1. 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

2. 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
This presentation reviews the latest guidance provided by the ESC on antithrombotic therapy in patients with atrial fibrillation.
The Canadian Cardiovascular Society and American College of Chest Physicians guidelines have been included to show the impact of the novel oral anticoagulants on international treatment guidelines.
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

3. 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
Management of AF patients is aimed at reducing symptoms and at preventing severe complications associated with AF.
Prevention of AF-related complications relies on antithrombotic therapy, control of ventricular rate, and adequate therapy of concomitant cardiac diseases.
ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
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

4. Assessing stroke risk: CHADS2
Annual stroke rate (%)*
CHADS2 score 30 2 3 4 5 6 10 15 20 25 1
CHADS2 criteria
Score
CHF 1
Hypertension
Age ≥75 yrs
Diabetes mellitus
Stroke/TIA 2
The CHADS2 score is a simple system for stratifying patients with atrial fibrillation according to their risk of stroke.1
It has been validated in a large national registry of patients with atrial fibrillation1
This system of stroke risk scoring has traditionally been recommended in treatment guidelines.2
Gage BF et al. JAMA 2001;285:2864–70
ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101–98
CHF = congestive heart failure; TIA = transient ischaemic attack
Gage BF et al. JAMA 2001;285:2864–70

5. Assessing stroke risk: CHA2DS2-VASc
CHA2DS2-VASc criteria
Score
CHF/LV dysfunction 1
Hypertension
Age 75 yrs 2
Diabetes mellitus
Stroke/TIA/TE
Vascular disease
Age 65–74 yrs
Sex category (i.e. female gender)
Total score
Patients (n=7329)
Adjusted stroke rate (%/year)* 1
0.0
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 9 14
15.2
The CHADS2 score has been criticized for being too simplistic and for predominately classifying patients as at intermediate risk of stroke.1
The CHA2DS2-VASc score was developed to more accurately predict patients’ stroke risk by taking additional stroke risk factors into account.1
The CHA2DS2-VASc score has since been validated in multiple cohorts.2
The accumulated evidence shows that CHA2DS2-VASc is better at identifying ‘truly low-risk’ patients with AF and is as good as, and possibly better than, scores such as CHADS2 in identifying patients who develop stroke and thromboembolism.2
Lip G et al. Chest 2010;137:263-72
Camm AJ et al. Eur Heart J 2012;33:2719–47
*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

6. Assessing bleeding risk: HAS-BLED
HAS-BLED risk criteria
Score
Hypertension 1
Abnormal renal or liver function (1 point each)
1 or 2
Stroke
Bleeding
Labile INRs
Elderly (e.g. age >65 yrs)
Drugs or alcohol (1 point each)
HAS-BLED total score N
Number of bleeds
Bleeds per 100 patient-yrs*
798 9
1.13 1
1286 13
1.02 2
744 14
1.88 3
187 7
3.74 4 46
8.70 5 8
12.5 6
0.0 –
A number of bleeding risk scoring systems have been developed for use in patients with atrial fibrillation including HAS-BLED, HEMORR2AGES and ATRIA.
The HAS-BLED score has been validated in several independent cohorts and has recently been included in the updated ESC guidelines as a formal bleeding risk assessment tool for all patients with atrial fibrillation.
Camm AJ et al. Eur Heart J 2012;33:2719–47
*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

7. ESC 2012 focused update: antithrombotic therapy general recommendations (1)
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
CHA2DS2-VASc score is recommended as a means of assessing stroke risk in nonvalvular AF
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 B
The ESC released a focused update to their 2010 guidelines for the management of atrial fibrillation to reflect the approval of dabigatran and the publication of the ROCKET AF, AVERROES and ARISTOTLE studies.
The update recommends a practice shift towards identification of ‘truly low risk’ patients who do not require antithrombotic therapy rather than focusing on identification of high-risk patients.
CHA2DS2-VAsc score is recommended for assessing stroke risk.
0 (low risk) = no antithrombotic therapy recommended.
Camm AJ et al. Eur Heart J 2012;33:2719–47
Camm AJ et al. Eur Heart J 2012;33:2719–47

8. ESC 2012 focused update: antithrombotic therapy general recommendations (2)
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 direct thrombin inhibitor (dabigatran); or
… should be considered, based upon an assessment of the risk of bleeding complications and patient preferences
IIa
In patients with a CHA2DS2-VAsc score ≥2, OAC with a VKA, dabigatran, or oral direct factor Xa inhibitor is recommended.
In patients with a CHA2DS2-VAsc score of 1, OAC with a VKA, dabigatran, or oral direct factor Xa inhibitor should be considered.
Camm AJ et al. Eur Heart J 2012;33:2719–47
*Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J 2012;33:2719–47

9. ESC 2012 focused update: choice of anticoagulant
Yes
Atrial fibrillation
Valvular AF*
<65 years and lone AF (including females)
Assess risk of stroke CHA2DS2-VASc score
No antithrombotic therapy
Oral anticoagulant therapy
NOAC
VKA 1
No (i.e. non-valvular) No ≥2
Assess bleeding risk (HAS-BLED score) Consider patient values and preferences
= CHA2DS2-VASc 0
= best option
= CHA2DS2-VASc 1
= CHA2DS2-VASc ≥2
= alternative option
The process of choosing anticoagulant therapy, based on the ESC 2012 update, can be summarized in this flow diagram.
A key point to note is that antiplatelet therapy with ASA plus clopidogrel or – less effectively – ASA only should be considered in patients who refuse any OAC or cannot tolerate anticoagulation for reasons unrelated to bleeding.
Camm AJ et al. Eur Heart J 2012;33:2719–47
*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

10. ESC 2012 focused update: choice of oral anticoagulant
Recommendation
Class
Level
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 I B
When OAC is recommended, one of the NOACs, either: in:
… should be considered rather than adjusted-dose VKA (INR 2–3) for most patients with nonvalvular AF, based on their net clinical benefit
IIa A
The update notes that the novel OACs (dabigatran, rivaroxaban, and apixaban) offer better efficacy, safety, and convenience compared with OAC therapy with VKAs.
Where an OAC is recommended, dabigatran or an oral FXa inhibitor should be considered instead of adjusted dose VKA (INR 2–3) in most patients with AF.
Where an OAC is recommended and a VKA cannot be used, dabigatran or an oral FXa inhibitor are recommended.
Camm AJ et al. Eur Heart J 2012;33:2719–47
*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

11. 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) C
The guidelines recommend the use of dabigatran 150 mg in preference to 110 mg in the majority of patients.
In patients with moderate renal impairment (CrCl 30–49 mL/min), dabigatran 110 mg has a higher level of evidence than rivaroxaban 15 mg.
Camm AJ et al. Eur Heart J 2012;33:2719–47
BID = twice daily; CrCl = creatinine clearance; OD = once daily
Camm AJ et al. Eur Heart J 2012;33:2719–47

12. 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
All of the NOACs have a degree of renal excretion, therefore, assessment of renal function (by CrCl) is recommended at initiation of therapy with any NOAC.
All of the NOACs are not recommended in patients with severe renal impairment.
Camm AJ et al. Eur Heart J 2012;33:2719–47
CrCl = creatinine clearance; NOAC = novel oral anticoagulant
Camm AJ et al. Eur Heart J 2012;33:2719–47

13. ESC 2012 focused update: NOACs in special situations (1)
Cardioversion
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
ACS
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
Cardioversion
Anticoagulation (with VKA or dabigatran) should be initiated 3 weeks prior to cardioversion and should continue for a minimum of 4 weeks following the procedure.
ACS
Concomitant use of OAC and antiplatelet therapy significantly increases bleeding risk.
Data on the use of triple therapy with a NOAC is limited.
Camm AJ et al. Eur Heart J 2012;33:2719–47
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

14. 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
Ablation
Ablation of a patient whilst still taking uninterrupted NOACs may carry a small theoretical risk, given the lack of a reversal agent, should a major bleeding complication arise.
Camm AJ et al. Eur Heart J 2012;33:2719–47
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

15. ESC 2012 focused update: bleeding recommendations
Class
Level
Assessment of bleeding risk is recommended when prescribing antithrombotic therapy (whether with VKA, NOAC, ASA/clopidogrel, or ASA alone) 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
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
IIa B
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
Assessment of bleeding risk using HAS-BLED is recommended for all patients receiving antithrombotic therapy.
HAS-BLED score:
allows clinicians to make informed assessment of bleeding risk
Enables clinicians to think of the correctable risk factors for bleeding
has been validated in several independent cohorts
correlates well with ICH risk.
Note that high HAS-BLED score per se should not be used to exclude patients from OAC therapy.
Also, contrary to some perceptions, the major bleeding risk with antiplatelet therapy should be considered as being similar to OAC.
Camm AJ et al. Eur Heart J 2012;33:2719–47
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

16. 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)
Dabigatran 150 mg BID (rather than dose-adjusted VKA†) (Grade 2B recommendation)
Previous stroke/TIA
Looking at the US perspective, in 2012 the ACCP also published guidance on antithrombotic therapy in patients with AF.
Oral anticoagulation is recommended for patients with a CHADS2 score of ≥1 (in preference to antiplatelet therapy).
Dabigatran etexilate 150 mg BID should be considered for patients at intermediate risk of stroke or higher, in preference to dose-adjusted VKA.
Additional information
These guidelines use the CHADS2 stroke risk scoring system to stratify patients. However, they recommend using the additional criteria from the CHA2DS2-VASc scoring system (age 65–74 years, female gender and vascular disease) to guide treatment decisions in patients with a CHADS2 score of ≤1.
You JY et al. Chest 2012;141;e531S–75S
*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

17. 2012 AHA/ASA science advisory: antithrombotic therapy in AF
Agents indicated for prevention of stroke in patients with nonvalvular AF
Warfarin (Class I; Level of evidence A)
Dabigatran (Class I; Level of evidence B)
Apixaban (Class I; Level of evidence B)
Rivaroxaban (Class 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
20 mg/day: reasonable alternative to warfarin in patients with NVAF at moderate–high risk of stroke
An additional US perspective was provided in 2012 by the AHA/ASA.
They also now include the NOACs in the list of indicated agents for stroke prevention in patients with nonvalvular AF, though the strength of recommendation differs between the novel agents (lower for rivaroxaban than for dabigatran or apixaban)
Furie KL et al. Stroke 2012;43:3442–53
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

18. 2012 CCS guidelines: antithrombotic therapy in AF
Risk category
CHADS2 score
Recommended therapy
Low risk
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*
The 2012 Canadian guidelines use the CHADS2 score to stratify patients.
As with the ACCP guidelines, aspects of the CHA2DS2-VASc score (female gender and vascular disease) have been incorporated into the guidelines to further stratify patients.
As with the 2012 ESC focused update, the Canadian guidelines recommend the use of novel oral agents (dabigatran, rivaroxaban, or apixaban) in preference to warfarin in patients requiring oral anticoagulation.
CCS guidelines: Skanes AC et al. Can J Cardiol 2012;28:125–36
*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

19. 2011 Japanese scientific statement on dabigatran
Nonvalvular AF
CHADS2 score
Other risk factors
65–74 yrs
Female
CAD or cardiomyopathy
Thyrotoxicosis
≥2 points
1 points
Recommended
Dabigatran
Warfarin*
Recommended
Dabigatran
Option to be considered
Warfarin*
Options to be considered
Dabigatran
Warfarin*
In 2011, the Japanese Circulation Society issued a statement providing guidance on the use of dabigatran etexilate for stroke prevention in patients with AF, to also reflect the arrival of the novel anticoagulants.
The Japanese recommendations use the CHADS2 score to assess stroke risk but also include ‘Other risk factors’ which may indicate the use of OAC.
Available at: accessed September 2012
*<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: accessed September 2012

20. 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

21. Appendix

22. ESC 2012: classes of recommendation
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
III
Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful
Is not recommended
Camm AJ et al. Eur Heart J 2012;33:2719–47

23. Data derived from multiple randomized clinical trials or meta-analyses
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