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
ACTIVE W Results
AHA Meeting: November 14,1350g.1
2005
 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.

ACTIVE W Results
AHA Meeting: November 14,1350g.2
2005
 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

ACTIVE W Results
AHA Meeting: November 14,1350g.3
2005
 ACTIVE Program: Three Trials
Documented AF + 1 risk factor:

Age 75, Hypertension, Prior stroke/TIA,

LVEF<45, PAD, Age 55-74 + CAD or diabetes

Contra-indications to OAC or Unwilling

ACTIVE W ACTIVE A
6500 patients 7500 patients
Clopidogrel+ASA vs. OAC Clopidogrel+ASA vs. ASA

No Exclusion criteria for ACTIVE I

Partial Factorial
ACTIVE I Design
~9000 patients
Irbesartan vs placebo

ACTIVE W Results
AHA Meeting: November 14,1350g.4
2005
 ACTIVE W: Treatments
OAC
Standard Care (INR 2.0 3.0)
INR at least monthly

Clopidogrel plus ASA

Clopidogrel 75 mg once daily
ASA 75-100 mg once daily

ACTIVE W Results
AHA Meeting: November 14,1350g.5
2005
 Outcome Events
Primary Outcome
Stroke, Non-CNS Systemic Embolism,
MI, Vascular Death

Safety Outcome
Major Bleeding

ACTIVE W Results
AHA Meeting: November 14,1350g.6
2005
 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

ACTIVE W Results
AHA Meeting: November 14,1350g.7
2005
 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 77 United Kingdom 294
Finland 53 Poland 641 United States 1074
Portugal 33

ACTIVE W Results
AHA Meeting: November 14,1350g.8
2005
 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

ACTIVE W Results
AHA Meeting: November 14,1350g.9
2005
 Risk Factor Profile
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 54-75 with diabetes or CAD 25.2 25.1
CHADS 2 Risk Score 2.01.1 2.01.1
ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.10
 Pre-Randomization Anti-thrombotic
Medications

OAC (%) C+A (%)

(n = 3371 ) (n = 3335)

ASA 26.2 30.1

Clopidogrel 2.3 2.6

OAC 78.0 75.7

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.11
ACTIVE W - INR Control

Percent patient
INR Range
months in range

<2.0 20.8

2.0-3.0 63.9

>3.0 15.4

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.12
 Stroke, Non-CNS Systemic Embolism,
MI & Vascular Death
0.10

5.64 %/year
0.08

RR = 1.45
P = 0.0002
Clopidogrel+ASA
Cumulative Hazard Rates

0.06

3.93 %/year
0.04

OAC
0.02
0.0

# at Risk 0.0 0.5 1.0 1.5

C+A 3335 3149 2387 916
OAC 3371 3220 2453 911
ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.13
 Major Bleeding
2.4 %/year
0.04

RR = 1.06
P = 0.67
0.03
Cumulative Hazard Rates

2.2 %/year
0.02
0.01

OAC

Clopidogrel+ASA
0.0

# at Risk 0.0 0.5 1.0 1.5

C+A 3335 3172 2403 914
OAC 3371 3212 2423 901
ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.14
 Primary Outcome Components &
Death
Rate per 100
C+A vs. OAC
patient years
Outcome
OAC C+A RR 95% CI p

Primary Outcome 3.93 5.64 1.45 1.19-1.77 0.0002

Stroke 1.40 2.44 1.75 1.27-2.41 0.0006

MI 0.55 0.84 1.54 0.91-2.60 0.11

Non-CNS Embol 0.10 0.48 5.13 1.75-15.0 0.0028

Vascular Death 2.57 2.85 1.11 0.85-1.44 0.45

Total Death 3.80 3.80 1.00 0.80-1.25 1.00

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.15
Subgroup Analyses

1350g.16
 Permanent Study Drug Discontinuation
Entry OAC No Entry OAC
Cumulative Hazard Rates

13.4% 13.2%
0.15

0.15
C+A
0.10

0.10
OAC
12.4%
0.05

0.05
C+A
6.1%
OAC
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

Years ACTIVE W Results

AHA Meeting: November 14, 2005
1350g.17
 INR Control
On OAC Not on OAC
P
at Entry at Entry
INR in
range 64.8 60.4 0.001
(2-3)
INR low
19.2 24.6 0.001
(<2)
INR High
15.5 15.1 0.14
(>3)

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.18
Stroke, Non-CNS Systemic Embolism,
MI, Vascular Death
Interaction P = 0.55
Entry OAC No Entry OAC
0.10

0.10
RR = 1.50 RR = 1.32
0.08

0.08
P = 0.0006 P = 0.17
Cumulative Hazard Rates

C+A C+A
0.06

0.06
0.04

0.04
OAC OAC
0.02

0.02
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.19
 Major Bleeding
Entry OAC Interaction P = 0.032 No Entry OAC
0.05

0.05
RR = 1.27 RR = 0.58
0.04

0.04
P = 0.14 P = 0.09
Cumulative Hazard Rates
0.03

0.03
OAC
C+A
0.02

0.02
OAC
0.01

0.01
C+A
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.20
 Primary Outcome +Major Bleeding
Entry OAC Interaction P = 0.17 No Entry OAC
0.14

0.14
RR = 1.51 RR = 1.14
P < 0.0001 P = 0.45
Cumulative Hazard Rates
0.10

0.10
C+A
0.06

0.06
OAC

OAC
C+A
0.02

0.02
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.21
Primary Outcome by Center INR Control
65% INR in Range Interaction P = 0.013 <65% INR in Range
0.10

0.10
RR = 1.83 RR = 1.11
0.08

0.08
P < 0.0001 P = 0.47
Cumulative Hazard Rates

C+A
0.06

0.06
C+A
0.04

0.04
OAC
0.02

0.02
OAC
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.22
Major Bleeding by Center INR Control
65% INR in Range Interaction P = 0.0006 <65% INR in Range
0.05

0.05
RR = 1.55 RR = 0.68
0.04

0.04
P = 0.027 P = 0.08
Cumulative Hazard Rates
0.03

0.03
OAC
C+A
0.02

0.02
OAC
0.01

0.01
C+A
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.23
Primary+Major Bleed by Centre INR Control
65% INR in Range Interaction P = 0.002 <65% INR in Range
0.15

0.15
RR = 1.80 RR = 1.06
P < 0.0001 P = 0.66
Cumulative Hazard Rates
0.10

0.10
C+A
0.05

0.05
OAC
OAC C+A
0.0

0.0

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE W Results
Years
AHA Meeting: November 14, 2005
1350g.24
 Conclusions

Oral anticoagulation is superior to

clopidogrel plus ASA for prevention of
vascular events

Rates of major hemorrhage are similar

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.25
 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

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.26
 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

ACTIVE W Results
AHA Meeting: November 14, 2005
1350g.27