early initiation of prophylactic anticoagulation for prevention of coronavirus disease CORD-Papers-2022-06-02 (Version 1)

Title: Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study
Abstract: OBJECTIVE: 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.
Published: 2021-02-11
Journal: BMJ
DOI: 10.1136/bmj.n311
DOI_URL: http://doi.org/10.1136/bmj.n311
Author Name: Rentsch Christopher T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/rentsch_christopher_t
Author Name: Beckman Joshua A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/beckman_joshua_a
Author Name: Tomlinson Laurie
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tomlinson_laurie
Author Name: Gellad Walid F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/gellad_walid_f
Author Name: Alcorn Charles
Author link: https://covid19-data.nist.gov/pid/rest/local/author/alcorn_charles
Author Name: Kidwai Khan Farah
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kidwai_khan_farah
Author Name: Skanderson Melissa
Author link: https://covid19-data.nist.gov/pid/rest/local/author/skanderson_melissa
Author Name: Brittain Evan
Author link: https://covid19-data.nist.gov/pid/rest/local/author/brittain_evan
Author Name: King Joseph T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/king_joseph_t
Author Name: Ho Yuk Lam
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ho_yuk_lam
Author Name: Eden Svetlana
Author link: https://covid19-data.nist.gov/pid/rest/local/author/eden_svetlana
Author Name: Kundu Suman
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kundu_suman
Author Name: Lann Michael F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lann_michael_f
Author Name: Greevy Robert A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/greevy_robert_a
Author Name: Ho P Michael
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ho_p_michael
Author Name: Heidenreich Paul A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/heidenreich_paul_a
Author Name: Jacobson Daniel A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jacobson_daniel_a
Author Name: Douglas Ian J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/douglas_ian_j
Author Name: Tate Janet P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tate_janet_p
Author Name: Evans Stephen J W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/evans_stephen_j_w
Author Name: Atkins David
Author link: https://covid19-data.nist.gov/pid/rest/local/author/atkins_david
Author Name: Justice Amy C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/justice_amy_c
Author Name: Freiberg Matthew S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/freiberg_matthew_s
sha: ce14f5b41bfedeb7d1e102849c033fee00ff046c
license: cc-by-nc
license_url: https://creativecommons.org/licenses/by-nc/4.0/
source_x: Medline; PMC
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 33574135
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/33574135
pmcid: PMC7876672
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876672
url: https://doi.org/10.1136/bmj.n311 https://www.ncbi.nlm.nih.gov/pubmed/33574135/
has_full_text: TRUE
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Extracted Text Content in Record: First 5000 Characters: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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (covid- 19) , continues to spread worldwide. Deaths among people with covid-19 have been partially attributed to venous thromboembolism and arterial thromboses. 1 Deaths among patients with coronavirus disease 2019 (covid-19) are partially attributed to venous thromboembolism and arterial thromboses Anticoagulants prevent thrombosis formation, possess antiviral and potentially anti-inflammatory properties, and might be particularly effective in patients with covid-19 Evaluations of the efficacy of prophylactic anticoagulation in patients with covid-19 in randomized clinical trials are underway but not yet reported; previous observational studies have been limited in sample size or used relatively small healthcare systems This study found that initiation of prophylactic anticoagulation compared with no anticoagulation within 24 hours of hospital admission was associated with a relative risk reduction of 30 day mortality as high as 34% and an absolute risk reduction of 4.4% among patients admitted to hospital with covid-19 In a post hoc safety analysis, receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion 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 doi: 10 .1136/bmj.n311 | BMJ 2021;372:n311 | the bmj of venous thromboembolism among patients with covid-19 has been reported at about 30%. 3 In response, several expert organizations, including the American Society of Hematology, 4 International Society on Thrombosis and Haemostasis, 5 CHEST Guideline and Expert Panel, 6 and others 1 7 have recommended prophylactic anticoagulation for patients admitted with covid-19, who do not have a contraindication to this treatment, to reduce the risk of thromboembolism. Heparin based anticoagulants are commonly used in hospital settings. Given evidence that shows these drugs might also possess anti-inflammatory properties, [8] [9] [10] heparin-based treatments might be particularly effective in patients with covid-19. 11 Randomized clinical trials evaluating the efficacy of prophylactic anticoagulation in patients with covid-19 are underway. 12 Previous observational cohort studies have found evidence that use of anticoagulation in patients with covid-19 was associated with decreased risk of mortality 13 14 ; however, these studies were limited in sample size or used relatively small healthcare systems. In this study we estimated the effect of early initiation of prophylactic anticoagulation compared with no anticoagulation on risk of 30 day mortality among patients admitted to hospital with covid-19 in the largest integrated healthcare system in the United States. This study is reported according to the strengthening the reporting of observational studies in epidemiology (STROBE) and reporting of studies conducted using observational routinely collected health data (RECORD) guidelines (see supplementary appendix). We conducted an observational cohort study using electronic health record data from the US Department of Veterans Affairs, which comprises more than 1200 points of care nationwide, including hospitals, medical centers, and community outpatient clinics. All care is recorded in a central data repository, with daily uploads into the Veterans Affairs Corporate Data Warehouse. Available data include demographics, outpatient and inpatient encounters, diagnoses, procedures, smoking and alcohol health behaviors, pharmacy dispensing records, vital signs, laboratory measures, and death information. We included all patients admitted to hospital between 1 March and 31 July 2020 who had a laboratory confirmed positive SARS-CoV-2 test result on or within 14 days before hospital admission. We excluded patients who had no history of care (defined as at least one outpatient o
Keywords Extracted from PMC Text: balanced,23 rivaroxaban venous thromboembolism Doses (AUDIT-C)15 overestimated.24 oral anticoagulants anticoagulation.38 cardiac covid-19.12 fibrinogen.72 SARS-CoV-2 people 5th warfarin covid-19.10 n=198 anticoagulants anti-inflammatory properties,8 9 systems13 venous intravenous heparin patient cancer alcohol dabigatran log-log fig 3 women heparin covid-19 bradykinin dalteparin interleukin 6 arterial thromboembolism Haemostasis,5 CHEST Guideline intravenous dexamethasone17 Panel,6 US C reactive blood cell Patients oral thromboembolism Hematology,4 International Society underway.12 subcutaneous heparin coronavirus disease 2019 alanine aminotransferase appendix lymphocyte transfusions aspartate aminotransferase cholesterol arterial enoxaparin covid-19.11 intravenous remdesivir18 baseline).19 arterial thromboses.1 patients inpatients mortality.30 fondaparinux estimation28 organ US.71
Extracted PMC Text Content in Record: First 5000 Characters:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (covid-19), continues to spread worldwide. Deaths among people with covid-19 have been partially attributed to venous thromboembolism and arterial thromboses.1 2 In intensive care settings, prevalence of venous thromboembolism among patients with covid-19 has been reported at about 30%.3 In response, several expert organizations, including the American Society of Hematology,4 International Society on Thrombosis and Haemostasis,5 CHEST Guideline and Expert Panel,6 and others1 7 have recommended prophylactic anticoagulation for patients admitted with covid-19, who do not have a contraindication to this treatment, to reduce the risk of thromboembolism. Heparin based anticoagulants are commonly used in hospital settings. Given evidence that shows these drugs might also possess anti-inflammatory properties,8 9 10 heparin-based treatments might be particularly effective in patients with covid-19.11 Randomized clinical trials evaluating the efficacy of prophylactic anticoagulation in patients with covid-19 are underway.12 Previous observational cohort studies have found evidence that use of anticoagulation in patients with covid-19 was associated with decreased risk of mortality13 14; however, these studies were limited in sample size or used relatively small healthcare systems. In this study we estimated the effect of early initiation of prophylactic anticoagulation compared with no anticoagulation on risk of 30 day mortality among patients admitted to hospital with covid-19 in the largest integrated healthcare system in the United States. We conducted an observational cohort study using electronic health record data from the US Department of Veterans Affairs, which comprises more than 1200 points of care nationwide, including hospitals, medical centers, and community outpatient clinics. All care is recorded in a central data repository, with daily uploads into the Veterans Affairs Corporate Data Warehouse. Available data include demographics, outpatient and inpatient encounters, diagnoses, procedures, smoking and alcohol health behaviors, pharmacy dispensing records, vital signs, laboratory measures, and death information. We included all patients admitted to hospital between 1 March and 31 July 2020 who had a laboratory confirmed positive SARS-CoV-2 test result on or within 14 days before hospital admission. We excluded patients who had no history of care (defined as at least one outpatient or inpatient encounter in the two years before 1 March 2020), received anticoagulation treatment in the 30 days before hospital admission (to mitigate the effect of prevalent use of anticoagulation), received a red blood cell transfusion within 24 hours of admission (as active bleeding or severe anemia could have been a contraindication for anticoagulation), or experienced any outcome within 24 hours of admission and therefore did not have equal chance to be classified as having received anticoagulation in this study. We extracted inpatient pharmacy records for warfarin, intravenous heparin, low molecular weight heparin (enoxaparin, fondaparinux, dalteparin), and direct oral anticoagulants (apixaban, rivaroxaban, dabigatran). Doses and routes considered prophylactic and therapeutic anticoagulation are listed in supplementary box 1 in the appendix. We compared prophylactic anticoagulation in the first 24 hours of hospital admission with no receipt of anticoagulation in the same time frame. The primary outcome was mortality within 30 days of hospital admission, which included in-hospital deaths (those during hospital admission) and those that occurred after discharge. Secondary outcomes were inpatient mortality and initiation of therapeutic anticoagulation. Algorithms to identify thromboembolic events during hospital admission of patients with covid-19 have yet to be validated; thus, we considered initiation of therapeutic levels of anticoagulation after the first 24 hours of admission to be a proxy for clinical deterioration, including thromboembolic events. For all outcomes, we followed patients from date of hospital admission until the earliest date of the outcome, a maximum of 30 days, or 30 August 2020. Some Veterans Affairs hospitals report observation periods and admissions separately, even when patients have not moved beds or changed providers. We combined these periods and considered a full hospital admission to begin at first presentation in a Veterans Affairs hospital and end when there was no subsequent hospital stay that began within 24 hours. Figure 1 shows the study design. Potential confounders in the relation between prophylactic anticoagulation and covid-19 mortality or thromboembolic events were identified by review of the existing literature and discussions with clinicians. We extracted information on age, race, ethnicity, sex, urban or rural residence, US census region, clinical comorbidities, Charl
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