ESPS 2 was a multicentre, randomized, double-blind, placebo-controlled, 2 x 2
factorial design large-scale trial involving 6,602 patients enrolled through 59 centres throughout Europe. The study drugs
were Aspirin 25 mg bid plus extended-release dipyridamole 200 mg bid vs. placebo bid. Inclusion of a placebo group was
critical to determine the independent efficacies of ASA and ER-DP at the doses used to access tolerability. The placebo
group was approved by the Ethics Committees of the individual study centers and by an international Study Ethics
Committee at the time ESPS 2 was designed. The factorial design provided statistical power for evaluation of
individual drug effects and for the comparison of individual treatment groups. Follow-up consisted of examinations
at 1 month, 3 months, and then every 3 months for 2 years, regardless of compliance with the study protocol.
The primary endpoints were fatal/non-fatal stroke, death from any cause, stroke and/or death. Secondary endpoints
were TIA, MI, vascular events (APT definition: vascular death,.non-fatal stroke, non-fatal myocardial infarction),
OVE (other vascular events: deep venous thrombosis, pulmonary embolism, peripheral arterial obstruction, venous
retinal events).
ESPS 2: Treatment Arms
ESPS 2: Effects on Stroke - Relative Risk Reduction (Pairwise Comparisons)
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.
Background
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.
PubMed Abstract
ESPS 2: Effects on Stroke - Survival Curves ("Non-event" Probability)
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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 |
This 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.
Reference:
ESPS 2 Group. J Neurol Sci 1997; 151(Suppl): S1-S77.
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.
Background
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.
Reference:
Diener et al. J Neurol Sci 1996; 143: 1-13.
PubMed Abstract
ESPS 2 Secondary Endpoints: Combined Endpoint - Stroke, MI, Sudden Death
In ESPS 2, the composite endpoint vascular events comprised all patients with non-fatal stroke, non-fatal MI, non-fatal other vascular events, or sudden death. As such, this endpoint closely resembles the vascular events reported in a number of previous stroke-prevention trials and in the meta-analysis of ATT. This data emphasizes the additional role of ER-DP in antiplatelet therapy aimed at secondary prevention of stroke.
ESPS 2 Secondary Endpoint: TIA (Pairwise Comparison)
An important observation in ESPS 2 is that antiplatelet therapy cannot only prevent stroke but also lowers 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).
Background
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: Adverse Events.(Percent within each group)
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Treatment group |
Dyspepsia |
GI Bleeding |
Headache |
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ASA/ER-DP |
4 |
4.1 |
39.2 |
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Placebo |
7 |
2.1 |
32.9 |
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ASA |
18.1 |
3.2 |
33.8 |
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ER-DP |
17.4 |
2.2 |
38.3 |
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ER-DP = Extended-Release Dipyridamole
ASA = Acetylsalicylic Acid |
This shows the excellent record of safety of ASA/ER-DP, summarizing the incidences of the most common
adverse events reported in the 4 study groups. Dyspepsia, gastrointestinal bleedings, and headache were the most
frequently reported adverse events, including the placebo group.
Gastrointestinal events were comparable to aspirin
The incidence of dyspepsia with ASA/ER-DP was similar to that with aspirin alone (18.4% vs. 18.1%). The incidence
of GI bleeding with ASA/ER-DP was comparable to aspirin (4.1% vs. 3.2%).
Headache
The most common adverse event with ASA/ER-DP was headache: (39.2% vs. 29.9% vs. placebo).
Headache was more frequent at the onset of therapy, but diminished over time
- In healthy volunteers, tolerance developed in a few days.
- Rates fell by half on the second day of dosing, and by the 11th day were 3%-12%(27,35)
Reference:
ESPS 2 Group. J Neurol Sci 1997; 151(Suppl): S1-S77.
Rapid Development of Tolerance to Dipyridamole-Associated Headaches
This shows results from a trial with healthy volunteers comparing the bioequivalence of the
combination of ASA/ER-DP in order to explore predicting factors for headaches associated with this drug combination.
The occurence of headaches was not related to individual differences of the pharmacokinetic parameters.
Headache
The most common adverse event with ASA/ER-DP was headache: (39.2% vs. 29.9% vs. placebo).
Headache was more frequent at the onset of therapy, but diminished over time.
In healthy volunteers, tolerance developed in a few days.
Rates fell by half on the second day of dosing, and by the 11th day were 3-12%.
"Intensity" in this model was the product of the severity of the headache episodes and their duration
(hours). This product was chosen as the outcome variable because it reflects 2 components of the headaches that are
a measure of subjective discomfort.
Any reported event of headache was stratified according to the WHO System Organ Class and rated according to severity
(1 = mild, awareness of a sign or symptom that is easily tolerated; 2 = moderate, discomfort enough to cause interference
with usual activity; 3 = severe, incapacitating
Reference:
Theis et al. Br J Clin Pharmacol 1999; 48: 7550-7555.
PubMed Abstract
ESPS 2: Safety Severe or Fatal Bleeding
| Placebo |
ER-DP |
ASA |
ER DP + ASA |
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6 |
20 |
27 |
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(0.4%) |
(1.2%) |
(1.6%) |
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| The addition of ER-DP to ASA does not cause significantly increased bleeding. |
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ER-DP = Extended-Release Dipyridamole
ASA = Acetylsalicylic Acid |
Reference:
ESPS 2 Group. J Neurol Sci 1997; 151(Suppl): S1-S77.
Cardiac Safety of ER-DP in ESPS 2 Patients with IHD at Baseline.
ER-DP had no undesirable effect on cardiac patients with stroke..
The post hoc analysis of the ESPS 2 data demonstrates that ER-DP for stroke prevention
does not lead to an increased risk of angina pectoris or MI
No statistically significant difference between dipyridamole-treated patients and aspirin-treated
patients After 2 years of follow-up, the number of myocardial infarcions was not significantly increased after ER-DP
treatment.
PubMed Abstract
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
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.
Background
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.
References:
ESPS 2 Group. J Neurol Sci 1997; 151 (Suppl): S1-S77.
Diener et al. Int J Clin Pract 2001; 55: 162-163. |
