Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report
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Abstract
Background
Thrombosis may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic anticoagulation would improve outcomes in critically ill patients with Covid-19.
Methods
We conducted an open-label, adaptive, multiplatform, randomized, clinical trial. Patients with severe Covid-19, defined as the requirement for organ support with high flow nasal cannula, non-invasive ventilation, invasive ventilation, vasopressors, or inotropes, were randomized to receive therapeutic anticoagulation with heparin or pharmacological thromboprophylaxis as per local usual care. The primary outcome was an ordinal scale combining in-hospital mortality (assigned –1) and days free of organ support to day 21.
Results
Therapeutic anticoagulation met the pre-defined criteria for futility in patients with severe Covid-19. The primary outcome was available for 1,074 participants (529 randomized to therapeutic anticoagulation and 545 randomized to usual care pharmacological thromboprophylaxis). Median organ support-free days were 3 days (interquartile range –1, 16) in patients assigned to therapeutic anticoagulation and 5 days (interquartile range –1, 16) in patients assigned to usual care pharmacological thromboprophylaxis (adjusted odds ratio 0.87, 95% credible interval (CrI) 0.70-1.08, posterior probability of futility [odds ratio<1.2] 99.8%). Hospital survival was comparable between groups (64.3% vs. 65.3%, adjusted odds ratio 0.88, 95% CrI 0.67-1.16). Major bleeding occurred in 3.1% of patients assigned to therapeutic anticoagulation and 2.4% of patients assigned to usual care pharmacological thromboprophylaxis.
Conclusions
In patients with severe Covid-19, therapeutic anticoagulation did not improve hospital survival or days free of organ support compared to usual care pharmacological thromboprophylaxis.
Trial registration numbers NCT02735707 , NCT04505774 , NCT04359277 , NCT04372589
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SciScore for 10.1101/2021.03.10.21252749: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Participants were randomized to receive therapeutic anticoagulation with unfractionated or low molecular weight heparin or usual care pharmacological thromboprophylaxis in an open label fashion. Blinding Thrombotic and bleeding events were adjudicated by independent platform-specific adjudication committees blinded to treatment assignment (Protocol Appendix, p. 478). Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Re…SciScore for 10.1101/2021.03.10.21252749: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Participants were randomized to receive therapeutic anticoagulation with unfractionated or low molecular weight heparin or usual care pharmacological thromboprophylaxis in an open label fashion. Blinding Thrombotic and bleeding events were adjudicated by independent platform-specific adjudication committees blinded to treatment assignment (Protocol Appendix, p. 478). Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:One limitation of our trial is the open-label design, although clinician or participant awareness likely had little or no impact on the primary outcome that incorporated mortality and duration of organ support. The open label strategy may also introduce systematic bias in the ascertainment of thrombotic events. Additionally, the pragmatic design of this trial allowed clinicians to employ local site practice in the usual care pharmacological thromboprophylaxis arm. A substantial majority of enrollment in the severe patient group was in the United Kingdom where national practice guidelines changed during the trial to recommend that Covid-19 patients admitted to an ICU receive intermediate dose anticoagulation for thromboprophylaxis. Many participants in the usual care arm therefore received an intermediate dose of thromboprophylaxis. It is possible that the benefit of therapeutic anticoagulation varies according to management of the comparator group. However, in pre-specified subgroup analyses, the treatment effect of therapeutic dose anticoagulation did not vary meaningfully according to site proclivity for low or intermediate dose thromboprophylaxis. Whether intermediate dose thromboprophylaxis is superior to standard low dose thromboprophylaxis in critically ill patients is uncertain. Moreover, the effect of therapeutic anticoagulation in hospitalized, non critically ill patients with Covid-19 remains to be determined. In conclusion, in critically ill patients with Covid-19,...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT02735707 Recruiting Randomized, Embedded, Multifactorial Adaptive Platform Trial… NCT04505774 Recruiting Anti-thrombotics for Adults Hospitalized With COVID-19 (ACTI… NCT04359277 Terminated A Randomized Trial of Anticoagulation Strategies in COVID-19 NCT04372589 Active, not recruiting Antithrombotic Therapy to Ameliorate Complications of COVID-… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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