Update on Antiplatelets

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Update on Anti-platelets

• Gabriel A. Vidal, MD
• Vascular Neurology
• Ochsner Medical Center
• October 14th, 2009

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Primary Stroke Prevention
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Primary Vascular Disease PreventionPrimary
Prevention Trials Meta-AnalysisLancet 2009
3731849-60

• Meta-analysis for serious vascular events
• MI, CI, VD
• Major bleeding
• 6 primary prevention trials 95,000 individuals
• Aspirin trials
• 12 reduction in vascular events
• Statistically significant
• MI reduced 1/5
• No effect on stroke, hemorrhagic stroke, vascular
  death
• Effect similar for men and women

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Primary Vascular Disease PreventionPrimary
Prevention Trials Meta-AnalysisLancet 2009
3731849-60
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Primary Vascular Disease PreventionPrimary
Prevention Trials Meta-AnalysisLancet 2009
3731849-60
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Secondary Stroke Prevention
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Clinical Trials

• CAST - Chinese Acute Stroke Trial (1997)
• Randomized, placebo-controlled trial of 21,106
  patients
• 10,554 patients were randomized to receive
  aspirin (160 mg/day) and 10,552 received placebo
• Significant (14) reduction in mortality and
  fewer recurrent ischemic strokes in patients
  receiving aspirin during treatment period
• At discharge, 11.4 fewer patients per 1000 were
  dead or dependent in the group receiving aspirin
• IST - International Stroke Trial (1997)
• Randomized, open trial involving 19435 patients
• Half of the participating patients received
  unfractionated heparin and half were told to
  avoid heparin
• In a factorial design, half received aspirin 300
  mg daily and half were told to avoid aspirin
• No statistically significant difference in death
  at 14 days, or death or dependence at 6 months
  between patients receiving heparin vs. no heparin
• Statistically significant difference in the
  number of deaths and recurrent strokes between
  patients receiving aspirin vs. no aspirin
• Taken together, CAST and IST show reliably that
  aspirin started early in hospital produces a
  small but definite net benefit
• About 9 fewer deaths or non-fatal strokes per
  1000 in the first few weeks
• About 13 fewer dead or dependent per 1000 after
  some weeks or months of follow-up

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Clinical Trials

• ESPS2 European Stroke Prevention Study 2 (1996)
• Patients were randomized to participate in 1 of 4
  groups
• 24-month stroke rate (Statistically significant)
• 12.9 in the aspirin-alone group (18 risk
  reduction)
• 12.2 in the dipyridamole-alone group (16 risk
  reduction)
• 9.9 in the combination group (37 risk
  reduction vs placebo 23 vs. ASA)
• 15.8 in the placebo group
• No significant difference among the groups for
  the endpoint of death
• ESPIRIT - European / Australasian Stroke
  Prevention in Reversible Ischemia Trial (2006)
• Anticoagulants versus aspirin comparison of
  ESPRIT
• Prematurely ended because ESPRIT reported that
  the combination of aspirin and dipyridamole was
  more effective than aspirin alone
• Primary outcome events arose in 13 patients on
  combination treatment vs. 16 on aspirin alone
• Hazard ratio for the primary outcome event
  comparing anticoagulants with the combination
  treatment of aspirin and dipyridamole was 1.31,
  for ischemic events was 0.73 and for major
  bleeding complications 2.56
• Patients on the combination of aspirin and
  dipyridamole discontinued trial medication more
  often than those on aspirin alone, mainly because
  of headache

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Antiplatelet Agents in StrokeESPS II
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ESPIRITPrimary outcome nonfatal CI, MI,
vascular death, major bleedingLancet, 2006
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Aspirin DipyridamoleMeta-analysisVerro,
Stroke, 2008

• Non-fatal stroke endpoint

• Composite endpoint of nonfatal CI, MI, or
  vascular death

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Aspirin DipyridamoleMeta-analysis Non-fatal
stroke endpointImmediate Release VS Extended
Release (Verro, Stroke, 2008)

• Immediate release trials

• Extended release trials

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Clinical Trials

• WARSS Warfarin vs Aspirin Recurrent Stroke
  Study (2001)
• Randomized to receive either aspirin (325 mg/day)
  or warfarin (INR 1.4-2.8) for at least two years
• Primary end point of death or recurrent ischemic
  stroke was reached by 17.8 of patients assigned
  to warfarin and 16 of those assigned to aspirin
• Rates of major hemorrhage were low (2.22 per 100
  patient-years in the warfarin group and 1.49 in
  the aspirin group)
• There were no statistical differences in primary
  or secondary endpoints or in major hemorrhage
• WASID Warfarin vs Aspirin Symptomatic
  Intracranial Disease (2005)
• Randomized to receive either aspirin 1300 mg/day
  or warfarin, titrated to an INR of 2 - 3
• There was 4.3 rate of death in the aspirin group
  and a 9.7 rate in the warfarin group
• There was a 3.2 rate of major hemorrhage in the
  aspirin group and a 8.3 rate in the warfarin
  group
• The primary end point occurred in 22.1 percent of
  the patients in the aspirin group and 21.8
  percent of those in the warfarin group

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WARSS
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WARSS
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WASID
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WASID
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WASID
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Clinical Trials

• CAPRIE Clopidogrel vs Aspirin in Patients at
  Risk for Ischaemic Events (1996)
• Randomized double dummy Clopidogrel 75 mg vs
  Aspirin 325 mg
• Patients treated with clopidogrel had a 5.32
  annual risk of ischemic stroke, myocardial
  infarction or vascular death vs 5.83 in patients
  treated with aspirin
• Statistically significant relative-risk reduction
  of 8.7 in favor of clopidogrel
• MATCH Management of ATherothrombosis with
  Clopidogrel in High-risk patients with recent TIA
  or ischemic stroke (2004)
• Randomized to Clopidogrel ASA or Clopidogrel
  placebo
• Compared to clopidogrel, combination with ASA had
  no significant effect on recurrent ischemic
  events
• 15.7 of patients taking combination had a
  further ischemic event vs 16.73 of patients
  taking clopidogrel placebo
• Patients taking clopidogrel ASA also had
  significantly more life-threatening hemorrhage vs
  patients taking clopidogrel placebo
• CHARISMA Clopidogrel for High Atherothrombotic
  Risk and Ischemic Stabilization, Management and
  Avoidance (2006)
• Randomized to receive either clopidogrel or
  placebo, in combination with aspirin
• Clopidogrel plus aspirin was not significantly
  more effective than aspirin alone in reducing the
  rate of myocardial infarction, stroke, or death
  from cardiovascular causes

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CAPRIE
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CAPRIE
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CAPRIE
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MATCH
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MATCH
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CHARISMA
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CHARISMA
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Clinical Trials

• PRoFESS Prevention Regimen For Effectively
  avoiding Second Strokes (2008)
• 18,500 patients will be randomized to receive
  active antiplatelet medication, either
  clopidogrel or extended-release dipyridamole and
  aspirin
• Primary Outcome Time to first recurrent stroke
• Recurrent strokes occurred in 9 patients
  randomly assigned to ASA with ER-DP and 9
  patients randomly assigned to clopidogrel
• mRS scores were not statistically different in
  patients with recurrent stroke who were treated
  with ASA and ER-DP versus clopidogrel
• There was no significant difference in the
  proportion of patients with recurrent stroke with
  a good outcome, as measured with the Barthel
  index, across all treatment groups
• There is no evidence that either of the two
  treatments was superior to the other in the
  prevention of recurrent stroke

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PRoFESS
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PRoFESS
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