early initiation of prophylactic anticoagulation for prevention of covid 19 mortality CORD-Papers-2022-06-02 (Version 1)

Title: Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States
Abstract: IMPORTANCE. Deaths 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. OBJECTIVE. To evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19. DESIGN. Observational cohort study. SETTING. Nationwide cohort of patients receiving care in the Department of Veterans Affairs the largest integrated healthcare system in the United States. PARTICIPANTS. All patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31 2020 without a history of therapeutic anticoagulation. EXPOSURES. Prophylactic doses of subcutaneous heparin low-molecular-weight heparin or direct oral anticoagulants. MAIN OUTCOMES AND MEASURES. 30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation. RESULTS. Of 4297 patients hospitalized with COVID-19 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) 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 13.115.5) among those receiving prophylactic anticoagulation and 18.7% (95% CI 15.122.9) 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 0.660.81). 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 RELEVANCE. Early 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.
Published: 2020-12-11
Journal: medRxiv
DOI: 10.1101/2020.12.09.20246579
DOI_URL: http://doi.org/10.1101/2020.12.09.20246579
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 JW
Author link: https://covid19-data.nist.gov/pid/rest/local/author/evans_stephen_jw
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: a34383f0f7241306a778d23d178c352f7aebbb7d
license: cc-by
license_url: https://creativecommons.org/licenses/by/4.0/
source_x: MedRxiv; Medline; PMC; WHO
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/https://www.who.int/
pubmed_id: 33330896
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/33330896
pmcid: PMC7743107
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743107
url: https://doi.org/10.1101/2020.12.09.20246579 https://www.ncbi.nlm.nih.gov/pubmed/33330896/ http://medrxiv.org/cgi/content/short/2020.12.09.20246579v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: arterial low-molecular-weight heparin patients SARS-CoV-2 COVID-19 patients 3,627 venous thromboembolism oral anticoagulants COVID-19 enoxaparin coronavirus disease 2019 Anticoagulants fondaparinux cardiac alanine aminotransferase ACE women non-Veteran populations dexamethasone [6] [7] [8] heparin-based 3,627 bradykinin oral alcohol medRxiv preprint warfarin ICD-9/10 enoxaparin low-molecularweight heparin coronavirus disease 2019 blood cell pulmonary lymphocyte angiotensin II receptor LDL intravenous heparin arterial non-steroidal anti-inflammatory RBC SARS-CoV-2 US angiotensin heparin-based rivaroxaban aspartate aminotransferase COVID-19. cancer venous thromboembolism glomerular HDL high-density lipoprotein body COVID-19 heparin arterial thromboembolism Doses dalteparin therapeutic-dose dabigatran NSAID glucose alanine/aspartate aminotransferase LMWH ARB CIs COVID-19 patients laboratoryconfirmed Alcohol Box 1 heparin's interleukin-6 haemoglobin platelet patients anticoagulants intravenous dexamethasone oxygen intravenous red blood cell Notes C-reactive patient non-Veterans intravascular heart DOACs low-density lipoprotein medRxiv PMH UK National Health Service National Lung VIReC@va.gov JanOne Bristol-Myers Squibb Janssen Blood GlaxoSmithKline
Extracted Text Content in Record: First 5000 Characters:Importance. Deaths among patients with coronavirus disease 2019 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. Objective. To evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19. Design. Observational cohort study. Setting. Nationwide cohort of patients receiving care in the Department of Veterans Affairs, the largest integrated healthcare system in the United States. Participants. All patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31, 2020, without a history of therapeutic anticoagulation. Exposures. Prophylactic doses of subcutaneous heparin, low-molecular-weight heparin, or direct oral anticoagulants. Main Outcomes and Measures. 30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation. Of 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. Early 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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 , continues to spread worldwide. Deaths among individuals 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 to be over 40%. 3 In response, several expert organizations including the American Society of Hematology, the International Society on Thrombosis and Haemostasis, and the CHEST Guideline and Expert Panel have recommended the use of prophylactic anticoagulation for patients admitted with COVID-19 who do not have a contraindication to this therapy. 1, 4, 5 The most commonly used anticoagulants in hospital settings are heparin-based. Given these drugs also possess anti-inflammatory properties, [6] [7] [8] heparin-based therapies may be particularly effective in treating patients with COVID-19. 9 Evaluations of the efficacy of prophylactic anticoagulation in COVID-19 patients in randomized clinical trials are underway but yet to be reported. 10 Previous observational cohort studies have shown evidence that use of anticoagulation in COVID-19 patients was associated with decreased risk of mortality; 11, 12 however, these studies were limited in sample size or relatively small healthcare systems. Our objective was to estimate the effect of early initiation of prophylactic anticoagulation on the risk of 30-day mortality among patients hospitalized with COVID-19 in the largest integrated healthcare system in the United States. We conducted an observational cohort study using electronic health record (EHR) data from the US Department of Veterans Affairs (VA), which comprises over 1,200 points of care nationwide including hospitals, medical centers, and community outpatient clinics. All care is recorded in an EHR with daily uploads into the VA 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 hospitalized between March 1 and July 31, 2020 who had a laboratoryconfirmed positive SARS-CoV-2 test result on or within 14 days prior to hospital admission. We excluded patients who had no history of care (defined as at least one outpatient or inpatient encounter in the two years prior to March 1, 2020), rec
Keywords Extracted from PMC Text: arterial system.35–37 weighting.24 women US intravenous COVID-19 population.59–61 therapeutic-dose heparin-based oral ICD-9/10 COVID-19.10 patients cholesterol body patient coronavirus disease 2019 venous thromboembolism dalteparin dexamethasone alcohol dabigatran effects.22 cancer n=2,017 heart studies.48–50 fondaparinux COVID-19.9 Doses cardiac intravenous heparin intravenous remdesivir16 arterial thromboembolism 5th/95th bradykinin blood cell CIs C-reactive interleukin-6 heparin's hospitalization.14 " effects,6,7 lymphocyte anti-inflammatory properties,6–8 heparin-based SARS-CoV-2 anticoagulants COVID-19 patients reported.10 rivaroxaban DOACs heparin mortality;11,12 LMWH intravascular coagulation.51–58 Box 1 low-molecular-weight heparin alanine aminotransferase oxygen enoxaparin Alcohol aspartate aminotransferase non-Veteran populations;11,12 warfarin
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 individuals 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 to be over 40%.3 In response, several expert organizations including the American Society of Hematology, the International Society on Thrombosis and Haemostasis, and the CHEST Guideline and Expert Panel have recommended the use of prophylactic anticoagulation for patients admitted with COVID-19 who do not have a contraindication to this therapy.1,4,5 The most commonly used anticoagulants in hospital settings are heparin-based. Given these drugs also possess anti-inflammatory properties,6–8 heparin-based therapies may be particularly effective in treating patients with COVID-19.9 Evaluations of the efficacy of prophylactic anticoagulation in COVID-19 patients in randomized clinical trials are underway but yet to be reported.10 Previous observational cohort studies have shown evidence that use of anticoagulation in COVID-19 patients was associated with decreased risk of mortality;11,12 however, these studies were limited in sample size or relatively small healthcare systems. Our objective was to estimate the effect of early initiation of prophylactic anticoagulation on the risk of 30-day mortality among patients hospitalized with COVID-19 in the largest integrated healthcare system in the United States. We conducted an observational cohort study using electronic health record (EHR) data from the US Department of Veterans Affairs (VA), which comprises over 1,200 points of care nationwide including hospitals, medical centers, and community outpatient clinics. All care is recorded in an EHR with daily uploads into the VA 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 hospitalized between March 1 and July 31, 2020 who had a laboratory-confirmed positive SARS-CoV-2 test result on or within 14 days prior to hospital admission. We excluded patients who had no history of care (defined as at least one outpatient or inpatient encounter in the two years prior to March 1, 2020), received therapeutic anticoagulation in the 30 days prior to hospital admission (to mitigate the effect of prevalent use of anticoagulation), received a red blood cell transfusion with 24 hours of admission (as active bleeding or severe anemia may have been a contraindication for anticoagulation), or experienced any of the primary outcomes (i.e., died or initiated therapeutic anticoagulation) within 24 hours of admission and therefore did not have equal chance to be classified as exposed in this study. We extracted inpatient pharmacy records for warfarin, intravenous heparin, low-molecular-weight heparin (LMWH; i.e., enoxaparin, fondaparinux, dalteparin), and direct oral anticoagulants (DOAC; i.e., apixaban, rivaroxaban, dabigatran). Doses and routes considered prophylactic anticoagulation are listed in Box 1. Any dose higher than these levels, in addition to warfarin at any dose, were considered therapeutic anticoagulation. The exposure of interest was receipt of prophylactic anticoagulation in the first 24 hours of hospitalization compared to no receipt of prophylactic anticoagulation in the same time frame. Primary outcome was mortality within 30 days of hospital admission ("30-day mortality"), which included in-hospital deaths as well as those that occurred after discharge. Secondary outcomes were inpatient mortality and initiation of therapeutic anticoagulation. Algorithms to identify thromboembolic events during hospitalizations of COVID-19 patients have yet to be validated; thus, we considered initiation of therapeutic levels of anticoagulation after the first 24 hours of admission a proxy for a thromboembolic event. For all outcomes, we followed patients from date of hospital admission until earliest of date of outcome or a maximum of 30 days. Some VA hospitals report observation periods and admissions separately, even when a patient has not moved beds or changed providers. We combined these periods and considered a full hospitalization to begin at first presentation in a VA hospital and end when there was not a subsequent "stay" that began within 24 hours. Study design is depicted in Figure 1. Potential confounders in the relationship between receipt of anticoagulation and COVID-19 mortality or thromboembolic events were identified by reviewing existing literature and through discussions with clinicians. We extracted information on age, race/ethnicity, sex, urban/rural residence, US Census region, clinical comorbidities, Charlson Comorb
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