The miracle of DICE therapy for acute stroke: fact or fictional product of subgroup analysis?
OBJECTIVE
To determine whether inappropriate subgroup analysis together with chance could change the conclusion of a systematic review of several randomised trials of an ineffective treatment.


METHODS
44 randomised controlled trials of DICE therapy for stroke were performed (simulated by rolling different coloured dice; two trials per investigator). Each roll of the dice yielded the outcome (death or survival) for that "patient." Publication bias was also simulated. The results were combined in a systematic review.


METHODS
Edinburgh.


METHODS
Mortality.


RESULTS
The "hypothesis generating" trial suggested that DICE therapy provided complete protection against death from acute stroke. However, analysis of all the trials suggested a reduction of only 11% (SD 11) in the odds of death. A predefined subgroup analysis by colour of dice suggested that red dice therapy increased the odds by 9% (22). If the analysis excluded red dice trials and those of poor methodological quality the odds decreased by 22% (13, 2P = 0.09). Analysis of "published" trials showed a decrease of 23% (13, 2P = 0.07) while analysis of only those in which the trialist had become familiar with the intervention showed a decrease of 39% (17, 2P = 0.02).


CONCLUSIONS
The early benefits of DICE therapy were not confirmed by subsequent trials. A plausible (but inappropriate) subset analysis of the effects of treatment led to the qualitatively different conclusion that DICE therapy reduced mortality, whereas in truth it was ineffective. Chance influences the outcome of clinical trials and systematic reviews of trials much more than many investigators realise, and its effects may lead to incorrect conclusions about the benefits of treatment.
Counsell
C E
CE
Department of Clinical Neurosciences, Western General Hospital, Edinburgh.
Clarke
M J
MJ
Slattery
J
J
Sandercock
P A
PA
D015982:Bias; D002561:Cerebrovascular Disorders / Q000401:mortality / Q000628:therapy; D006801:Humans; D015201:Meta-Analysis as Topic; D011336:Probability; D016032:Randomized Controlled Trials as Topic; D013663:Teaching / Q000379:methods*