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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
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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.
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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
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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
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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
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Outcome Events Primary Outcome
Stroke, Non-CNS Systemic Embolism, MI, Vascular Death Safety Outcome Major Bleeding
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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
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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
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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
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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 2.01.1
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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
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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
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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
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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
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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
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Subgroup Analyses
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Permanent Study Drug Discontinuation
Entry OAC No Entry OAC 13.4% 13.2% Cumulative Hazard Rates 12.4% 6.1% Years
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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
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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
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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
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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
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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
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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
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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
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Conclusions Oral anticoagulation is superior to clopidogrel plus ASA for prevention of vascular events Rates of major hemorrhage are similar
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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
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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
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