Transcript Managing anticoagulation in atrial fibrillation

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.
2.
3.
4.
5.
AF - the burden of disease
Recognition of those at risk of stroke
Warfarin - current standard of care
Anticoagulant service provision
New oral anticoagulants
Themes of talk
1.
2.
3.
4.
5.
AF - the burden of disease
Recognition of those at risk of stroke
Warfarin - current standard of care
Anticoagulant service provision
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 RenfrewPaisley 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%)
Estimated new AF
patients/year
2,375
340
Themes of talk
1.
2.
3.
4.
5.
AF - the burden of disease
Recognition of those at risk of stroke
Warfarin - current standard of care
Anticoagulant service provision
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
0
1
2
3
4
5
6
Risk%
1.9
2.8
4.0
5.9
8.5
12.5
18.2
Patients with AF
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:
Low risk:
• Age >65 with
no moderate or
high risk factors
no high risk
factors
• Age <75 with
hypertension,
diabetes or
vascular
disease
• Age <65 with
Patients with AF
Determine stroke/thromboembolic risk
High
risk
Moderate
risk
Low
risk
Consider anticoagulation
Consider anticoagulation
or aspirin
Aspirin 75 to 300 mg/day
if no contraindications
Contraindications to
warfarin?
NO
Warfarin, target INR = 2.5
(range 2.0 to 3.0)
YES
Reassess risk stratification
whenever individual risk
factors are reviewed
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.
2.
3.
4.
5.
AF - the burden of disease
Recognition of those at risk of stroke
Warfarin - current standard of care
Anticoagulant service provision
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
Slow
AF
No heparin needed
Less likely to ‘overshoot’
Less frequent monitoring
Fast
Acute 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.
2.
3.
4.
5.
AF - the burden of disease
Recognition of those at risk of stroke
Warfarin - current standard of care
Anticoagulant service provision
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 seconda ry to primary care
For pat ients st arted on warfarin in secondary care, once the INR is stable (at least 2 or 3
consecut ive INRs wit hin 0.5 of target INR), pat ient s in the following categories may be
t ransferred to primary care:

At rial Fibrillat ion

Art ificial Heart Valves

Long-term anticoagulat ion for recurrent venous thrombosis (except
ant iphospholipid syndrome)

Mural T hrombus

Cardiomyopathy
Transfer should be arranged by writ ten reque st from the general pract it io ner to the
lead clinician for the hospital based ant icoagulant service. This allows formal review
of the pat ient’s anticoagulant records before t ransfer as some patients in the above
categories may be best served by remaining with t he secondary care service. P rior to
t ransfer, the hospital clinic will provide the GP with a det ailed history of t he pat ient ’s
ant icoagulat ion. This will usually take the form of a printed summary from the
DAWN ant icoagulat ion 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 admit tin g medical team)

Pregnancy (urgent referral to anticoagulant clinic)

P lanned surgical intervent ion (writ ten referral to lead clinician for anticoagulant
service)

Cardioversion (writ ten referral to lead clinician for ant icoagulant service)

Unstable INR (writ ten referral to lead clinician for ant icoagulant service)

Pat ients requiring conversion from warfarin to low molecular weight heparin e.g.
those requiring treat ment for act ive cancer (writ ten referral to lead clinician for
ant icoagulant service)
With prior agreement with the lead clinician for the secondary care ant icoagulant service,
some GPs with experience and expertise in anticoagulant monitoring may wish to
cont inue to manage pat ient s in the above categories
Themes of talk
1.
2.
3.
4.
5.
AF - the burden of disease
Recognition of those at risk of stroke
Warfarin - current standard of care
Anticoagulant service provision
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-indications
951 centers in 44 countries
Blinded Event Adjudication.
R
Open
Warfarin
adjusted
(INR 2.0-3.0)
N=6000
Blinded
Dabigatran
Etexilate
110 mg BID
N=6000
Dabigatran
Etexilate
150 mg BID
N=6000
Trial Execution
 Performed December 2005-March 2009
 Median Follow up 2.0 years
 Follow up 99.9% complete
 Mean time in therapeutic range = 64% (patients
on warfarin)
0.08
0.06
D 150 mg vs.
Warfarin
RR
= 0.76
95% CI = 0.600.98
P
= 0.03
0.04
D 110 mg vs.
Warfarin
RR
=1.11
95% CI = 0.891.40
P
= 0.35
Dabigatran110
0.02
Warfarin
Dabigatran150
0.0
Cumulative Hazard Rates
Ischaemic/Unspecified Stroke
0
0.5
1.0
1.5
Years of Follow-up
2.0
2.5
RR
= 0.31
95% CI =0.170.56
P
<0.001
D 150 mg vs.
Warfarin
RR
=0.26
95% CI =0.14-0.49
P
<0.001
0.02
0.03
D 110 mg vs.
Warfarin
0.01
Warfarin
Dabigatran110
Dabigatran150
0.0
Cumulative Hazard Rates
0.04
Hemorrhagic Stroke
0
0.5
1.0
1.5
Years of Follow-up
2.0
2.5
Bleeding
D
110mg
D
150mg
warfarin
Annual
rate
Annual
rate
Annual
rate
RR
95% CI
0.91
<0.001
0.86-0.97
0.002
D 110mg vs.
Warfarin
p
D 150mg vs.
Warfarin
RR
95% CI
p
Total
14.6%
16.4%
18.2%
0.78
0.74-0.83
Major
2.7 %
3.1 %
3.4 %
0.80
0.69-0.93
0.003
0.93
0.81-1.07
0.31
LifeThreatenin
g major
1.2 %
1.5 %
1.8 %
0.68
0.55-0.83
<0.001
0.81
0.66-0.99
0.04
1.0 %
1.10
0.86-1.41
0.43
1.50
1.19-1.89
<0.001
Gastrointestinal
Major
1.1 %
1.5 %
MI, Death and Net clinical Benefit
D 110mg D 150mg
warfari
n
Annual
rate
Annual
rate
RR
95% CI
Annual
rate
D 110mg vs.
Warfarin
D 150mg vs.
Warfarin
p
RR
95% CI
p
0.07
1.38
1.00-1.91
0.048
MI
0.7%
0.7 %
0.5 %
1.35
0.98-1.87
Death
3.8 %
3.6 %
4.1 %
0.91
0.80-1.03
0.13
0.88
0.77-1.00
0.05
Net
Clinical
Benefit
7.1 %
6.9 %
7.6 %
0.92
0.84-1.02
0.10
0.91
0.82-1.00
0.04
Net Clinical Benefit includes vascular events, death and major bleed
Dabigatran 150 mg vs. 110 mg
Stroke and systemic
embolism
Hemorrhagic
stroke
Major Hemorrhage
Net Clinical Benefit
Dabigatran
110mg
Dabigatran
150mg
Number
rate/yr
Number
rate/yr
Relative Risk
95% CI
p
1.1 %
0.73
0.58-0.91
0.005
0.1 %
0.85
0.39-1.83
0.67
3.1 %
1.16
1.00-1.34
0.05
6.9 %
0.98
0.89-1.08
0.66
1.5%
0.1%
2.7 %
7.1 %
D 150mg vs. D 110 mg
*Net Clinical Benefit includes vascular events, death and major bleed
0.3
Dabigatran150
0.2
Dabigatran110
0.1
Warfarin
0.0
Stopping Rates
0.4
Permanent Discontinuation
0
0.5
1.0
1.5
Years of Follow-up
2.0
2.5
Common Adverse Events
Adverse events occurring in
>5% of any group
Dyspepsia *
Dyspnea
Dizziness
Peripheral edema
Fatigue
Cough
Chest pain
Arthralgia
Back pain
Nasopharyngitis
Diarrhea
Atrial fibrillation
Urinary tract infection
Upper respiratory tract
infection
Dabigatran Dabigatra
110 mg
n 150 mg Warfarin
%
%
%
11.8
11.3
5.8
9.3
9.5
9.7
8.1
8.3
9.4
7.9
7.9
7.8
6.6
6.6
6.2
5.7
5.7
6.0
5.2
6.2
5.9
4.5
5.5
5.7
5.3
5.2
5.6
5.6
5.4
5.6
6.3
6.5
5.7
5.5
5.9
5.8
4.5
4.8
5.6
4.8
*Occurred more commonly on dabigatran p<0.001
4.7
5.2
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 scenarios
Scenario
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