Real-world causal evidence for planned predictive enrichment in critical care trials: A scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness due, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Although causal evidence from rich real-world critical care can help overcome these challenges by informing predictive enrichment, no overview exists. METHODS: We conducted a scoping review, systematically searching 10 general and speciality journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We collected trial metadata on 22 variables including recruitment period, intervention type and early stopping (including reasons) as well as data on the use of causal evidence from secondary data for planned predictive enrichment. RESULTS: We screened 9020 records and included 316 unique RCTs with a total of 268,563 randomised participants. One hundred seventy-three (55%) trials tested drug interventions, 101 (32%) management strategies and 42 (13%) devices. The median duration of enrolment was 2.2 (IQR: 1.3-3.4) years, and 83% of trials randomised less than 1000 participants. Thirty-six trials (11%) were restricted to COVID-19 patients. Of the 55 (17%) trials that stopped early, 23 (42%) used predefined rules; futility, slow enrolment and safety concerns were the commonest stopping reasons. None of the included RCTs had used causal evidence from secondary data for planned predictive enrichment. CONCLUSION: Work is needed to harness the rich multiverse of critical care data and establish its utility in critical care RCTs. Such work will likely need to leverage methodology from interventional and analytical epidemiology as well as data science.

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Lower or higher oxygenation targets for acute Hypoxaemic respiratory failure: Protocol for an individual patient data meta-analysis.

BACKGROUND: Supplemental oxygen therapy is central to the treatment of acute hypoxaemic respiratory failure, a condition which remains a major driver for morbidity and mortality in intensive care. Despite several large randomised clinical trials comparing a higher versus a lower oxygenation target for these patients, significant differences in study design impede analysis of aggregate data and final clinical recommendations. METHODS: This paper presents the protocol for conducting an individual patient data meta-analysis where full individual patient data according to the intention-to-treat principle will be pooled from the HOT-ICU and HOT-COVID trials in a one-step procedure. The two trials are near-identical in design. We plan to use a hierarchical general linear mixed model that accounts for data clustering at a trial and site level. The primary outcome will be 90-day all-cause mortality while the secondary outcome will be days alive without life-support at 90 days. Further, we outline 14 clinically relevant predefined subgroups which we will analyse for heterogeneity in the intervention effects and interactions, and we present a plan for assessing the credibility of the subgroup analyses. CONCLUSION: The presented individual patient data meta-analysis will synthesise individual level patient data from two of the largest randomised clinical trials on targeted oxygen therapy in intensive care. The results will provide a re-analysis of the intervention effects on the pooled intention-to-treat populations and facilitate subgroup analyses with an increased power to detect clinically important effect modifications.

Association between days alive without life support/out of hospital and health-related quality of life.

BACKGROUND: Trials in critically ill patients increasingly focus on days alive without life support (DAWOLS) or days alive out of hospital (DAOOH) and health-related quality of life (HRQoL). DAWOLS and DAOOH convey more information than mortality and are simpler and faster to collect than HRQoL. However, whether these outcomes are associated with HRQoL is uncertain. We thus aimed to assess the associations between DAWOLS and DAOOH and long-term HRQoL. METHODS: Secondary analysis of the COVID STEROID 2 trial including adults with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial including adult intensive care unit patients with acute hypoxaemic respiratory failure. Associations between DAWOLS and DAOOH at day 28 and 90 and long-term HRQoL (after 6 or 12 months) using the EuroQol 5-dimension 5-level survey (EQ VAS and EQ-5D-5L index values) were assessed using flexible models and evaluated using measures of fit and prediction adequacy in both datasets (comprising internal performance and external validation), non-parametric correlation coefficients and graphical presentations. RESULTS: We found no strong associations between DAWOLS or DAOOH and HRQoL in survivors at HRQoL-follow-up (615 and 1476 patients, respectively). There was substantial variability in outcomes, and predictions from the best fitted models were poor both internally and externally in the other trial dataset, which also showed inadequate calibration. Moderate associations were found when including non-survivors, although predictions remained uncertain and calibration inadequate. CONCLUSION: DAWOLS and DAOOH were poorly associated with HRQoL in adult survivors of severe or critical illness included in the COVID STEROID 2 and HOT-ICU trials.

Long-term effects of lower versus higher oxygenation levels in adult ICU patients-A systematic review.

BACKGROUND: Oxygen therapy is a common treatment in the intensive care unit (ICU) with both potentially desirable and undesirable long-term effects. This systematic review aimed to assess the long-term outcomes of lower versus higher oxygenation strategies in adult ICU survivors. METHODS: We included randomised clinical trials (RCTs) comparing lower versus higher oxygen supplementation or oxygenation strategies in adults admitted to the ICU. We searched major electronic databases and trial registers. We included all non-mortality long-term outcomes. Prespecified co-primary outcomes were the long-term cognitive function measures, the overall score of any valid health-related quality of life (HRQoL) evaluation, standardised 6-min walk test, and lung diffusion capacity. The protocol was published and prospectively registered in the PROSPERO database (CRD42021223630). RESULTS: The review included 17 RCTs comprising 6592 patients, and six trials with 825 randomised patients reported one or more outcomes of interest. We observed no difference in cognitive evaluation via Telephone Interview for Cognitive Status (one trial, 409 patients) (mean score: 30.6 ± 4.5 in the lower oxygenation group vs. 30.4 ± 4.3 in the higher oxygenation group). The trial was judged at overall high risk of bias and the certainty of evidence was very low. Any difference was neither observed in HRQoL measured via EuroQol 5 dimensions 5 level questionnaire and EQ Visual Analogue Score (one trial, 499 patients) (mean score: 70.1 ± 22 in the lower oxygenation group vs. 67.6 ± 22.4 in the higher oxygenation group). The trial was judged as having high risk of bias, the certainty of evidence was very low. No trial reported neither the standardised 6-min walk test nor lung diffusion test. CONCLUSION: The evidence is very uncertain about the effect of a lower versus a higher oxygenation strategy on both the cognitive function and HRQoL. A lower versus a higher oxygenation strategy may have a little to no effect on both outcomes but the certainty of evidence is very low. No evidence was found for the effects on the standardised 6-min walking test and diffusion capacity test.

Health-related quality of life and days alive without life support or out of hospital: Protocol.

BACKGROUND: Mortality is often the primary outcome in randomised clinical trials (RCTs) conducted in critically ill patients. Due to increased awareness on survivors after critical illness and outcomes other than mortality, health-related quality of life (HRQoL) and days alive without life support (DAWOLS) or days alive and out of hospital (DAAOOH) are increasingly being used. DAWOLS and DAAOOH convey more information than mortality, are easier to collect than HRQoL, and are usually assessed at earlier time points, which may be preferable in some situations. However, the associations between DAWOLS-DAAOOH and HRQoL are uncertain. METHODS: We will assess associations between DAWOLS-DAAOOH at day 28 and 90 (independent variables/predictors) and HRQoL assessed using the EuroQol EQ-5D-5L questionnaire (EQ-VAS and EQ-5D-5L index values) at 6 or 12 months (dependent variables) in two RCTs: the COVID STEROID 2 RCT conducted in adult patients with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) RCT conducted in adult intensive care patients with acute hypoxaemic respiratory failure. We will describe associations using best-fitting fractional polynomial transformations separately in each dataset, with the resulting models presented and assessed in both datasets graphically and using measures of fit and prediction adequacy (i.e., internal performance and external validation). We will use multiple imputation if missingness exceeds 5%. DISCUSSION: The outlined study will provide important knowledge on the associations between DAWOLS-DAAOOH and HRQoL in adult critically ill patients, which may help researchers and clinical trialists prioritise and select outcomes in future RCTs conducted in this population.

Causal inference for planning randomised critical care trials: Protocol for a scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness owing, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Planned predictive enrichment based on secondary critical care data (often very rich with respect to both data types and temporal granularity) and causal inference methods may help overcome these challenges, but no overview exists about their use to this end. METHODS: We will conduct a scoping review to assess the extent and nature of the use of causal inference from secondary data for planned predictive enrichment of randomised clinical trials in critical care. We will systematically search 10 general and specialty journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We will collect trial metadata (e.g., recruitment period and phase) and, when available, information pertaining to the focus of the review (predictive enrichment based on causal inference estimates from secondary data): causal inference methods, estimation techniques and software used; types of patient populations; data provenance, types and models; and the availability of the data (public or not). The results will be reported in a descriptive manner. DISCUSSION: The outlined scoping review aims to assess the use of causal inference methods and secondary data for planned predictive enrichment in randomised critical care trials. This will help guide methodological improvements to increase the utility, and facilitate the use, of causal inference estimates when planning such trials in the future.

Patient-important outcomes other than mortality in recent ICU trials: Protocol for a scoping review.

BACKGROUND: Randomised clinical trials (RCTs) conducted in intensive care units (ICUs) frequently focus on all-cause mortality, but other patient-important outcomes are increasingly used and recommended. Their use, however, is not straightforward: choices and definitions, operationalisation of death, handling of missing data, choice of effect measures, and statistical analyses for these outcomes vary greatly. METHODS: We will conduct a scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. We will search 10 selected general and speciality journals for RCTs conducted in adult ICU patients from 2018 and onwards reporting at least 1 patient-important outcome other than mortality (including days alive without life support/days alive and out of hospital-type outcomes, health-related quality of life, functional/cognitive/neurological outcomes, and other general patient-important outcomes). We will summarise data on outcome measures and definitions, assessment time points, proportions and handling of death, proportions and handling of missing data, and effect measures and statistical methods used for analysis. DISCUSSION: The outlined scoping review will provide an overview of choices, definitions and handling of patient-important outcomes other than mortality in contemporary RCTs conducted in adult ICU patients. This may guide discussions with patients and relatives, the design of future RCTs, and research on optimal outcome choices and handling.

Lower or Higher Oxygenation Targets in Patients With COVID-19 in the ICU: A Secondary Bayesian Analysis of the Handling Oxygenation Targets in COVID-19 Trial.

BACKGROUND: In the Handling Oxygenation Targets in COVID-19 (HOT-COVID) trial, a Pao2 target of 60 mm Hg compared with 90 mm Hg resulted in more days alive without life support at 90 days in adults in the ICU with COVID-19 and hypoxemia. The trial was stopped after enrolling 726 of 780 planned patients because of slow recruitment. Herein, we present the preplanned Bayesian analysis of the HOT-COVID trial. RESEARCH QUESTION: What are the probabilities of any benefits and of clinically relevant benefits resulting from a Pao2 target of 60 mm Hg vs 90 mm Hg in adult patients with COVID-19 and hypoxemia in the ICU and does heterogeneity of treatment effects (HTE) exist according to selected baseline characteristics?. STUDY DESIGN AND METHODS: We analyzed days alive without life support and 90-day mortality in the HOT-COVID intention-to-treat population (n = 697) using Bayesian general linear models to assess probabilities for benefit or harm, including clinically relevant benefits defined as > 1 day alive without life support and > 2 percentage points lower 90-day mortality. HTE was evaluated based on baseline Sequential Organ Failure Assessment scores, Pao2 to Fio2 ratio, norepinephrine doses, and lactate concentrations. RESULTS: The mean difference in days alive without life support was 5.7 days (95% credible interval [CrI], 0.2-11.2), with a 95.2% probability of clinically relevant benefit and a 98.0% probability of any benefit from the lower Pao2 target. The risk difference in 90-day mortality was -4.6 percentage points (95% CrI, -11.8 to 2.6 percentage points), with a 76.5% probability of a clinically relevant benefit from the lower target. HTE analyses revealed potential interaction with baseline norepinephrine dose and lactate concentrations for both outcomes. INTERPRETATION: In patients with COVID-19 and hypoxemia in the ICU, we found a high probability for a clinically relevant benefit of targeting a Pao2 of 60 mm Hg vs 90 mm Hg on number of days alive without life support. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04425031; URL: www. CLINICALTRIALS: gov.

Long-term mortality and health-related quality of life with lower versus higher oxygenation targets in intensive care unit patients with COVID-19 and severe hypoxaemia.

PURPOSE: The aim of this study was to evaluate one-year outcomes of lower versus higher oxygenation targets in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We conducted pre-planned analyses of one-year mortality and health-related quality of life (HRQoL) in the Handling Oxygenation Targets in COVID-19 trial. The trial randomised 726 ICU patients with COVID-19 and hypoxaemia to partial pressure of arterial oxygen targets of 8 kPa (60 mmHg) versus 12 kPa (90 mmHg) during ICU stay up to 90 days, including readmissions. HRQoL was assessed using EuroQol visual analogue scale (EQ-VAS) and 5-level 5-dimension questionnaire (EQ-5D-5L). Outcomes were analysed in the intention-to-treat population. Non-survivors were assigned the worst possible score (zero), and multiple imputation was applied for missing EQ-VAS values. RESULTS: We obtained one-year vital status for 691/726 (95.2%) of patients and HRQoL data for 642/726 (88.4%). At one year, 117/348 (33.6%) of patients in the lower-oxygenation group had died compared to 134/343 (39.1%) in the higher-oxygenation group (adjusted risk ratio: 0.85; 98.6% confidence interval (CI) 0.66-1.09; p = 0.11). Median EQ-VAS was 50 (interquartile range, 0-80) versus 40 (0-75) (adjusted mean difference: 4.8; 98.6% CI - 2.2 to 11.9; p = 0.09) and EQ-5D-5L index values were 0.61 (0-0.81) in the lower-oxygenation group versus 0.43 (0-0.79) (p = 0.20) in the higher-oxygenation group, respectively. CONCLUSION: Among adult ICU patients with COVID-19 and severe hypoxaemia, one-year mortality results were most compatible with benefit of the lower oxygenation target, which did not appear to result in more survivors with poor quality of life.

An overview of methodological considerations regarding adaptive stopping, arm dropping, and randomization in clinical trials.

BACKGROUND AND OBJECTIVES: Adaptive features may increase flexibility and efficiency of clinical trials, and improve participants' chances of being allocated to better interventions. Our objective is to provide thorough guidance on key methodological considerations for adaptive clinical trials. METHODS: We provide an overview of key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, and response-adaptive randomization. We cover pros and cons of different decisions and provide guidance on using simulation to compare different adaptive trial designs. We focus on Bayesian multi-arm adaptive trials, although the same general considerations apply to frequentist adaptive trials. RESULTS: We provide guidance on 1) interventions and possible common control, 2) outcome selection, follow-up duration and model choice, 3) timing of adaptive analyses, 4) decision rules for adaptive stopping and arm dropping, 5) randomization strategies, 6) performance metrics, their prioritization, and arm selection strategies, and 7) simulations, assessment of performance under different scenarios, and reporting. Finally, we provide an example using a newly developed R simulation engine that may be used to evaluate and compare different adaptive trial designs. CONCLUSION: This overview may help trialists design better and more transparent adaptive clinical trials and to adequately compare them before initiation.

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia.

PURPOSE: We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. METHODS: Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. RESULTS: We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93-1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50-80) in the lower oxygenation group versus 67 (50-80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. CONCLUSION: Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

Letter the editor: serious methodological concerns about a recently published meta-analysis on oxygen therapy.

In a recent paper, Chen et al. report the findings of a systematic review with meta-analysis concerning conservative versus conventional oxygen therapy for critically ill patients. We wish to commend the authors for their interest in the matter. However, the authors appear to misquote findings, fail to report results for all specified analyses, do not identify all relevant trials, have post hoc changed the eligibility criteria, and have seemingly switched directions of effects in analyses of secondary outcomes. These issues have led to incorrect conclusions concerning the effects of targeted oxygen therapy in critically ill patients.