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Lawler PR, Goligher EC, Berger JS, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4. (Original study)

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.

RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.

CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Discipline Area Score
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Intensivist/Critical Care 6 / 7
Infectious Disease 6 / 7
Emergency Medicine 5 / 7
Comments from MORE raters

Emergency Medicine rater

Moderately ill patients with COVID-19 who are hospitalized (i.e., survival to hospital discharge without organ support) seem to benefit from full anticoagulation vs "usual care" by 4%. When broken down by D-dimer, however, this seems to hold true mainly for the "high D-dimer" and "unknown D-dimer," but not the "low D-dimer." Secondary outcomes seem to trend toward benefit with anticoagulation. Interestingly, these results are different than those who are "critical" and need of organ support. As most things, there's a signal of benefit, but how we can better define which population will benefit will be key.

Emergency Medicine rater

Useful article as emergency physicians can start patients on anticoagulation that will likely be continued as an inpatient. The effect size is modest.

Infectious Disease rater

This large trial should help clarify the role of therapeutic anticoagulation in hospitalized patients with COVID-19.

Intensivist/Critical Care rater

This is an important RCT that supports using therapeutic heparin to manage hospitalized non-critically ill patients with COVID. There was an absolute reduction of 4 percentage points in the probability of survival to hospital discharge without the need for organ support. It adds further support to the pro-thrombotic nature of the disease, as well as providing best practice for management.

Internal Medicine rater

Looks like therapeutic anticoagulation in hospitalized (non-ICU) COVID has modest benefits and modest harms. I'm not sure why an RCT needs adjustment of the RR for baseline imbalances, which seemed modest - I didn't see the unadjusted results. Previous similar studies were likely under-powered to show small differences - might be useful to look at a meta-analysis.
Comments from EvidenceAlerts subscribers

Dr. Brian Alper (8/11/2021 5:49 AM)

The COVID-19 Knowledge Accelerator is coordinating efforts for many to contribute to post-publication review of the primary outcome of this trial. You can view the living summary of the evidence for the primary outcome of organ support-free days at https://fevir.net/resources/Evidence/7637 and for survival to hospital discharge without organ support at https://fevir.net/resources/Evidence/7639. Citations for these evidence summaries can be found at https://fevir.net/resources/Citation/7638 and https://fevir.net/resources/Citation/7640. You can contribute your feedback at https://fevir.net/createcertaintyrating

As of August 11 the assertion associated with this evidence is "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." and the risk of bias is rated as extremely serious concern with specific concerns (each sufficient to explain the differences reported) including: Adaptive randomization method prone to bias, Lack of blinding (and awareness of anticoagulation may influence clinical decision to initiate some types of organ support), and Early trial termination (based on statistical stopping rule without attention to magnitude of effect).

You can learn more about the COVID-19 Knowledge Accelerator at https://confluence.hl7.org/pages/viewpage.action?pageId=97468919 and you can use the Fast Evidence Interoperability Resources (FEvIR) Platform at https://fevir.net/