Modified-release Dipyridamole Combined with Aspirin for Secondary Stroke Prevention
BACKGROUND AND PURPOSE
Patients suffering from transient ischaemic attack (TIA) or ischaemic stroke have a high risk of suffering a first or recurrent stroke, with an annual risk of between 5 and 15%. In the ESPS 2 Study the 2-year relative risk reduction of stroke in the aspirin plus MR-dipyridamole group (37.0%) was significantly higher than in either the aspirin group (18.1%) or the MR-dipyridamole group (16.3%). The results of ESPS 2 were at odds with all prior trials with dipyridamole alone or in association with aspirin, but it was also the only trial sufficiently powered to show a significant difference.
ESPS 2 Study
References:
Diener HC. Aging Health 2005; 1 (1): 19-26.
ESPS 2 Group. J Neurol Sci 1997; 151 (Suppl): S1-S77.
For this reason, a meta-analysis was performed based on a systematic review of individual patient data from randomised controlled trials involving dipyridamole in patients with prior ischaemic stroke or TIA. Recurrent stroke was reduced by dipyridamole compared with placebo, and by combined aspirin and dipyridamole versus aspirin alone, dipyridamole alone or placebo.
Metaanalysis
References:
Diener HC. Aging Health 2005; 1 (1): 19-26.
Leonardi-Bee et al. Stroke 2005; 36 (1): 162-168.
In two post hoc analyses the efficacy of aspirin plus extended-release dipyridamole was compared with aspirin alone for the prevention of recurrent stroke among high-risk groups. Stroke models from the Framingham Study and the Stroke Prognostic Instrument II were applied to subjects in ESPS 2 to assign patients to risk groups. Compared with aspirin alone, aspirin plus MR-dipyridamole demonstrated a more pronounced efficacy in reducing the risk for stroke and vascular events among patients younger than 70 years of age, with hypertension, or prior stroke; current smokers; and those with any prior cardiovascular disease.
ESPS 2 Study
References:
Diener HC. Aging Health 2005; 1 (1): 19-26.
Sacco et al. Arch Neurol 2005; 62 (3): 403-408.
In another post hoc analysis the authors applied a risk score developed from the clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial. The category "other cardiovascular" included ischaemic heart disease, cardiac failure and ventricular arrhythmia.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
| Risk factor |
Points |
 |
|
|
|
| < 65 years |
0 |
|
| 65-75 years |
1 |
|
| > 75 years |
2 |
|
| Hypertension |
1 |
|
| Diabetes |
1 |
|
| Previous MI |
1 |
|
| Other cardiovascular disease (except MI and atrial fibrillation) |
1 |
|
| Peripheral arterial disease |
1 |
|
| Smoker |
1 |
|
| Additional TIA or ischaemic stroke in addition to qualifying event |
1 |
|
|
|
CAPRIE: Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events;
MI: Myocardial infarction; TIA: Transient ischaemic attack. |
A total score of 3 or more reflects a high recurrence risk for stroke (= 4%/year).
Patients with a low risk score of 0-2 show no difference between aspirin and MR-dipyridamole aspirin. Patients with a high risk of recurrent stroke had a much greater benefit from aspirin plus MR-dipyridamole compared with aspirin monotherapy than patients with a low risk. This result shows that stratification of patients according to risk of recurrent stroke will lead to different treatment regimens.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
The need for a direct comparison of the MR-dipyridamole aspirin combination with clopidogrel is being addressed in the PRoFESS® trial, which is currently underway. PRoFESS® is comparing MR- dipyridamole aspirin with clopidogrel.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
| Agent |
Plus |
n |
|
|
|
|
|
MR-dipyridamole
-aspirin* |
Clopidogrel placebo and telmisartan § |
4625 |
|
|
Clopidogrel placebo and telmisartan placebo |
4625 |
|
| Clopidogrel‡ |
MR-dipyridamole-aspirin placebo and telmisartan § |
4625 |
|
|
MR-dipyridamole-aspirin placebo and telmisartan placebo |
4625 |
|
|
|
* MR-dipyridamole-aspirin: 200 mg/25 mg twice daily.
‡ Clopidogrel: 75 mg once daily.
§ Telmisartan: 80 mg once daily.
MR: Modified release; PRoFESS®: Prevention Regime For Effectively avoiding Second Strokes. |
PRoFESS® Study
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
All-site bleeding episodes and gastrointestinal bleeds were significantly more frequent and more often moderate or severe/fatal in patients receiving aspirin compared with those receiving aspirin alone. Similarly, there was no significant difference between rates of severe or fatal bleeding in the MR-dipyridamole-aspirin group compared with the aspirin monotherapy group.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26.
EFFICACY
The European Stroke Prevention Study ESPS 2, the only trial to use the current modified-release (MR) dipyridamole-aspirin formulation, found the combination to be superior to either drug alone in preventing strokes in people with recent ischaemic stroke or transient ischaemic attack (TIA). The combination reduced stroke risk by 37% compared with placebo (p = 0.001) over 2 years.
Post hoc analysis of cardiac events in those patients with coronary heart disease or myocardial infarction at entry to ESPS 2 showed that dipyridamole is not effective in preventing cardiac events but neither is it harmful in such patients.
TOLERABILITY & SAFETY
In the ESPS 2 trial, bleeding episodes were not significantly more frequent with combination therapy than with aspirin alone.
Headaches were the most frequent reason for discontinuation in patients taking dipyridamole in ESPS 2. Their incidence and severity decreases rapidly within the first few days if patients persist with treatment.
COMPARISON WITH OTHER ANTITHROMBOTIC OPTIONS
MR-dipyridamole-aspirin and clopidogrel are being directly compared in the ongoing Prevention Regime For Effectively avoiding Second Strokes (PRoFESS®) trial.
TREATMENT GUIDELINES & EVIDENCE-BASED PRESCRIBING
Based on current evidence, most guidelines include MR-dipyridamole-aspirin as a first-line option for secondary prevention after ischaemic stroke or TIA, and some recent versions suggest it may be preferable to the other options.
Reference:
Diener HC. Aging Health 2005; 1 (1): 19-26. |
