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

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 7554 6706

Mean age 71 ± 10 70 ± 9

Male 58% 66%

Mean systolic BP (mmHg) 136 ± 19 133 ± 19

Permanent AF 64% 68%

Baseline VKA 8.5% 77%

Baseline aspirin 83% 26%

ACTIVE

Risk Factor Profile

ACTIVE A ACTIVE W

Prior MI 14% 18%

Heart failure 33% 31%

Hypertension 85% 83%

Diabetes mellitus 20% 21%

Prior stroke or TIA 13% 15%

Mean CHADS2 score 2.1 ± 1.1 2.0 ± 1.1

ACTIVE

Pe

rma

ne

nt

Dis

con

tinu

atio

n R

ate

s

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4

Aspirin

Clopidogrel+Aspirin

3772 2997 2536 1841 8143782 3026 2590 1928 849

No. at Risk

ASAC+A

Years

ACTIVE

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.1

0.2

0.3

0.4

0 1 2 3 4

Aspirin

Clopidogrel+Aspirin

HR=0.89 (0.81-0.98) p=0.014

3772 3453 3176 2519 11743782 3427 3103 2459 1154

No. at Risk

ASAC+A

Years

ACTIVE

Cu

mu

lativ

e H

aza

rd R

ate

s

0.0

0.05

0.10

0.15

0 1 2 3 4

Aspirin

Clopidogrel+Aspirin

HR=0.72 (0.62-0.84) p=0.00002

3772 3488 3225 2567 11973782 3459 3155 2516 1184

No. at Risk

ASAC+A

Years

ACTIVE

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4

Aspirin

Clopidogrel+Aspirin

HR=0.77 (0.59-1.02) p=0.067

3772 3526 3293 2632 12563782 3523 3261 2633 1263

No. at Risk

ASAC+A

Years

ACTIVEACTIVE

Outcome

Clopidogrel + Aspirin

Aspirin Clopidogrel + Aspirin versus Aspirin

# rate/

year

# rate/ year

RR 95% CI P

Primary 838 6.8 924 7.6 0.90 0.82-0.98 0.023

Vascular Death 601 4.7 600 4.7 1.0 0.91-1.13 0.81

MI 90 0.7 116 0.9 0.77 0.59-1.02 0.068

Stroke 297 2.4 409 3.3 0.72 0.62-0.84 0.00002

Non-CNS systemic embolism

53 0.4 54 1.4 0.98 0.67-1.43 0.93

Stroke, MI, Systemic Embolus, Vascular Death

ACTIVE

Outcome

Clopidogrel + Aspirin

Aspirin Clopidogrel + Aspirin versus Aspirin

# rate/

year

# rate/ year

RR 95% CI P

All Stroke 297 2.4 409 3.3 0.72 0.62-0.84 <0.0001

Ischemic 236 1.9 343 2.8 0.68 0.58-0.80 <0.0001

Hemorrhagic 30 0.23 22 0.17 1.37 0.79-2.37 0.26

Type uncertain 41 0.32 52 0.41 0.79 0.53-1.19 0.27

ACTIVE

Stroke SeverityClopidogr

el + Aspirin

AspirinClopidogrel +

Aspirin vs. Aspirin

NRate

N Rate RR 95% CI P

Total strokes 297 2.38 409 3.32 0.720.62-0.84

<0.001

Non-disabling strokesm0d. Rankin 0-2

108 0.85 154 1.23 0.700.55-0.89

0.004

Disabling or fatal strokes mod. Rankin 3-6

198 1.56 267 2.12 0.740.62-0.89

0.001

ACTIVE

0

20

40

60

80

100

Total Ischem/Unc Hemorrhagic

# S

tro

kes

Type of Stroke

Aspirin

Clopidogrel& Aspirin

-24

-27

+3

ACTIVE

Hemorrhage

Outcome

Clopidogrel + Aspirin

Aspirin Clopidogrel + Aspirin versus Aspirin

# rate/

year

# rate/ year

RR 95% CI P

Major 249 2.0 161 1.3 1.57 1.29-1.92 <0.0001

Severe 189 1.5 122 1.0 1.57 1.25-1.97 <0.0001

Fatal 41 0.3 28 0.2 1.47 0.91-2.38 0.12

Total 1014 9.7 651 5.7 1.68 1.52-1.85 <0.0001

Minor 409 3.5 175 1.4 2.43 2.03-2.90 <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 ACTIVE A

Warfarin vs. Aspirin*

(RRR)

Clopidogrel + Aspirin

vs. Aspirin**(RRR)

Reduction in stroke - 38% -28%

Increase in intra-cranial major bleed

+128% +87%

Increase in extra-cranial major bleed

+70% +52%

*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 results

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