Advances in the Antiplatelet Management of Cardiovascular Disease

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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
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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, LVEFlt45, PAD, Age
55-74 CAD or diabetes
Contra-indications to OAC or Unwilling
ACTIVE W ClopidogrelASA vs. OAC
ACTIVE A ClopidogrelASA vs. ASA
6500 patients
7500 patients
No Exclusion criteria for ACTIVE I
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 75-100 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
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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
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Pre-Randomization Anti-thrombotic Medications
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ACTIVE W - INR Control
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Stroke, Non-CNS Systemic Embolism, MI Vascular
Death
5.64 /year
RR 1.45 P 0.0002
3.93 /year
Cumulative Hazard Rates
at Risk CA 3335 3149
2387 916 OAC 3371
3220 2453
911
Years
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Major Bleeding
2.4 /year
RR 1.06 P 0.67
2.2 /year
Cumulative Hazard Rates
at Risk CA 3335 3172
2403 914 OAC 3371
3212 2423
901
Years
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Primary Outcome Components Death
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Subgroup Analyses
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Permanent Study Drug Discontinuation
Entry OAC
No Entry OAC
13.4
13.2
12.4
Cumulative Hazard Rates
6.1
Years
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INR Control
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Stroke, Non-CNS Systemic Embolism, MI, Vascular
Death
Entry OAC
No Entry OAC
Interaction P 0.55
RR 1.32 P 0.17
RR 1.50 P 0.0006
Cumulative Hazard Rates
Years
20
Major Bleeding
Entry OAC
No Entry OAC
Interaction P 0.032
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 1.14 P 0.45
RR 1.51 P lt 0.0001
Cumulative Hazard Rates
Years
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Primary Outcome by Center INR Control
? 65 INR in Range
lt65 INR in Range
Interaction P 0.013
RR 1.83 P lt 0.0001
RR 1.11 P 0.47
Cumulative Hazard Rates
Years
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Major Bleeding by Center INR Control
? 65 INR in Range
lt65 INR in Range
Interaction P 0.0006
RR 1.55 P 0.027
RR 0.68 P 0.08
Cumulative Hazard Rates
Years
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PrimaryMajor Bleed by Centre INR Control
? 65 INR in Range
lt65 INR in Range
Interaction P 0.002
RR 1.80 P lt 0.0001
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