In stroke trials, aspirin's effect is independent of doses between 50 to 1,500 mg/day
FDA:
Professional labeling for aspirin recommends 50 to 325 mg/day
ACCP:
Aspirin recommended at 50 to 325 mg/day
References:
Albers et al. Neurology 1999; 53(Suppl 4): S25-S38.
FDA. Federal Register 1998; 63: 56802.
Albers et al. Chest 2001; 119: 300-320.
The Food and Drug Administration (FDA) and the American College of Chest Physicians (ACCP)
have issued treatment guidelines for the use of aspirin for secondary stroke prevention.
Both of these agencies recommend low-dose aspirin, in the range of 50 to 325 mg/day, for stroke prevention.
These recommendations are based on the preponderance of evidence that no dose of aspirin is superior to any other,
but that gastrointestinal side effects may increase with increasing doses.
Prevention of Vascular Events in Stroke/TIA Patients
Reference:
Albers et al. Neurology 1999; 53(Suppl 4): S25-S38.
This slide gives the results from a meta-analysis of the efficacy of aspirin in preventing stroke,
myocardial infarction, or vascular death, combining the results of trials according to the aspirin dose used.
The relative risks and 95% CI for the 3 dose categories (1,000-1,300 mg/d; 300 mg/d; 50-75 mg/d) of aspirin
and for all doses combined are presented here. The relationship between the benefit of aspirin and the dose
is as follows: comparison of 3 doses (50-75 mg/d, 300 mg/d, and 1,000-1,300 mg/d) showed that the relative
risk is identical in all 3 dose categories. In each case, the relative risk is about 0.87, corresponding to
a 13% relative risk reduction.
Outcomes of 2 single trials that directly compared different doses of aspirin strongly suggest that the benefit
of aspirin is independent of dose in this patient population. Lower doses (50-325 mg/daily) are now recommended
because of their more favorable side effect profiles.
Sixth ACCP Consensus Conference on Antithrombotic Therapy
"The absorption of dipyridamole from conventional formulations is quite variable and may result
in low systemic bioavailability of the drug. .A modified-release (extended-release) formulation of dipyridamole with
improved bioavailability has been developed in association with low-dose aspirin."
Reference:
Patrono et al. Chest 2001; 119: 39-63.
"The absorption of dipyridamole from conventional formulations is quite variable and may result in low systemic bioavailability of the drug. A modified-release (extended-release) formulation of dipyridamole with improved bioavailability has been developed in association with low-dose aspirin."
Dipyridamole is a pyrimodipyrimidine derivative with vasodilator and antiplatelet properties.
Dipyridamole is eliminated primarily by biliary excretion as a glucuronide conjugate and is subject to enterohepatic recirculation. A terminal half-life of 10 hr has been reported. This is consistent with the twice-daily regimen used in recent clinical studies.
 
ESPS 2: Effects on Stroke - Relative Risk Reduction (Pairwise Comparisons)
Reference:
ESPS 2 Group. J Neurol Sci 1997; 151(Suppl): S1-S77.
Extended-release dipyridamole (ER-DP) and aspirin seem to have an additive effect on the prevention of stroke, as indicated by results from pairwise comparisons of relative risk reduction.
Treatment with aspirin alone and with ER-DP alone lead to a similar risk reduction of 18.1% and 16.3%, respectively. Combined therapy with ASA/ER-DP showed significantly better stroke prevention vs. placebo (37.0%) as well as vs. aspirin alone (23.1%). Additionally, the statistically significant effect of ER-DP alone is a new element in the field of secondary prevention of stroke, since ER-DP 400 mg daily is shown here to be as effective as aspirin when given alone.
The efficacy of ER-DP in the secondary prevention of stroke and its significant additive effect when combined with aspirin are observations resulting from ESPS 2. ESPS 2 is the largest stroke prevention trial ever conducted.
ESPS 2: Effects on Stroke - Events Prevented (Pairwise Comparisons)
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Events Prevented
per 1,000 patients |
NNT
to prevent 1 event |
RRR (%) |
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ASA/ER-DP vs. Placebo |
58 |
18 |
37.0 |
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ER-DP vs. Placebo |
26 |
39 |
16.3 |
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ASA vs. Placebo |
29 |
32 |
18.1 |
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ASA/ER-DP vs. ASA |
30 |
31 |
23.1 |
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ER-DP = Extended-Release Dipyridamole
ASA = Acetylsalicylic Acid
NNT = Number Needed to Treat |
Reference:
ESPS 2 Group. J Neurol Sci 1997; 151(Suppl): S1-S77.
This slide indicates the pairwise comparisons of risk reduction as number of strokes
prevented per 1,000 patients treated for 2 years. For 1,000 patients treated with ER-DP and aspirin, 58
strokes could be prevented; with ER-DP alone, 26; with aspirin alone, 29. A comparison of ASA/ER-DP vs.
aspirin alone revealed that an additional 30 strokes per 1,000 patients were prevented by the combination
therapy with ER-DP and aspirin. These numbers reflect all strokes, fatal or not.
ESPS 2: Effects on Stroke - Survival Curves ("Non-event" Probability)
Reference:
Diener et al. J Neurol Sci 1996; 143: 1-13.
The factorial design increases the ability to detect (statistically) the effects of each drug.
The 2x2 design also allows the detection of any interaction between the 2 drugs. The types of interactions include:
- Synergy—the effect of the combination is greater than would be expected, based on the individual effects of the 2 drugs
- Interference—the effect of the combination is less than would be expected, based on the individual effects of the 2 drugs
- Additive—the effect of the combination is the same as the sum of the 2 drugs given independently (i.e., additive)
Lack of interaction between the drug effects allows independent comparison of any 2 treatment arms.
ESPS 2 was conducted along a 2x2 factorial design to be able to detect potentially small differences in the efficacies
of ASA, ER-DP, and the combination, involving a large number of patients. This design allows the detection of interactions
between the 2 study drugs when they are administered together.
ESPS 2 Secondary Endpoint: TIA (Pairwise Comparison)
Reference:
ESPS 2 Group. J Neurol Sci 1997: 151(Suppl): S1-S77.
An important observation in ESPS 2 is that antiplatelet therapy cannot only prevent stroke but also
lower the incidence of TIA in patients at risk. The observed risk reduction vs. placebo for TIAs was 35.9% for ER-DP
and aspirin, 20.1% for ER-DP alone, and 24.5% for aspirin alone. The combination of ER-DP and aspirin revealed a
relative risk reduction of 15.2% as compared to aspirin alone. The overall magnitude of prevention is the same for
TIA and stroke (see Slide ESPS 2: Effects on Stroke -Relative Risk Reduction in this section).
In conclusion, optimal secondary preventative treatment of stroke and/or TIA appears to be the combination therapy of
aspirin and ER-DP, with the fallback position of using 1 of the 2 in case of intolerance of the other.
ESPS 2 Conclusions
- ASA/ER-DP is about twice as effective as aspirin alone in stroke prevention
- There was a 21% RRR in the secondary endpoint stroke / MI / sudden death with ASA/ER-DP vs. aspirin
- Bleeding rate of the combination of ASA/ER-DP is not higher than with aspirin alone
- No increase in cardiac events with ASA/ER-DP 2 x 200 mg
References:
ESPS 2 Group. J Neurol Sci 1997; 151(Suppl): S1-S77.
Diener et al. Int J Clin Pract 2001; 55: 162-163.
ESPS 2 was a large-scale clinical trial powered to detect meaningful differences between treatment
groups statistically. The results show:
The combination of low-dose aspirin and ER-DP is about twice as effective as either agent alone Aspirin and
ER-DP alone are independently effective for stroke prevention
Although there were some significant associations between treatments and specific side effects, the overall incidence
of side effects was only moderately higher in the treatment groups than in the placebo group.
The results of ESPS 2 compare favorably with the results of trials and meta-analyses of antiplatelet agents in patients
with prior ischemic stroke or TIA. A meta-analysis by the Antiplatelet Trialists’ Collaboration reported a 23% reduction
in the odds of non-fatal stroke with antiplatelet treatment, while ESPS 2 is very similar to the 13-14% reductions in
risk of stroke, MI, or vascular death reported in meta-analyses of aspirin treatment by Algra and van Gijn and
Johnston. Overall, the results of ESPS 2 establish the value of low-dose ASA/ER-DP, and the combination for
secondary stroke prevention with relative benefits that parallel those observed in other studies. |
