Session Antiplatelet Therapy: How, Why and When? In patients with ischemic stroke/tia

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1 GROUPE HOSPITALIER BICHAT-CLAUDE BERNARD PARIS DIDEROT UNIVERSITY - PARIS 7 Session Antiplatelet Therapy: How, Why and When? In patients with ischemic stroke/tia Pierre Amarenco INSERM U-698 and Denis Diderot University - Paris VII Department of Neurology and Stroke Center Bichat hospital, Paris, France Disclosure None

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3 CVD population CAD N=18,957 Cerebrovascular Disease RISK FACTORS ONLY Patient Profile Total: N=63,129 TIA: N=8,741 (48%) Stroke: N=13,650 (73%) N=5,704 CVD N=11,339 N=1,120 PAD N=794 Of the total CVD population: 40.2% have more than 1 disease location 34.3% have 2 disease locations 5.9% have 3 disease locations --> Polyvascular disease

4 All p values <0.001 *Pts with 3 risk factors but no symptoms are counted as 0, even in the presence of asymptomatic carotid plaque or reduced ABI **TIA, unstable angina, other ischemic arterial event including worsening of peripheral arterial disease 18,957 PATIENTS WITH CerebroVascular Disease (CVD) 1-year cardiovascular event rates as function of number of symptomatic disease locations* CVD Alone + CAD + PAD + CAD + PAD

5 Percent of secondary events Natural History of Stroke vs. MI Patients with prior stroke %100 % % Patients with prior MI 81.1% % % 0 0 Secondary Event = Stroke Secondary Event = MI Secondary Event = Stroke Secondary Event = MI Vickrey BG, et al. Stroke. 2002;33:

6 Identification of Presymptomatic CHD Individuals Among Stroke Patients Epidemiologic Data: 655 Patients Aged >40 Years % Day-30 1 yr 5 yrs Dhamoon MS, et al. Neurology. 2006;66: Stroke (%) Stroke Deaths MI (%) at 5 yrs (%) MI Deaths at 5 yrs (%)

7 CHD and Vascular Death Risk After a Stroke Meta-Analysis of RCTs and Epidemiological Studies 25 Vascular Death 25 Total MI % % Follow-up (years) Follow-up (years) 10 Non-fatal MI 20 Fatal MI % % Follow-up (years) Follow-up (years) Touzé E, et al. Stroke. 2005;36:

8 MASS Autopsy Study: Prevalence of CAD in 808 Patients with Fatal Stroke 808 Autopsies Coronary Plaque Coronary Stenosis>50% MI (silent or not) % 60 68% % 44% 33% 32% BI ATH CE Lacunar UNK BH OND * 27% * * 13% 10% N = * P<.001 for the comparison with patients with cerebrovascular disease Gongora F, Labreuche J, Jaramillo A, Steg PG, Hauw J-J, Amarenco P. Stroke. 2007;38:

9 MASS Autopsy Study: 381 Patients With Stroke Autopsy Prevalence of Coronary Plaque, Stenosis, or Myocardial Infarction in Case of Brain Artery Stenosis Any Segment of the Cerebral Arteries Internal Carotid Artery Origin Coronary Plaques Coronary Stenosis Myocardial Infarction Coronary Plaques Coronary Stenosis Myocardial Infarction % % No Plaque Plaque Stenosis 30% or Occlusion 0 No Plaque Plaque Stenosis 30% or Occlusion on Cerebral Arteries on Carotid Arteries Gongora F, Labreuche J, Jaramillo A, Steg PG, Hauw J-J, Amarenco P. Stroke. 2007;38:

10 ANTIPLATELET AGENTS Platelets play a central role in thrombus formation Initiate thrombus formation on atherosclerotic plaque Platelet aggregation inhibitors inhibit formation of platelet-rich thrombi on disrupted plaque Prevention of thrombus formation can prevent all kinds of cardiovascular ischemic events: e.g., myocardial infarction, ischemic stroke, and vascular death

11 Antithrombotic Trialist s Collaboration % of Patients with Stroke, MI or Vascular Death ATT, BMJ 2002;324:71-86

12 SPIRIT Stroke Prevention In Reversible Ischemia Trial All Major Ischemic Events * P = NS Major bleeding complications P < ,316 pts 53 F-U 14 months Oral Anticoagulant INR ASA 30 mg/d n = 651 n = 665 * (Nonhemorrhagic vascular death, nonfatal ischemic stroke, non fatal MI) Ann Neurol 1997;42:

13 WARSS: Warfarin Aspirin in Recurrent Stroke Study N Eng J Med 2001;345: At 2 years All hemorrhages major W:44 (2.2%) A:30 (1.5%) 1.48 ( ) p=0.10 minor W:413 (20.8%) A:259 (12.9%) 1.61 ( )<0.001 Stroke/death/major hemorrhages: W:222 (20.0%) A:196 (17.8%) 1.15 ( ) p=0.16

14 WASID Warfarin and Aspirin in Symptomatic Intracranial Stenosis PRIMARY END-POINT: Stroke and death DEATH MAJOR HEMORRHAGES INR vs. Recurrent stroke and Hemorrhage N Engl J Med 2005;352:

15 Ulcerated Plaques in the Aortic Arch and Brain Infarction : Autopsy 500 Autopsy Cases * 26% Event Rates Risk of Recurrent BI 12%/yr * Risk of Vasc Event 26%/yr * 100 5% 80 No Plaque (<1 mm) Plaques 1 to 3.9 mm Other Neurological Diseases Cerebrovascular Disease * Amarenco et al. N Engl J Med 1992;326:221 Adjusted OR 4.0 [95%CI, ] Event-free rate (%) Aortic Arch Plaque and Brain Infarction :TEE Adjusted Odds Ratio (95% CI) ( ) ( ) ( ) ( ) Aortic Arch Ulcer Thrombus Plaque Months Plaques 4 mm Log rank P<0.001 * Amarenco et al. FAPS Study N Engl J Med 1996;334:1216 * Amarenco P et al. N Engl J Med 1994;331:1474

16 AORTIC ARCH ATHEROMA: PROSPECTIVE STUDIES McLeod M, Amarenco P, Davis SM, Donnan GA. Lancet Neurol. 2004;3:408-14

17 Mean F-U 34 ±26 months Retrospective study Non randomized Unblinded Beneficial Statin* Antiplatelet 0.77 Harmful Warfarin Effects of treatment Tunick et al. Am J Cardiol 2002;90: Figure 2: Patients With Severe Aortic Plaque (N = 519) Statin Warfarin Antiplatelet Risk of stroke and other emboli Years * p =

18 THE A.R.C.H. TRIAL Aortic arch Related Cerebral Hazard Non disabling Brain Infarct & Aortic Arch Plaque 4 mm Oral Anticoagulant INR 2 to 3 Aspirin 75 mg/d Plus Clopidogrel 325 pts 325 pts

19 Cumulative Hazard Rates ACTIVE-W: Stroke, Non-CNS Systemic Embolism, MI & Vascular Death RR = 1.45 P = Clopidogrel+ASA 5.64 %/year 3.93 %/year OAC # at Risk C+A OAC Years

20 ACTIVE-A: Stroke, Non-CNS Systemic Embolism, MI & Vascular Death Patients with Atrial Fibrillation N Engl J Med ; 360

21 Total # of events (2 yr follow-up) ESPS 2 : ASA vs ER-DP+ASA 250 (n=3,299) Aspirin ER-DP + aspirin Stroke 23% RRR p=0.006 MI Diener et al, J Neurol Sci 1996;143:1-13

22 2739 pts Open-labelled F/U: 3.5 yrs 7% had prior CAD 34% drop out (A+D) 13% drop-out (A) ESPRIT: A+D vs. A 0.80 [ ]

23 Clopidogrel More effective than ASA (and safer) More effective than placebo in patients with MI, UA, PCI on top of ASA (additionnal antithrombotic effect demonstrated) In PRoFESS similarly effective than ERDP on stroke, MI, VD less major and intracranial hemorrhages, less headache

24 Cumulative event rate (%) CAPRIE: Higher Long-Term Benefit of Clopidogrel Compared with ASA 1,2 in Reducing Ischemic Events Cumulative Event Rate (Myocardial Infarction, Ischemic Stroke or Vascular Death) ASA (n=9,586) Clopidogrel (n=9,599) 8.7% * Overall relative Risk Reduction p= *Intention to treat analysis Months of follow-up 1. CAPRIE Steering Committee. Lancet 1996; 348: Antiplatelet Trialists' Collaboration. BMJ 2002; 324:

25 CAPRIE Study Efficacy of Clopidogrel in Preventing Stroke vs. MI Relative Risk Reduction (%)* All Events Stroke (fatal or not) 5.2 MI (fatal or not) Aspirin Better Clopidogrel Better *ITT analysis; + P=0.045; ++ P= CAPRIE Steering Committee. Lancet. 1996;348: Gent M. Circulation. 1997;96 (Suppl):I-467.

26 Clopidogrel More effective than ASA (and safer) More effective than placebo in patients with MI, UA, PCI on top of ASA (additionnal antithrombotic effect demonstrated) In PRoFESS similarly effective than ERDP on stroke, MI, VD less major and intracranial hemorrhages, less headache

27 12562 pts F.-u mo /Ave 9 mo ASA mg CURE % n = 6303 n = 6259 ASA+Placebo p<0.001 ASA+Clopidogrel % 6.68% 5.19% p<0.001 p NS 0 CV Death+MI+Stroke MI 1.4% 1.2% Stroke 20% 23% 15%

28 Patients with endpoint (%) Clopidogrel Reduced Clinical Events by 20% at 30 Days 1 15 Clopidogrel 300 mg loading dose/75 mg once daily Placebo (14.1%) n=1,752 20%* p= Thrombolysis, heparin and ASA* R Study treatment until angiography (2 8 days) or hospital discharge (maximum 8 days) Clinical follow-up at 30 days Clopidogrel (11.6%) 5 Placebo n=1,739 Primary endpoint: occluded artery (Thrombolysis In Myocardial Infarction [TIMI] flow grade [TFG] 0/1) on the pre-discharge angiogram or death/mi by time of angiography Time (days) *Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization 1. Sabatine M et al. New Engl J Med 2005; 352:

29 Patients with endpoint (%) Clopidogrel Reduced Clinical Events by 20% at 30 Days 1 15 Placebo (14.1%) 20%* p= Clopidogrel (11.6%) Time (days) *Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization 1. Sabatine M et al. New Engl J Med 2005; 352:

30 Events (%) Clopidogrel Reduced the Composite of Death, MI or Stroke by 9% 1 >45,000 pts with MI RRR=relative risk reduction Days (up to 28 days) 1. COMMIT Collaborative Group. Lancet 2005; 366: Placebo (10.1%) Clopidogrel (9.2%) RRR=9% p=0.002

31 Effects of Clopidogrel on Stroke 1 Clopidogrel Placebo Type (n=22,961) (n=22,891) Odds ratio & 95% CI Clopidogrel better Placebo better Ischemic (or unknown) 164 (0.7%) 194 (0.8%) Hemorrhagic 55 (0.2%) 56 (0.2%) ALL* 217 (0.9%) 250 (1.1%) 14% reduction p=ns *Two patients (both in the clopidogrel group) had both an ischemic and a hemorrhagic stroke 1. COMMIT Collaborative Group. Lancet 2005; 366:

32 Cumulative event rate MATCH: Clopidogrel + ASA vs. Clopidogrel Primary Endpoint (ITT) IS, MI, VD, rehospitalization for acute ischemic event Placebo + Clopidogrel ASA + Clopidogrel 16,73% 15,70% 0.12 RRR: 6.4% (p=0.244) Months of follow-up Lancet 2004

33 Life-threatening and Major Bleeding Type of Bleeding Events * (%) Placebo + Clopidogrel (n=3,781) ASA + Clopidogrel (n=3,759) % Absolute Difference (95% CI) p value Defined as Life-threatening Events (%) Gastrointestinal Intracranial 49 (1.3) 21 (0.6) 25 (0.7) 96 (2.6) 51 (1.4) 40 (1.1) 1.26 (0.64, 1.88) <0.001 Major Bleeding Events (%) 22 (0.6) 73 (1.9) 1.36 (0.86,1.86) <0.001 Gastrointestinal 11 (0.3) 42 (1.1) * Defined as Life threatening : any fatal bleeding event, or a drop in hemoglobin of 5g/dl, or significant hypotension with the need of inotropes (hemorrhagic shock) or, symptomatic intracranial hemorrhage, or requiring transfusion of 4 units of RBC or equivalent amount of whole blood Defined as Major bleeding : significantly disabling (with persistent sequelae), or intraocular bleeding leading to significant loss of vision or, requiring transfusion of 3 units of RBC or equivalent amount of whole blood

34 Primary Efficacy Results (MI/Stroke/CV Death)* by Category of Inclusion Criteria Population N RR (95% CI) p value Qualifying CV Disease 12, (0.77, 0.998) Coronary 5, (0.71, 1.05) 0.13 Cerebrovascular 4, (0.69, 1.03) 0.09 PAD 2, (0.67, 1.13) 0.29 Multiple Risk Factors 3, (0.91, 1.59) 0.20 Overall Population 15, (0.83, 1.05) 0.22 Bhatt DL. Presented at ACC Clopidogrel Better Placebo Better * First Occurrence of MI (fatal or not), Stroke (fatal or not), or CV Death

35 Overall Population: Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 1.44 (0.79, 2.63) 0.23 Primary ICH 26 (0.3) 27 (0.4) 0.93 (0.54, 1.58) 0.78 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

36 Meta-analysis of 90-days risk* with dual APT in patients included within 24 hours * Stroke, TIA, ACS, death Kennedy et al. Lancet Neurol. 2007

37 CARESS Markus et al. Circulation. 2005

38 Clopidogrel More effective than ASA (and safer) More effective than placebo in patients with MI, UA, PCI on top of ASA (additionnal antithrombotic effect demonstrated) In PRoFESS similarly effective than ERDP on stroke, MI, VD less major and intracranial hemorrhages, less headache

39 PRoFESS - Net Benefit

40 Characterization of First Recurrent Stroke (8.8%) 45 (0.4%) 915 (9.0%) 83 (0.8%) 17 Strokes 38 Hemorrhagic (7.9%) 780 (7.7%) 25 Ischemic Clopidogrel 48 (0.5%) ASA+ER-DP 52 (0.5%) 4 Unknown

41 Secondary Outcome Analysis Stroke, MI, Vascular Death ASA+ER-DP Clopidogrel HR* 95% CI p-value 1313 (12.9%) 1320 (13.0%) , * Covariates in cox model are age, baseline ACE-inhibitor use, Modified Rankin, and baseline diabetes status.

42 Major Hemorrhagic Event Life-threatening 128 (1.3%) 116 (1.1%) ASA+ER-DP Clopidogrel HR 95% CI p-value 419 (4.1%) 365 (3.6%) ,

43 Recurrent Stroke or Intracranial Hemorrhage First recurrent stroke ASA+ER-DP Clopidogrel HR 95% CI p-value 916 (9.0%) 898 (8.8%) , All intracranial hemorrhage* ASA+ER-DP Clopidogrel HR 95% CI p-value 147 (1.4%) 103 (1.0%) , * 128 of the 250 reported ICH events are also reported in the primary outcome

44 PRoFESS - Safety AD C

45 PRoFESS - SAEs

46 Medical History Number of Randomized Patients Previous Stroke or TIA Previous Stroke TIA Atherosclerotic Disease Ischemic Coronary Artery Disease MI PAOD ASA+ER-DP % 18.1% 8.6% 19.3% 16.1% 6.7% 2.9% Clopidogrel % 18.4% 8.8% 19.5% 16.4% 6.7% 3.0%

47 PRoFESS - Entry Event TOAST Subtypes AD C

48 PRoFESS - Atherosclerostic Subgroup AD better C better

49 PRoFESS Treatment Implications Clopidogrel and ASA-ERDP have similar efficacy in PRoFESS There is no need to change treatment in stable patients tolerating current Rx Choice between clopidogrel and ASA-ERDP Tolerability/side effects C > ERDP Ease of use : once vs. twice daily C > ERDP Safety : C > ERDP Cost/re-imbursement issues - depend on the country Diffuse disease C > ERDP

50 In summary Clopidogrel and Aspirin-Dipyridamole more effective and safer than aspirin in atherothrombotic stroke Clopidogrel and Aspirin-Dipyridamole similarly effective in the Profess trial Clopidogrel plus aspirin : significantly more bleeding complication than clopidogrel alone (MATCH trial) Other trials on-going testing the combination started within 12 hours (POINT, NIH sponsored) or 48 hours (CHANCE trial) in acute TIA and minor strokes

51 European Stroke Organisation Secondary stroke/tia prevention 2008 Recommandations Cerebrovasc Dis. 2008;25(5): Epub 2008 May 6

52 Lancet 2011;377: