1. Presenter Disclosure Information
Stuart J. Connolly
The Atrial Fibrillation Clopidogrel Trial
with Irbesartan for Prevention of Vascular Events
(ACTIVE)
DISCLOSURE INFORMATION:
The following relationships exist related to this presentation:
ACTIVE was sponsored by Sanofi-Aventis and by Bristol-Myers Squibb

2. Background
AF is a risk factor for stroke and other vascular events (VE)
Oral anticoagulation (OAC) reduces the risk of stroke and VE, but is difficult to use and is poorly tolerated by some patients.

3. Clopidogrel Plus ASA ASA reduces the risk of stroke in AF by 20%
Addition of clopidogrel to ASA in ACS and acute MI further reduces risk of vascular events
Addition of clopidogrel to ASA in AF could provide an easy to use alternate to OAC

4. ACTIVE Program: Three Trials
Documented AF + 1 risk factor:
Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age CAD or diabetes
Contra-indications to OAC or Unwilling
ACTIVE W
Clopidogrel+ASA vs. OAC
ACTIVE A
Clopidogrel+ASA vs. ASA
6500 patients
7500 patients
No Exclusion criteria for ACTIVE I
ACTIVE is a phase III, multicenter, multinational, parallel randomized controlled evaluation of clopidogrel plus ASA, with factorial evaluation of irbesartan, for the prevention of vascular events in patients with atrial fibrillation.
Patients will be enrolled over 2 years and followed to common termination date (expected to be about 4 years after enrollment of the first patient).
About 14,000 patients will be included in the ACTIVE W or ACTIVE A trials. Due to the partial factorial design, patients will only be randomized in ACTIVE I once first randomized into either ACTIVE A or ACTIVE W.
Three separate but related trials are included in the ACTIVE study. These are known as ACTIVE W, ACTIVE A, and ACTIVE I.
ACTIVE W (n= 6,500): A multicenter, prospective, randomized, non-inferiority trial of clopidogrel plus ASA versus standard care oral anticoagulation (open trial with blinded outcome evaluation).
ACTIVE A (n= 7,500): A multicenter, randomized, double-blind, placebo-controlled superiority trial of clopidogrel plus ASA versus ASA alone.
ACTIVE I (n= at least 10,000): A multicenter, partial factorial, randomized, double-blind, placebo-controlled superiority trial of irbesartan.
Partial Factorial Design
ACTIVE I
Irbesartan vs placebo
~9000 patients

5. ACTIVE W: Treatments OAC Standard Care (INR 2.0 – 3.0)
INR at least monthly
Clopidogrel plus ASA
Clopidogrel 75 mg once daily
ASA mg once daily

6. Outcome Events Primary Outcome
Stroke, Non-CNS Systemic Embolism, MI, Vascular Death
Safety Outcome
Major Bleeding

7. Non-Inferiority Trial
Preserves  50% of a conservative estimate of the proven effect of oral anticoagulation in AF
Non-inferiority margin = 1.186
With an expected event rate of 6 %/year, 6500 patients needed for 84% power

8. 6706 pts from 522 centers in 31 countries
Argentina
301
France
103
Russia
257
Australia
216
Germany
581
Singapore 25
Austria 12
Greece 99
South Africa 98
Belgium
141
Hong Kong 30
Spain 77
Brazil
246
Italy
166
Sweden
125
Canada
1100
Malaysia 45
Switzerland 46
Chile 75
Mexico 71
Taiwan 40
Czech Republic
233
Netherlands
375
Turkey 17
Denmark 56
Norway
United Kingdom
294
Finland 53
Poland
641
United States
1074
Portugal 33

9. Early Termination of ACTIVE W
DSMB recommended early termination of ACTIVE W due to evidence of superiority of oral anticoagulation
Recommends continuation of the
ACTIVE A & ACTIVE I studies

10. Risk Factor Profile No. Randomized 3371 3335 Age  75 yrs 35.4 34.5
OAC (%)
C + A (%)
No. Randomized
3371
3335
Age  75 yrs
35.4
34.5
LVEF < 45
16.9
16.5
Hypertension on treatment
81.5
81.2
Prior Stroke/TIA/Embolus
15.2
14.8
Peripheral Arterial Disease
3.0
2.9
Age with diabetes or CAD
25.2
25.1
CHADS 2 Risk Score
2.01.1

11. Pre-Randomization Anti-thrombotic Medications
OAC (%)
(n = 3371 )
C+A (%)
(n = 3335)
ASA
26.2
30.1
Clopidogrel
2.3
2.6
OAC
78.0
75.7

12. Percent patient months in range
ACTIVE W - INR Control
INR Range
Percent patient months in range
<2.0
20.8
63.9
>3.0
15.4

13. Stroke, Non-CNS Systemic Embolism, MI & Vascular Death
5.64 %/year
RR = 1.45
P =
3.93 %/year
Cumulative Hazard Rates
# at Risk
C+A
OAC
Years

14. Cumulative Hazard Rates
Major Bleeding
2.4 %/year
RR = 1.06
P = 0.67
2.2 %/year
Cumulative Hazard Rates
# at Risk
C+A
OAC
Years

15. Primary Outcome Components & Death
Rate per 100 patient years
C+A vs. OAC
OAC
C+A RR
95% CI p
Primary Outcome
3.93
5.64
1.45
0.0002
Stroke
1.40
2.44
1.75
0.0006 MI
0.55
0.84
1.54
0.11
Non-CNS Embol
0.10
0.48
5.13
0.0028
Vascular Death
2.57
2.85
1.11
0.45
Total Death
3.80
1.00

16. Subgroup Analyses

17. Permanent Study Drug Discontinuation
Entry OAC
No Entry OAC
13.4%
13.2%
Cumulative Hazard Rates
12.4%
6.1%
Years

18. INR Control On OAC at Entry Not on OAC at Entry P INR in range (2-3)
64.8
60.4
0.001
INR low
(<2)
19.2
24.6
INR High
(>3)
15.5
15.1
0.14

19. Stroke, Non-CNS Systemic Embolism, MI, Vascular Death
Entry OAC
Interaction P = 0.55
No Entry OAC
RR = 1.50
P =
RR = 1.32
P = 0.17
Cumulative Hazard Rates
Years

20. Cumulative Hazard Rates
Major Bleeding
Entry OAC
Interaction P = 0.032
No Entry OAC
RR = 1.27
P = 0.14
RR = 0.58
P = 0.09
Cumulative Hazard Rates
Years

21. Primary Outcome +Major Bleeding
Entry OAC
No Entry OAC
Interaction P = 0.17
RR = 1.51
P <
RR = 1.14
P = 0.45
Cumulative Hazard Rates
Years

22. Primary Outcome by Center INR Control
 65% INR in Range
<65% INR in Range
Interaction P = 0.013
RR = 1.83
P <
RR = 1.11
P = 0.47
Cumulative Hazard Rates
Years

23. Major Bleeding by Center INR Control
 65% INR in Range
<65% INR in Range
Interaction P =
RR = 1.55
P = 0.027
RR = 0.68
P = 0.08
Cumulative Hazard Rates
Years

24. Primary+Major Bleed by Centre INR Control
 65% INR in Range
<65% INR in Range
Interaction P = 0.002
RR = 1.80
P <
RR = 1.06
P = 0.66
Cumulative Hazard Rates
Years

25. Conclusions
Oral anticoagulation is superior to clopidogrel plus ASA for prevention of vascular events
Rates of major hemorrhage are similar

26. Conclusions: Sub-groups
Benefit and safety of oral anticoagulation versus clopidogrel plus aspirin is uncertain for patients not on oral anticoagulation at entry
For patients at centers not achieving good INR control, oral anticoagulation may offer little benefit over clopidogrel plus ASA

27. Clinical Implication
Oral anticoagulation is the most effective currently available antithrombotic therapy for use in AF.
To achieve its benefits it must be used optimally