Managing anticoagulation in atrial fibrillation

Dr Katy Rice

June 2011

Atrial fibrillation

• Commonest chronic arrhythmia

• Increasing prevalence - ageing population-improved survival from CHD

• Morbidity/mortality from stroke, heart failure

• Stroke risk reduced by warfarin

Themes of talk

1. AF - the burden of disease

2. Recognition of those at risk of stroke

3. Warfarin - current standard of care

4. Anticoagulant service provision

5. New oral anticoagulants

Themes of talk

1. AF - the burden of disease

2. Recognition of those at risk of stroke

3. Warfarin - current standard of care

4. Anticoagulant service provision

5. New oral anticoagulants

Burden of disease

AF Prevalence per 1000 population in Scotland 2001-2 (Murphy NF et al 2007)

Overall 8.7

<45 years 0.3

65-74 years 30.5

>85 years 70.7

Prevalence of AF in the Renfrew-Paisley study

Cohort of men and women aged 45–64 years (n = 15,406)

Reproduced with permission of the BMJ Publishing Group from Stewart S et al, Heart 2001: 86:516-21

Extrapolating to Sutton and Merton population

PCT population 392,300

Registered AF patients (QOF 2009-10)

3,959

AF anticoagulated (40%) 1,584

Potential AF needing anticoagulation (60%)

2,375

Estimated new AF patients/year

340

Themes of talk

1. AF - the burden of disease

2. Recognition of those at risk of stroke

3. Warfarin - current standard of care

4. Anticoagulant service provision

5. New oral anticoagulants

Recognition of those at risk of stroke

• Patients with AF have x 5 risk of stroke

• AF and no risk factors 1% per year

• AF and previous stroke/TIA 12% per year

• Stroke in AF has poorer outcome

Annual stroke rates in AF according to CHADS2 score

Score Risk%

0 1.9

1 2.8

2 4.0

3 5.9

4 8.5

5 12.5

6 18.2

Determine stroke/thromboembolic risk

High risk:

• Previous ischaemic stroke/TIA or thromboembolic event

• Age >75 with hypertension, diabetes or vascular disease

• Clinical evidence of valve disease, heart failure, or impaired left ventricular function on echocardiography

Moderate risk:

• Age >65 with no high risk factors

• Age <75 with hypertension, diabetes or vascular disease

Low risk:

• Age <65 with no moderate or high risk factors

Patients with AF

Determine stroke/thromboembolic risk

High risk

Moderate risk

Low risk

Consider anticoagulationConsider anticoagulation

or aspirinAspirin 75 to 300 mg/day

if no contraindications

Contraindications towarfarin?

Warfarin, target INR = 2.5(range 2.0 to 3.0)

Reassess risk stratificationwhenever individual risk

factors are reviewed

NOYES

Patients with AF

New risk scoring systems

• CHA(2)DS(2)-Vasc (Cong heart failure, Hypertension, Age≥75,Diabetes, Stroke, Vascular disease, Age 65-74, Sex category)

• HAS-BLED - (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly)

Themes of talk

1. AF - the burden of disease

2. Recognition of those at risk of stroke

3. Warfarin - current standard of care

4. Anticoagulant service provision

5. New oral anticoagulants

Warfarin and AF

• Oral anticoagulation reduces stroke risk in AF by 2/3………..but only if time in therapeutic range (INR 2-3) is greater than 65%

• Oral anticoagulation leads to 2 extra intracranial bleeds per annum per 1000 patients

Benefits versus risks

Stroke risk

• Valvular AF

• CHADS2

Bleeding risk• >75 years• Uncontrolled hypertension• History of bleeding or

intracranial haemorrhage• Anaemia• Polypharmacy• History of poor anticoagulation

control • Anti-platelet drugs

Warfarin (relative) contraindications

• Advanced age

• Multiple comorbidities

• Cognitive impairment

• Visual impairment

• History of falls

• Alcohol

• Previous bleed on warfarin

• Recent history of GI bleeding

• Uncontrolled hypertension

• Recent major surgery

• Pregnancy

• Inherited coagulation defect

• Thrombocytopenia

Warfarin preassessment

• FBC - anaemia (?bleeding)

- platelets <100 x 109/l

• INR or APTT ratio >1.4 needs investigation (liver disease, lupus inhibitor, factor deficiency)

• Liver function tests

Warfarin determinants of dose

• Genetic e.g. VKORC1, CYP2C9 genes

• Age

• Comorbidities (heart, liver disease, poor nutrition)

• Medication

Warfarin induction protocols

SlowAF

No heparin needed

Less likely to ‘overshoot’

Less frequent monitoring

FastAcute DVT or PE

Need heparin until INR therapeutic

Often results in high INRs

Frequent tests

AF Induction Protocol

• Start 3mg daily and check INR after one week

• If INR <1.4 increase to 5 mg daily and repeat INR in 3 days

• If INR 1.4-1.8 increase to 4mg daily and repeat in one week

• If INR 1.9-2.5 continue 3mg daily and repeat INR in one week

• If INR >2.5 consider dose reduction or omitting dose

Cardioversion for persistent AF

• NICE guidance : INR 2.5 (range 2-3) for 3 weeks prior and 4 weeks after

• At Epsom & St Helier we aim for target 2.5-3.5 to reduce likelihood of cancellation due to low INR

• Monitor weekly

• Cardiologists insist on venous samples (but probably no need if using Coaguchek)

• For urgent cardioversion give therapeutic LMWH before and warfarin for 4 weeks after

Aspirin for AF

• Alternative to warfarin if contraindications or intolerance or patient preference

• Less effective than warfarin

• Reduces stroke risk by 22% compared with placebo (warfarin 68%)

Themes of talk

1. AF - the burden of disease

2. Recognition of those at risk of stroke

3. Warfarin - current standard of care

4. Anticoagulant service provision

5. New oral anticoagulants

Anticoagulant service provision

• General practice

• Secondary care

• Self monitoring

-and various combinations of the above!

Anticoagulant service provision

9.1 Indications for referral from secondary to primary care

For patients started on warfarin in secondary care, once the INR is stable (at least 2 or 3consecutive INRs within 0.5 of target INR), patients in the following categories may betransferred to primary care:

Atrial Fibrillation

Artificial Heart Valves

Long-term anticoagulation for recurrent venous thrombosis (exceptantiphospholipid syndrome)

Mural Thrombus

Cardiomyopathy

Transfer should be arranged by written request from the general practitioner to thelead clinician for the hospital based anticoagulant service. This allows formal reviewof the patient’s anticoagulant records before transfer as some patients in the abovecategories may be best served by remaining with the secondary care service. Prior totransfer, the hospital clinic will provide the GP with a detailed history of the patient’santicoagulation. This will usually take the form of a printed summary from theDAWN anticoagulation software.

Anticoagulation service at St Helier

• Estimated AF patients on books

• new AF patients per month

• Pressure to reduce ‘new:follow-up ratios’

• Need to work with GPs to transfer patients to primary care

9.2 Indications for referral from primary to secondary care:

Bleeding with high INR (urgent referral to admitting medical team)

Pregnancy (urgent referral to anticoagulant clinic)

Planned surgical intervention (written referral to lead clinician for anticoagulantservice)

Cardioversion (written referral to lead clinician for anticoagulant service)

Unstable INR (written referral to lead clinician for anticoagulant service)

Patients requiring conversion from warfarin to low molecular weight heparin e.g.those requiring treatment for active cancer (written referral to lead clinician foranticoagulant service)

With prior agreement with the lead clinician for the secondary care anticoagulant service,some GPs with experience and expertise in anticoagulant monitoring may wish tocontinue to manage patients in the above categories

Themes of talk

1. AF - the burden of disease

2. Recognition of those at risk of stroke

3. Warfarin - current standard of care

4. Anticoagulant service provision

5. New oral anticoagulants

The new anticoagulants

• Oral• Wide therapeutic index• Predictable pharmacokinetics and dynamics

negating need for monitoring• Rapid onset of action• Antidote• Minimal non-anticoagulant side-effects• Minimal interactions with other drugs and food

The new oral anticoagulant drugs

• Dabigatran (Pradaxa - Boehringer-Ingelheim)• Rivaroxaban (Xarelto - Bayer)

- both licensed in UK for thromboprophylaxis post knee and hip replacement. Dabigatran licence for AF expected late June 2011.

• Apixaban (Pfizer)- awaiting FDA approval

Dabigatran

• Dabigatran etexilate, a pro-drug, is rapidly converted to dabigatran

• 80% excreted by kidney

• Half-life of 12-17 hours

• Phase 2 data identified 110 mg BID and 150 mg BID as viable doses

RE-LY: A Non-inferiority Trial

Atrial fibrillation ≥1 Risk Factor

Absence of contra-indications951 centers in 44 countries

R

Warfarinadjusted

(INR 2.0-3.0)N=6000

Dabigatran Etexilate

110 mg BIDN=6000

Dabigatran Etexilate

150 mg BIDN=6000

Blinded Event Adjudication.

Open Blinded

Trial ExecutionPerformed December 2005-March 2009

Median Follow up 2.0 years

Follow up 99.9% complete

Mean time in therapeutic range = 64% (patients on warfarin)

Ischaemic/Unspecified StrokeD 110 mg vs.

WarfarinD 150 mg vs.

Warfarin

RR =1.1195% CI = 0.89-1.40P = 0.35

RR = 0.7695% CI = 0.60-0.98P = 0.03

Years of Follow-up

Cu

mu

lati

ve H

azar

d R

ates

0.0

0.02

0.04

0.06

0.08

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

Hemorrhagic StrokeD 110 mg vs.

WarfarinD 150 mg vs.

Warfarin

RR = 0.31

95% CI =0.17-0.56

P <0.001

RR =0.26

95% CI =0.14-0.49

P <0.001

Years of Follow-up

Cu

mu

lati

ve H

azar

d R

ates

0.0

0.01

0.02

0.03

0.04

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

Bleeding

D

110mg

D

150mgwarfarin

D 110mg vs. Warfarin

D 150mg vs. Warfarin

AnnualAnnual

raterate

AnnualAnnual

raterate

AnnualAnnual

raterate

RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

Total 14.6% 16.4% 18.2%0.78

0.74-0.83<0.001

0.91

0.86-0.970.002

Major 2.7 % 3.1 % 3.4 %0.80

0.69-0.930.003

0.93

0.81-1.070.31

Life-Threatening major

1.2 % 1.5 % 1.8 %0.68

0.55-0.83<0.001

0.81

0.66-0.990.04

Gastro-intestinal

Major1.1 % 1.5 % 1.0 %

1.10

0.86-1.410.43

1.50

1.19-1.89<0.001

MI, Death and Net clinical Benefit

D 110mg

D 150mgwarfari

nD 110mg vs.

WarfarinD 150mg vs.

Warfarin

AnnualAnnual

raterate

AnnualAnnual

raterate

AnnualAnnual

raterate

RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

MI 0.7% 0.7 % 0.5 %1.35

0.98-1.870.07

1.38

1.00-1.910.048

Death 3.8 % 3.6 % 4.1 %0.91

0.80-1.030.13

0.88

0.77-1.000.05

Net Clinical Benefit

7.1 % 6.9 % 7.6 %0.92

0.84-1.020.10

0.91

0.82-1.000.04

Net Clinical Benefit includes vascular events, death and major bleed

Dabigatran 150 mg vs. 110 mg

Dabigatran 110mg

Dabigatran 150mg

D 150mg vs. D 110 mg

Number Number

rate/yrrate/yr

Number Number

rate/yrrate/yr

Relative RiskRelative Risk

95% CI95% CIpp

Stroke and systemic embolism

1.5% 1.1 %0.73

0.58-0.910.005

Hemorrhagic stroke

0.1% 0.1 %0.85

0.39-1.830.67

Major Hemorrhage 2.7 % 3.1 %1.16

1.00-1.340.05

Net Clinical Benefit 7.1 % 6.9 %0.98

0.89-1.080.66

*Net Clinical Benefit includes vascular events, death and major bleed

Permanent Discontinuation

Years of Follow-up

Sto

pp

ing

Ra

tes

0.0

0.1

0.2

0.3

0.4

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

Adverse events occurring in >5% of any group

Dabigatran 110 mg

%%

Dabigatran 150 mg

%%

Warfarin

%%

Dyspepsia * 11.8 11.3 5.8Dyspnea 9.3 9.5 9.7Dizziness 8.1 8.3 9.4Peripheral edema 7.9 7.9 7.8Fatigue 6.6 6.6 6.2Cough 5.7 5.7 6.0Chest pain 5.2 6.2 5.9Arthralgia 4.5 5.5 5.7Back pain 5.3 5.2 5.6Nasopharyngitis 5.6 5.4 5.6Diarrhea 6.3 6.5 5.7Atrial fibrillation 5.5 5.9 5.8Urinary tract infection 4.5 4.8 5.6Upper respiratory tract infection

4.8 4.7 5.2

Common Adverse Events

*Occurred more commonly on dabigatran p<0.001

RE-LY Study Conclusions

• Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding

• Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding

• Both doses reduced intra-cerebral, life-threatening and total bleeding

• Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding

Conclusions• Both Dabigatran doses offer advantages over

warfarin

• Dabigatran 150 is more effective and dabigatran 110 has a better safety profile

• Taken twice daily

• No reversal agent

Dabigatran - financial impact

• £2.50/day

• £912.50/year

• Warfarin cost £383/year(NICE)?

• Annual cost pressure for S London £6 - 10.3 million

Planned introduction needed

S & M implementation scenariosScenario Cost (£)

All patients switch from warfarin (minus warfarin costs)

839k

New patients only at 60% rate 186k

Out of range on warfarin only (,65% TTR)

479k

Currently untreated only (assuming 50% identified)

593k

Warfarin contraindicated only (11%)

159-238k

Key issues

• Can a budget be identified from June 2011?• Can subgroups be specified pending NICE HTA?• How can clinicians be encouraged to comply with

guidance?• Can money be released from anticoag services for

2012/13?• How should public pressure be dealt with if no

money for widespread use?

Recommendations from S London Cardiac and Stroke Network

• Warfarin to remain agent of choice in short term• Dabigatran in patients with contraindications to

warfarin• Establish S London working group to ensure

consistent approach and develop prescribing guidance

• Develop communication plan and patient information strategy