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Brain Trauma Stroke
release of results from the PRoFESS trial has served only to reinforce the only failed to show the superiority of aspirin plus extended-release
available knowledge about antiplatelet use in secondary stroke prevention. dipyridamole over clopidogrel, but was also unable to reach the non-
The much anticipated head-to-head comparison between aspirin plus inferiority margin in spite of the global enrollment of over 20,000 patients.
extended-release dipyridamole and clopidogrel demonstrated comparable Indeed, the study and methodology of PRoFESS clearly show that non-
efficacy in secondary stroke prevention, with similar ability in preventing inferiority analyses are valid only if the prior assumptions are met. Although
cardiovascular events, contrary to any advantage that may have been the primary outcome of recurrent stroke was essentially identical between
assumed through indirect comparisons. Despite the modest effect of aspirin the treatment groups, the failure to demonstrate non-inferiority is
in preventing recurrent stroke and vascular events, the big advantage is its attributed to the stringent and conservative non-inferiority margin of 7.5%,
cost-effectiveness and worldwide availability. Although it is necessary for selected under the initial assumptions of the trial design that the use of
better and improved pharmaceuticals, it is also necessary to have affordable aspirin plus extended-release dipyridamole would be superior to
treatments for patients worldwide. clopidogrel. However, it is necessary to take the results of PRoFESS and
compare them with previous evidence suggestive of clear superiority for
Previous studies had shown evidence in support of ARBs in reducing the aspirin plus extended-release dipyridamole over aspirin, the latter of which
frequency of recurrent stroke independent of blood-pressure lowering. had similar efficacy in secondary stroke prevention of clopidogrel.
Patients in PRoFESS receiving telmisartan did experience a greater decrease
in blood pressure relative to patients in the placebo group, but telmisartan The efforts of PRoFESS investigators were not in vain. Although their desired
could not be shown to have any significant benefit in reducing recurrent outcome was not achieved in the study, the information provided does add
stroke or cardiovascular events by study end, although a number of limiting a positive feature in secondary stroke prevention, where the comparable
factors have been implicated in these results. efficacy between the antiplatelet treatments has reinforced the availability
of options within the armamentarium against recurrent stroke. With this in
PRoFESS was also unable to demonstrate any advantage with the mind, patients and physicians have a choice in their antiplatelet therapy
antiplatelet therapies and prophylactic telmisartan in reducing stroke-based after initial stroke, and may not have to base their decisions on efficacy
disability and restoration of cognitive function. However, recent stroke alone, but possibly also on frequency of dosing, tolerability, adverse effects,
research has revealed new developments where the cerebral endothelium and cost. Notably, aspirin plus extended-release dipyridamole conferred a
has been shown to secrete neuroprotective trophic factors that protect significant advantage over clopidogrel in reducing the risk for new or
against stressful and damaging conditions.
75
This information suggests that worsening congestive heart failure, an unexpected but welcome benefit
targeting the cerebral endothelium to salvage the trophic signals originating that warrants further research.
from the matrix-trophic coupling between neurons and the cerebral
endothelium may provide novel therapeutic opportunities within stroke and In the ARB segment of PRoFESS, telmisartan demonstrated only a non-
neurodegenerative diseases. significant trend toward a benefit, appearing only in the later stages of the
follow-up period; factors such as sub-optimal adherence, the use of
What Have We Learned from the Prevention Regimen for counterbalancing blood-pressure-lowering agents, and a short follow-up
Effectively Avoiding Second Strokes Study? period have been implicated in this result. Also observed was a small trend
From the information available from historical antiplatelet studies alone, it toward a lower rate of new-onset diabetes. To further evaluate the role of
was likely that many favored low-dose aspirin plus extended-release ARBs in the prevention of recurrent stroke, two large trials are currently
dipyridamole over clopidogrel in secondary stroke prevention. However, the under way with expected mean follow-ups of more than four years.
76,77
■
results from the first ever head-to-head comparison between the two
antiplatelet agents in PRoFESS emphasized the need for direct studies, a This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. The
clear demonstration of the unreliability of indirect comparisons. Contrary to author had full control over content and received editorial assistance from
what many had expected based on indirect comparisons alone, PRoFESS not Patrick Wong, PhD, Touch Briefings.
1. Rosamond WD, Folsom AR, Chambless LE, et al., Stroke (6):1583–1633. recommendation for antithrombotic agents, Chest, 2001;119
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34 US NEUROLOGY
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