ACTIVE

Clopidogrel plus Aspirin versus Aspirin in Patients Unsuitable for Warfarin

ACTIVE

Vitamin K Antagonists (VKA) in AF

38% reduction in strokes, compared to aspirin*
Increase in hemorrhage, compared to aspirin* 70% increase extra-cranial 128% increase intra-cranial Recommended for high-risk patients Monitoring required Drug interactions Often not used
*Hart RC et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular AF. Ann Intern Med 2007: 146: 857-67

ACTIVE

Platelet Activation in AF
Elevated markers of platelet activation in AF Aspirin reduces stroke by 22% in AF* Addition of clopidogrel to aspirin achieves greater suppression of platelet activity reduces major vascular events in ACS

*Hart RC et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular AF. Ann Intern Med 2007: 146: 857-67

ACTIVE

Hypothesis of ACTIVE A
In high-risk AF patients unsuitable for VKA because of specific bleeding risk physician assessment VKA not appropriate patient preference not to receive VKA Addition of clopidogrel to ASA will reduce major vascular events and stroke, at acceptable risk for major hemorrhage

ACTIVE

Patient Eligibility
Inclusion Documented AF (permanent or intermittent) 1 Risk factor for stroke Unsuitable for VKA Exclusions include excessive risk of hemorrhage such as: Peptic ulcer disease Intra-cerebral bleed

ACTIVE

Treatments
Background Aspirin (75-100 mg/day, recommended) in all patients

Randomized to: Clopidogrel 75 mg per day OR Double-blind matching placebo

ACTIVE

Outcomes and Statistical Power

Primary Outcome is Major Vascular Events Stroke, MI, non-CNS Systemic Embolism, Vascular Death Secondary Outcomes Stroke Major bleeding 7500 patients required to have 85% power to detect 15% risk reduction

ACTIVE

Study Conduct
33 countries, 561 centres
Enrolment of 7554 patients June 2003 May 2006 Follow-up ended November 2009 median 3.6 years 0.6% lost to follow-up

ACTIVE

Baseline Demographics
ACTIVE A ACTIVE W

N
Mean age Male Mean systolic BP (mmHg) Permanent AF Baseline VKA Baseline aspirin

7554
71 10 58% 136 19 64% 8.5% 83%

6706
70 9 66% 133 19 68% 77% 26%

ACTIVE

Risk Factor Profile

ACTIVE A Prior MI 14% ACTIVE W 18%

Heart failure
Hypertension Diabetes mellitus Prior stroke or TIA Mean CHADS2 score

33%
85% 20% 13% 2.1 1.1

31%
83% 21% 15% 2.0 1.1

ACTIVE

Permanent Discontinuation Rates

0.3

0.4

0.5

Permanent Study Medication Discontinuation

Clopidogrel+Aspirin Aspirin

0.0
0
No. at Risk C+A 3772 ASA 3782

0.1

0.2

1
2997 3026

2
2536 2590

3
1841 1928

4
814 849

Years

ACTIVE

Primary Outcome
0.4
Cumulative Hazard Rates
HR=0.89 (0.81-0.98) p=0.014

0.3

0.2

Aspirin

0.0

0.1

Clopidogrel+Aspirin

0
No. at Risk C+A 3772 ASA 3782

1
3453 3427

2
3176 3103

3
2519 2459

4
1174 1154

Years

ACTIVE

Stroke
Cumulative Hazard Rates

0.10

0.15

HR=0.72 (0.62-0.84) p=0.00002

Aspirin

0.05

Clopidogrel+Aspirin

0.0
0
No. at Risk C+A 3772 ASA 3782

1
3488 3459

2
3225 3155

3
2567 2516

4
1197 1184

Years

ACTIVE

Myocardial Infarction
0.01 0.02 0.03 0.04 0.05
HR=0.77 (0.59-1.02) p=0.067

Cumulative Hazard Rates

Aspirin

Clopidogrel+Aspirin

0.0 0
No. at Risk C+A 3772 ASA 3782

1
3526 3523

2
3293 3261

3
2632 2633

4
1256 1263

Years

ACTIVE

Stroke, MI, Systemic Embolus, Vascular Death

Outcome
Clopidogrel + Aspirin # rate/ year 6.8 4.7 0.7 2.4 0.4 Aspirin # rate/ year 7.6 4.7 0.9 3.3 1.4 Clopidogrel + Aspirin versus Aspirin RR 95% CI P

Primary Vascular Death MI Stroke Non-CNS systemic embolism

838 601 90 297 53

924 600 116 409 54

0.90 1.0 0.77 0.72 0.98

0.82-0.98 0.91-1.13 0.59-1.02 0.62-0.84 0.67-1.43

0.023 0.81 0.068 0.00002 0.93

ACTIVE

Strokes
Outcome
Clopidogrel + Aspirin # rate/ year Aspirin # rate/ year Clopidogrel + Aspirin versus Aspirin RR 95% CI P

All Stroke
Ischemic Hemorrhagic Type uncertain

297
236 30 41

2.4
1.9 0.23 0.32

409
343 22 52

3.3
2.8 0.17 0.41

0.72
0.68 1.37 0.79

0.62-0.84
0.58-0.80 0.79-2.37 0.53-1.19

<0.0001
<0.0001 0.26 0.27

ACTIVE

Stroke Severity
Clopidogrel + Aspirin N Rate Aspirin Clopidogrel + Aspirin vs. Aspirin RR 95% CI P

Rate

Total strokes Non-disabling strokes m0d. Rankin 0-2 Disabling or fatal strokes mod. Rankin 3-6

297

2.38

409

3.32

0.72

0.62-0.84 <0.001

108

0.85

154

1.23

0.70

0.55-0.89

0.004

198

1.56

267

2.12

0.74

0.62-0.89

0.001

ACTIVE

Fatal strokes prevented

100

-24
80

-27
# Strokes

60 40

Aspirin Clopidogrel& Aspirin

+3
20

0
Total Ischem/Unc Hemorrhagic

Type of Stroke

ACTIVE

Hemorrhage
Outcome Clopidogrel + Aspirin #
Major Severe 249
189

Aspirin #
161
122

Clopidogrel + Aspirin versus Aspirin RR

1.57
1.57

rate/ year
2.0
1.5

rate/ year
1.3
1.0

95% CI
1.29-1.92
1.25-1.97

P
<0.0001
<0.0001

Fatal
Total Minor

41
1014 409

0.3
9.7 3.5

28
651 175

0.2
5.7 1.4

1.47
1.68 2.43

0.91-2.38
1.52-1.85 2.03-2.90

0.12
<0.0001 <0.0001

ACTIVE

Risk Benefit Ratio: Addition of Clopidogrel to Aspirin

1000 AF patients treated for 3 years

Will prevent:

28 strokes

17 disabling or fatal

6 myocardial infarctions
At a Cost of:

20 (non-stroke) major bleeds

ACTIVE

Warfarin versus Clopidogrel plus Aspirin (against Aspirin Alone)

Meta-Analysis Warfarin vs. Aspirin* (RRR) Reduction in stroke Increase in intra-cranial major bleed Increase in extra-cranial major bleed
*Hart RC et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular AF Ann Intern Med 2007: 146: 857-67

ACTIVE A Clopidogrel + Aspirin vs. Aspirin** (RRR) -28% +87% +52%

**ACTIVE A results

- 38% +128% +70%

ACTIVE

Conclusion
Addition of Clopidogrel to Aspirin
Reduces major vascular events (11%) 28% reduction in stroke 23% reduction in MI Increases major bleeding (58%)
Overall benefit to many patients, at acceptable risk