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Multicentre, randomized, double-blind, placebo-controlled trial 6,602 patients randomized within 3 months of qualifying event (TIA or stroke) Treatment and follow-up time: 2 years Visits at 1 month and 3 months, then at 3-month intervals. ESPS-2: European Stroke Prevention Study .

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esps 2 european stroke prevention study
Multicentre, randomized, double-blind, placebo-controlled trial

6,602 patients randomized within 3 months of qualifying event (TIA or stroke)

Treatment and follow-up time: 2 years

Visits at 1 month and 3 months, then at 3-month intervals

ESPS-2: European Stroke Prevention Study

Diener et al. J Neurol Sci 1997;151:S1-S77

Diener et al. J Neurol Sci 1996;143:1-13

esps 2 treatment arms
n=6,602ESPS-2: Treatment Arms

ASA/ER DP

25 mg ASA/

200 mg ER DP

bid

(n=1,650)

ASA

25 mg bid

(n=1,649)

ER DP

200 mg bid

(n=1,654)

Placebo

(n=1,649)

slide3

Dipyridamole Extended Release Pellets

Dipyridamole

HP cellulose

protective

coating:

water soluble

polymers

ASA

Tartaric acid:

dipyridamole solubiliser

Sustained release coating:

water insoluble polymers

Aggrenox® Capsule

mechanisms of action of aggrenox
Mechanisms of Actionof Aggrenox®

Dipyridamole

ASA

Increases

plasma

adenosine

Inhibits

platelet

phosphodiesterase

Irreversibly inhibits

cyclooxygenase and thromboxane A2

Inhibition of platelet

activation and aggregation

esps 2 results stroke rates at 24 months
ESPS-2 Results: Stroke Rates at 24 Months

16

15.2%

12.8%*

12.5%*

12

9.5%*

Incidence (%)

8

4

0

Placebo

ASA

ER DP

ASA/ER DP

*p<0.001 vs. placebo

esps 2 results stroke free survival

100

95

ASA

90

85

80

6

12

18

24

ESPS-2 Results:Stroke-Free Survival

ER DP

ASA/ER DP

Patients without stroke (%)

Placebo

Time (months)

Kaplan-Meier stroke-free survival curves

slide7

ESPS-2: Secondary Endpoint

Vascular Events*

(MI, Stroke, Vascular Death After Two Years)

Number of events

%

vascular events / N

ER DP + ASA

ER DP

ASA

Placebo

246 / 1650

324 / 1654

314 / 1649

361 / 1649

14.9

19.6

19.0

21.9

ER DP = Extended release dipyridamole

ASA = Acetylsalicylic acid

*Antiplatelet Trialists’ Collaboration (APT) definition

Diener et al. J Neurol Sci 1997;151:S1-S77

esps 2 effects on stroke rrr pairwise comparisons
ESPS-2: Effects on Stroke – RRR (Pairwise Comparisons)

40

37.0%*

30

23.1%**

18.1%†

20

16.3%†

RRR (%)

10

0

ASA/ ER DP vs. Placebo

ER DP vs.Placebo

ASA vs.Placebo

ASA/ER DP vs. ASA

ER DP = Extended release dipyridamole

ASA = Acetylsalicylic acid

RRR = Relative Risk Reduction

* p<0.001, **p<0.006, †p<0.05

Diener et al. J Neurol Sci 1997;151:S1-S77

Diener et al. J Neurol Sci 1996;143:1-13

slide9

ESPS-2: Effects on Stroke

– Events Prevented

(Pairwise Comparisons)

Events

prevented

NNT

ER DP + ASA vs. Placebo

ER DP vs. Placebo

ASA vs. Placebo

ER DP + ASA vs. ASA

58‰

26‰

29‰

30‰

18

39

35

34

ER DP = Extended release dipyridamole

ASA = Acetylsalicylic acid

NNT = Number Needed to Treat

Diener et al. J Neurol Sci 1997;151:S1-S77

antiplatelet agents vs asa prevention of combined endpoint indirect comparison across studies
Antiplatelet Agents vs. ASA: Prevention of Combined Endpoint*(Indirect Comparison Across Studies)

25

22%

Clopidogrel

CAPRIE: n=6,431

p=0.003†

20

Ticlopidine

TASS: n=3,069

RRR (%)

15

9%

7.3%

ASA/ER DP

ESPS-2: n=3,299

p=0.20

10

p=0.26

5

0

CAPRIE

-6–19

TASS

-12–30

ESPS-2

7–36

95% CI:

* TASS, CAPRIE & ESPS-2: stroke, MI, vascular death

Adapted from Albers et al. Chest 1998;114:683S-698S

Albers, personal communication

† Statistically significant

CI = confidence interval

slide11

Number Needed to Treat (NNT)

To prevent one stroke in

Antiplatelet therapy

a. ESPS-2 (ER DP + ASA vs. ASA)

b. CAPRIE (Clopidogrel vs. ASA)

(patients with inclusion criterion stroke)

Antihypertensive therapy

vs. placebo in the elderly (MRC)

Lipid-lowering therapy

Simvastatin vs. placebo (4S)

Intervention

NNT

34

143

70

101

2 years

1.91 years

5 years

5 years

ER DP = Extended release dipyridamole

ASA = Acetylsalicylic acid

esps 2 adverse events
ESPS-2: Adverse Events

100

Placebo

ASA

80

ER DP

60

ASA/ER DP

Patients reporting (%)

*

*

*

*

40

20

*

*

0

Headache

GI Events

Dizziness

Bleeding

events

* Significantly associated with treatment according to factorial analysis

slide13

ESPS-2: Safety

Severe or Fatal Bleeding

Placebo

7

(0.4%)

ER DP

6

(0.4%)

ASA

20

(1.2%)

ER DP + ASA

27

(1.6%)

no significant difference

Diener et al. J Neurol Sci 1997;151:S1-S77

ER DP = Extended release dipyridamole

ASA = Acetylsalicylic acid

slide14

Aggrenox® Precautions

  • Use caution in patients with severe coronary artery disease (e.g. unstable angina or recently sustained myocardial infarction) as DP may aggravate chest pain
  • The dose of ASA in Aggrenox® has not been proven to provide adequate treatment for recurrent MI or angina pectoris
  • Avoid use in children or teenagers with viral infections
  • Avoid use in patients with severe renal failure and in patients with severe hepatic insufficiency
  • Use caution in patients with inherited or acquired bleeding disorders
  • Patients should be alerted to signs and symptoms of GI side effects due to ASA component
slide15

ESPS-2: Conclusions

  • Treatment with low-dose ASA or ER DP alone is effective in preventing secondary stroke (factorial analysis RRR 18.1% (p=0.013) and 16.3% (p=0.039), respectively; statistically significant)
  • Combined treatment with ER DP + ASA reduces the risk of stroke by 37% vs. placebo (p<0.001)
  • Combined treatment with ER DP + ASA is significantly superior to ASA alone (RRR 23.1%, p<0.006)
  • ER DP and ASA have an additive effect in secondary prevention of stroke
  • The addition of ER DP to ASA does not increase the risk of bleeding

Diener et al. J Neurol Sci 1997;151:S1-S77

Diener et al. J Neurol Sci 1996;143:1-13

if you take 1000 patients and follow them for 2 years
with ASA, you prevent 29 strokes

with clopidogrel, you prevent 39 strokes

with Aggrenox you prevent 58 strokes

If you take 1000 patients and follow them for 2 years...