Anti-platelet and Stroke

Surat Tanprawate, MD, MSc(Lond.), FRCP(T) Division of Neurology, Chiang Mai University
12.9.2011 CMCC, Chaing Mai,Thailand
Wednesday, September 14, 2011

TOAST subtype of acute ischemic stroke

1) large-artery atherosclerosis 2) cardioembolism 3) small-vessel occlusion 4) stroke of other determined etiology 5) stroke of undetermined etiology
Stroke. 1993 Jan;24(1):35-41.

Wednesday, September 14, 2011

ASA/ Dipyridamol
-ESPS-2

ASA/Dipyridamol vs Clopidogrel
-PRoFESS study

ASA/Dipyridamol vs ASA
-ESPRIT study

Clopidogrel
-CAPRIES

Cilostazol
-CSPS

Triusal

-TACIP study

ESO stroke guideline

1978 1989 1996 1997 2000

Aspirin

2002

2003

2006

2008 2011
ASA/ AHA stroke guideline

-Canadian Cooperation Study Group: NEJM

Ticlopidine
-TASS: NEJM - CATS: Lancet

Antithrombotic Trialist Collaboration: BMJ Aspirin ASA vs ASA/ Clopidogrel

-MATCH study

-CAST: Lancet -IST: Lancet

Wednesday, September 14, 2011

Aspirin
Large scale trials & Meta-analysis

Acute ischemic stroke: 300 mg of ASA can reduce RR of recurrent ischemic stroke by 24-28% Long tern prevention: 30-1500 mg of ASA can reduce RR of subsequent vascular events (including stroke) by 13-18%

IST trial. Lancet 1997;349:15691581 CAST Collaboration Group. Lancet 1997;349:16411649 Algra et al. J Neurol Neurosurg Psychiatry 1996;60:197199
Wednesday, September 14, 2011

GI bleeding

Meta-analysis 24 RCTs with 66,000 patients 0.45% annual bleeding rate OR 1.68 (95% CI 1.51-1.88)

Hemorrhagic stroke risk

16 trials, 66542 patients 108 hemorrhagic strokes Risk 0.05% per year

Wednesday, September 14, 2011

Clopidogrel 1996 CAPRIE

(Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events)

ASA/Dipyridamole ESPS-2
(European Stroke Prevention Study-2)
Wednesday, September 14, 2011

CAPRIE study

N=19185 History of ischemic stroke, MI, or peripheral vascular disease Clopidogrel 75mg vs aspirin 325mg

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CAPRIE Study: Efficacy*

Endpoint
Stroke Patients

RRR
MI Patients PAD Patients Total

Stroke Stroke, MI, or vascular death

8.0% 7.3%

1.0% 3.7%

1.2% 23.8%

6.1% 8.7%

* Clopidogrel (75 mg qd) vs ASA (325 mg qd).

2-year

study, N = 19,185, endpoint incidence calculated per year. P < 0.05

CAPRIE Steering Committee. Lancet. 1996;348:1329.

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ASA+dipyridamole

A D
Tested efficacy of ASA/ER-DP for secondary stroke prevention N=6602 (ASA 50 mg/d, Dipyridamole 400 mg/d)
Wednesday, September 14, 2011

ESPS 2: Effects on StrokeRelative Risk Reduction

40.0% 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% RRR ER-DP = Extended-Release Dipyridamole ASA = Acetylsalicylic Acid RRR = Relative Risk Reduction 16.3% P = 0.039 18.1% P = 0.013 23.1% P = 0.006 37.0% P < 0.001

(Pairwise Comparisons)
ASA/ER-DP vs. Placebo ER-DP vs. Placebo ASA vs. Placebo ASA/ER-DP vs. ASA

ESPS 2 Group. J Neurol Sci. 1997; 151(suppl):S1-S77.

Wednesday, September 14, 2011

ESPS 2: Adverse Events

(Percent within each group)
Treatment group Dyspepsia GI Bleeding Headache ASA/ER-DP Placebo ASA ER-DP 18.4 16.7 18.1 17.4 4.1 * 2.1 3.2 2.2 39.2 32.9 33.8 38.3

*Not statistically different from aspirin

ER-DP = Extended-Release Dipyridamole ASA = Acetylsalicylic Acid

19

Aggrenox (aspirin/extended-release dipyridamole) 25 mg/200 mg capsules product information, Boehringer Ingelheim Pharmaceuticals, Inc.

Wednesday, September 14, 2011

Clopidogrel 1996 CAPRIE

(Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events)

ASA/Dipyridamole ESPS-2
(European Stroke Prevention Study-2)
Wednesday, September 14, 2011

Clopidogrel + vs Clopidogrel ASA

2004

ASA 75 mg + Clopidogrel 75 mg 7599 patients with ischemic stroke or TIA

Wednesday, September 14, 2011

Primary Endpoint
Stroke, MI, Vascular Death, Rehospitalization
20 15 % 10 5 0 C C+A 16.7 15.7
RRR = 6.4% p=.244

A non-significant difference in reducing major vascular events. The risk of lifethreatening or major bleeding is increased by the addition of aspirin.
C C+A

Hemorrhage Rates
3 2.5 2 % 1.5 1 0.5 0
Life-threatening Major

2.6 1.9 1.3 0.6

Wednesday, September 14, 2011

Trifusal vs Aspirin...
TACIP study
Stroke 2003
N=2113 TIA or non-disabling stroke

Wednesday, September 14, 2011

CLINICAL TRIALS
TACIP Study
Combined incidence of non-fatal ischemic stroke, non-fatal AMI, cardiovascular death
20

Results: PRIMARY ENDPOINT

Incidence
1.0

Survival analysis
Log-Rank; p = 0.5

P= 0.65

12.4%
10

13.1%
Survival Function

0.9

0.8

0.7

ASPIRIN TRIFLUSAL

130
0 ASPIRIN N= 1.052
Stroke 2003; 34: 840-848
Wednesday, September 14, 2011

138
0.6

Triflusal N= 1.055

100 200 300 400 500 600 700 800 900 1000 1100

days

3 years

CLINICAL TRIALS
TACIP Study
Results: Patients with hemorrhagic adverse events
ASPIRIN N= 1.052 TRIFLUSAL P value N= 1.055

ANY MINOR ANY MAJOR* ANY MAJOR OR MINOR Gastro-intestinal Skin haematoma Respiratory Urinary Cerebral Ocular

22.1% 4.0% 25.2% 8.5% 7.8% 7.0% 2.3% 1.0% 1.0%

15.2% 1.9% 16.7% 5.6% 4.5% 5,3% 1,9% 0.7% 0.6%

<0.001 0.004 <0.001 0.01 0.001 n.s. n.s. n.s. n.s.

*Include: systemic and cerebral haemorrhage, fatal and non-fatal

Stroke 2003; 34: 840-848
Wednesday, September 14, 2011

Triusal vs Aspirin

TACIP Study

This study showed a similar

efcacy of triusal and aspirin in the long term prevention of vascular events after stroke. signicantly lower rate of hemorrhagic complications.

Triusal was associated with a

Stroke 2003; 34: 840-848
Wednesday, September 14, 2011

Other clinical trials

CSPS Cilostazol = ASA Less hemorrhagic risk PRoFESS study ASA/Dipyridamole vs Clopidogrel Similar rate of recurrent stroke between
two groups
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Thank You for Your Kind Attention

My Deep Gratitude to...
Asso.Prof. Siwaporn Chankrachang Dr. Kanokwan Watcharasaksin Dr. Nantaporn Teeyapan and my colleagues
Wednesday, September 14, 2011