The Future Is Now: Management of AF The RE-LY Study and New Guidelines

The Future is Now
Management of AF
The RE-LY Study and
New Guidelines
Stroke Prevention in Atrial Fibrillation
Affected
portion of the brain  AF is the most common heart rhythm
disturbance1
 It is estimated that 1 in 4 individuals
aged 40 years or older will develop
AF1
 In 2007, 6.3 million people in the US,
Japan, Germany, Italy, Spain, France
and the UK were living with
diagnosed AF2
 Due to the aging population, this
number is expected to double within
30 years3
Thrombus (clot)
1. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046.

2. Decision Resources. Atrial Fibrillation Report. Dec 2008.
3. Go AS, et al. JAMA 2001;285:2370-2375.
AF-RELATED STROKES ARE ASSOCIATED WITH GREATER
DISABILITY AND A HIGHER MORTALITY RATE
Strokes with AF (N=216) Strokes without AF (N=845)

Patients with clinical parameter (%)
Disability at clinical presentation1 30-day post-stroke mortality2

60 30
P<0.005 P<0.0005 P<0.048
50
Fatal strokes (%)

25
40
20
30
15
20
10 10
0 0
Severe limb weakness Bedridden Strokes Strokes
with AF without AF
(N=103) (N=398)
1. Dulli DA, et al. Neuroepidemiology 2003;22:118-123. 2. Lin HJ, et al. Stroke 1996;27:1760-1764.
Atrial Fibrillation
and Stroke
Current Treatments
AF-RELATED STROKE IS PREVENTABLE
 Effective stroke prevention is a priority for patients with AF1

 Two-thirds of strokes due to AF are preventable with
appropriate anticoagulant therapy2
 A meta-analysis of 29 trials in 28,044 patients showed that
the vitamin K antagonist (VKA) warfarin reduces the risk of
stroke and all-cause mortality2
- 64% reduction in stroke and 24% reduction in all-cause mortality
compared with placebo
- Aspirin also reduced the risk of stroke, but less effectively than warfarin
(19% reduction compared with placebo)
 However, VKAs are associated with complications, such as
increased bleeding risk
 Guidelines for antithrombotic therapy in AF recommend
Aspirin or VKA depending on the presence of risk factors for
stroke1
1. Fuster V, et al. Circulation 2006;114:e257–354. 2. Hart RG, et al. Ann Intern Med 2007;146:857-867.
ACC/AHA/ESC GUIDELINES FOR
ANTITHROMBOTIC THERAPY IN AF
Risk category CHADS2 score Recommended therapy
No risk factors 0 Aspirin 81–325 mg daily

Aspirin 81–325 mg daily or
One moderate-risk factor 1
warfarin (INR 2.0–3.0, target 2.5)*
Any high-risk factor or 2
2 Warfarin (INR 2.0–3.0, target 2.5)†
moderate-risk factors
Less validated/
Moderate-risk factors High-risk factors
weaker-risk factors
Age 75 yrs
Female gender Previous stroke, TIA or
Hypertension
Age 65–74 yrs embolism
Heart failure
Coronary artery disease Mitral stenosis
LVEF 35%
Thyrotoxicosis Prosthetic heart valve*
Diabetes mellitus
*Choice of agent should be based on consideration of bleeding risk, ability to sustain chronic anticoagulation safely and patient
preference; †If mechanical valve, target INR >2.5.
ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology;
INR = International normalized ratio; LVEF = left ventricular ejection fraction; TIA = transient ischaemic attack.
Fuster V, et al. Circulation 2006;114:e257–354.
Estimation of stroke risk in AF: CHADS2
Validated using the National Registry of Atrial Fibrillation (NRAF)

Most widely used to guide the choice of antithrombotic therapy
CHADS2 risk criteria Score
Cardiac failure 1
Hypertension 1
Age ≥75 yrs 1
Diabetes mellitus 1
Stroke or TIA (previous history) 2
TIA = transient ischaemic attack

Gage BF et al. JAMA 2001;285:2864–70
7
Estimation of stroke risk in AF: CHADS2
Patients Adjusted stroke rate (%/year)a

CHADS2 score
(n = 1733) (95% confidence interval)
0 120 1.9 (1.2–3.0)
1 463 2.8 (2.0–3.8)
2 523 4.0 (3.1–5.1)
3 337 5.9 (4.6–7.3)
4 220 8.5 (6.3–11.1)
5 65 12.5 (8.2–17.5)
6 5 18.2 (10.5–27.4)
Gage BF et al. JAMA 2001;285:2864–70
• At CHADS2 score ≥ 2 oral anticoagulation is recommended
• At CHADS2 score = 1 there is a choice between oral

anticoagulation and Aspirin
ACC/AHA/ESC AF guidelines 2006 and ACCP 8th guidelines

Approach to Thromboprophylaxis in AF Patients
CHADS2 Recommendation
>2 OAC
1 Either OAC or Aspirin, prefer OAC
0 Either Aspirin or no therapy, prefer no therapy
There is no room for Aspirin in

Stroke Prevention in Atrial Fibrillation
European Heart Journal (2010) 31, 2369-2429

LIMITATIONS OF VKA THERAPY
Unpredictable Numerous food–drug

response interactions
VKA therapy has

Narrow therapeutic several limitations Numerous drug–drug
window (INR range 2.0–3.0) that make it difficult interactions
to use in practice
Slow onset/
Warfarin resistance
offset of action
Routine coagulation Frequent dose

monitoring adjustments
INR = International normalized ratio; VKA = vitamin K antagonist

Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137.
Nutescu EA, et al. Cardiol Clin 2008;26:169-187.
Summary of the 5 patient profile
TYPICAL CATEGORIZATION OF SPAF PATIENTS
1 AGE: retirement age (60+) STROKE RISK: Moderate – High

COMMORBIDITIES: hypertension, ischemic BLEEDING RISK: Low –
ASPIRIN or Clopi heart disease, diabetes, obesity, etc. Moderate
2 AGE: relatively young, mid-50s STROKE RISK: Low (e.g.,

CHADS2-Score of 0)
COMORBIDITIES: not existent
ASPIRIN BLEEDING RISK: Low – High
3 AGE: very old (80+) STROKE RISK: Moderate — High

COMMORBIDITIES: similar to typical VKA BLEEDING RISK: High (due to
ASPIRIN or Clopi patient and possibly dementia risk of falls)
4 AGE: retirement age (60+) STROKE RISK: Moderate — High

COMMORBIDITIES: hypertension, ischemic BLEEDING RISK: High (due to
ASPIRIN or Clopi heart disease, diabetes, obesity, etc. risk of falls)
5 AGE: retirement age (60+) STROKE RISK: High

COMMORBIDITIES: hypertension, coronary BLEEDING RISK: Low –
artery disease, (stent) ischemic heart disease, Moderate
ASPIRIN or Clopi obesity, etc.
Base: All drs (n=85)
Atrial Fibrillation
and Stroke
New Treatments
Targets for antithrombotic agents in the
coagulation cascade1
Vitamin K antagonists:
Warfarin
Tissue factor/VIIa
X IX
Indirect factor Xa inhibitors:

VIIIa NA
IKa
Direct factor Xa inhibitors:
Va
Apixaban (Not yet approved by AT= antithrombin
BPOM) Xa AT
Rivaroxaban (Not yet approved
by BPOM)
Direct thrombin inhibitors:
Dabigatran etexilate (Approved by BPOM)
II Thrombin
Anti-platelets:
Aspirin
Clopidogrel
Fibrinogen Fibrin
1Adapted from Turpie AG. Eur Heart J 2008;29 13

Hasil studi oral OAC
Study RRR P-value

RE-LY
•SSE 35% < 0.001 (signifikan)
* Stroke iskemik 25% 0.03 (signifikan)
* Stroke hemorrhagik 74% <0.001 (signifikan)
ROCKET-AF
* SSE (per protocol) 12% <0.001 (signifikan)
* Stroke Iskemik 6% 0.581 (tidak signifikan)
* Stroke hemorrhagik 41% 0.024 (signifikan)
ARISTOTLE
* SSE 21% 0.01 (signifikan)
* Stroke iskemik 8% 0.42 (tidak signifikan)
* Stroke hemorrhagik 49% <0.001 (signifikan)
14

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The Future is Now

1. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046.

Strokes with AF (N=216) Strokes without AF (N=845)

Disability at clinical presentation1 30-day post-stroke mortality2

Fatal strokes (%)

 Effective stroke prevention is a priority for patients with AF1

No risk factors 0 Aspirin 81–325 mg daily

Validated using the National Registry of Atrial Fibrillation (NRAF)

CHADS2 risk criteria Score

Age ≥75 yrs 1

Stroke or TIA (previous history) 2

TIA = transient ischaemic attack

Patients Adjusted stroke rate (%/year)a

• At CHADS2 score ≥ 2 oral anticoagulation is recommended

• At CHADS2 score = 1 there is a choice between oral

ACC/AHA/ESC AF guidelines 2006 and ACCP 8th guidelines

1 Either OAC or Aspirin, prefer OAC

0 Either Aspirin or no therapy, prefer no therapy

There is no room for Aspirin in

European Heart Journal (2010) 31, 2369-2429

Unpredictable Numerous food–drug

VKA therapy has

Routine coagulation Frequent dose

INR = International normalized ratio; VKA = vitamin K antagonist

TYPICAL CATEGORIZATION OF SPAF PATIENTS

1 AGE: retirement age (60+) STROKE RISK: Moderate – High

2 AGE: relatively young, mid-50s STROKE RISK: Low (e.g.,

3 AGE: very old (80+) STROKE RISK: Moderate — High

4 AGE: retirement age (60+) STROKE RISK: Moderate — High

5 AGE: retirement age (60+) STROKE RISK: High

Indirect factor Xa inhibitors:

1Adapted from Turpie AG. Eur Heart J 2008;29 13

Study RRR P-value

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