Statistical methods to compare functional outcomes in randomized controlled trials with high mortality

Colantuoni, Elizabeth; Scharfstein, Daniel O.; Wang, Chenguang; Hashem, Mohamed D.; Leroux, Andrew; Needham, Dale M.; Girard, Timothy D.

doi:10.1136/bmj.j5748

Cited by 73 publications

(102 citation statements)

References 20 publications

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“…Importantly, though, results were similar in the sensitivity analyses conducted after redefining the time periods. Finally, the assessment of secondary outcomes according to time of first CIB event may be subject to survival bias and a competing risk of death before CIB, as the most severely ill patients may be more likely to develop CIB, but also more likely die before that happens. We did not account for this in the descriptive presentations of secondary outcome data.…”

Section: Discussionmentioning

confidence: 99%

Time to onset of gastrointestinal bleeding in the SUP‐ICU trial: A pre‐planned substudy

Granholm

Lange

Anthon

et al. 2019

Acta Anaesthesiol Scand

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Background:The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to the onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP). Methods: We assessed the time to CIB in the Stress Ulcer Prophylaxis in the IntensiveCare Unit (SUP-ICU) trial. We assessed if associations between baseline characteristics including allocation to SUP and CIB changed during time in the ICU, specifically in the later (after day 2) compared to the earlier (first 2 days) period, using Cox models adjusted for SAPS II and allocation to SUP. Additionally, we described baseline characteristics and CIB episodes stratified by earlier/later/no CIB and 90-day mortality status. Results:Clinically important gastrointestinal bleeding occurred in 110/3291 (3.3%) patients after a median of 6 (interquartile range 2-13) days; 25.5% of the episodes occurred early. Higher SAPS II was consistently associated with increased risk of CIB (hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05 in the earlier period vs HR 1.02, 95% CI 1.01-1.03 in the later period; P = .37); university hospital admission was associated with decreased risk of earlier CIB (HR 0.30, 95% CI 0.14-0.63); | 1347 GRANHOLM et AL.

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Section: Discussionmentioning

confidence: 99%

Time to onset of gastrointestinal bleeding in the SUP‐ICU trial: A pre‐planned substudy

Granholm

Lange

Anthon

et al. 2019

Acta Anaesthesiol Scand

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“…We will present a Kaplan‐Meier curve for the crude data. EQ‐5D‐5L, EQ‐VAS and Mini MoCA scores using a GLM or non‐parametric test stratified for site (rating and calculation are described in the Supplemental File ). We have considered the challenge of handling patients ‘truncated due to death’ when analysing functional outcomes in trials . In consensus, we decided to assume that death is worse than a low HRQoL or low cognitive function score.…”

Section: Methodsmentioning

confidence: 99%

Long‐term patient‐important outcomes after septic shock: A protocol for 1‐year follow‐up of the CLASSIC trial

Kjær

Meyhoff

Madsen

et al. 2019

Acta Anaesthesiol Scand

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Background In patients with septic shock, mortality is high, and survivors experience long‐term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard‐care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient‐important long‐term outcomes. Aim To assess the predefined patient‐important long‐term outcomes in patients randomised into the CLASSIC trial. Methods In this pre‐planned follow‐up study of the CLASSIC trial, we will assess all‐cause mortality, health‐related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1‐year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5‐Dimension, ‐5‐Level (EQ‐5D‐5L) and EuroQol‐Visual Analogue Scale and Montreal Cognitive Assessment 5‐minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. Discussion With this pre‐planned follow‐up study of the CLASSIC trial, we will provide patient‐important data on long‐term survival, HRQoL and cognitive function of restrictive vs standard‐care IV fluid therapy in patients with septic shock.

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“…262 patients in total, will have 80% power to detect a decrease of PDS-5 in the intervention group as described above compared to the control group using a Wilcoxon–Mann–Whitney rank-sum test with a 0.05 two-sided significance level (software used: nQuery Advisor 7.0). To incorporate the death of patients (resulting in the efficacy outcome being truncated due to death), we apply a non-parametric worst rank score analysis ([ 41 , 42 ], for details see below) and decided to randomize an additional 78 (= 2 × 39) patients [an increase of about 30% (= 39 / 131) derived from a simulation study]. Thus, the sample size to be allocated to the trial is 2 × (131 + 39) = 340 patients in total.…”

Section: Methodsmentioning

confidence: 99%

“…It is assumed that death is the most likely cause of missingness. Therefore, a composite endpoint approach will be applied, combining information about the change in PDS total score and mortality into a single variable [ 41 ].…”

Section: Methodsmentioning

confidence: 99%

Effect of a combined brief narrative exposure therapy with case management versus treatment as usual in primary care for patients with traumatic stress sequelae following intensive care medicine: study protocol for a multicenter randomized controlled trial (PICTURE)

Gensichen¹,

Schultz²,

Adrion

et al. 2018

Trials

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BackgroundTraumatic events like critical illness and intensive care are threats to life and bodily integrity and pose a risk factor for posttraumatic stress disorder (PTSD). PTSD affects the quality of life and morbidity and may increase health-care costs. Limited access to specialist care results in PTSD patients being treated in primary care settings. Narrative exposure therapy (NET) is based on the principles of cognitive behavioral therapy and has shown positive effects when delivered by health-care professionals other than psychologists.The primary aims of the PICTURE trial (from “PTSD after ICU survival”) are to investigate the effectiveness and applicability of NET adapted for primary care with case management in adults diagnosed with PTSD after intensive care.Methods/designThis is an investigator-initiated, multi-center, primary care-based, randomized controlled two-arm parallel group, observer-blinded superiority trial conducted throughout Germany. In total, 340 adult patients with a total score of at least 20 points on the posttraumatic diagnostic scale (PDS-5) 3 months after receiving intensive care treatment will be equally randomized to two groups: NET combined with case management and improved treatment as usual (iTAU). All primary care physicians (PCPs) involved will be instructed in the diagnosis and treatment of PTSD according to current German guidelines. PCPs in the iTAU group will deliver usual care during three consultations. In the experimental group, PCPs will additionally be trained to deliver an adapted version of NET (three sessions) supported by phone-based case management by a medical assistant. At 6 and 12 months after randomization, structured blinded telephone interviews will assess patient-reported outcomes.The primary composite endpoint is the absolute change from baseline at month 6 in PTSD symptom severity measured by the PDS-5 total score, which also incorporates the death of any study patients. Secondary outcomes cover the domains depression, anxiety, disability, health-related quality-of-life, and cost-effectiveness. The principal analysis is by intention to treat.DiscussionIf the superiority of the experimental intervention over usual care can be demonstrated, the combination of brief NET and case management could be a treatment option to relieve PTSD-related symptoms and to improve primary care after intensive care.Trial registrationClinicalTrials.gov, NCT03315390. Registered on 10 October 2017.German Clinical Trials Register, DRKS00012589. Registered on 17 October 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2853-7) contains supplementary material, which is available to authorized users.

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Statistical methods to compare functional outcomes in randomized controlled trials with high mortality

Cited by 73 publications

References 20 publications

Time to onset of gastrointestinal bleeding in the SUP‐ICU trial: A pre‐planned substudy

Time to onset of gastrointestinal bleeding in the SUP‐ICU trial: A pre‐planned substudy

Long‐term patient‐important outcomes after septic shock: A protocol for 1‐year follow‐up of the CLASSIC trial

Effect of a combined brief narrative exposure therapy with case management versus treatment as usual in primary care for patients with traumatic stress sequelae following intensive care medicine: study protocol for a multicenter randomized controlled trial (PICTURE)

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