation. Clinical Guideline 180. NICE, 2014. Available at: www.nice.org.uk/guidance/CG180

2. Cowan C, Healicon R, Robson I et al. Heart 2013; 99 (16): 1166–1172.

3. National Clinical Guideline Centre. Atrial fibrillation: the management of atrial fibrillation. Clinical Guideline. 2014, NICE.

4. NICE. Atrial fibrillation: medicines to help reduce your risk of a stroke —what are the options? Patient decision aid. NICE, 2014. Available at: guidance.nice.org.uk/CG180/PatientDecisionAid/pdf/English

Algorithm reproduced with permission from: National Clinical Guideline Centre. Atrial Fibrillation. Clinical Guideline 180, Methods, evidence and recommendations. National Clinical Guideline Centre, 2014. Available at: www.nice.org.uk/guidance/cg180/resources/cg180-atrial-fibrillation-update-full-guideline3

Non-VKA oral anticoagulants are rivaroxaban, dabigatran, and apixaban

• Atrial flutter is diagnosed and the patient’s condition is suitable for ablation therapy.

• Clinical judgement suggests a rhythm control strategy could be more suitable.

If rate control with beta-blockers, diltiazem, or digoxin, individually or any two in combination, is unsuccessful in symptom management then a rhythm control strategy should be considered.

The guideline recommends that patients should be referred promptly (within 4 weeks) for specialised management if symptoms remain uncontrolled, despite treatment.

In patients with symptomatic paroxysms of AF we should initially consider pharmacological interventions; however, if this strategy fails to control the AF then ablation therapy should be considered.


Antiplatelet therapy – Does it still have a place in AF

Stroke prevention?

Dr Jim Moore

For too long the use of aspirin has been considered as a reasonable alternative to anticoagulation in protecting AF patients.

The evidence supporting the use of aspirin is unconvincing. A meta-analysis comparing the use of aspirin with placebo or no treatment in patients with AF showed a non-significant 19% reduction in the incidence of stroke in the aspirin treated group. This compares unfavourably with similar studies looking at dose adjusted warfarin that showed a highly significant 64% reduction in stroke incidence.

The risk reduction achieved by aspirin is very similar to that achieved when it is used as prophylaxis in patients with established vascular disease. Vascular disease is a common finding in patients with atrial fibrillation and the limited benefit of aspirin in this group of patients is likely to be due to its effect on vascular disease.

Guidelines for using aspirin

Recommendations in recent guidelines written both in the UK and abroad1 clearly state that aspirin monotherapy should not be used as thromboprophylaxis for patients with AF as the modest benefit derived from taking aspirin is offset by the risk of major bleeding or intracranial haemorrhage.

Dual antiplatelet therapy in the form of aspirin combined with clopidogrel may provide better protection against stroke but at the expense of increased bleeding. As a consequence some guidelines recommend that dual therapy should not be offered as thromboprophylaxis. Recent NICE guidance does suggest that this combination may be considered in exceptional circumstances for patients who are intolerant of all forms of anticoagulant therapy or where anticoagulants are contraindicated.

It is worth noting that the majority of patients unsuitable for anticoagulant therapy are so because they are at increased risk of major bleeding and, as dual antiplatelet therapy increases the risk of serious bleeding, it should not be considered in this group.

The use of aspirin with warfarin therapy in patients who have either chronic AF alone


1. NICE CG 180, Royal College of Physicians of Edinburgh UK Consensus Conference 2012; European Society of Cardiology Focussed update on management of AF 2012

or the combination of chronic AF and stable vascular disease does not further reduce the risk of arterial thromboembolism when compared to those on oral anticoagulant therapy alone. Antiplatelet drugs (aspirin or clopidogrel) may be used in the short term with anticoagulant therapy for AF patients with concomitant coronary artery disease (CAD) following ACS or PCI. Such combination therapy is associated with an increased risk of bleeding and it is therefore recommended that warfarin should be used alone in patients with AF and stable vascular disease.

Aspirin for elderly patients

Elderly patients are commonly denied anticoagulation and prescribed aspirin in preference to warfarin because of concerns over their risk of haemorrhage associated with falling. Research suggests that an anticoagulated patient would have to fall 295 times for the risks associated with falling to outweigh the benefits in stroke reduction.

Reassuringly, the Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA) also showed that AF patients aged ≥75 years had no significant difference in the risk of major bleeding (or intracranial bleeding) when those taking warfarin were compared to patients given aspirin.

In summary, NICE guidance recommends oral anticoagulants as first-line therapy for AF patients at increased stroke risk. Anticoagulation should be offered to people with a CHA2DS2VASc score of 2 or more, and considered for men with a CHA2DS2VASc score of 1, taking bleeding risk into account.

Aspirin monotherapy should not be offered solely for protection against stroke and should be used in combination with clopidogrel only in exceptional circumstances.


Overview of AF-related stroke prevention guides

The following guides are intended to assist clinicians in managing the anticoagulation of people with AF.

Guidance is designed to support primary care clinicians in the anticoagulation of AF patients.

The decision to initiate anticoagulation and by what therapy remains a clinical decision, and should be made following discussions with patients.

Working in tandem with the 2014 update to the NICE AF (CG180), this toolkit provides a wealth of resources to aid the decision making process for GPs and to promote shared decision making in AF thromboprophylaxis. It also aims to address myths surrounding the anticoagulation of patients through the presentation of the best available evidence including input from haematology.

Most importantly, this toolkit includes the West of England; Optimising Anticoagulation to Prevent AF-Related Stroke Protocol. This document should provide a platform when clinical consideration is being given to the decision to initiate a patient on anticoagulation.

In line with NICE updates, the toolkit also provides information on the use of antiplatelet monotherapy in AF thromboprophylaxis.

Contents

1. West of England AF–related stroke prevention guidance

2. Key factors influencing anticoagulant choice in Non-Valvular AF

3. Oral anticoagulants: Frequently Asked Questions

4. Identifying stroke & bleed risk

5. Managing & predicting bleeding & switching between anticoagulants

6. Anticoagulating the frail and elderly

7. Managing patients with a labile INR

8. Shared decision making with patients

9. Local formulary guidance

Section Two:

Af–Related Stroke Prevention:

Guides to Clinical Practice


AF-related stroke prevention guide 1:

West of England AF-related stroke

prevention guidance

West of England Anticoagulation for AF Related Stroke Prevention Guidance

All AF Patients with non-valvular (paroxysmal, persistent or permanent)

Assess stroke risk stratifi cation using CHA2DS2-VASc

Increased risk: CHA2DS2-VASc score= ≥2 (consider men ≥1)

Assess bleeding risk stratifi cation using HAS-BLED

NOTE: BENEFITS OF STROKE PREVENTION OUTWEIGH RISK OF BLEED AT ALMOST ANY HAS-BLED LEVEL (for guidance)

Discuss risks and benefi ts of anticoagulation

No anticoagulation at current point

Low risk or patient declines treatment (review as per review criteria)

No anticoagulation at current point

Unmodifi ably high bleed risk or patient declines treatment (review as per review criteria)

Discuss options for anticoagulation with patient and base choice on clinical features and preferences

Review criteria for anticoagulation for AF stroke prevention

a) All patients with a new diagnosis of AF

b) Patients with existing diagnosis of AF e.g identifi ed through audit

c) All AF patients when turning 65 and over

d) Patients with labile INRs (discount initial 6 weeks):

• 2 INR values > 5 or 1 INR value > 8 within past 6 months

• 2 INR values < 1.5 within less than 6 months

• TTR less than 65%.

e) Annually from decision to not anticoagulate

f) For all AF patients on development of:

• Diabetes

• Heart failure

• Peripheral arterial disease

• Coronary heart disease

• Stroke, transient ischaemic attack

• Systemic thromboembolism.

• Hypertension

ANTICOAGULATE

DABIGATRAN, RIVAROXABAN, APIXABAN

Consider for patients who:

• are not taking warfarin because of allergy or intolerance or where INR monitoring is impractical (access to Renal & LFTs monitoring necessary)

• have labile INR despite evidence of adherence or practical diffi culties with treatment

• have drug interactions with warfarin

• ask to start a NOAC

ASPIRIN IS NOT EFFECTIVE IN PREVENTING AF RELATED STROKE AND SHOULD NOT BE INITIATED IN AF PATIENTS IN PLACE OF ANTICOAGULATION

WARFARIN

Consider for patients who:

• when reviewed are currently well controlled on warfarin • are at risk of drug interactions with a NOAC• have CrCL (eGFR)< 30 ml/min

Note:

• consider bridging with heparin or LWMH for acute onset AF or for patients at a high risk of stroke

• consider self-monitoring where appropriate • calculate TTR at each patient contact • review warfarin use if Iabile INR

...don’t wait to

anticoagulate

Low risk: CHA2DS2-VASc score= 0 (men) or 1 (women)

&

V1: Draft Jan 2015




Key factors influencing anticoagulant choice in

Non-Valvular AF

Licensing

All novel OACS (NOACs) are licensed for prevention of stroke in non valvular AF plus at least one additional risk factor. Warfarin is licensed for use without additional risk factors present. http://www.medicines.org.uk/emc/

NICE Guidance and patient choice

The decision about whether to start treatment with any anticoagulant in AF should be made after an informed discussion between the clinician and the patient about the risks and benefits of individual agents.

Compliance

NOACs are not a safe option in patients who are not suitable for warfarin for reasons of poor compliance or in those deemed to have too high a risk of bleeding for warfarin. Patients prescribed NOACs should have an on-going review of treatment, preferably after one month and then on a 3-monthly basis1.

Risk of haemorrhage

NOACs have been demonstrated to have a lower risk of catastrophic intracerebral haemorrhage but some (Rivaroxaban and Dabigatran 150mg) have a slightly higher risk of gastrointestinal haemorrhage.

Reversal

The major concern with the new anticoagulants is the lack of an effective antidote. This is counterbalanced to some degree by the lower risk of severe haemorrhage reported within clinical trials when compared to warfarin. NOACs however have a relatively short half-life compared to

warfarin and protocols for managing bleeding events in NOAC treated patients are available.

Acute bleeding

In the event of acute bleeding patients receiving a NOAC may require surgical haemostasis, fluid replacement or blood products. These may also be appropriate for those receiving warfarin in addition to vitamin K. Suggested approaches to the management of bleeding complications are outlined in the EHRA practical guide on the use of NOACs1

Renal function

Dose reduction (or cessation) of the newer drugs is required with reduced renal function

Frequency of dosing

Dabigatran and Apixaban require twice daily dosing, compared to once daily for Rivaroxaban and warfarin.

Extremes of BMI

The relative dose of NOACs may vary by 20-30% at extremes of bodyweight (<50 kg or >100-120 kg). This may be problematic given the difficulties in monitoring the therapeutic effects.

Specific indications

E.g. need for elective cardioversion, plans for ablation etc. Where continuation of anticoagulation therapy, up to and during the procedure, would be considered advantageous, the use of a NOAC could be appropriate where patient compliance can be


reliably confirmed. Warfarin may however be preferred given the possibility of reversal in the case of major bleeding.

Monitored Dosage Systems

Neither warfarin nor Dabigatran is suitable for use in a compliance aid.

Comparative costs

Each of the newer drugs has a considerably higher acquisition cost than warfarin. When the cost of INR monitoring is taken into account, warfarin is likely to remain the least expensive option up-front. Comparative cost-effectiveness is not clear. If a NOAC is preferred and where all other factors are equal the NOAC with the lowest acquisition cost should be chosen

Time in therapeutic range

The newer drugs are likely to be more beneficial in patients whose INR is regularly outside the therapeutic range despite good medication adherence.

INR testing

INR testing with warfarin is time consuming, but provides an opportunity to monitor adherence and effectiveness.

Experience

Compared to warfarin, there is less clinician experience of long term use of the NOACs.

Identifying patients taking anticoagulants

Patients anticoagulated with either warfarin or newer agents should carry a card identifying their medication and who to contact in case of emergency related to their anticoagulation.

When might warfarin be the preferred option?

In patients with a history of GI problems warfarin may be the preferred option as it has a more favourable GI side effect profile, and was associated with a lower rate of GI haemorrhage compared with Rivaroxaban and Dabigatran (at the 150 mg twice daily dose). Compared with warfarin, Apixaban does not significantly alter the risk of major GI bleeding. Warfarin has the additional advantage of being reversible.

Patients on co-administered medication

Some co-administered medications may inhibit metabolism and potentiate bleeding risk with novel agents (e.g. azole anti fungals, ritonavir) are probably safer managed on warfarin as the INR may be adjusted accordingly. Patients will still need appropriate dose adjustment of warfarin on commencement or withdrawal of such therapy.

Active swapping from warfarin to novel agents

Where patients are established on warfarin with a stable INR there is little or no reason to actively swap over to novel agents. Inadequate control of INR may be a reason to consider a NOAC as are warfarin-specific side effects e.g. alopecia. There is a potential for inadequate anticoagulation during the transition between OACs.



Frequently Asked Questions

1. How do oral anticoagulants work?

Warfarin2 Dabigatran3 Rivaroxaban4 Apixaban5

Inhibits the production of vitamin K dependent clotting factors II, VII, IX and X

Acts as a direct thrombin (factor IIa) inhibitor. It is formulated as Dabigatran etexilate; a pro-drug converted to Dabigatran after administration.

Acts as a 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.

Inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban prevents thrombin generation and thrombus development. No direct effects on platelet aggregation, but indirectly inhibits aggregation induced by thrombin.


2. What are their main contraindications?

Warfarin Dabigatran Rivaroxaban Apixaban

Known hypersensitivity to warfarin or any 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

Hypersensitivity to the active substance or any excipients.

Severe renal impairment (CrCL < 30 mL/min)

Active clinically significant bleeding.

Any lesion or condition considered a significant risk factor for bleeding.

Concomitant treatment with any other anticoagulant

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

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

Prosthetic heart valves requiring anticoagulant treatment.




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

Pregnancy and breast feeding.

Prosthetic heart valves requiring anticoagulation treatment

Severe renal impairment (CrCL <15ml/min)

Dronaderone and other drug interactions



Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

Any lesion or condition considered a significant risk factor for bleeding.


Prosthetic heart valves requiring anticoagulation treatment

Severe renal impairment (CrCL <15ml/min)

Dronaderone and other drug interactions


3. Do the preparations contain wheat and lactose?

4. When should specific OACs be avoided?


Yes - Lactose

Yes - Maize starch (Marevan)

No - lactose

No - wheat

Yes- Lactose

No - wheat

Yes -Lactose

No - wheat

Warfarin Dabigatran, Rivaroxaban, Apixaban

Intolerance to warfarin including allergy and rash.

Demonstrated impossibility of monitoring arrangements

Warfarin is teratogenic and should not be given in the first trimester of pregnancy

AVOID in patients with a history of poor medication adherence (unless poor adherence relates to e.g. difficulty managing flexible warfarin dosage that may be addressed through a fixed dose regime)

The NOACs are not a suitable alternative to warfarin in patients with bleeding complications associated with warfarin treatment, contraindications to warfarin therapy due to a high bleeding risk, alcohol abuse, drug overdose or trivial side effects related to warfarin.

Dabigatran is not stable in compliance aids such as dosette boxes.

Manufacturers advise to avoid use in pregnancy.



Tests prior to starting treatment

Clotting screen, U& E’s, LFTs, FBC, BP, CrCl, Thyroid status

Ongoing monitoring requires adjustment to the individual needs of the patient and therefore requires regular monitoring using blood tests.


Clotting screen, U& E’s, LFTs, FBC, BP, CrCl

Monitoring until patient is stabilised

Ideally assess every 3 months to:

• Assess compliance and reinforce advice regarding regular dosing schedule.

• Enquire about adverse effects such as bleeding.

• Assess for the presence of thromboembolic events

• Enquire about other medicines, including OTC medicines.

Ongoing monitoring U& E’s, LFTs, FBC at least once a year especially in elderly and patients with renal impairment.


Clotting screen, U& E’s, LFTs, FBC, BP, CrCl


Ideally assess every 3 months to:




• Enquire about other medicines, including OTC medicines.

Ongoing Monitoring U& E’s, LFTs, FBC at least once a year.

Repeat U&E’s every


Clotting screen, U& E’s, LFTs, FBC, BP, CrCl, body weight


Ideally assess patient every 3 months to:




• Enquire about other medicines, including OTC medicines

Ongoing monitoring U& E’s, LFTs, FBC at least once a year.

Repeat U&E’s every 6 months if CrCl 30–60

Repeat U&E’s every 6 months if CrCl 30–60 mL/min, patient > 75 years or fragile.

Repeat U&E’s every 3 months if CrCl 15–30 mL/min.

More frequent U&E’s/LFTs advised where intercurrent illness may impact on renal or hepatic function.

6 months if CrCl 30–60 mL/min or every 3 months if CrCl 15– 30 mL/min.


mL/min or every 3 months if CrCl 15–30 mL/min.


5. What pre-testing and monitoring are necessary?


6. What doses should be given and what adjustments as necessary for renal impairment?

Dabigatran Rivaroxaban Apixaban

(CrCl above 50ml/min)

Patients under 80 years: 150 mg twice daily

Patients >80 years: 110 mg twice daily (due to the increased risk of bleeding in this population)

Reduce to 110 mg twice daily in patients who are taking verapamil

Consider 110 mg twice daily when the thromboembolic risk is low and the bleeding risk is high (e.g. CrCL 30-50 mL/min) or patients weigh <50kg.

20 mg once daily with food

5 mg twice daily

Reduce to 2.5 mg twice daily in patients with two or more of the following characteristics:

Age ≥80 years

Body weight ≤60kg

Serum creatinine

≥1.5mg/dL (133 micromoles/L)

CrCl 30-49ml/min

110-150mg twice daily Reduce dose to 15mg daily

Use normal dose

CrCl 15-29ml/min

Do not use Reduce dose to 15mg daily

Reduce dose to 2.5mg twice daily

CrCl < 15ml/min

Do not use Do not use Do not use

Warfarin

For patients who require rapid anticoagulation the usual adult induction dose of warfarin is 5–10 mg on the first day (elderly patients should receive a lower induction dose).

For patients who do not require rapid anticoagulation, a lower loading dose can be used over 3–4 weeks.

In both cases subsequent doses depend upon the prothrombin time, reported as INR (international normalised ratio).

Consider Apixaban in preference to warfarin with eGFR of 30–50 ml/min/1.73 m2.


7. How safe are oral anticoagulants?

Warfarin Dabigatran, Rivaroxaban, Apixaban

Long-term safety based on 50 years use in clinical practice

No information available on long-term safety.

Reduce dose in renal impairment (based on Cockcroft Gault calculation of CrCl)

8. What are the main drug interactions?

Warfarin Dabigatran Rivaroxaban, Apixaban

Drug-food interactions

Cranberry juice and alcohol interact with warfarin. Some foods interact with warfarin (e.g. foods containing high amounts of Vitamin K).

Drug-drug interactions

Many interactions requiring additional INR monitoring.


There are no known food interactions.


Contraindicated with the strong P-gp inhibitors ketoconazole, cyclosporine, itraconazole, tacrolimus and dronedarone.

Use with caution if co-administered with mild to moderate P-gp inhibitors such as amiodarone, quinidine, verapamil, & ticagrelor.

Co-administration with P-gp inducers such as rifampicin, St John’s Wort, carbamazepine or phenytoin) should be avoided.

SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups.


There are no known food interactions.


Not recommended with concomitant systemic administration of strong inhibitors of both CYP3A4 and P-gp, such as ketoconazole, itraconazole, voriconazole, posaconazole or HIV protease inhibitors.

Strong inducers of both CYP3A4 and P-gp (such as rifampicin, phenytoin, carbamazepine, phenobarbital or St John’s Wort) should be co-administered with caution because of the risk of a loss of effectiveness.

Concomitant administration with any other anticoagulants is contraindicated (some overlap may be necessary whilst transferring between anticoagulants).

Consult the SPC for full details of interactions.


9. What are the common side effects?


Nausea, vomiting, diarrhoea, jaundice, alopecia, rash, hepatic dysfunction, pyrexia

Dyspepsia more frequent with both doses of Dabigatran than warfarin. GI adverse events frequently led to drug discontinuation (7%, 6.5% and 3.9% in the Dabigatran 150 mg, 110 mg and warfarin groups respectively)4.

The rate of myocardial infarction (MI) was numerically, but not statistically significantly, higher with Dabigatran in the pivotal trial (0.82% for 110 mg and 0.81% for 150 mg vs. 0.64% p=0.12).7-9

A meta-analysis combining 7 studies showed Dabigatran was associated with a significantly higher risk of MI or ACS. The control group varied and included enoxaparin, warfarin and placebo.10

There were no significant differences in the incidence of any adverse event other than bleeding in the pivotal Rivaroxaban trial.11

The rate of MI was numerically, but not statistically significantly lower, in the Rivaroxaban arm compared with warfarin.

There were no significant differences between warfarin and Apixaban in the incidence of any adverse events in the pivotal Apixaban trial.12



Identifying stroke & bleed risk

CHA2DS2-VASc and HASBLED

Dr Dipankar Dutta, Consultant Physician, Gloucestershire Royal Hospital

Using CHA2DS2-VASc to assess stroke risk

The CHA2DS2-VASc stroke risk score should be used in people with paroxysmal, persistent, or permanent AF (regardless of symptoms), atrial flutter, and people with continuing risk of AF recurrence after cardioversion.

The GRASP-AF toolkit includes options to risk stratifies patients using CHA2DS2-VASc scores. The tool also highlights those who would benefit from review to assess their appropriateness for anticoagulation.

CHA2DS2-VASc HAS-BLED

Item Score Item Score

C Congestive heart failure 1 H Hypertension (uncontrolled BP) 1

H Hypertension 1 A Abnormal renal/ liver function 1 or 2

A2 Age≥ 75 years 2 S Stroke history 1

D Diabetes mellitus 1 BBleeding tendency or predisposition

1

S2Previous stroke, TIA or thromboembolism

2 L Labile INR 1

VVascular disease (MI, PVD, aortic plaque)

1 E Elderly (Age ≥ 65 years) 1

A Age 65 -75 years 1 DDrugs (concurrent aspirin or NSAIDs ) or alcohol

1 or 2

Sc Sex category (female gender) 1

Maximum total 9 Maximum total 9

Anticoagulation with warfarin or NOACs should be considered in men with a CHA2DS2-VASc score of 1. Men or women with a CHA2DS2-VASc score of 2 or above should definitely be offered anticoagulants.

Assessment of bleeding risk using HAS-BLED

Use of the score prompts users to identify bleeding risk factors which, in some instances, may be modifiable. It must be emphasised it is not primarily intended to deny people anticoagulants but to identify modifiable risk factors, such as hypertension, high alcohol intake, and the use of concurrent aspirin and NSAIDs, that could be addressed. In most instances, preventing strokes will take priority over avoidance of a bleed.



Managing & predicting bleeding &

switching between anticoagulants

When a patient is anticoagulated they can encounter bleeding either spontaneously or as a result of trauma. In primary care, your role is to reassure patients that regardless of the anticoagulant agent used; there are procedures to deal with bleeding effectively. Practices should consider the key actions to be taken for the management of anticoagulation associated bleeding in primary care, including the development of an emergency policy. The management of patients post-bleed should also be considered in planning the practice stroke prevention action plan.

For anticoagulated patients in primary care, the key to good management is to ensure that they are sent to an accident and emergency department immediately if they are actively bleeding or bleeding from a significant site e.g. the eye. This is a situation where calling an ambulance for the patient should be employed.

Once the patient is in hospital the level of bleeding will be assessed. This assessment will direct care for bleeding associated with both warfarin and novel oral anticoagulants (NOACs), as seen in table 1.

If a patient has a major bleed, they will be kept in hospital where their anticoagulation and drug therapies will be reviewed. All changes should be recorded in the discharge letter to the GP surgery. It is important that as the practice nurse managing a patient’s anticoagulation, you are aware of these events and changes, and arrange to review their care.

Management of bleeding associated with anticoagulation

The approach taken to the management of bleeding will depend on the type of anticoagulant used. It is therefore important to ensure that staff managing the bleeding are aware of the anticoagulant that has been prescribed.

Warfarin

Over anticoagulation and bleeding can occur as a result of non-compliance, drug interactions, liver failure, variations in diet, misuse of alcohol and underlying conditions e.g. gastric ulcer. Management is dependent on the international normalised ratio (INR) and the presence of active bleeding. Treatments include stopping warfarin for a short time, the use of the antidote Vitamin K and in more severe bleeding, the Prothrombin Complex Compound (PCC).


3

Warfarin

Over anticoagulation and bleeding can occur as a result of non-compliance, drug interactions, liver failure, variations in diet, misuse of alcohol and underlying conditions e.g. gastric ulcer.1,2 Management is dependent on the international normalised ratio (INR) and the presence of active bleeding. Treatments include stopping warfarin for a short time, the use of the antidote Vitamin K and in more severe bleeding, the Prothrombin Complex Compound (PCC).3

Table 1 below provides an example of the steps that are to be taken in the management of warfarin and the associated bleeding risks which require admission to secondary care. In primary care your role is to ensure that the patient is referred to secondary care in a timely manner, which we will be discussing further during this webinar.

Table 1: Management of warfarin associated bleeding (adapted from BCSH 2011)

Identify warfarin indication and therapeutic INR range, as well as the patient’s weightUrgent blood tests to be taken: full blood count, clotting screen, INR, urea and

electrolytes, liver function test

** Hemoglobin drop > 2.0g/l and/or bleeding in a critical site o Administer PCC as soon as available from laboratory o Re-check INR within 30-60 min after administration o Contact Haematologist if INR not reversed or ongoing bleeding is taking place

INR < 5.0No evidence of bleeding

Reduce warfarin dose

INR > 5.0 plus bleedingStart resuscitation measures

Monitor blood pressure and urine output

Life threatening bleeding **

And /or emergency surgery

As for moderate bleeding plus give Vitamin K 10mg IV

Contact Haematologist for PCC

Moderate bleeding **

Local first aid measures including surgery

Give Vitamin K 5-10mg IV

Contact Haematologist

Consider PCC

Mild or no bleeding

If other risk factors for bleeding reversal is required in 48 hours

Give Vitamin K orally 1-2mg

Restart warfarin when INR < 5.0 at reduced

dose

NOACs

Studies have shown that the bleeding profile of NOACs especially with regard to life-threatening bleeding, is more favourable than warfarin. However, as more people start taking NOACs the number of bleeds is expected to rise.


1. Does the risk of a bleed vary between OACs?


See respective agent for comparison

Major bleeding:

No difference between Dabigatran 150 mg BD and warfarin. Less common with Dabigatran 110 mg BD than warfarin

GI bleeding:

More common with Dabigatran 150 mg BD than warfarin (p=0.0008). No difference between Dabigatran 110 mg BD and warfarin.

Intracranial bleeding:

Less common with both doses of Dabigatran than with warfarin (p<0.001).

Bleeding risk high in the frail and elderly, particularly with renal impairment and low body weight.

Major bleeding:

No difference between Rivaroxaban and warfarin.

GI bleeding:

More common with Rivaroxaban than warfarin (p<0.001)


less common with Rivaroxaban than warfarin (p=0.02)

Major bleeding:

Less common with Apixaban than warfarin (p<0.001)

GI bleeding:

No difference between Apixaban and warfarin


Less common with Apixaban than warfarin (p<0.001)


2. Can bleeding be reversed?

3. What are the half-lives of the OACs?


Effective and well known antidote, should a severe bleed occur whilst being treated

No antidote currently known. Patients with bleeding risk factors excluded from pivotal trial.

Clearance can be increased with haemodialysis.

Prolonged bleeding has increased morbidity and possibly contributed to deaths13.

No antidote currently known although prothrombin complex concentrate has been successful in showing normalisation of laboratory clotting parameters (prothrombin time and endogenous thrombin potential) in a small preliminary trial.14

No antidote currently known


About 40 hours

GFR [mL/min] half-life (range) hours]

5 to 9 hours in young individuals,

11 to 13 hours in the elderly.

12 hours

≥ 80 13.4 (11.0-21.6)

≥ 50-< 80 15.3 (11.7-34.1)

≥ 30-< 50 18.4 (13.3-23.0)

< 30 27.2 (21.6-35.0)


4. How should the dose of OACs be adjusted when patients are having dental treatment or surgery?

Warfarin

OAC use with no clinically important bleeding risk

Dental procedures — outpatient dental surgery (including extractions) can usually be undertaken without temporarily stopping or reducing the dose of warfarin. It is recommended that the INR is checked 72 hours before dental surgery. The risk of significant bleeding in people with a stable INR within the range of 2 to 4 is very small, but the risk of thrombosis may be increased if oral anticoagulants are temporarily discontinued

Surgery — in general, warfarin is usually stopped 5 days before planned surgery, and once the person’s international normalised ratio (INR) is less than 1.5 surgery can go ahead. warfarin is usually resumed at the normal dose on the evening of surgery or the next day if haemostasis is adequate.

OAC use and undergoing surgery with a low bleeding risk

OAC use and undergoing surgery with a high bleeding risk

Restarting OACs after surgery

See local guidelines. Treatment should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician. Onset of action of NOACs is much faster than that of warfarin.


Dabigatran Rivaroxaban Apixaban

OAC use with no clinically important bleeding risk

The procedure can be performed just before the next dose of Dabigatran, Rivaroxaban or Apixaban is due, or approximately 18–24 hours after the last dose was taken (treatment should be restarted 6 hours later).

For dental procedures, consider prescribing tranexamic acid 5% mouth wash; instruct the person to use 10 mL as a mouth wash four times a day for 5 days.

OAC use and undergoing surgery with a low bleeding risk

Dabigatran should be stopped 24 hours before the procedure.

If the person has creatinine clearance 50–80 mL/min Dabigatran should be stopped 36 hours before the intervention.


Rivaroxaban should be stopped 24 hours before the procedure.

If the person has a creatinine clearance between 15–30 mL/min Rivaroxaban should be stopped 36 hours before the procedure.

Apixaban should be stopped 24 hours before the procedure.

If the person has a creatinine clearance between 15–30 mL/min, Apixaban should be stopped 36 hours before the procedure.

OAC use and undergoing surgery with a high bleeding risk

Dabigatran should be stopped 48 hours before the procedure.



Rivaroxaban should be stopped 48 hours before the procedure.

If the person has a creatinine clearance between 15–30 mL/min Rivaroxaban should be stopped 96 hours before the procedure.

Apixaban should be stopped 48 hours before the procedure.

If the person has a creatinine clearance between 15–30 mL/min Apixaban should be stopped 96 hours before the procedure.

Restarting OACs after surgery

See local guidelines. Treatment should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician. Onset of action of NOACs is much faster than that of warfarin.


Predicting Bleed Risk when managing anticoagulation for surgical procedures

No clinically important bleeding risk

• dental interventions such as; extraction of 1 to 3 teeth, periodontal surgery, incision of abscess and implant positioning, cataract or glaucoma interventions.

• endoscopy without surgery.

• minor surgery (e.g. abscess incision and small dermatologic excisions).

Examples of low bleeding risk (not exhaustive)

• endoscopy with biopsy.

• prostate or bladder biopsy.

• electrophysiological study or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation via single trans-septal puncture).

• angiography.

• pacemaker or implantable cardioverter defibrillator (icd) implantation (unless complex anatomical setting, e.g. congenital heart disease).

Examples of high bleeding risk (not exhaustive)

• complex left-sided ablation (pulmonary vein isolation; vt ablation).

• spinal or epidural anaesthesia.

• lumbar diagnostic puncture.

• thoracic surgery.

• abdominal surgery.

• major orthopaedic surgery.

• liver biopsy.

• transurethral prostate resection.

• kidney biopsy.


4

NOACs

Studies have shown that the bleeding profile of NOACs especially with regard to life-threatening bleeding, is more favourable than warfarin. However, as more people start taking NOACs the number of bleeds is expected to rise.4

Bleeding Direct thrombin(dabigatran)

Factor Xa inhibitors(rivaroxaban /apixaban )

Possible measures

*

*

Table 2: Possible measures to take in case of NOAC associated bleeding4linical

• Establish last dose and dosing regime

• Estimate normalisation of haemostasis, depending on renal function o Normal renal function 12-24 hours o CrCl 50-80 mL/min 24-36 hours o CrCl 30- 50 mL/min 36-48 hours o CrCl < 30mL/min ≥ 48 hours

• Maintain diuresis

• Local haemostasis measures

• Fluid replacement

• Red blood cell (RBC) substitution if necessary

• Plasma substitution if necessary

• Fresh frozen plasma as plasma expander (not reversal agent)

• Tranexamic acid can be considered as adjuvans

• Desmopressin can be considered in special cases

• Consider dialysis

• All of the above

• PCC 25U/kg

• Activated PCC – if PCC not available

• Activated Factor VII (rFVIIa 90 µg/kg) o no data about additional benefit and it is expensive

Non life- threatening bleeding

Life- threatening bleeding

• Establish last dose and dosing regime

• Normalisation of haemostasis 12-24 hours

• Maintain diuresis

• Local haemostasis measures

• Fluid replacement

• Red blood cell (RBC) substitution if necessary

• Plasma substitution if necessary

• Fresh frozen plasma as plasma expander (not reversal agent)

• Tranexamic acid can be considered as adjuvans

• Desmopressin can be considered in special cases

• All of the above

• PCC 25U/kg

• Activated PCC – if PCC not available

• Activated Factor VII (rFVIIa 90 µg/kg) o no data about additional benefit and it is expensive


Table 2 shows that there are slightly different measures to administer depending on which NOAC has been taken. In addition, as NOACs have a relatively short elimination half life, it is important to note that time is an important antidote. This means that it is very important that you discover when a patient took their last anticoagulation dose and send this information to the hospital as soon as possible.

The hospital will also need details of which drug they are using, their medical history, specifically history of liver or kidney disease and any other factors that influence haemostasis, such as antiplatelet therapy. As with warfarin, appropriate transfer to A&E is extremely important.

5. Switching between anticoagulants

It is important to safeguard the continuation of anticoagulant therapy whilst minimising the risk of bleeding when switching between different anticoagulant therapies.



How do you switch between anticoagulants?

There is a potential for inadequate anticoagulation during the transition between NOACs and Warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternative anticoagulants

When converting patients from warfarin therapy to a NOAC, discontinue warfarin and start:

• Dabigatran when the INR is below 2.0

• Rivaroxaban when INR is below 3.0

• Apixaban when INR is below 2.0

INR values will be falsely elevated after the intake of Rivaroxaban.

When converting from Dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:

For CrCl>50mL/min, start warfarin 3 days before discontinuing Dabigatran.

For CrCl 31-50mL/min, start warfarin 2 days before discontinuing Dabigatran.

For CrCl 15-30mL/min, start warfarin 1 day before discontinuing Dabigatran

When converting from Rivaroxaban to warfarin, Rivaroxaban should be continued until the INR is ≥ 2.0.

For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by warfarin dosing guided by INR testing.

While patients are on both Rivaroxaban and warfarin, the INR should

When converting from Apixaban to warfarin, continue Apixaban for at least 2 days after starting warfarin therapy.

After 2 days of co-administration of Apixaban and warfarin, obtain an INR prior to the next scheduled dose of Apixaban.

Continue co-administration of Apixaban and warfarin until the INR is 2 or more

For CrCl<15mL/min, no recommendations can be made – consult with haematologist.

Because Dabigatran can contribute to an elevated INR, the INR will better reflect warfarin’s effect after Dabigatran has been stopped for at least 2 days.

not be tested earlier than 24 hours after the previous dose but prior to the next dose of Rivaroxaban. Once Rivaroxaban is discontinued INR testing may be done reliably at least 24 hours after the last dose



Converting from parenteral anticoagulants

The exact regimen depends on individual circumstances. Parenteral anticoagulants are generally continued until the INR is in the desired range.

Discontinue the parenteral anticoagulant and start Dabigatran 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment.

For patients currently receiving a parenteral anticoagulant, Rivaroxaban should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).

Switching treatment from parenteral anticoagulants Apixaban (and vice versa) can be done at the next scheduled dose. These agents should not be administered simultaneously.


AF-related stroke prevention guide 6: Anticoagulating

Anticoagulating the frail and elderly

Dr Gopinath Ramadurai, Stroke Physician, Dr Sameer Maini, Consultant Physician and Geriatrician, Great Western Hospital, Swindon

Atrial fibrillation (AF) is the most common sustained arrhythmia which tends to increase in incidence with age. AF has a prevalence of around 7% in persons aged 65 or over and increases to over 12% in those aged 75 or over. AF is an independent risk factor for stroke, causes more severe strokes, and can account for up to 25% of strokes in patients aged 80-89.

Anti-coagulation with warfarin or one of the novel anti-coagulant agents (NOACs) is now the mainstay in prevention of stroke in the population with AF especially the frail elderly (NICE guidelines, CG180, June 2014). But the fear of increased risk of bleeding added to the risk of falls has led physicians to be cautious in using anti-coagulants in this group of patients. Widespread poly-pharmacy and non-compliance with monitoring has also added to the underuse of anti-coagulation in this population with the highest stroke risk.

Anti-coagulation and falls risk – Addressing the myths

Elderly patients are at increased risk of falls. Studies point out that approximately one-third of patients over the age of 65 years fall every year. Many physician surveys have pointed out falls as the main deterrent to the use of warfarin. A meta-analysis which studied the risk of anti-thrombotic use in elderly at high falls risk concluded that the propensity for falling alone should not be used as an important factor when deciding whether the patient should be a candidate for anti-coagulation. Studies have also shown that an elderly patient on warfarin should have approximately 300 falls per year or at least one fall per day for the risks of warfarin to outweigh its benefits. The most common bleeding risk score (HAS-BLED) does not include falls when calculating the bleeding

risk. If a falls risk is identified, then the priority should be to take measures that minimise this risk, which include environmental modification, medication review and treating the underlying medical cause of falls instead of withholding anticoagulation.

Novel anti-coagulants in anti-coagulating the elderly

Novel anticoagulants (Dabigatran, Rivaroxaban, Apixaban) provide a very good alternative to warfarin especially in patients where a tight control is difficult and medicine compliance is difficult. Also the newer agents have shown good ischemic stroke reduction that is non-inferior to warfarin without an increase in hemorrhagic strokes. The novel agents also come with the convenience of fixed daily dosing without the need for monitoring and less susceptibility to drug or food interactions.

Anti-coagulation in the frail elderly can provide a considerable challenge as this is the population at the highest risk of stroke but also perceived to be at high risk of complications due to anti-coagulation.

Available evidence suggests that these risks are overemphasized, especially falls and the risk of falling alone should not be used as a reason to withhold anti-coagulation. Recognising patients at risk of falling should be used as a trigger to identify risk factors for falls and subsequently managing them to minimise this risk. The use of NOACs could reduce complications in carefully selected patients. Finally, involving the patient in this decision making process about the risks and benefits of anti-coagulation could minimise the complication rates and improve compliance.



Managing patients with a labile INR

Sue Rhodes, VTE Specialist Nurse and Joint Anti-Coagulant Lead, Great Western Hospital

The time in therapeutic range (TTR) is one indicator of poor compliance. However, when making a decision as to whether this can be used to assess for suitability for a NOAC other factors need to be taken into consideration.

Measuring INR

To measure the effectiveness of warfarin patients need to have regular INR blood tests. The INR is a standardised test to measure the clotting ability of the blood. People not taking warfarin will have a normal INR of approximately 1.0. Once a patient is given warfarin the INR will be raised. The level that it should be raised to will depend on the condition being treated. In AF the target INR should be 2.5. However it is acceptable for the INR to be within the range of 2.0 and 3.0. Blood needs to be taken to get the INR result, either using a citrated tube or a finger prick test - the venous citrated tube sample is the most accurate test. A full tube is required and it needs to be analysed in a laboratory.

Near patient testing with a finger prick test is potentially more convenient for the patient however the same rigorous standards as for venous samples must be applied. All equipment must be regularly quality controlled and meet stringent NEQAS (National External Quality Assessment Service) standards. Further information about NEQAS services can be obtained www.ukneqasbc.org

Poor control

A patient’s most appropriate range will be decided by their clinician and on-going monitoring will ensure they are effectively anticoagulated. Poor control, as defined by the NICE 2014 AF Guideline, is any of the following:

• Two INR values higher than 5 or one INR value higher than 8 within the past six months

• Two INR values less than 1.5 within the past six months

• TTR less than 65%

If control cannot be improved a patient’s stroke prevention strategy will need to be re-evaluated, and other treatment options considered.

Initiating warfarin

There are several initiation protocols that are used to commence warfarin. A baseline INR should be performed, as well as renal and liver function tests if applicable.

It is important that whilst a patient is being ‘loaded’ onto warfarin their INR is regularly checked. AF patients can be frail so commencing warfarin should be done carefully. It is clear that whilst the patient is insufficiently anticoagulated they are at risk of clotting and an AF-related stroke. It is not therefore acceptable for this process to be extended as necessary. For AF patients with acute onset AF or at a high risk of stroke consider bridging with heparin or LWMH.

All patients will need to be counselled about their condition, the need for anticoagulation and the safe use of warfarin.


In calculating the TTR

• Use a validated method of measurement such as the Rosendaal method for computer assisted dosing or proportion of tests in range for manual dosing

• Exclude measurements taken in the first 6 weeks of treatment

• Calculate TTR over a maintenance period of at least 6 months

• Exclude any period of deliberately omitted anticoagulation (e.g. surgical procedure)

• If the TTR is >65% this is an acceptable level of anticoagulant control

• A TTR of < 65% indicates that the patient requires review of medication and consideration of additional factors which may contribute to poor control, such as:

- Cognitive function

- Adherence to prescribed therapy

- Illness

- Interacting drug therapy, including herbal or over the counter preparations

- Lifestyle factors including diet and alcohol

If poor anticoagulant control cannot be improved by adjusting any of these factors alternative drug therapy with one of the NOACs needs to be discussed with the patient.

Patients with diminished cognitive function

Patients who experience difficulty with taking variable doses of warfarin and find it difficult to cope with constantly changing doses may be suitable for one of the NOACs as this would give a fixed dose on a once or twice daily regime giving a constant level of anticoagulation.

A NOAC may also be more suitable for patients already utilising a dosette tray for medicine administration.

Adherence to prescribed therapy

Where patients appear to be genuinely non-compliant with medicines then a NOAC may not be more suitable than warfarin due to their short half-life and therefore increased risk of stroke if a dose is omitted.

However, if the non-adherence is related to the difficulty in attending for regular blood tests then a NOAC may be suitable.

Illness

An illness may have temporarily caused warfarin therapy to become unstable and in this case a NOAC may not be more suitable. Any longer term illness requires options for anticoagulation therapy to be reviewed and a NOAC may be more suitable than warfarin. It would be advisable to seek specialist advice.


Interacting drug therapy

Many drugs interact with warfarin. If a known interacting drug is prescribed resulting in labile INRs, this may not necessarily be an indication to prescribe a NOAC.

Ensure adequate INR monitoring is always actioned whenever an interacting drug is prescribed concurrently with warfarin as this will reduce fluctuations in INRs.

If frequent prescriptions of interacting drugs are necessary such as regular antibiotics then a NOAC may be more suitable.

Many drugs interact with warfarin. If a known interacting drug is prescribed resulting in labile INRs, this may not necessarily be an indication to prescribe a NOAC.

Ensure adequate INR monitoring is always actioned whenever an interacting drug is prescribed concurrently with warfarin as this will reduce fluctuations in INRs.

If frequent prescriptions of interacting drugs are necessary such as regular antibiotics then a NOAC may be more suitable.

Lifestyle factors

Diet and alcohol can have significant interactions with warfarin therapy resulting in labile INRs. Patients should be educated regarding the impact of dietary changes when taking warfarin and if despite adhering to recommendations they are still experiencing labile INRs then a NOAC may be more suitable.

Excessive, fluctuating alcohol intake will adversely affect INR stability. For patients with a low risk of bleeding (utilising the HAS-BLED scoring system) then a NOAC may be more suitable.

For patients with a high risk of bleeding specialist advice should be sought as with a current lack of a reversal agent a NOAC may not be suitable.



Shared Decision Making with Patients

Shared Decision Making is defined by The Health Foundation as:

“a collaborative process through which a health care professional supports a patient to reach a decision about a specific course of action, such as deciding on a strategy to manage pain from knee arthritis.”

The NHS is increasingly focused on partnership, respect and helping people take control and responsibility for their own health. Shared decision making brings together clinical expertise. In the case of AF this involves an assessment of risk and benefit regarding anticoagulation alongside the patient as an expert in their own lifestyle, preferences, ideals etc. A shared decision making approach is particularly useful when utilized in decisions that carry significant potential risks and benefits. In the case of facilitating decision making around anticoagulation, shared decision making is essential to promoting good person centred care as called for by NICE CG180.

Key Guidelines on shared decision making

1. NICE – CG180 guidance on shared decision making

(1.2) Personalised package of care and information

1.2.1 Offer people with AF a personalised package of care. Ensure that the package of care is documented and delivered, and that it covers:

• stroke awareness and measures to prevent stroke

• rate control

• assessment of symptoms for rhythm control

• who to contact for advice if needed

• psychological support if needed

• up-to-date and comprehensive education and information on:

• cause, effects and possible complications of atrial fibrillation

• management of rate and rhythm control

• anticoagulation

• practical advice on anticoagulation in line with recommendation 1.3.1 in

• ‘Venous thromboembolic diseases’ (NICE clinical guideline 144)

• support networks (for example, cardiovascular charities). [new 2014]

2. User guide: Don’t wait to anticoagulate patient toolkit:

Following extensive patient involvement and clinical consultation, the Don’t Wait to Anticoagulate patient toolkit has been developed based on the NICE patient decision aid. It is designed to assist clinicians in explaining and demonstrating stroke prevention and bleed risk through personalised risk sheets.

The patient toolkit covers:

• What is AF?

• Update on aspirin

• Risk of major internal bleeding

• Treatment options to reduce risk of stroke in AF

• Frequently Asked Questions


The pack contains a shared decision making support tool which can be pre populated with CHADSVASC and HAS-BLED scores as well as suitable OAC options and can be sent out with letters calling patients into the practice for AF review. There is also a shorter guide to OAC and AF that can accompany the shared decision making support tool and the risk and benefit sheets. The tool also includes a list of questions that patients may wish to ask clinicians about during the planned review.

The toolkits are also designed to be worked through in consultation alongside clinicians. As an innovator practice you can test the toolkit with patients and make changes to the process or materials as necessary, but this should be captured in a PDSA cycle approach. How the toolkits are used and shared with patients is a decision to be made within innovator practices, as the utilisation of them is a live experiment to find the most effective way to promote shared decision making amongst clinicians and patients.

For practices that use System One, it is possible to download the materials from within the system. The WEAHSN QIT can assist with this. Work is currently being undertaken to trial this within.

3. CARE AF – Supported by Bayer and in collaboration with AFA

We recommend the CARE AF: Protecting you from AF-Related Stroke Pack to accompany the decision aid if required, this was produced following an update of the NICE guidelines for AF (June 2014).

The CARE AF pack was produced following an update of the NICE guidelines for AF (June 2014) and contains:

1. What is AF, causes and symptoms?

2. How AF is a stroke risk.

3. Practical advice on effective management and different treatment options.

4. Patient stories and how they live with the condition.

5. Healthy living – tips for good health including nutritional advice, exercise tips and managing stress.

6. Additional information and frequently asked questions.

Supplies of the CARE AF pack can be obtained via the WEAHSN QIT.

Resources to support shared decision making:

There are a range of resources designed to support shared decision making and patient centred care. The following resources and links were accurate at the time of print (November 2011):

• Patient support programme for people with AF - www.careaf.org

• Further information on Shared Decision Making: www.personcentredcare.health.org.uk/person-centred-care/shared-decision-making/

• Shared Decision Making guide by NHS: http://sdm.rightcare.nhs.uk/about/shared-decision-making/

• XIMPACT NURSE: Anticoagulation in Atrial Fibrillation (AF) webinar series, Bayer HealthCare, 2014.

• NHS, Shared Decision Making Programme, Measuring shared decision making: A review of research evidence, London, 2012.

• Coulter. A, Collins. A, Making Shared Decision making a reality: No decision about me, without me, London, The King’s Fund, 2011.

• Summit report: Leading the way to shared decision making, The Health Foundation, 2012.

• De Silva.D, Evidence: Helping people share decision making, The Health Foundation, 2012.



Local formulary guidance summaries

Bristol, North Somerset and South Gloucestershire (BNSSG):

NHS Bristol CCG, NHS North Somerset CCG, NHS South Gloucestershire CCG, North Bristol NHS Trust, University Hospitals Bristol NHS Foundation Trust and Weston Area Health NHS Trust.

Local Formulary Guidelines:

The Bristol, North Somerset and South Gloucestershire (BNSSG) Joint Formulary http://www.bnssgformulary.nhs.uk/28-Anticoagulants-and-protamine

Decision Aid: Guidance on the use of Apixaban, Dabigatran, Rivaroxaban

http://www.bnssgformulary.nhs.uk/includes/documents/BNSSG%20NOAC%20Decision%20guideV3%20APRIL%2013final%20.pdf

Swindon and North Wiltshire:

Great Western Hospitals NHS Foundation Trust

Local Formulary Guidelines: 3T’s Drug Formulary

http://www.gwh.nhs.uk/patients-and-visitors/pharmacy/3ts-drugs-formulary/guidelines/

AF - Oral Anticoagulant Decision Aid: http://www.gwh.nhs.uk/media/150917/new_decision_aid_oct_2013_v5.pdf

Gloucestershire:

Gloucestershire Joint Formulary

Local Formulary Guidelines: Gloucestershire Joint Formulary

http://www.formulary.glos.nhs.uk/en/Content-Page/Chapter-2---Cardiovascular/#2.8

Prescribing Guideline: http://www.formulary.glos.nhs.uk/PageFiles/199/Glos%20NOAC%20for%20NVAF%20guidance.pdf

Bath and North East Somerset (BANES):

NHS BANES CCG, NHS Wiltshire CCG, Royal United Hospital Bath NHS Trust, Avon and Wiltshire Mental Health Partnership NHS Trust, Royal National Hospital for Rheumatic Diseases NHS Foundation Trust

Local Formulary Guidelines: BCAP Formulary

http://www.bcapformulary.nhs.uk/282-oral-anticoagulants

Decision aid: Written by Wiltshire CCG

http://www.bcapformulary.nhs.uk/includes/documents/Updated-decision-aid-for-NOACs-in-AF-October-2014.pdf

Please note this information was correct at going to print November 2014. The following local guidance is relevant only to the CCG it serves. If your local formulary is not here please contact local Medicines Management for further information.


References

1. Heidbuchel H et al. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J Apr 2013. www.NOACforAF.eu,

2. Amdipharm Mercury Company Limited. Summary of Product Characteristics - Marevan 5 mg tablets. Date of revision of the text: 18/09/2012.

3. Boehringer Ingelheim. Summary of Product Characteristics - Pradaxa 150 mg hard capsules. Date of revision of the text: 07/2013.

4. Bayer plc. Summary of Product Characteristics - Xarelto 20 mg film-coated tablets. Date of revision of the text: June 2013.

5. Bristol-Myers Squibb-Pfizer. Summary of Product Characteristics - Eliquis 5 mg film-coated tablets. Date of revision of the text:12 February 2013.

6. Personal communication, Dr Jane Skinner Consultant Community Cardiologist, Newcastle upon Tyne Hospitals. Sept 2013.

7. Connolly SJ et al. Dabigatran versus warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-51.

8. Connolly S et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875-6.

9. Hohnloser SH. Myocardial ischaemic events in patients with atrial fibrillation treated with Dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-term anticoagulation therapy) Trial. Circulation 2012;125:669-76.

10. Uchino K et al. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med 2012;172:397-402.

11. Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2010;365:883-91.

12. Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.

13. Harper P. Bleeding risk with Dabigatran in the frail elderly. N Engl J Med 2012;366:864-6.

14. Eerenberg ES et al. Reversal of Rivaroxaban and Dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9.

Additional Key References

A. Suggestions for Drug Monitoring in Adults in Primary Care 2014 http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20monitoring%20document%20Feb%202014.pdf

Clinical Knowledge Summaries http://cks.nice.org.uk/anticoagulation-oral

British National Formulary https://www.evidence.nhs.uk/formulary/bnf/current

Desai J et al Thromobosis and Haemostasis 2013 https://www5.medicine.wisc.edu/~williams/NOAC_GI_bleeding_2013.pdf

NICE Guidance CKD 2014. https://www.nice.org.uk/guidance/cg182/chapter/1-recommendations


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National Institute for Health and Care Excellence (2014 Adapted from CG 180 Atrial fibrillation: the management of atrial fibrillation. Manchester: NICE. Available from www.nice.org.uk/CG180 Reproduced with permission

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