Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke

Transcription

1 Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke N Eng J Med, 2012 Karen Hecht und Thomas Gattringer

2 Introduction Stroke 20% ICH 80% ischemia atherosclerosis cardioembolism 20-25% 1 lacunar other small cerebral ischemic lesion with a maximum diameter of < 15 (20) mm located in white matter, basal ganglia, brainstem small vessel disease (SVD) 1 Sudlow CLM et al. Stroke, 1997

3 Background Intracranial atherosclerosis (small vessel disease) Dual antiplatelet therapy reduces (compared with aspirin) Recurrence of MI Stroke risk among patients with atrial fibrillation Moderate effect of ASS in stroke secondary prevention (NNT= 83) Increased bleeding risk No RCT with brain MRI in lacunar stroke patients so far

4 PICO Patients Symptomatic (lacunar) stroke patients (MRI lesion <=2cm) > 30 years Within last 180 days Exclusion of other obvious stroke mechanisms (carotid disease, heart/rhythm abnormalities), cerebral hemorrhage At least 2 weeks after qualifying stroke (blood pressure arm) Intervention and control 325mg aspirin + clopidogrel 75mg versus 325mg aspirin + placebo Outcome Stroke recurrence (any ischemic strokes or intracranial hemorrhage) Prespecified subgroup analyses Primary outcome according to ethnicity (hispanics vs. non-hispanics) Use of aspirin previous to qualifying event Diabetes yes/no Not prespecified subgroup analyses: age, sex, region

5 Outcome Secondary Outcome Acute MI Death (vascular, non-vascular, unknown) Primary safety outcome Major extracranial bleeding (life-threatening) All efficacy and safety outcomes confirmed by central adjudication commitee

6 Study design Multicenter 82 Centers in North- and Southamerica, Spain Period: Randomised Permuted block-design, variable block size Protected from previewing Stratified according to center and baseline hypertensive status 2x2 Design 1. Therapy (Aspirin/Placebo vs. Aspirin/Clopidogrel) 2. Blood pressure (< 130 mmhg vs mmhg) Double blind (therapy) Adherence checked by pill counting (quarterly FU) Investigator initiated trial (NINDS) Clopidogrel and placebo sponsored by industry

7 Statistics Type I error 0.05, type II error 0.1 Sample size calculation participants Log-rank test Cox proportinal hazard models (HR) ITT principle Preliminary study termination August 2012 Independent data and safety monitoring committee Two planned interim analyses after one thirds ans two thirds Haybittle Peto boundary

8 Baseline characteristics 3020 patients Median stroke-randomization: 62 days Range? Estimated average rate of adherence 94% Permanent discontinuation 30% dual therapy 27% aspirin (p=0.02) 2% lost to FU, 7% withdrew consent, 5% site closure, 1% other reasons Group differences?

9 Results 58% acute small subcortical infarct on MRI 71% classified lacunar (clinicoradiological)

10 Results

11 HR for subgroups

12 Results - safety

13 Discussion Kein Benefitvon dualer Plättchenhemmertherapie bei lakunären(subkortikalen) SchlaganfallpatientInnen Erhöhtes Risiko extrakraniellerblutungen (GI) Dualtherapie ist riskant und bringt nichts! Adherence? Lacunar stroke definition? Blood pressure arm CVE till initiation of study?