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