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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
Thromboembolic Events
Control Patients in AF Trials
Cerebral 49 (91%)
Systemic 5 (9%)
Mild: 23 (45%)
30,000
100 0
0
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
INR Ratio
1.0
Aspirin Better
*Total risk reduction for all 3 studies combined is 21%
Aspirin Worse
6
5 4 3 2 1 0 Stroke or Systemic Embolism Major Bleeding Intracranial Hemorrhage Lancet 1996; 348; 633-638.
% per year
95% CI
% per year
95% CI
(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
2.5 x
1.6 x 1.7 x
1.4 x
NHLBI-NIH supported
Patients with AF at high risk of stroke
or death
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
Ischemic stroke
ICH
SDH/SAH
All stroke
High Risk
Age >75 years Rheumatic mitral valve disease Prosthetic heart valves Diabetes mellitus
Moderate Risk
Age 65-75
Recommended Therapy
Warfarin
(target INR 2.5, range 2.0-3.0)**
Aspirin 325 mg qd
**target INR > 2.5 for patients with mechanical heart valves
60
40
35%
20
0
<55 55-64 65-74 Age (years) 75-84
85
No warfarin 65%
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.
open-label
(n=3,407)
(n=3,913)
SPORTIF Program
Primary Analyses Intention-to-treat Analysis
Ximelagatran Better Warfarin Better
-0.66
-4
-3
-2
-1
SPORTIF V
Hemorrhage
p<0.0001
50
Event Rate (% /year)
Warfarin Ximelagatran
47% 37%
40 30 20
p=NS p=0.16
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
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