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Developments in Secondary Stroke Prevention
Figure 1: Trial Profile and Patient Distribution
40
20,332 randomized
5,086 randomly assigned to 5,095 randomly assigned to 5,060 randomly assigned to 5,091 randomly assigned to
ASA + ER-DP and telmisartan ASA + ER-DP and placebo clopidogrel and telmisartan clopidogrel and placebo
21 lost to long-term 39 lost to long-term 30 lost to long-term 35 lost to long-term
follow-up; 375 died follow-up; 364 died follow-up; 380 died follow-up; 376 died
4,690 completed the study 4,692 completed the study 4,650 completed the study 4,680 completed the study
ASA = acetylsalicylic acid; ER-DP = extended-release dipyridamole.
Figure 2: Distribution of Types of Recurrent Stroke Under
pre-specified criteria for non-inferiority were not met in the comparison of
Antiplatelet Therapy
41
aspirin plus extended-release dipyridamole versus the active comparator
clopidogrel, the authors of the study
42
note that neither drug could be shown
10
to be superior in secondary stroke prevention. Rather, results indicate that the
916 (9%) 898 (8.8%)
two drugs have similar rates of recurrent stroke and effects in reducing the
composite outcome of vascular events following stroke. Although the
8
combination therapy was associated with increased incidence of major
hemorrhagic events and intracranial bleeds, the absolute risks were low and
780
805
6
partially offset by a lack of ischemic events in the primary outcome. The results
of this study highlight the importance of conducting direct comparisons in the
entage of patients 4
context of secondary stroke prevention in lieu of relying on indirect
r
c
Pe
comparisons that can be limited by trial design, patient populations,
comparator drugs, and definitions of study outcomes. The authors of the
2
study have also noted that the trial was considerably underpowered to show
83
45
non-inferiority at 30% power, given the study outcome of equivalency
53 48
0
between the antiplatelet regimens. Although no significant difference could Aspirin–ER-DP Clopidogrel
be found between the antiplatelet agents in question in terms of their ability Ischemic Hemorrhagic Other or unknown
to prevent secondary stroke, study results suggest a significant benefit for
ER-DP = extended-release dipyridamole.
aspirin plus extended-release dipyridamole in reducing the risk for new or
worsening congestive heart failure, the reason for which has been purported The primary outcome of first recurrent stroke was not significantly different
to be related to increased adenosine levels and coronary collateralization.
43
between the treatments, occurring in 916 patients (9%) receiving aspirin
The study also disproved the frequently quoted hypothesis that clopidogrel is plus extended-release dipyridamole and 898 (8.8%) receiving clopidogrel
the drug of choice for large-vessel disease and will decrease the rate of cardiac (hazard ratio [HR] 1.01, 95% CI 0.92–1.11).
42
Being close to 1.00, the HR
events while aspirin plus dipyridamole is preferred in patients with small-vessel indicated that the rates of primary outcome were essentially identical.
disease and will reduce primary strokes. However, due to the study’s statistical design, the upper boundary of the
95% CI for the HR was required to lie below the value of 1.075 in order to
Aspirin plus Extended-release demonstrate non-inferiority of aspirin plus extended-release dipyridamole
Dipyridamole versus Clopidogrel compared with clopidogrel—a requirement that was not met in this case.
Although aspirin is known to confer a benefit in terms of reducing the risk for Of these first recurrent strokes, there were 25 fewer ischemic strokes, 38
recurrent stroke, clopidogrel has also been implicated in a role for reducing more hemorrhagic strokes, and five more strokes of other or unknown
stroke recurrence by approximately 8% compared with aspirin,
16
while the causes with combination therapy compared with clopidogrel (see Figure 2).
combination of aspirin plus extended-release dipyridamole compared with This overall difference of 16 increased strokes was not significant between
aspirin have indicated an RR reduction of 20–23%
22,28
From indirect the two treatment arms. The secondary outcome of stroke, myocardial
comparisons alone, one would gather that aspirin plus extended-release infarction, or death from vascular causes were nearly identical, occurring in
dipyridamole would be superior to clopidogrel in secondary stroke prevention. 1,333 patients (13.1%) from each treatment group (HR for combination
With no guideline recommendations for any one of these therapies over the versus clopidogrel 0.99, 95% CI 0.92–1.07). The rates of tertiary outcomes
other,
5,6,44
the antiplatelet segments of the PRoFESS study aimed to compare of myocardial infarction, deaths, and other designated vascular events were
the efficacy and safety of aspirin plus extended-release dipyridamole versus similar between the two groups. No significant difference was found in the
clopidogrel in patients who had recently suffered an ischemic stroke.
41
rates of recurrent stroke or major hemorrhagic event between patients
US NEUROLOGY 31
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