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Trials in adult critical care that show increased mortality of the new
intervention: Inevitable or preventable mishaps?
#MMPMID26909519
Russell JA
; Williams MD
Ann Intensive Care
2016[Dec]; 6
(1
): 17
PMID26909519
show ga
Several promising therapies assessed in the adult critically ill in large,
multicenter randomized controlled trials (RCTs) were associated with
significantly increased mortality in the intervention arms. Our hypothesis was
that there would be wide ranges in sponsorship (industry or not), type(s) of
intervention(s), use of DSMBs, presence of interim analyses and early stopping
rules, absolute risk increase (ARI), and whether or not adequate prior
proof-of-principle Phase II studies were done of RCTs that found increased
mortality rates of the intervention compared to control groups. We reviewed RCTs
that showed a statistically significant increased mortality rate in the
intervention compared to control group(s). We recorded source of sponsorship,
sample sizes, types of interventions, mortality rates, ARI (as well as odds
ratios, relative risks and number needed to harm), whether there were
pre-specified interim analyses and early stopping rules, and whether or not there
were prior proof-of-principle (also known as Phase II) RCTs. Ten RCTs (four
industry sponsored) of many interventions (high oxygen delivery, diaspirin
cross-linked hemoglobin, growth hormone, methylprednisolone, hetastarch,
high-frequency oscillation ventilation, intensive insulin, NOS inhibition, and
beta-2 adrenergic agonist, TNF-? receptor) included 19,126 patients and were
associated with wide ranges of intervention versus control group mortality rates
(25.7-59 %, mean 29.9 vs 17-49 %, mean 25 %, respectively) yielding ARIs of
2.6-29 % (mean 5 %). All but two RCTs had pre-specified interim analyses, and
seven RCTs were stopped early. All RCTs were preceded by published
proof-of-principle RCT(s), two by the same group. Seven interventions (except
diaspirin cross-linked hemoglobin and the NOS inhibitor) were available for use
clinically at the time of the pivotal RCT. Common, clinically available
interventions used in the critically ill were associated with increased mortality
in large, pivotal RCTs even though safety was often addressed by interim analyses
and early stopping rules.
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