The Fragility Index in Multicenter Randomized Controlled Critical Care Trials*

Ridgeon, Elliott; Young, Paul; Bellomo, Rinaldo; Mucchetti, Marta; Lembo, Rosalba; Landoni, Giovanni

doi:10.1097/ccm.0000000000001670

Cited by 200 publications

(146 citation statements)

References 16 publications

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“…Indeed, a recent study noted that the statistical conclusions of over half of the identified randomized clinical trials could be flipped either by using a more conservative statistical test or just changing the number of deaths to survivors by two, even in multi-centered trials in adult ICUs where mortality rates are approximately three to four times as high as pediatric units. 10 Critical care in general—especially pediatric critical care, due to the relatively low mortality rate—needs a more frequent outcome than mortality for robust and reliable studies.…”

Section: Why Does Assessing Morbidity Matter For Pediatric Critical Cmentioning

confidence: 99%

Morbidity

Heneghan

Pollack

2017

Pediatric Clinics of North America

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The focus of critical care has evolved from saving lives to preservation of function. Morbidity rates in pediatric critical care are about double mortality rates. Morbidity includes complications of disease and medical care. In pediatric critical care, functional status morbidity is an intermediate outcome in the progression towards death, and is the result of the same factors associated with mortality including physiological profiles (PRISM), and case-mix factors. The Functional Status Scale (FSS) developed by CPCCRN, a NIH research consortium, is a validated, granular, age-independent measure of functional status that has proven valuable and practical even in large outcome studies.

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Section: Why Does Assessing Morbidity Matter For Pediatric Critical Cmentioning

confidence: 99%

Morbidity

Heneghan

Pollack

2017

Pediatric Clinics of North America

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“…In one study, researchers reported positive results in 10 (14%) of 72 multicenter RCTs with mortality as the primary endpoint published before August 2006 [20]; in a second, investigators reported that 7 (18%) of 38 trials published in 5 major medical journals between 1999 and 2009 showed positive results [5]; and in a third study, in evaluating ICU-based trials published between January 2007 and May 2013 in 16 high-impact general or critical care journals, researchers identified that 3 (9%) of 34 were positive [21]. Authors of a more recent systematic review identified that 44 (5%) of 862 multicenter critical care medicine trials reported significant differences in mortality [22]. These data confirm that ICU-based trials with mortality endpoints are frequently negative and indicate that the median predictions of prior probability offered by survey respondents in our study are broadly congruent with the observed frequency of positive trials in the critical care medicine literature.…”

Section: Discussionmentioning

confidence: 99%

Effect sizes in ongoing randomized controlled critical care trials

et al. 2017

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BackgroundAn important limitation of many critical care trial designs is that they hypothesize large, and potentially implausible, reductions in mortality. Interpretation of trial results could be improved by systematic assessment of the plausibility of trial hypotheses; however, such assessment has not been attempted in the field of critical care medicine. The purpose of this study was to determine clinicians’ views about prior probabilities and plausible effect sizes for ongoing critical care trials where the primary endpoint is landmark mortality.MethodsWe conducted a systematic review of clinical trial registries in September 2015 to identify ongoing critical care medicine trials where landmark mortality was the primary outcome, followed by a clinician survey to obtain opinions about ten large trials. Clinicians were asked to estimate the probability that each trial would demonstrate a mortality effect equal to or larger than that used in its sample size calculations.ResultsEstimates provided by individual clinicians varied from 0% to 100% for most trials, with a median estimate of 15% (IQR 10–20%). The median largest absolute mortality reduction considered plausible was 4.5% (IQR 3.5–5%), compared with a median absolute mortality reduction used in sample size calculations of 5% (IQR 3.6–10%) (P = 0.27).ConclusionsFor some of the largest ongoing critical care trials, many clinicians regard prior probabilities as low and consider that plausible effects on absolute mortality are less than 5%. Further work is needed to determine whether pooled estimates obtained by surveying clinicians are replicable and accurate or whether other methods of estimating prior probability are preferred.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1726-x) contains supplementary material, which is available to authorized users.

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“…The final result of ELAIN -an absolute difference of 15.4% in 90 day mortality in favour of early RRTexceeds the survival benefit that one might expect from early RRT initiation or perhaps from any experimental intervention evaluated in a cohort of critically ill patients with an increased risk of death. Importantly, the ELAIN trial has a low fragility index of three (if three more deaths occurred in the early RRT group or three less deaths occurred in the delayed RRT group the trial would have showed no between-group difference in mortality) 9 . The instability and the likely inflation of the effect estimate in the ELAIN trial were appropriately acknowledged by the researchers.…”

Section: Sean M Bagshaw and Ron Waldmentioning

confidence: 99%

Timing of renal replacement therapy in AKI

Bagshaw

Wald

2016

Nat Rev Nephrol

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Refers to: Gaudry, S. et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N. Engl. J Med. http://dx.doi.org/10.1056/NEJMoa1603017 (2016) | Zarbock, A. et al. Effect of early versus delayed Initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial. JAMA 315, 2190-2199 (2016). Neither [the AKIKI nor the ELAIN trial] … has yielded definitive results NATURE REVIEWS | NEPHROLOGY www.nature.com/nrneph NEWS & VIEWS© 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . A l l r i g h t s r e s e r v e d .

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The Fragility Index in Multicenter Randomized Controlled Critical Care Trials*

Cited by 200 publications

References 16 publications

Morbidity

Morbidity

Effect sizes in ongoing randomized controlled critical care trials

Timing of renal replacement therapy in AKI

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