Guidelines for stroke prevention in
patients with atrial fibrillation
December 2012
Disclaimer: Dabigatran etexilate, rivaroxaban, and apixaban are now approved for clinical use in stroke prevention in atrial fibrillation in certain countries.
Please check local prescribing information for further details
1
Dec 2012
Development of novel antithrombotic agents has
caused a paradigm shift in treatment
NOACs found to be either superior (dabigatran and
apixaban) or non-inferior (rivaroxaban) to VKA therapy
for stroke prevention, with an improved safety profile
Availability of these agents has led to revisions in
treatment guidelines – specifically, the range of
patients who should be given antithrombotic therapy
has been broadened
Most recent and comprehensive guidelines were
published by the ESC in August 2012
ESC = European Society of Cardiology; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist
Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6; Patel MR et al.
N Engl J Med 2011;365:883–9; Granger CB et al. N Engl J Med 2011;365:981–92; Camm AJ et al. Eur Heart J
2012;33:2719–47
2
Dec 2012
Management of AF has two broad objectives
Prevention of
complications, including
thromboembolism
(particularly ischaemic
stroke) and heart failure
Relief of symptoms
Choice of antithrombotic therapy should be tailored to the patient based on:
Risk of
thromboembolism
Risk of
bleeding
ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429;
ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101–98
3
Dec 2012
Assessing stroke risk: CHADS2
CHADS2 criteria
0
CHADS2 score
1
2
Score
CHF
1
Hypertension
1
Age ≥75 yrs
1
Diabetes mellitus
1
Stroke/TIA
2
3
4
5
6
0
5
10
15
20
25
30
Annual stroke rate (%)*
CHF = congestive heart failure; TIA = transient ischaemic attack
Gage BF et al. JAMA 2001;285:2864–70
4
Dec 2012
Assessing stroke risk: CHA2DS2-VASc
CHA2DS2-VASc criteria
Score
CHF/LV dysfunction
1
Hypertension
1
Age 75 yrs
2
Diabetes mellitus
1
Stroke/TIA/TE
2
Vascular disease
1
Age 65–74 yrs
1
Sex category (i.e. female gender)
1
Total
score
Patients
(n=7329)
Adjusted
stroke rate
(%/year)*
0
1
0.0
1
422
1.3
2
1230
2.2
3
1730
3.2
4
1718
4.0
5
1159
6.7
6
679
9.8
7
294
9.6
8
82
6.7
9
14
15.2
*Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk,
based on Hart RG et al. 2007; TE = thromboembolism; TIA = transient ischaemic attack; LV = left ventricular
Lip G et al. Chest 2010;137:263-72; Lip G et al. Stroke 2010;41:2731–8;
Camm J et al. Eur Heart J 2010; 31:2369–429; Hart RG et al. Ann Intern Med 2007;146:857–67
5
Dec 2012
Assessing bleeding risk: HAS-BLED
HAS-BLED risk criteria
Hypertension
Abnormal renal or liver
function (1 point each)
Score
1
1 or 2
HAS-BLED
total score
N
Number Bleeds per 100
of bleeds patient-yrs*
0
798
9
1.13
1
1286
13
1.02
2
744
14
1.88
3
187
7
3.74
4
46
4
8.70
Stroke
1
Bleeding
1
Labile INRs
1
5
8
1
12.5
Elderly (e.g. age >65 yrs)
1
6
2
0
0.0
7
0
–
–
8
0
–
–
9
0
–
–
Drugs or alcohol
(1 point each)
1 or 2
*P value for trend = 0.007; INR = international normalized ratio
Pisters R et al. Chest 2010;138:1093–100; ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
6
Dec 2012
ESC 2012 focused update: antithrombotic therapy
general recommendations (1)
Recommendation
Class
Level
Antithrombotic therapy to prevent thromboembolism is recommended
for all patients with AF, except those (both male and female) who are at
low risk (aged <65 years and lone AF), or with contraindications
I
A
Choice of antithrombotic therapy should be based upon the absolute
risks of stroke/thromboembolism and bleeding and the net clinical
benefit for a given patient
I
A
CHA2DS2-VASc score is recommended as a means of assessing stroke
risk in nonvalvular AF
I
A
In patients with a CHA2DS2-VASc score of 0 (i.e. aged <65 years with
lone AF) who are at low risk, with none of the risk factors, no
antithrombotic therapy is recommended
I
B
Camm AJ et al. Eur Heart J 2012;33:2719–47
7
Dec 2012
ESC 2012 focused update: antithrombotic therapy
general recommendations (2)
Recommendation
Class
Level
In patients with CHA2DS2-VASc score ≥2, OAC therapy with:
• a dose-adjusted VKA (INR 2–3); or
• a direct thrombin inhibitor (dabigatran etexilate); or
• an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)
… is recommended unless contraindicated
I
A
In patients with CHA2DS2-VASc score 1, OAC therapy with:
• a dose-adjusted VKA (INR 2–3); or
• a direct thrombin inhibitor (dabigatran); or
• an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)
… should be considered, based upon an assessment of the risk
of bleeding complications and patient preferences
IIa
A
*Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J 2012;33:2719–47
8
Dec 2012
ESC 2012 focused update:
choice of anticoagulant
Atrial fibrillation
= CHA2DS2-VASc 0
Yes
Valvular AF*
Yes
= CHA2DS2-VASc ≥2
No (i.e. non-valvular)
<65 years and lone AF (including females)
= best option
No
= alternative option
Assess risk of stroke
CHA2DS2-VASc score
0
1
= CHA2DS2-VASc 1
≥2
Oral anticoagulant therapy
Assess bleeding risk
(HAS-BLED score)
Consider patient values and
preferences
No antithrombotic
therapy
NOAC
VKA
*Includes rheumatic valvular disease and prosthetic valves; NOAC = novel oral anticoagulant;
VKA = vitamin K antagonist; Camm AJ et al. Eur Heart J 2012;33:2719–47
9
Dec 2012
ESC 2012 focused update:
choice of oral anticoagulant
Recommendation
When adjusted-dose VKA (INR 2–3) cannot be used in a patient
with AF where an OAC is recommended, due to difficulties in keeping
within therapeutic anticoagulation, experiencing side effects of VKAs, or
inability to attend/undertake INR monitoring, one of the NOACs, either:
• a direct thrombin inhibitor (dabigatran); or
• an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)
… is recommended
When OAC is recommended, one of the NOACs, either: in:
• a direct thrombin inhibitor (dabigatran); or
• an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)
… should be considered rather than adjusted-dose VKA
(INR 2–3) for most patients with nonvalvular AF, based on their net
clinical benefit
Class
Level
I
B
IIa
A
*Pending approval; INR = international normalized ratio; NOAC = novel oral anticoagulant; VKA = vitamin K
antagonist; Camm AJ et al. Eur Heart J 2012;33:2719–47
10
Dec 2012
ESC 2012 focused update:
dosing of NOACs
Recommendation
Class
Level
When dabigatran is prescribed, a dose of 150 mg BID should be
considered for most patients in preference to 110 mg BID, with the
latter dose recommended in:
• elderly patients, age ≥80 years
• concomitant use of interacting drugs (e.g. verapamil)
• high bleeding risk (HAS-BLED score ≥3)
• moderate renal impairment (CrCl 30–49 mL/min)
IIa
B
Where rivaroxaban is being considered, a dose of 20 mg OD
should be considered for most patients in preference to 15 mg OD,
with the latter dose recommended in:
• high bleeding risk (HAS-BLED ≥3)
• moderate renal impairment (CrCl 30–49 mL/min)
IIa
C
BID = twice daily; CrCl = creatinine clearance; OD = once daily
Camm AJ et al. Eur Heart J 2012;33:2719–47
11
Dec 2012
ESC 2012 focused update:
NOACs in patients with renal impairment
Recommendation
Class
Level
Baseline and subsequent regular assessment of renal function (by CrCl)
is recommended in patients following initiation of any NOAC, which
should be done annually but more frequently in those with moderate
renal impairment where CrCl should be assessed 2–3 times per year
IIa
A
NOACs (dabigatran, rivaroxaban, and apixaban) are not recommended
in patients with severe renal impairment (CrCl <30 mL/min)
III
A
CrCl = creatinine clearance; NOAC = novel oral anticoagulant
Camm AJ et al. Eur Heart J 2012;33:2719–47
12
Dec 2012
ESC 2012 focused update:
NOACs in special situations (1)
Cardioversion
ACS
• Available data suggest cardioversion can be safely
performed in patients receiving dabigatran
• OAC should be continued long-term (VKA or dabigatran)
• No published data for rivaroxaban or apixaban
• Little evidence to support switching to another OAC in
dabigatran patients who present with an ACS
• Low-dose rivaroxaban used with some benefit in ACS but
no data on ACS relating to the dose used in AF (20 mg OD)
• Apixaban 5 mg BID when used in ACS in combination with
ASA and clopidogrel was associated with no reduction in CV
events but an excess of major bleeding
ACS = acute coronary syndrome; BID = twice daily; CV = cardiovascular; OAC = oral anticoagulation;
OD = once daily; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J 2012;33:2719–47
13
Dec 2012
ESC 2012 focused update:
NOACs in special situations (2)
AIS
• If aPTT is prolonged in a patient taking dabigatran, the
patient is anticoagulated and thrombolysis should not be
administered
• Should an AIS occur while a patient is taking rivaroxaban or
apixaban, the clinician may consider dabigatran 150 mg BID
instead
Ablation
• Currently no controlled data on the risk–benefit profile of
catheter ablation in patients receiving uninterrupted NOACs
• Data from a limited case series suggest that appropriate
post-ablation management with dabigatran is associated
with a low risk of embolic or bleeding complications,
although brief interruption of dabigatran use is associated
with more thromboembolic and bleeding complications
AIS = acute ischaemic stroke; aPTT = activated partial thromboplastin time; BID = twice daily; NOAC = novel oral
anticoagulant; Camm AJ et al. Eur Heart J 2012;33:2719–47
14
Dec 2012
ESC 2012 focused update:
bleeding recommendations
Recommendation
Assessment of bleeding risk is recommended when prescribing antithrombotic
therapy (whether with VKA, NOAC, ASA/clopidogrel, or ASA alone)
Class
Level
I
A
HAS-BLED score should be considered as a calculation to assess bleeding risk,
whereby a score ≥3 indicates ‘high risk’ and some caution and regular review is
needed, following initiation of antithrombotic therapy, whether with OAC or
antiplatelet therapy
Correctable factors for bleeding (e.g. uncontrolled blood pressure, labile INRs if
patient was receiving a VKA, concomitant drugs [ASA, NSAIDs, etc.], alcohol, etc.)
should be addressed
A
IIa
HAS-BLED score should be used to identify modifiable bleeding risks that need to
be addressed, but should not be used on its own to exclude patients from OAC
therapy
Risk of major bleeding with antiplatelet therapy (with ASA–clopidogrel combination
therapy and – especially in the elderly – also with ASA monotherapy) should be
considered as being similar to OAC
B
B
IIa
B
ASA = acetylsalicylic acid; INR = international normalized ratio; NOAC = novel oral anticoagulant;
NSAIDs = non-steroidal anti-inflammatory drugs; OAC = oral anticoagulation; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J 2012;33:2719–47
15
Dec 2012
2012 ACCP guidelines:
antithrombotic therapy in AF
Patient features
Recommended antithrombotic therapy
Low risk of stroke
(e.g. CHADS2 = 0)*
None (rather than antithrombotic therapy)
Intermediate risk of stroke
(e.g. CHADS2 = 1)*
OAC (rather than no therapy, ASA, or ASA & clopidogrel)
 Dabigatran 150 mg BID (rather than dose-adjusted VKA*)
(Grade 2B recommendation)
High risk of stroke
(e.g. CHADS2 = 2)
OAC (rather than no therapy, ASA, or ASA & clopidogrel)
 Dabigatran 150 mg BID (rather than dose-adjusted VKA†)
(Grade 2B recommendation)
Previous stroke/TIA
OAC (rather than no therapy, ASA, or ASA & clopidogrel)
 Dabigatran 150 mg BID (rather than dose-adjusted VKA†)
(Grade 2B recommendation)
*Other factors that may influence the choice of OAC are bleeding risk and other stroke risk factors, including age
65–74 years, female gender, and vascular disease. The presence of multiple non-CHADS2 risk factors favours OAC
therapy
†Target range for international normalized ratio: 2.0–3.0
ACCP = American College of Chest Physicians; ASA = acetylsalicylic acid; BID = twice daily;
OAC = oral anticoagulation; TIA = transient ischaemic attack; VKA = vitamin K antagonist
You JY et al. Chest 2012;141;e531S–75S
16
Dec 2012
2012 AHA/ASA science advisory:
antithrombotic therapy in AF
Agents indicated for prevention of stroke in patients with nonvalvular AF
–
–
–
–
Warfarin
Dabigatran
Apixaban
Rivaroxaban
(Class
(Class
(Class
(Class
I; Level of evidence A)
I; Level of evidence B)
I; Level of evidence B)
IIa; Level of evidence B)
Existing AHA recommendation
New recommendation
Dabigatran
Useful alternative to warfarin for prevention
of stroke/SE in patients with paroxysmal to
permanent AF and risk factors for stroke/SE
(without prosthetic heart valves,
haemodynamically significant valve disease,
CrCl <15 mL/min, or advanced liver disease)
150 mg BID: efficacious alternative to warfarin in
patients with NVAF and ≥1 additional risk factor
(and CrCl >30 mL/min)
Apixaban
None
5 mg BID: relatively safe and efficacious alternative
to warfarin in patients with NVAF deemed appropriate
for VKA therapy, with ≥1 additional risk factor and
≤1 of: age ≥80 years; weight ≥60 kg; serum
creatinine ≥1.5 mg/dL
Rivaroxaban
None
20 mg/day: reasonable alternative to warfarin in
patients with NVAF at moderate–high risk of stroke
AHA = American Heart Association; ASA = American Stroke Association; BID = twice daily; CrCl = creatinine clearance;
NVAF = nonvalvular AF; SE = systemic embolism; VKA = vitamin K antagonist; Furie KL et al. Stroke 2012;43:3442–53
17
Dec 2012
2012 CCS guidelines:
antithrombotic therapy in AF
Risk category
Low risk
CHADS2 score Recommended therapy
0
No additional risk factors for stroke: None
Female gender or vascular disease: ASA
Female gender & vascular disease: OAC*†
Age ≥65 yrs: OAC*†
Intermediate risk
1
OAC*†
High risk
2
OAC*
*When OAC therapy is indicated, most patients should receive dabigatran, rivaroxaban, or
apixaban in preference to warfarin
†ASA
is a reasonable alternative for some patients based on individual risk−benefit considerations
ASA = acetylsalicylic acid; CCS = Canadian Cardiovascular Society; OAC = oral anticoagulation
CCS guidelines: Skanes AC et al. Can J Cardiol 2012;28:125–36
18
Dec 2012
2011 Japanese scientific statement
on dabigatran
Nonvalvular AF
CHADS2 score
≥2 points
Recommended
Dabigatran
Warfarin*
Other risk factors
1 points
Recommended
Dabigatran
•
•
•
•
65–74 yrs
Female
CAD or cardiomyopathy
Thyrotoxicosis
Options to be considered
Option to be considered
Warfarin*
Dabigatran
Warfarin*
*<70 years: target INR 2.0–3.0; ≥70 years: target INR 1.6–2.6
CAD = coronary artery disease; INR = international normalized ratio
Available at: http://www.j-circ.or.jp/guideline/pdf/statement.pdf; accessed September 2012
19
Dec 2012
Summary
Recent guidelines recommend use of CHA2DS2-VASc
to stratify patients by stroke risk
OAC now recommended for all except ‘truly low-risk’
patients (CHA2DS2-VASc = 0)
Role of ASA for stroke prevention has diminished
– ESC now recommends that use of ASA should be limited to
patients who refuse any form of OAC
Where oral anticoagulation is indicated, NOACs,
such as dabigatran, are recommended in preference
to dose-adjusted VKA therapy
ASA = acetylsalicylic acid; OAC = oral anticoagulation; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist
20
Dec 2012
Appendix
21
Dec 2012
ESC 2012: classes of recommendation
Class
Definition
Suggested wording
I
Evidence and/or general agreement that a given
treatment or procedure is beneficial, useful, effective
Is recommended/
Is indicated
II
Conflicting evidence and/or a divergence of opinion
about the usefulness/efficacy of the given treatment
or procedure
IIa
Weight of evidence/opinion is in favour of
usefulness/efficacy
Should be considered
IIb
Usefulness is less well established by
evidence/opinion
May be considered
Evidence or general agreement that the given
treatment or procedure is not useful/effective, and in
some cases may be harmful
Is not recommended
III
Camm AJ et al. Eur Heart J 2012;33:2719–47
22
Dec 2012
ESC 2012: level of evidence
Level of evidence A
Data derived from multiple randomized clinical
trials or meta-analyses
Level of evidence B
Data derived from a single randomized clinical
trial or large non-randomized studies
Level of evidence C
Consensus of opinion of the experts and/or
small studies, retrospectives analyses, registries
Camm AJ et al. Eur Heart J 2012;33:2719–47
23
Dec 2012