Update on Anti-platelets Gabriel A. Vidal, MD Vascular Neurology Ochsner Medical Center October 14 th, 2009

Primary Stroke Prevention

Primary Vascular Disease Prevention Primary Prevention Trials Meta-Analysis Lancet 2009; 373: 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

Primary Vascular Disease Prevention Primary Prevention Trials Meta-Analysis Lancet 2009; 373:

Secondary Stroke Prevention

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 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

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

Antiplatelet Agents in Stroke ESPS II

ESPIRIT Primary outcome: nonfatal CI, MI, vascular death, major bleeding Lancet, 2006

Aspirin + Dipyridamole Meta-analysis Verro, Stroke, 2008 Non-fatal stroke endpoint Composite endpoint of nonfatal CI, MI, or vascular death

Aspirin + Dipyridamole Meta-analysis: Non-fatal stroke endpoint Immediate Release VS Extended Release (Verro, Stroke, 2008) Immediate release trials Extended release trials

Clinical Trials WARSS – Warfarin vs Aspirin Recurrent Stroke Study (2001) –Randomized to receive either aspirin (325 mg/day) or warfarin (INR ) 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 –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

WARSS

WASID

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

CAPRIE

MATCH

CHARISMA

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

PRoFESS