Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States

Abstract

ImportanceDeaths among patients with coronavirus disease 2019 (COVID-19) are partially attributed to venous thromboembolism and arterial thromboses. Anticoagulants prevent thrombosis formation, possess anti-inflammatory and anti-viral properties, and may be particularly effective for treating patients with COVID-19.ObjectiveTo evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19.DesignObservational cohort study.SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, the largest integrated healthcare system in the United States.ParticipantsAll patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31, 2020, without a history of therapeutic anticoagulation.ExposuresProphylactic doses of subcutaneous heparin, low-molecular-weight heparin, or direct oral anticoagulants.Main Outcomes and Measures30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation.ResultsOf 4,297 patients hospitalized with COVID-19, 3,627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3,600) received subcutaneous heparin or enoxaparin. We observed 622 deaths within 30 days of admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospitalization. In inverse probability of treatment weighted analyses, cumulative adjusted incidence of mortality at 30 days was 14.3% (95% CI 13.1-15.5) among those receiving prophylactic anticoagulation and 18.7% (95% CI 15.1-22.9) among those who did not. Compared to patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30-day mortality (HR 0.73, 95% CI 0.66-0.81). Similar associations were found for inpatient mortality and initiating therapeutic anticoagulation. Quantitative bias analysis demonstrated that results were robust to unmeasured confounding (e-value lower 95% CI 1.77). Results persisted in a number of sensitivity analyses.Conclusions and RelevanceEarly initiation of prophylactic anticoagulation among patients hospitalized with COVID-19 was associated with a decreased risk of mortality. These findings provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.

Different Anticoagulant Regimens, Mortality, and Bleeding in Hospitalized Patients with COVID-19: A Systematic Review and an Updated Meta-Analysis

“…Two of us (S.C. and R.P.) independently reviewed the identified studies, then jointly excluded the articles not adhering with one or both criteria and agreed on a final selection of 29 studies, including three published as preprints in MedRxiv, the preprint server for health science, 21,24,45 and one congress abstract. 27 No randomized controlled clinical trial was retrieved.…”

“…Four studies were from China, 20,21,42,47 14 from Europe, 22,23,28,29,31,32,34,35,40,41,43,44,46,48 and 11 from United States (►Table 1). [24][25][26][27]30,33,[36][37][38][39]45 All were retrospective observational studies. Studies included ICU or hospitalized COVID-19 patients, except for the study by Tremblay et al that included both ambulatory and hospitalized COVID-19 patients.…”

“…[20][21][22][23]28,[30][31][32]34,35,[40][41][42][43][44][46][47][48] Six studies investigated the role of any anticoagulant treatment, including LMWH or UFH, direct thrombin inhibitors, and/or direct oral anticoagulants. 24,33,[36][37][38]45 Only one study investigated three types of anticoagulant drugs separately (i.e., apixaban, enoxaparin, UFH). 39 No information was provided on the type of anticoagulant used by the remaining four studies (►Table 2).…”

“…[25][26][27]29 The studies mainly used as a reference a group formed by patients not treated with any anticoagulant. 20,21,23,[25][26][27]29,[31][32][33][34][35][36][37]39,41,42,45,47,48 Additionally, 13 studies compared two groups of patients at different dosages of anticoagulant (therapeutic vs. prophylactic) (►Table 2). 22,24,28,30,33,34,37,38,40,43,44,46,48 The studies were mostly considered of good quality (23/29) (►Supplementary Table S1).…”

Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

“…Expression of the receptor for SARS-CoV-2 infection, angiotensin-converting enzyme 2 (ACE2), was also reported to be higher in smoking mice and humans, suggesting that smokers may be at a higher risk of infection 6 . On the other hand, several reports suggested fewer smokers among patients infected with SARS-CoV-2 or lower numbers of SARS-CoV-2 positive cases among smokers than among non-smokers 7 – 10 . Therefore, the impact of smoking on SARS-CoV-2 infection is unclear.…”