Generated Narrative: Evidence

StructureDefinition Work Group: cds

url: https://fevir.net/resources/Evidence/7637

identifier: FEvIR Object Identifier: 7637

version: 1.0.0-ballot

name: Critically_appraised_summary_of_primary_outcome_of_multi_platform_RCT_of_anticoagulation_for_non_critically_ill_patients_with_COVID_19

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

citeAs: Citation/7638: Critically appraised summary of primary outcome of multi-platform RCT of anticoagulation for non-critically ill patients with COVID-19 [FHIR Resource]. Contributors: Brian S Alper, Harold Lehmann, Ahmad Sofi-Mahmudi, Joanne Dehnbostel, Ilkka Kunnamo [Authors], Janice Tufte, Vignesh Subbian, Bhagvan Kommadi, Alfonso Iorio, Muhammad Afzal, Kenneth J Wilkins, Surbhi Shah, Amy Price [Reviewers]. In: Fast Evidence Interoperability Resources (FEvIR) Platform, FOI 7637. Published August 05, 2021. Created August 05, 2021. Revised August 25, 2021. Available at: https://fevir.net/resources/Evidence/7637. Computable resource at: https://fevir.net/resources/Evidence/7637.

status: active

date: 2022-08-05 14:49:11+0000

publisher: HL7 International / Clinical Decision Support

contact: HL7 International / Clinical Decision Support: http://www.hl7.org/Special/committees/dss

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

reviewer: Janice Tufte: , Vignesh Subbian: , Bhagvan Kommadi: , Alfonso Iorio: , Muhammad Afzal: , Kenneth J. Wilkins: , Surbhi Shah: , Amy Price:

UseContexts

copyright: https://creativecommons.org/licenses/by-nc-sa/4.0/

relatedArtifact

type: citation

label: data source

display: Anticoagulation for COVID-19 Combined RCTs in NEJM

citation: Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 [Journal Article]. Contributors: The ATTACC, ACTIV-4a, and REMAP-CAP Investigators. In: The New England Journal of Medicine, DOI 10.1056/NEJMoa2105911. Published August 04, 2021. Available at: https://doi.org/10.1056/NEJMoa2105911.

relatedArtifact

type: cites

citation: Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 [Journal Article]. Contributors: The ATTACC, ACTIV-4a, and REMAP-CAP Investigators. In: The New England Journal of Medicine, DOI 10.1056/NEJMoa2105911. Published August 04, 2021. Available at: https://doi.org/10.1056/NEJMoa2105911.

document

relatedArtifact

type: cite-as

citation: Critically appraised summary of primary outcome of multi-platform RCT of anticoagulation for non-critically ill patients with COVID-19 [Evidence]. Contributors: Brian S. Alper, Harold Lehmann, Ahmad Sofi-Mahmudi, Joanne Dehnbostel, Ilkka Kunnamo [Authors/Creators]. Janice Tufte, Vignesh Subbian, Bhagvan Kommadi, Alfonso Iorio, Muhammad Afzal, Kenneth J. Wilkins, Surbhi Shah, Amy Price [Reviewers]. In: Fast Evidence Interoperability Resources (FEvIR) Platform, FOI 7637. Revised 2022-08-05. Available at: https://fevir.net/resources/Evidence/7637. Computable resource at: https://fevir.net/resources/Evidence/7637.

description: Patients who were hospitalized for COVID-19 and who were not critically ill were randomized in a response-adaptive manner to therapeutic-dose anticoagulation with heparin vs. usual-care pharmacologic thromboprophylaxis. The outcome reported here is the effect on organ support-free days (i.e. days without oxygen delivered by high-flow nasal cannula, noninvasive or invasive mechanical ventilation, or the use of vasopressors or inotropes). The statistical result was a median adjusted odds ratio 1.27 (95% credible interval 1.03 to 1.58), based on 1,740 events among 2,219 participants with known outcome out of 2,244 enrolled participants. The probability of superiority of therapeutic-dose anticoagulation with heparin was 98.6%. The risk of bias in this effect estimate is of extremely serious concern based on a serious concern for confounding covariate bias (confounding difference in calendar time), a very serious concern for performance bias (inadequate blinding of intervention deliverers who may determine the outcome based in part on exposure status), and very serious concern for analysis bias (bias related to selection of the analysis, and early trial termination).

assertion: It is uncertain whether therapeutic-dose anticoagulation with heparin affects the rate of organ support-free days in patients hospitalized for COVID-19 who are not critically ill.

note: Results not consistent with critically ill cohort., Title changed from 'Critically appraised summary of primary outcome of multi-platform RCT of anticoagulation for non-critically ill COVID-19' to 'Critically appraised summary of primary outcome of multi-platform RCT of anticoagulation for non-critically ill patients with COVID-19' on August 17, 2021.

variableDefinition

VariableDefinitionVariableRoleCode: population

description: Patients who were hospitalized for COVID-19 and who were not critically ill

note: critically ill defined as patients on respiratory or cardiovascular organ support (i.e., oxygen delivered by high-flow nasal cannula, noninvasive or invasive mechanical ventilation, or the use of vasopressors or inotropes) in an ICU, ATTACC and ACTIV-4a limited inclusion to patients with confirmed COVID-19 (and excluded initially entered participants who did not have confirmed SARS-CoV-2. REMAP-CAP however included patients with confirmed COVID-19 or suspected COVID-19 with intent to test for COVID-19., population

variableRole: Use extension:variableRoleCode instead. (EvidenceVariableRole#population "population")

observed: Group/7750: Participants in Anticoagulation for COVID-19 Combined (ATTACC, ACTIV-4a, and REMAP-CAP) RCT "Participants_in_Anticoagulation_for_COVID_19_Combined_ATTACC_ACTIV_4a_and_REMAP_CAP_RCT_hospitalized_not_critically_ill"

intended: Group/7749: Patients who are hospitalized for COVID-19 and who are not critically ill "Patients_who_are_hospitalized_for_COVID_19_and_who_are_not_critically_ill"

directnessMatch: High quality match between observed and intended variable (EvidenceDirectness[1.0.0]#high)

variableDefinition

VariableDefinitionVariableRoleCode: exposure

VariableDefinitionComparatorCategory: Usual-care pharmacologic thromboprophylaxis

description: GroupAssignment: Therapeutic-dose anticoagulation with heparin vs. Usual-care pharmacologic thromboprophylaxis

note: Therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin was administered according to local protocols for the treatment of acute venous thromboembolism for up to 14 days or until recovery; the latter was defined as hospital discharge or a discontinuation of supplemental oxygen for at least 24 hours., Usual-care pharmacological thromboprophylaxis included both intermediate-intensity (in 27%) and prophylactic-intensity dosing (in 72%). Subgroup analyses may be informative to determine if there is a difference related to the intensity used in the control arm of the trial. Thromboprophylaxis was provided at a dose and duration determined by the treating clinician according to local practice., exposure

variableRole: Use extension:variableRoleCode instead. (EvidenceVariableRole#exposure "exposure")

observed: EvidenceVariable/179784: GroupAssignment: Therapeutic-dose anticoagulation with heparin vs. Usual-care pharmacologic thromboprophylaxis "Therapeutic_dose_anticoagulation_with_heparin_vs_Usual_care_pharmacologic_thromboprophylaxis"

variableDefinition

VariableDefinitionVariableRoleCode: outcome

description: Organ support-free days

note: The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. Patients who were discharged from the hospital before day 21 were assumed to be alive and free of organ support through day 21. Any death during the index hospitalization through 90 days was assigned the worst score on the outcome scale (–1). This end point reflects both the use of ICU-level interventions and survival, with higher values indicating better outcomes., Organ support was defined as oxygen delivered by high-flow nasal cannula, noninvasive or invasive mechanical ventilation, or the use of vasopressors or inotropes., 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", outcome

variableRole: Use extension:variableRoleCode instead. (EvidenceVariableRole#measuredVariable "measured variable")

observed: EvidenceVariable/7753: Organ support-free days "Organ_support_free_days"

synthesisType: integration of 3 trials into a single multiplatform trial (Evidence Based Medicine on FHIR Implementation Guide Code System#defined-in-text "Defined in text")

studyDesign: Bayesian Adaptive Design (response-adaptive randomized controlled trial) (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:01009 "adaptive randomization"), open label (Evidence Based Medicine on FHIR Implementation Guide Code System#defined-in-text "Defined in text")

statistic

description: median adjusted odds ratio 1.27 (95% credible interval 1.03 to 1.58)

note: 939 out of 1171 (80.2%) in therapeutic-dose anticoagulation group, 801 out of 1048 (76.4%) in usual-care thromboprophylaxis group

statisticType: Odds Ratio (StatisticStatisticType[0.1.0]#C16932)

quantity: 1.27

numberOfEvents: 1740

SampleSizes

-	Note	NumberOfStudies	NumberOfParticipants	KnownDataCount
*	19 (1.6%) therapeutic-dose group and 6 (0.6%) usual-care group were excluded from primary analysis	3	2244	2219

attributeEstimate

type: Credible interval (StatisticAttribute Estimate Type[0.1.0]#0000455)

level: 0.95

range: 1.03-1.58

attributeEstimate

type: probability of superiority ()

quantity: 0.986

modelCharacteristic

code: Hierarchical Bayesian Cumulative Logistic Regression with Dynamic Borrowing (Evidence Based Medicine on FHIR Implementation Guide Code System#defined-in-text "Defined in text")

modelCharacteristic

code: weakly informative Dirichlet prior distributions for the number of days without organ support (Evidence Based Medicine on FHIR Implementation Guide Code System#defined-in-text "Defined in text")

modelCharacteristic

code: The model was fitted with the use of a Markov chain Monte Carlo algorithm with 100,000 samples from the joint posterior distribution, which allowed for calculation of the posterior distributions for the proportional odds ratios, including medians and 95% credible intervals, and the posterior probabilities of superiority and futility for the comparison between therapeutic-dose anticoagulation and usual-care thromboprophylaxis. (Evidence Based Medicine on FHIR Implementation Guide Code System#defined-in-text "Defined in text")

modelCharacteristic

code: median value used for reporting the effect estimate (Evidence Based Medicine on FHIR Implementation Guide Code System#defined-in-text "Defined in text")

modelCharacteristic

code: Adjustment variables include age, sex, trial site, d-dimer cohort, and enrollment period (in 2-week intervals). (Statistic Model Code#adjusted "Adjusted analysis")

variable

variableDefinition: : age

handling: continuous

variable

variableDefinition: : sex

handling: dichotomous

variable

variableDefinition: : trial site

handling: polychotomous

variable

variableDefinition: : d-dimer cohort

handling: polychotomous

variable

variableDefinition: : enrollment period

handling: ordinal

certainty

type: Risk of bias (Evidence Certainty Type[5.0.0]#RiskOfBias)

rating: extremely serious concern (Evidence Certainty Rating[5.0.0]#extremely-serious-concern)

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

subcomponent

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

note: Definition of Selection Bias = A bias resulting from methods used to select subjects or data, factors that influence initial study participation, or differences between the study sample and the population of interest

type: Selection Bias (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:00002)

rating: no serious concern (Evidence Certainty Rating[5.0.0]#no-concern)

rater: Brian S. Alper, Joanne Dehnbostel, Muhammad Afzal

subcomponent

description: 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.

note: 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., 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., 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.

type: Confounding Covariate Bias (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:00016)

rating: serious concern (Evidence Certainty Rating[5.0.0]#serious-concern)

rater: Brian S. Alper, Ilkka Kunnamo, Alfonso Iorio, Joanne Dehnbostel, Harold Lehmann, Kenneth Wilkins; clarifying explanation reviewed by Janice Tufte

subcomponent

subcomponent

subcomponent

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

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

type: Performance Bias (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:00017)

rating: very serious concern (Evidence Certainty Rating[5.0.0]#very-serious-concern)

rater: Brian S. Alper, Joanne Dehnbostel, Harold Lehmann, Muhammad Afzal

subcomponent

subcomponent

subcomponent

subcomponent

description: 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.

note: Definition of Detection Bias = A bias due to distortions in how variable values (data) are determined.

type: Detection Bias (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:00020)

rating: no serious concern (Evidence Certainty Rating[5.0.0]#no-concern)

rater: Brian S. Alper, Joanne Dehnbostel, Muhammad Afzal

subcomponent

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

note: Definition of Attrition Bias = A bias due to absence of expected participation or data collection after selection for study inclusion.

type: Attrition Bias (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:00019)

rating: no serious concern (Evidence Certainty Rating[5.0.0]#no-concern)

rater: Brian S. Alper, Joanne Dehnbostel, Muhammad Afzal

subcomponent

description: 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.

note: Definition of Analysis Bias = A bias related to the analytic process applied to the data.

type: Analysis Bias (Scientific Evidence Code System (SEVCO) -- EXAMPLE VERSION for EBMonFHIR Implementation Guide#SEVCO:00021)

rating: very serious concern (Evidence Certainty Rating[5.0.0]#very-serious-concern)

rater: Brian S. Alper, Joanne Dehnbostel, Muhammad Afzal, Janice Tufte

subcomponent

subcomponent