1. ACTIVE Clopidogrel plus Aspirin versus Aspirin in Patients Unsuitable for Warfarin

2. 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

3. 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

4. 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

5. 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

6. ACTIVE Treatments Background Aspirin  (75-100 mg/day, recommended) in all patients Randomized to: Clopidogrel 75 mg per day OR Double-blind matching placebo

7. 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

8. 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

9. ACTIVE Baseline Demographics ACTIVE AACTIVE W N75546706 Mean age71 ± 1070 ± 9 Male58%66% Mean systolic BP (mmHg)136 ± 19133 ± 19 Permanent AF64%68% Baseline VKA8.5%77% Baseline aspirin83%26%

10. ACTIVE Risk Factor Profile ACTIVE AACTIVE W Prior MI14%18% Heart failure33%31% Hypertension85%83% Diabetes mellitus20%21% Prior stroke or TIA13%15% Mean CHADS2 score2.1 ± 1.12.0 ± 1.1

11. ACTIVE Permanent Study Medication Discontinuation

12. ACTIVE Primary Outcome Cumulative Hazard Rates 0.0 0.1 0.2 0.3 0.4 01234 Aspirin Clopidogrel+Aspirin HR=0.89 (0.81-0.98) p=0.014 37723453317625191174 37823427310324591154 No. at Risk ASA C+A Years

13. ACTIVE Stroke

14. ACTIVE Myocardial Infarction Cumulative Hazard Rates 0.0 0.01 0.02 0.03 0.04 0.05 01234 Aspirin Clopidogrel+Aspirin HR=0.77 (0.59-1.02) p=0.067 37723526329326321256 37823523326126331263 No. at Risk ASA C+A Years

15. ACTIVE Outcome Clopidogrel + Aspirin AspirinClopidogrel + Aspirin versus Aspirin #rate/ year #rate/ year RR95% CIP Primary8386.89247.60.900.82-0.980.023 Vascular Death6014.76004.71.00.91-1.130.81 MI900.71160.90.770.59-1.020.068 Stroke2972.44093.30.720.62-0.840.00002 Non-CNS systemic embolism 530.4541.40.980.67-1.430.93 Stroke, MI, Systemic Embolus, Vascular Death

16. ACTIVE Strokes Outcome Clopidogrel + Aspirin AspirinClopidogrel + Aspirin versus Aspirin #rate/ year #rate/ year RR95% CIP All Stroke2972.44093.30.720.62-0.84<0.0001 Ischemic2361.93432.80.680.58-0.80<0.0001 Hemorrhagic300.23220.171.370.79-2.370.26 Type uncertain410.32520.410.790.53-1.190.27

17. ACTIVE Stroke Severity Clopidogrel + Aspirin Aspirin Clopidogrel + Aspirin vs. Aspirin NRateN RR95% CIP Total strokes2972.384093.320.720.62-0.84<0.001 Non-disabling strokes m0d. Rankin 0-2 1080.851541.230.700.55-0.890.004 Disabling or fatal strokes mod. Rankin 3-6 1981.562672.120.740.62-0.890.001

18. ACTIVE Fatal strokes prevented

19. ACTIVE Hemorrhage Outcome Clopidogrel + Aspirin AspirinClopidogrel + Aspirin versus Aspirin #rate/ year #rate/ year RR95% CIP Major2492.01611.31.571.29-1.92<0.0001 Severe 1891.51221.01.571.25-1.97<0.0001 Fatal410.3280.21.470.91-2.380.12 Total10149.76515.71.681.52-1.85<0.0001 Minor4093.51751.42.432.03-2.90<0.0001

20. 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

21. ACTIVE Warfarin versus Clopidogrel plus Aspirin ( against Aspirin Alone) Meta-AnalysisACTIVE 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

22. 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