ANTIPLATELET THERAPY FOR STROKE PREVENTION LESSONS LEARNED

FROM SPS3

Oscar R. Benavente, MD, FRCPCProfessor & Research Director of Cerebrovascular Health and Stroke

Division of Neurology

Vancouver Stroke Program - UBC

Vancouver. December 1, 2012

14TH WESTERN STROKE CONFERENCE

2

Stroke Facts Stroke Facts

15 million stroke / year

6 million deaths 5 million disable

Projected 8 million deaths by 2030

More than 60% deaths in <70 yrs of age

Reduction of 4%/yr = 6 million fewer deaths in the

next 10 yrs

stroke

MI or CHD

stroke, MI or VD

RISK OF RECURRENT STROKE, AND OTHER VASCULAR EVENTS AFTER

TIA AND STROKE

Pendlebury et al. Cerebrovascular Dis 2009

5

Atherothrombosis Is a Polyvascular Disorder: Overlap Between PAD, CAD, and

CVD

Atherothrombosis Is a Polyvascular Disorder: Overlap Between PAD, CAD, and

CVD

Bhatt DL et al. JAMA. 2006;295:180-189.

Patients with one manifestation often have coexistent disease in other vascular beds

PAD

4.7%

1.2%

4.7%

1.6%

CVD

CAD

N=7013

44.6%

16.6%

8.4%

Number of Patients

6602 ESPS-2 1

6431a CAPRIE 2

2435 UK-TIA 3

2500 ESPS-1 4

3069 TASS 5

1072 CATS 6

Stroke Patients With CAD (%)b

0 10 20 30 40

Prevalence of Coronary Artery Disease

in Stroke Patients

a CAPRIE data represent only the

stroke subset of patients.b CAD history includes MI, angina, unstable angina, ischemic heart disease.

CollagenTXA2

CollagenTXA2

ADP

TXA2

(Fibrinogenreceptor)

GP IIb/IIIa

Activation

COX

P2Y12 Inhibition:ClopidogrelTiclopidinePrasugrelTicagrelor

P2Y12 Inhibition:ClopidogrelTiclopidinePrasugrelTicagrelor

AspirinAspirin

cAMP

Mechanisms of Platelet Inhibition by Oral Anti-Platelet Therapies

PLATELET

P2Y12

PAR-1

ADPDipyridamoleDipyridamole

Secondary stroke prevention

No proven strategies for stroke prevention

1977

Aspirin 1978

Aspirin + dipyridamole 1987

Carotid endarterctomy in ≥70% stenosis

1991

Warfarin 1993

Clopidogrel 1996

Blood pressure reduction 2001

Statins 2006

Dabigatran 2009

Rivaroxaban 2010

Apixaban 2011

8

Major therapeutic advances in the last 30 yearsWell established interventions

Aspirin = Bayer brand name except in U.S.

First synthesized in pure form by Felix Hoffman of Bayer &

Co. in 1897.

(From the German (From the German aacetylcetylspirsspirsaure + chemical suffix –aure + chemical suffix – in in))

F. Hoffman. First synthesized ASA 1897 H. Dreser. Promoted ASA 1899

Acetylsalicylic Acid

Due to problems with the original Aspirin powder being counterfeited, it became the first pharmaceutical agent ever sold in pill

form in early 1900’s.

Bayer’s Latin America sales team for “Mejoral” – 1940s

Bayer factory in Leverkusen, Germany

L. Craven, MD. Glendale, CA

1465 males, one or two ASA / day

“Not a single case of detectable

coronary or cerebral thrombosis

occurred among patients who

faithfully have adhered to this

regimen”

Mississippi Valley Medical Journal. 1953

Aspirin

• Sir John Vane wins Nobel Prize for describing the

effect of aspirin on platelets – 1971

• FDA approved for secondary prevention of MI – 1986

• Aspirin remains the most commonly used drug in the

world. About 100 M tablets used daily in U.S.

Categories of oral antiplatelet agents by mechanism of platelet inhibition^

Mechanism Agent(s) Comments

Thromboxane inhibition aspirin Irreversible COX-I inhibitor

ADP blockade - irreversible thienopyridines (ticlopidine, clopidrogel, prasugrel)

Require conversion to active metabolite, genetic hypometabolizers; prasugrel the most potent.

ADP P2Y blockade – reversible

ticagrelor dyspnea difficult to distinguish from heart failure

Phosphodiesterase inhibition dipyridamole, cilostazol

Thrombin receptor blockade terutroban  

GPIIb/IIIa inhibition none marketed  

^Other antiplatelet drugs: indobufen, triflusal Reference: Eikelboom JW, Weitz J et al. Antiplatelet drugs. ACCP 2012 Chest 2012: 141: e89S-119s.

Completed trials of antiplatelet agents in patients with non-cardioembolic stroke

2001-2012StudyStudy NN InterventionsInterventions

WARSS - 2001 2,206 ASA OAC

AAASPS - 2003 1,809 ASA Ticlopidine

MATCH - 2004 7,599 Clop Clop + ASA

WASID - 2005 569 ASA OAC

CHARISMA - 2006 15,603 ASA Clop + ASA

ESPRIT - 2006 2,763 ASA DP + ASA

ESPRIT - 2007 1,064 ASA OAC

PRoFESS – 2008 22,000 ASA + DP Clop

CSPS 2 – 2010 2,757 ASA Cilostazol

PERFORM – 2011 19,100 ASA Terutroban

SPS3 - 2012 3,020 ASA Clop + ASA

Aggregate 63,043

Antithrombotic Trialists’ Collaboration 287 randomized trials & >135,000 patients

(BMJ 2002; 324: 71)

Aspirin reduces vascular events (including stroke) about equally in patients with vascular disease, including:- Young and old- Men and women- Hypertensives and non-hypertensives- Diabetics and non-diabetics

Relative risk reduction: 22% (13% secondary stroke prevention)

Aspirin vs. placebo

Clopidogrel vs. aspirin

ASA+ER-D vs. Aspirin

-10 0 10 20 30 40 50

Relative Risk Reduction %

20%

7.7%

13%

Relative effects of antiplatelet regimens in reducing stroke

Relative effects of antiplatelet agents in reducing stroke, MI or vascular death

Hankey, G. Lancet Neurol 2010;9:273

24

Population n RR (95%

CI) P Value

Documented CV disease 12,153 0.88 (0.77, 0.998) .046

Coronary 5835 0.86 (0.71, 1.05) .13

Cerebrovascular 4320 0.80 (0.65, 0.997) .05

PAD 2838 0.87 (0.67, 1.13) .29

Multiple risk factors 3284 1.20 (0.91, 1.59) .20

Overall population 15,603 0.93 (0.83, 1.05) .22

CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death)* by

Inclusion Criteria

0.6 0.8 1.41.2Clopidogrel betterPlacebo better

1.60.4

*First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), or CV death.Bhatt DL. Presented at: American College of Cardiology Annual Scientific Session; March 11-14, 2006, Atlanta, GA.Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.

25

10

8

6

4

2

0

Months since randomization

Pri

ma

ry o

utc

om

e e

ve

nt

rate

(%

)

RRR: 17.1 [95% Cl: 4.4%, 28.1%]

p=0.01

8.8%

7.3%

N=9,478

Placebo + ASA

Clopidogrel + ASA

0 6 12 18 24 30

Bhatt et al. JACC vol 49, No 19, 2007Cardiovascular Death, MI or Stroke

Prior Myocardial Infarction, Stroke or Peripheral Artery Disease

“CAPRIE-like cohort” Analysis from CHARISMA

14 events are prevented treating 1000 pts for 27 months at a cost of 14 events are prevented treating 1000 pts for 27 months at a cost of 2 severe bleeds2 severe bleeds

26

Prior MI

Prior IS

Prior PAD

Entire Cohort

0.5 1 2

Placebo Clopidogrel HR (95% & Cl) p-Value

8.3% 6.6% 0.774 (0.613, 0.978)0.031

10.7% 8.4% 0.780 (0.624, 0.976)0.029

8.7% 7.6% 0.869 (0.671, 1.125)0.285

8.8% 7.3% 0.829 (0.719, 0.956)0.010

Bhatt et al. JACC vol 49, No 19, 2007

3846

2838

3245

Prior Myocardial Infarction, Stroke or Peripheral Artery Disease

“CAPRIE-like cohort” Analysis from CHARISMA

28

Rates of Vascular Death, MI or Stroke at Different Time Intervals from Event to

Randomization

0.8 (.6-1)

HR (95% CI)HR (95% CI)

0.8 (.6-1.2)

0.8 (.6-1.2)

<= 30 d

30 - 300 d

300 d - 30 m

> 30 m

Hazard Ratio

2.01.51.0.5.0

Clp+ASAClp+ASA ASAASA

8.2% 10.5%

6.7% 8.0%

6.8% 8.0%

6.6% 7.2% 0.9 (.7-1.3)

Bhatt et al. JACC vol 49, No 19, 2007

StrokeStroke: ASA = 46 (6.9%) vs ASA + Cl = 34 (5.1%) HR 0.74, 0.46-1.16

CHARISMA Trial: effect of clopidogrel + ASA early after TIA/Stroke

International Journal of Stroke, Feb 2011, 3

PROFESS Stroke Recurrence

Note: Slides reproduced accurately based on data orally presented. Not validated with a published source. This data curve have been redrawn.R Sacco. Presented at ESCo 2008.

PROFESS Characterization of First Recurrent Stroke

Note: Slides reproduced accurately based on data orally presented. Not validated with a published source.R Sacco. Presented at ESCo 2008.

Terutroban vs aspirin in patients with stroke/TIA: PERFORM trial

19,000 patients in 802 centers in 46 countriesMean follow up 2.3 yrs

Primary endpoint: composite stroke, mi, vascular death

Terurobran: 11%

Aspirin: 11%

Bousser, MG. Lancet 2011;337:2013-22

33

Anticoagulant vs. Aspirin after Non-cardioembolic Brain Ischemia

The Major Randomized Trials

n achieved

INR

aspirin dosage

findings

SPIRIT (1997)

1316

3.3 30mg AC not safe;3.7%/yr ICH

WARSS (2001)

2206

1.9 325mg About equal

WASID (2005)

569 2.4 1300mg ended 05

ESPRIT (2007)

1064 2.6 30-325mg

ended 06

Stroke subtype and response to antithrombotic agents

SSecondary econdary PPrevention ofrevention ofSSmall mall SSubcortical ubcortical SStrokestrokes

(SPS3)(SPS3)

SPS3 is sponsored by National Institutes of HealthSPS3 is sponsored by National Institutes of HealthNINDS: 2 U01 NS38529-04A1NINDS: 2 U01 NS38529-04A1

n= 283

n= 1677

n= 165

n= 171

n= 186

n= 127

n= 45

n= 366

81 clinical sites8 countriesRandomization: March 2003 - April 2011

SPS3

SPS3 Design I• Randomized multicenter international trial.• Investigator initiated study.• Lacunar strokes within 180 days, verified by MRI.• No cortical stroke, cardioembolic disease / carotid stenosis.• Randomized to 2 interventions in a factorial design:

1) Antiplatelet therapy (double blind):-aspirin 325 mg + placebo-aspirin 325 mg + clopidogrel 75 mg

2) Target levels of blood pressure control (open label):

-”usual” 130-149 mmHg systolic-”intensive” <130 mmHg systolic

SPS3

www.clinicaltrials.gov NCT00059306

Benavente OR; Hart RG, et.al.

Primary Outcome: Ischemic & Hemorrhagic Stroke

SPS3

HR 0.92 (0.73, 1.2) p value 0.52

•Aspirin = 138 (2.7 %/yr)•Aspirin + Clopidogrel = 126 (2.5 %/yr)

Ischemic StrokeSPS3

HR: 0.85 (0.66, 1.1). p value: 0.21

•Aspirin = 125 (2.4 %/yr)•Aspirin + Clopidogrel = 105 (2.1 %/yr)

Efficacy Outcomes

Aspirin Aspirin + Clopidogrel

HR (95% CI) p value

N %/pt-yr N %/pt -yr

All stroke 138 2.7 126 2.5 0.92 (0.73, 1.2) 0.52

-Ischemic stroke 125 2.4 105 2.1 0.85 (0.66, 1.1) 0.21

-Hemorrhagic stroke 13 0.25 21 0.42 1.7 (0.83, 3.3) 0.15

Major vascular events* 174 3.4 153 3.1 0.89 (0.72, 1.1) 0.28

-Myocardial infarction 38 0.71 30 0.57 0.81 (0.50, 1.3) 0.39

SPS3

*Defined as: stroke, MI, vascular deaths.

All Cause Mortality SPS3

HR 1.5 (1.1, 2.0) p value 0.005

•Aspirin = 77 (1.4 %/yr)•Aspirin + Clopidogrel = 113 (2.1 %/yr)

SPS3Major Hemorrhages

56 1.1%/yr 105 2.1%/yr 2.0 (1.4, 2.7) <0.001

ASA ASA + Cl HR

Major HemorrhagesSPS3

Aspirin Aspirin + Clopidogrel

HR (95% CI) p value

N %/pt-yr N %/pt-yr

All hemorrhages 56 1.1 105 2.1 2.0 (1.4, 2.7) <0.001

CNS hemorrhages 15 0.28 22 0.42 1.5 (0.79, 2.9) 0.21

-Intracerebral* 7 0.13 13 0.25 1.9 (0.75, 4.7) 0.18

-Subdural # 6 0.11 6 0.11 1.0 (0.33, 3.2) 0.95

-Other ^ 3 0.005 2 0.038 0.70 (0.12, 4.2) 0.70

Non-CNS hemorrhages 42 0.79 87 1.7 2.2 (1.5, 3.1) <0.001

*Intraparenchymal, spinal# subdural, epidural^ subarachnoid, other

Visualization of index event on MRISPS3

MRI Localization of Index EventSPS3

Multiple infarcts 39%Mean size of infarct 1.3 cm (8% >2.0 cm)

N=3004

Aspirin Clopidogrel

plus aspirin

p-value

All ischemic strokes^ 124 100 0.08

Lacunar 67 66 0.89

Large artery atherosclerosis

- intracranial

- extracranial

17

11

6

9

6

3

0.11

0.21

0.34

Cardioembolism 10 9 0.80

Other 4 5 >0.99

Unknown strokes 26 11 0.01

Etiological Subtypes of Recurrent Ischemic Strokes

SPS3

Conclusions on SPS3 Results

• Dual antiplatelet therapy was not more effective than aspirin alone.

• Major bleeds were increased.

• Unexpectedly, mortality was increased.

• These results do not support the use of combination therapy for secondary stroke prevention in patients with lacunar strokes.

SPS3

EFFECT OF CLOPIDOGREL ADDED TO ASPIRIN ON STROKE: METANALYSIS OF 13 RCTS

OR=0.81, 95% CI 0.74,0.85

Palacio S, Hart RG et al. International J Stroke 2013 (in press)

Effect of antithrombotic drugs for stroke prevention cannot be meaningfully interpreted without

considering ischemic stroke subtypes. • Clopidogrel + aspirin clearly reduces ischemic stroke in

atrial fibrillation patients.(ACTIVE A)• Clopidogrel + aspirin does not reduce recurrent lacunar

stroke.(SPS3)• Warfarin is far superior to antiplatelet therapy for stroke

prevention in atrial fibrillation patients, but not for most other causes.(ACTIVE W, WARSS, WASID)

• Combining all causes of ischemic stroke in clinical trials (e.g. CHARISMA) masks clinically important differences.

Clopid 600 mg

ASA 50-325 mg

Placebo

ASA 50-325 mg ASA 50-325 mg from Day 2 to Day 90

Placebo from Day 2 to Day 90

R

Loading Dose

Group 1N=2075

Day 7

Patients with TIA or minor ischemic stroke within 12h of sx onset

Day 7

Group 2N=2075

Clopidogrel 75 mg from Day 2 to Day 90

ASA 50-325 mg from Day 2 to Day 90

Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT)A Randomized Trial

Phone F/U (7+2 days) Final Visit (90+14 days)

Open label ASA- dose at discretion of investigator

Johnston SC & Easton JDClinicalTrials.gov identifier: NCT00991029

Primary OutcomeNew ischemic stroke, MI, or vascular death

Participating Centers- 150 in USExpected enrolment- 0.75/ month

Guidelines for secondary stroke prevention. Following TIA/ischemic stroke non-cardioembolic

Best Practice Recommendation

•ASA 80-325 mg, daily

•Clopidogrel 75 mg daily or

•ER dipyridamole 200 mg + ASA 25 mg bid.

“All are appropriate options and selection should depend on the

clinical circumstances”

AHA Guidelines

•ASA 50-325 mg, daily

•ER dipyridamole 200 mg + ASA 25 mg bid or

•Clopidogrel 75 mg daily“The selection of an antiplatelet

agent should be individualized on the basis of patient risk factor

profiles, cost, tolerance and other clinical characteristics”

Canada - 2010 Canada - 2010 USA - 2011USA - 2011