Trials in adult critical care that show increased mortality of the new intervention: Inevitable or preventable mishaps?

James A Russell,Mark D Williams

doi:10.1186/s13613-016-0120-1

Abstract

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-α 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.

Highlights

In Critical Care Medicine (CCM), randomized controlled trials (RCTs) are the best evidence to determine whether novel drugs, devices and clinically available therapies are effective [1, 2], safe, superior to “conventional” therapies and recommended for clinical use [3]
Characteristics of included RCTs We found ten adult critical care-related RCTs that were designed and powered for mortality that showed significant increased mortality rates in the intervention compared to the control group(s) (Table 1)
We found a relatively small number of RCTs in adult CCM that showed that the new intervention was associated with increased mortality compared to control group

Summary

Introduction

In Critical Care Medicine (CCM), randomized controlled trials (RCTs) are the best evidence to determine whether novel drugs, devices and clinically available therapies are effective [1, 2], safe, superior to “conventional” therapies and recommended for clinical use [3]. We use the term “conventional” to refer to therapies and not to placebo. Superiority design RCTs are done because of prior clinical equipoise, and test the hypothesis that the new intervention is superior to the conventional intervention but use two-sided statistical testing to determine whether either the new or conventional intervention is statistically superior. New therapy must have clinical equipoise to satisfy ethical concerns. Russell and Williams Ann. Intensive Care (2016) 6:17

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