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Early Initiation of Prophylactic Anticoagulation Reduces COVID-19 Mortality in Patients Admitted to the Hospital
TAKE-HOME MESSAGE
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This observational cohort study used real world data from the US Department of Veteran's Affairs to show that patients admitted to the hospital with COVID-19 who received early initiation of prophylactic anticoagulation (within 24 hours) experienced reduced 30-day mortality compared with patients who did not receive early anticoagulation.
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These data support the practice of early prophylactic anticoagulation among hospitalized patients with COVID-19.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States.
DESIGN
Observational cohort study.
SETTING
Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system.
PARTICIPANTS
All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.
MAIN OUTCOME MEASURES
The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.
RESULTS
Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses.
CONCLUSIONS
Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.
Additional Info
Disclosure statements are available on the authors' profiles:
Early Initiation of Prophylactic Anticoagulation for Prevention of Coronavirus Disease 2019 Mortality in Patients Admitted to Hospital in the United States: Cohort Study
BMJ 2021 Feb 11;372(xx)n311, CT Rentsch, JA Beckman, L Tomlinson, WF Gellad, C Alcorn, F Kidwai-Khan, M Skanderson, E Brittain, JT King, YL Ho, S Eden, S Kundu, MF Lann, RA Greevy, PM Ho, PA Heidenreich, DA Jacobson, IJ Douglas, JP Tate, SJW Evans, D Atkins, AC Justice, MS FreibergFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Primary Care
Early Anticoagulation in Patients With Severe COVID-19
In the early days of the pandemic, reports of increased venous thromboembolism caught us by surprise as our focus was mainly on the respiratory system. As venous thromboembolism has been reported in 30% of severe cases, the current recommendation is to give prophylactic anticoagulation. Nevertheless, there is the nagging question if anticoagulating a patient is really the right thing to do and does it increase the risk of bleeding. Clinical trials are being done but they take time, and time is not on the side of patients.
This group evaluated Department of Veterans Affairs data and identified patients with severe SARS-CoV-2 infection. Of the 4297 patients admitted, 3627 (84.4%) received anticoagulation within the first 24 hours of admission. The question was did they do better or worse than the patients who did not get anticoagulation. The vast majority of patients were on enoxaparin (n = 2506, 69.1%) or subcutaneous heparin (n = 1094, 30.2%). The 30-day mortality rate was reduced by 27% (HR, 0.73; 95% CI, 0.66–0.81) in favor of anticoagulation on admission.
However, this study was not randomized, and there were differences in the patient population. The patients who were offered anticoagulation tended to be sicker in terms of their COVID-19 symptoms. They were more likely to have lower oxygen levels (<93%; 16.0% vs 10.7%), faster heart rates (>90 beats/min; 39.3% vs 34.6%), and higher temperatures (>38°C; 17.5% vs 10.4. However, they tended to have fewer comorbidities.
This makes sense because treatment for patients who are more symptomatic will be more aggressive; however, concerns about bleeding would temper the treatment in patients with a lot of comorbidities. Basically, we are seeing this balancing of risks and benefits being played out in these real-world data.
Thankfully, the bleeding risk, as measured by the need for transfusion, was not increased (HR, 0.87, 95% CI, 0.71–1.05). As for the mechanism of this benefit, there are many theories. One is that the virus can enter the endothelial cells and cause damage and hence cause denuding of the vessel lining. This exposed vessel wall would be a strong stimulus for clot formation. The anticoagulation blocks clot formation and thereby maintains blood flow to critical organs.
Also, there are some data that heparin may have a direct effect on the virus.1 It turns out that the virus needs to bind to the carbohydrate heparan sulfate, which is found on cell surfaces. The binding changes the shape of the spike protein to make it fit better into the ACE2 receptor. Thus, entry into the cell requires binding to both heparan sulfate and the ACE2 receptor.
Heparin can act as a decoy because the virus could bind to it thinking it is heparan sulfate. Therefore, heparin may bind the virus and keep it from entering the cell. The clinical significance of this is uncertain, but it is another possible mechanism that might explain the benefits that we are seeing.
In the end, whatever the mechanism, a 27% reduction in mortality is very significant, and hence early anticoagulation would seem to be the order of the day.
Reference