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Antithrombotic Therapy

for

Stroke Prevention in Atrial Fibrillation

To this variety of apoplexy those are most liable who lead an idle life, who are obese, whose face and hands are constantly livid and whose pulse constantly unequal.
Wepfer, 1658

Left Atrial Appendage (LAA)

Thromboembolic Events
Control Patients in AF Trials

Cerebral 49 (91%)

Systemic 5 (9%)

Severity of Ischemic Strokes in Atrial Fibrillation


Number of events in 1,092 control patients
Fatal: 5 (10%) Moderate to severe: 23 (45%)

Mild: 23 (45%)

Age Distribution of People With AF


Compared With U.S. General Population
Population with Atrial Fibrillation U.S. Population
20,000 500 400 300 200 10,000

30,000

U.S. Population (x 1000)

100 0
0

Arch Int Med. 1995;155:471.

Age, years

AF Population (x 10)

Efficacy of Warfarin
Compared with Control in Five Studies
No. of PatientEvents years AFASAK 27 811 Risk Reduction, %

BAATAF
CAFA SPAF SPINAF Combined*

15
14 23 29 108

922
478 508 972 3691

*Total risk reduction for all 5 studies combined is 68%

100 50 0 -50 -100 Warfarin Better Warfarin Worse

Patients Assigned to Warfarin in AF Trials


Intensity of Anticoagulation When Stroke Occurred
4.0 3.0 2.0 1.8 1.7 1.6 PT 1.5 Ratio 1.4 (ISI 2.4) 1.3 1.2 1.1 1.0 AFASAK CAFA SPAF I BAATAF SPINAF
Target range for individual study

INR Ratio

1.0

ACCP recommendation: INR: 2.03.0

Efficacy of Aspirin Compared with Control


No. of PatientEvents years AFASAK SPAF EAFT Combined* 35 65 130 230 807 1457 838 3102 100 50 0 -50 -100 Risk Reduction (%)

Aspirin Better
*Total risk reduction for all 3 studies combined is 21%

Aspirin Worse

SPAF III Study


Atrial Fibrillation Clinical Assessment Echocardiography (TTE)

Female > 75 years Systolic hypertension Impaired LV function Prior thromboembolism

Low Risk Cohort


Aspirin 325 mg/day

High Risk Cohort


Warfarin Combination INR 23 13 mg Warfarin + Monthly INR to 325 mg Aspirin adjust dose fixed dose

SPAF III Results


High Risk Cohort
8
Event Rate, % per Patient-year 7 Aspirin Plus Fixed-Dose Warfarin Adjusted-Dose Warfarin (INR 2-3)

6
5 4 3 2 1 0 Stroke or Systemic Embolism Major Bleeding Intracranial Hemorrhage Lancet 1996; 348; 633-638.

SPAF III Study


Atrial Fibrillation Clinical Assessment Echocardiography (TTE)

Female > 75 years Systolic hypertension Impaired LV function Prior thromboembolism

Low Risk Cohort


Aspirin 325 mg/day

High Risk Cohort


Warfarin Combination INR 23 13 mg Warfarin + Monthly INR to 325 mg Aspirin adjust dose fixed dose

SPAF III Non-Randomized Aspirin-Only Arm


Low Stroke Risk Cohort*
No History of Hypertension History of Hypertension

% per year

95% CI

% per year

95% CI

Stroke or syst. 1.1% embolism

(0.6%2.0%)

3.6%

(2.5%5.2%)

*Patients enrolled had none of these high risk features: female >75 years, impaired LV function, current SBP >160 mm Hg, prior thromboembolism

Risk Factors for Stroke and Efficacy of Antithrombotic Therapy in Atrial Fibrillation
Archives of Internal Medicine July 11, 1994

Predicting Stroke Risk in AFWho Benefits Most?


Multivariate Analysis of Pooled Data
Clinical risk factors Relative risk

Previous stroke or TIA


History of hypertension Diabetes

2.5 x
1.6 x 1.7 x

Increasing age (per decade)

1.4 x

Transthoracic Echocardiographic Predictors of Stroke in Patients with AF


Atrial Fibrillation Investigators

Combined databases from 3 randomized


trials (N=1,066)

Moderate to severe LV dysfunction was the


only independent predictor of stroke (RR 2.5, p<0.001)

Left atrial size did not predict stroke risk

Atrial Fibrillation Follow-up Investigation of Rhythm Management


AFFIRM
Multicenter, randomized clinical trial

NHLBI-NIH supported
Patients with AF at high risk of stroke
or death

Randomized to either rate-control or rhythmcontrol strategy

Primary endpoint: all-cause mortality


The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

AFFIRM
Stroke Events
9 8
Percent P=.79 P=.93 8.9 7.4

Rate

Rhythm

7 6 5 4 3 2 1 0

7.1
5.5

P=.73 P=.68 1.1 1.3 0.8 0.8

Ischemic stroke

ICH

SDH/SAH

All stroke

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

7th ACCP Consensus Conference on Antithrombotic Therapy


CHEST Supplement: 2004

ACCP Recommendations 2004


Risk Factors for Stroke
Prior stroke, TIA, systemic embolism Hypertension Moderate or severely impaired LV
systolic function and / or CHF

High Risk

Age >75 years Rheumatic mitral valve disease Prosthetic heart valves Diabetes mellitus

Moderate Risk

Age 65-75

ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation*


Risk Factors
Any High Risk Factor

Recommended Therapy
Warfarin
(target INR 2.5, range 2.0-3.0)**

Age 65-75 years and No high risk factors


No Risk Factors and age < 65

Aspirin 325 mg qd or Warfarin


(target INR 2.5, range 2.0-3.0)**

Aspirin 325 mg qd

*Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF

**target INR > 2.5 for patients with mechanical heart valves

ACCP Recommendations 2004


Cardioversion Continuation of anticoagulation beyond 4 weeks after successful pharmacological or electrical cardioversion is based on whether the patient has experienced more than 1 episode of AF and on their risk factor status. Patients experiencing more than 1 episode of AF should be considered as having paroxysmal AF

Warfarin for Atrial Fibrillation


Limitations Lead to Under-treatment
80
Warfarin Use in Eligible Patients (%)
58% 44% 61% 57% 55% Overall Use

60

40

35%

20

0
<55 55-64 65-74 Age (years) 75-84

85

Go A et al. Ann Intern Med 1999;131:927.

Warfarin for Atrial Fibrillation


Limitations Lead to Inadequate Treatment
Adequacy of Anticoagulation in Patients with AF in Primary Care Practice
INR above target 6% INR in target range 15%

No warfarin 65%

Subtherapeutic INR 13%


Samsa GP, et al. Arch Intern Med 2000;160:967.

Ximelagatran
Oral Direct Thrombin Inhibitor
Prompt onset and offset of anticoagulation Wider therapeutic margin than warfarin Predictable pharmacokinetics Low potential for food and drug interactions

No dose adjustment
No coagulation monitoring

Sarich TC, et al. J Am Coll Cardiol 2003;41:557. Eriksson H, et al. Drug Metab Disp 2003;31:294.

Stroke Prevention Using an ORal Direct Thrombin Inhibitor in Atrial Fibrillation


The SPORTIF III and V Trials
Patients with Nonvalvular AF and Risk Factors for Stroke n=7,320

Adjusted-dose Warfarin (INR 2-3)

Fixed-dose Ximelagatran (36 mg bid)

SPORTIF III 23 nations

open-label

(n=3,407)
(n=3,913)

SPORTIF V US, Canada double-blind

SPORTIF Program
Primary Analyses Intention-to-treat Analysis
Ximelagatran Better Warfarin Better

-0.66

SPORTIF III SPORTIF V Pooled

p=0.10 +0.45 p=0.13 -0.03 p=0.94

-4

-3

-2

-1

Difference in Absolute Event Rates (Ximelagatran Warfarin)

SPORTIF V
Hemorrhage
p<0.0001

50
Event Rate (% /year)

Warfarin Ximelagatran

47% 37%

40 30 20
p=NS p=0.16

10 0.1% 0.1% 0 ICH

3.1%2.4% Major Bleeding Major + Minor Bleeding

SPORTIF V
Liver Enzyme Elevation ALT >3 x ULN
14 Warfarin Ximelagatran

40

Warfarin Ximelagatran

Incidence (%)

50

12 10 8 6 4 2 0

p<0.001
6.0%

Number of Patients

30

0.8%

20

ALT >3x ULN

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Months

Conclusions
In high-risk patients with atrial fibrillation, ximelagatran offers:
Fixed oral dosing without coagulation monitoring Effectiveness non-inferior to well-controlled warfarin in
preventing stroke and systemic embolic events

Less bleeding than warfarin Elevated liver enzymes in ~6% of patients A promising treatment option for prevention of
thromboembolism

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