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