Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

The Antithrombotic Trialists conclude that adding
dipyridamole to aspirin produces "no further reduction in
vascular events." However, the second European Stroke
Prevention Study (ESPS-2) showed that combination treatment
with aspirin and extended-release dipyridamole was twice as
effective as aspirin alone for prevention of recurrent
stroke, leading to a 37% decrease.(1)

ESPS-2 was a very large (6,600 patients), well-controlled,
well-designed, well executed modern study. The other trials
included by the Trialists in their meta-analysis were much
older and smaller with, understandably, less robust and
meaningful results. In fact, the total number of patients
randomized in all 24 other trials of dypiridamole and
aspirin were less (36%) than the number of patients
entered in ESPS-2 (n=6602). ESPS-2 also used an
extended-release formulation of dipyridamole that is not
pH-dependent as to dissolution and from which
bioavailability of the drug can be assured, unlike the
formulation used in older trials. As the authors state.
dipyridamole is not purely an antiplatelet agent, like
aspirin. The effect of dipyridamole is at least partly
through interaction with the vessel wall, and the drug must
be well-absorbed to provide optimal benefit. The older
trials used smaller doses of dipyridamole than ESPS-2 and
were too small to provide definitive results. In the
authors current analysis of trials in patients with stroke
or transient ischemic attacks, the benefit from antiplatelet
agents in preventing non-fatal stroke was clearly magnified
(25 (SD 5) per 1000 vs 20 (SD 6) per 1000) from their last
analysis in 1994, largely due to the addtion of the data
from ESPS-2.

Nonetheless, even when the ESPS-2 data are aggregated with
previous studies combination therapy with aspirin and
dipyridamole significantly reduces the risk of recurrent
stroke alone by 23% over aspirin alone.(2) These are
important results for those looking for ways to manage
recurrent stroke, especially now that the WARSS study has
shown that warfarin is no more effective, and possibly more
risky, than aspirin.(3)

Louis R Caplan MD
Professor Neurology Harvard Medical School
Chief Cerebrovascular Disease
Beth Israel Deaconess Medical Center
Boston
Lcaplan@caregroup.harvard.edu

Pierre Fayad MD
Reynolds Centennial Professor and Chair
Dept Neurology
University of Nebraska

H Christoph Diener
Professor and Chair Neurology
University of Essen, Germany

References:

1. Diener HC, Cunha L, Forbes C, et al. European Stroke
Prevention Study. 2. Dipyridamole and acetylsalicylic acid
in the secondary prevention of stroke. J Neurol Sci.
1996;143:1-13.

2. Wilterdink JL, Easton D. Dipyridamole plus aspirin in
cerebrovascular disease. Arch Neurol. 1999;56:1087-92.

3. Mohr JP, Thompson JLP, Lazar RM, et al. A comparison of
warfarin and aspirin for the prevention of recurrent
ischemic