Generated Narrative: ArtifactAssessment 179692

Artifact URL: https://fevir.net/resources/ArtifactAssessment/179692

Artifact Description:

identifier: FEvIR Object Identifier/https://fevir.net/FOI/179692

title: Risk of Bias Assessment of Critically appraised summary of primary outcome of multi-platform RCT of anticoagulation for non-critically ill patients with COVID-19

date: 2021-12-29 22:35:49+0000

copyright:

artifact: Critically appraised summary of primary outcome of multi-platform RCT of anticoagulation for non-critically ill patients with COVID-19

content

type: Bias

classifier: Critical risk of bias

author: Brian S. Alper, Harold Lehmann, Ahmad Sofi-Mahmudi, Joanne Dehnbostel, Ilkka Kunnamo, Alfonso Iorio

freeToShare: true

component

summary:

Inclusion of suspected COVID-19 in 1 of 3 trials may introduce selection bias, but the impact appears limited.

type: Participant Selection Bias

classifier: limited potential to influence research results, Low risk of bias

Components

-	Summary
*	Participant Selection Bias Definition: A selection bias resulting from methods used to select participating subjects, factors that influence initial study participation, or differences between the study participants and the population of interest.

component

summary:

The study design used response-adaptive randomization in which group assignment ratios could be modified during the trial on the basis of response-adaptive interim analyses to favor the assignment of patients to the treatment group showing greater benefit. The confounding by time (imbalanced randomization with time period) is not adequately reported to determine the potential influence on results or adequacy of adjusted analyses.

type: Confounding Covariate Bias

classifier: high risk of bias

component

summary:

Response-adaptive randomization led to imbalanced randomization.

type: Allocation Bias

Components

-	Summary
*	Adaptive randomization is not a concern by itself, only if it results in a confounding difference.
*	Definition of Allocation Bias = A confounding covariate bias resulting from methods for assignment of the independent variable by the investigator to evaluate a response or outcome.
*	ATTACC implemented response-adaptive randomization on December 15, 2020, which led to imbalanced randomization.

component

summary:

There is an unequal distribution of calendar time between the groups being compared.

type: Confounding difference

classifier: Factor present, high potential to influence research results, risk of bias favoring experimental exposure, high risk of bias

Components

-	Summary
*	Definition of Confounding difference = A confounding covariate bias in which the unequal distribution of a potentially distorting variable is recognized.
*	Incomplete reporting limits the determination of the potential degree of influence of calendar time.
*	There is evidence of potential for calendar time to influence the results: In an observational study of 18,508 adults with laboratory-confirmed, COVID-19 associated hospitalization 'The percentage of hospitalized patients admitted to the ICU decreased from 37.8% in March to 20.5% in December' (Ann Intern Med 2021 Aug 10 https://www.acpjournals.org/doi/10.7326/M21-1991).

component

summary:

Definition of Confounding Covariate Bias = A situation in which the effect or association between an exposure and outcome is distorted by another variable. For confounding covariate bias to occur the distorting variable must be (1) associated with the exposure and the outcome, (2) not in the causal pathway between exposure and outcome, and (3) unequally distributed between the groups being compared.

component

summary:

ATTACC implemented response-adaptive randomization on December 15, 2020, which led to imbalanced randomization. No data reported to determine if intervention-specific outcome rates were similar or different before and after December 15, 2020 in the ATTACC cohort.

component

summary:

Insufficient details reported to judge whether there is an imbalance in outcomes related to the adaptive randomization which in turn could be used to judge the validity of adjustment methods in the statistical model for this concern and the appropriateness of any sensitivity analyses.

component

summary:

Awareness of treatment assignment may reduce clinical decision to initiate some types of "organ support" in patients with higher risk of major bleeding.

type: Performance Bias

classifier: high potential to influence research results, risk of bias favoring experimental exposure, Critical risk of bias

component

summary:

Lack of blinding may explain reported differences in the primary outcome.

type: Inadequate blinding of intervention deliverers

classifier: Critical risk of bias

Components

-	Summary
*	The absolute difference in survival without intubation was 1%, so 3% of the 4% absolute difference in the primary outcome can be considered "organ support without intubation".
*	The specific "organ support without intubation" was not reported. The methods for one of the included trials stated "Organ Support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen, vasopressor therapy, or ECMO support"
*	Awareness of treatment assignment may reduce clinical decision to initiate "organ support without intubation" in patients with higher risk of major bleeding.

component

summary:

Crossover to other intervention in 20%

type: Deviation from study intervention protocol

classifier: undetermined risk of bias

Components

-	Summary
*	Therapeutic dose anticoagulation (in the first 24-48 hours following randomization) was reported in 79.6% of the therapeutic arm and 0.9% of the usual care arm. (Table S3)
*	Definition of Deviation from study intervention protocol = A performance bias in which the intervention received differs from the intervention specified in the study protocol.

component

summary:

We discussed whether they may be a bias related to limited adherence to anticoagulation. Because this was an inpatient population, we did not expect adherence problems that are more common with outpatient thromboprophylaxis.

type: Nonadherence of implementation

classifier: Factor likely absent, Low risk of bias

Components

-	Summary
*	Initial adherence to the protocol-assigned anticoagulation dose after randomization was 88.3% in the therapeutic-dose anticoagulation group and 98.3% in the thromboprophylaxis group (Table S3).

component

summary:

Definition of Performance Bias = A bias resulting from differences between the received exposure and the intended exposure.

component

summary:

The influence of awareness of treatment assignment by the treating clinicians on the initiation of organ support (which is the primary outcome) was already addressed as Performance Bias so is not repeated here as a bias in detecting the outcome.

type: Detection Bias

classifier: Low risk of bias

component

summary:

Only 19 of 1190 (1.6%) therapeutic group and 6 of 1054 (0.6%) prophylactic group were excluded after randomization.

type: Attrition Bias

classifier: Low risk of bias

component

summary:

It is unknown if the results are sensitive to the analytic method, and the stopping criteria were based on statistical significance and not magnitude of effect.

type: Analysis Bias

classifier: Critical risk of bias

component

summary:

A frequentist analysis is not reported so we cannot determine if the results are sensitive to the analytic method

type: Bias related to selection of the analysis

classifier: Factor likely present, high potential to influence research results, risk of bias favoring experimental exposure, undetermined risk of bias

component

summary:

The stopping criteria were based on statistical significance and not magnitude of effect.

type: Early termination bias affecting enrollment

classifier: Factor present, high potential to influence research results, risk of bias favoring experimental exposure, Critical risk of bias

Components

-	Summary
*	There was no “minimally important difference”. So a 99% probability of having an odds ratio > 1 (even if the magnitude of effect is infinitesimal) was used to decide it was time to stop the trial.

component

summary:

Definition of Bias related to selection of the analysis = An analysis bias due to inappropriate choice of analysis methods before the analysis is applied.

component

summary:

There was no pre-specified frequentist analysis. There was no posthoc frequentist analysis reported.

component

summary:

It is uncertain what a frequentist analysis would show and uncertain whether the choice of Bayesian analysis or frequentist analysis has a substantial influence on the results.

content

type: Profile for use with Risk of Bias Assessment Tool

classifier: Randomized trial