Antithrombotic Therapy for Stroke Prevention in Atrial Fibrillation

1
Antithrombotic Therapy for Stroke Prevention
inAtrial Fibrillation
2
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
3
Left Atrial Appendage (LAA)
4
Thromboembolic EventsControl Patients in AF
Trials
Cerebral 49 (91)
Systemic 5 (9)
5
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)
6
Age Distribution of People With AFCompared With
U.S. General Population
30,000 20,000 10,000 0
500 400 300 200 100 0
Population with Atrial Fibrillation
U.S. Population
AF Population (x 10)
U.S. Population (x 1000)
lt5
59
1014
7579
gt95
2529
3539
4044
6064
9094
2024
5054
7074
8084
4549
5559
6569
8589
1519
3034
Age, years
Arch Int Med. 1995155471.
7
Efficacy of WarfarinCompared with Control in
Five Studies
No. of Events
Patient- years
Risk Reduction,
AFASAK 27 811 BAATAF 15 922 CAFA 14 478 SPAF 2
3 508 SPINAF 29 972 Combined 108 3691
100 50 0 -50
-100
Total risk reduction for all 5 studies
combined is 68
Warfarin Better
Warfarin Worse
8
Patients Assigned to Warfarin in AF
TrialsIntensity of Anticoagulation When Stroke
Occurred
1.8
4.0
1.7
1.6
3.0
PT
INR
1.5
Ratio
Ratio
1.4
(ISI 2.4)
2.0
1.3
1.2
1.1
1.0
1.0
AFASAK
SPAF I
BAATAF
SPINAF
CAFA
Target range for individual study
ACCP recommendation INR 2.03.0
9
Efficacy of Aspirin Compared with Control
No. of Events
Patient- years
Risk Reduction ()
AFASAK 35 807 SPAF 65 1457 EAFT 130 838 Combin
ed 230 3102
100 50 0 -50
-100
Aspirin Better
Aspirin Worse
Total risk reduction for all 3 studies combined
is 21
10
SPAF III Study
Atrial Fibrillation
Clinical Assessment Echocardiography
(TTE) Female gt 75 years Systolic
hypertension Impaired LV function Prior
thromboembolism


High Risk Cohort Warfarin Combination INR
23 13 mg Warfarin Monthly INR to 325 mg
Aspirin adjust dose fixed dose
Low Risk Cohort Aspirin 325 mg/day
11
SPAF III ResultsHigh Risk Cohort
Aspirin Plus Fixed-Dose Warfarin Adjusted-Dose
Warfarin (INR 2-3)
8
7
6
5
Event Rate, per Patient-year
4
3
2
1
0
Stroke or Systemic Embolism
Major Bleeding
Intracranial Hemorrhage
Lancet 1996 348 633-638.
12
SPAF III Study
Atrial Fibrillation
Clinical Assessment Echocardiography
(TTE) Female gt 75 years Systolic
hypertension Impaired LV function Prior
thromboembolism


High Risk Cohort Warfarin Combination INR
23 13 mg Warfarin Monthly INR to 325 mg
Aspirin adjust dose fixed dose
Low Risk Cohort Aspirin 325 mg/day
13
SPAF III Non-Randomized Aspirin-Only ArmLow
Stroke Risk Cohort
No History of
Hypertension History of Hypertension
per year 95 CI per year 95 CI Stroke or
syst. 1.1 (0.62.0) 3.6 (2.55.2)
embolism
Patients enrolled had none of these high risk
features female gt75 years, impaired LV function,
current SBP gt160 mm Hg, prior thromboembolism
14
Risk Factors for Stroke and Efficacy of
Antithrombotic Therapy in Atrial Fibrillation
Archives of Internal MedicineJuly 11, 1994
15
Predicting Stroke Risk in AFWho Benefits
Most?Multivariate Analysis of Pooled Data
Clinical risk factors Relative
risk Previous stroke or TIA 2.5 x History of
hypertension 1.6 x Diabetes 1.7 x Increasing age
(per decade) 1.4 x
Adapted from Arch Intern Med 1994 1541454
16
Transthoracic Echocardiographic Predictors of
Stroke in Patients with AF

• Atrial Fibrillation Investigators
• Combined databases from 3 randomized trials
  (N1,066)
• Moderate to severe LV dysfunction was the only
  independent predictor of stroke (RR 2.5, plt0.001)
• Left atrial size did not predict stroke risk

17
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
  rhythm-control strategy
• Primary endpoint all-cause mortality

The AFFIRM Investigators. N Engl J Med.
20023471825-1833.
18
AFFIRM Stroke Events
P.93
8.9
P.79
7.4
7.1
5.5
Percent
P.73
P.68
1.3
1.1
0.8
0.8
The AFFIRM Investigators. N Engl J Med.
20023471825-1833.
19
7th ACCP Consensus Conference on Antithrombotic
Therapy CHEST Supplement 2004
20
ACCP Recommendations 2004Risk Factors for Stroke

• Prior stroke, TIA, systemic embolism
• Hypertension
• Moderate or severely impaired LV systolic
  function and / or CHF
• Age gt75 years
• Rheumatic mitral valve disease
• Prosthetic heart valves
• Diabetes mellitus
• Age 65-75

High Risk

Moderate Risk
21
ACCP 2004 Recommendations for Stroke Prevention
in Atrial Fibrillation

• Risk Factors
  Recommended Therapy
• Any High Risk Factor
  Warfarin
• 
  (target INR 2.5, range 2.0-3.0)
• Age 65-75 years and
  Aspirin 325 mg qd
• No high risk factors or
  Warfarin
• 
  (target INR 2.5, range 2.0-3.0)
• No Risk Factors and age lt 65 Aspirin 325
  mg qd
• Applies to persistent (sustained or permanent)
  and paroxysmal (intermittent) AF
• target INR gt 2.5 for patients with mechanical
  heart valves

22
ACCP Recommendations 2004Cardioversion

• 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
  

23
Warfarin for Atrial FibrillationLimitations Lead
to Under-treatment
55 Overall Use
61
58
57
44
Warfarin Use inEligible Patients ()
35
lt55
55-64
65-74
75-84
?85
Age (years)
Go A et al. Ann Intern Med 1999131927.
24
Warfarin for Atrial Fibrillation Limitations
Lead to Inadequate Treatment
Adequacy of Anticoagulation inPatients with AF
in Primary Care Practice
INR above target6
No warfarin65
INR intarget range15
Subtherapeutic INR 13
Samsa GP, et al. Arch Intern Med 2000160967.
25
XimelagatranOral 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
200341557. Eriksson H, et al. Drug Metab Disp
200331294.
26
Stroke Prevention Using anORal Direct Thrombin
Inhibitor in Atrial FibrillationThe SPORTIF III
and V Trials
Patients with Nonvalvular AF and Risk Factors for
Stroke n7,320
SPORTIF III 23 nations open-label
(n3,407) SPORTIF V US, Canada double-blind (n3,
913)
27
SPORTIF ProgramPrimary AnalysesIntention-to-trea
t Analysis
Ximelagatran Better
Warfarin Better
-1
0
1
2
3
4
-2
-3
-4
Difference in Absolute Event Rates(Ximelagatran
Warfarin)
28
SPORTIF VHemorrhage
plt0.0001
Event Rate ( /year)
p0.16
pNS
29
SPORTIF VLiver Enzyme ElevationALT gt3 x ULN
30
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