key: cord-0807568-p445i03a
authors: Moll, Matthew; Zon, Rebecca L.; Sylvester, Katelyn W.; Chen, Evan C.; Ghosh, Auyon J.; Abston, Eric; Cheng, Vivien; Hakim, Aaron; Connell, Nathan T.; Fredenburgh, Laura E.; Baron, Rebecca M.; Hobbs, Brian D.; Cho, Michael H.; Mittleman, Murray A.; Woolley, Ann E.; Connors, Jean M.
title: Intermediate versus standard dose heparin prophylaxis in COVID-19 ICU patients: A propensity score-matched analysis
date: 2021-04-19
journal: Thromb Res
DOI: 10.1016/j.thromres.2021.04.009
sha: 72e231e5f494e017f07176942ead03b4678e01d8
doc_id: 807568
cord_uid: p445i03a

nan

Elevated VTE rates have been reported in COVID-19 patients 1,2 . Although ICU patients in general have an elevated VTE risk 3 we recently reported a higher incidence of VTE in ICU compared to ward patients with COVID-19 4 . As the optimal approach for thromboprophylaxis is unknown, we implemented intermediate dose anticoagulation in COVID-19 ICU patients. We hypothesized that intermediate dose heparin prophylaxis would be associated with lower incidences of symptomatic VTE, death, or a composite outcome of both in COVID-19 ICU patients.

Data were retrospectively collected on COVID-19 patients admitted to BWH or BWFH requiring ICU care. Participants were entered into the RRS-SARS-CoV-2 (IRB approved) from March 7 th to June 1 st , 2020, and followed until June 27 th , 2020. We implemented intermediate dose prophylaxis for COVID-19 ICU patients on April 24 th , 2020. Readmissions were not included. SARS-CoV-2 positivity was determined by reverse-transcription polymerase chain reaction on nasopharyngeal or endotracheal samples.

ICU admission criteria, laboratory monitoring, and treatment protocols were previously described 4 . Participants placed on standard (enoxaparin 40 mg daily, unfractionated heparin 5000 IU twice or three times daily) or intermediate (enoxaparin 40 mg twice daily, adjusted for extremes of weight (0.5 mg/kg twice daily) or 7500 IU unfractionated heparin three times daily) dose prophylactic J o u r n a l P r e -p r o o f anticoagulation at the time of ICU admission, adjusted for renal failure and thrombocytopenia, were included in the primary analysis.

Propensity scores were calculated (MatchIt R package) and patients were matched based on age, sex, body-mass index, DVT history, ferritin, creatinine, activated partial thromboplastin time, C-reactive protein, history of hematologic malignancy, total length of hospital stay, need for vasopressors within 24 hours of ICU admission, and type of respiratory support (no intubation, HFNC, BiPAP, intubation). Data on those receiving treatment dose anticoagulation (heparin continuous infusion) were also collected to compare event and bleeding rates, but were not part of the primary analysis.

The primary outcomes were time-to-death, symptomatic radiographically-confirmed VTE 4 , and a composite of death and symptomatic VTE. No surveillance imaging was performed. We assessed the association of a binary variable indicating standard (0) or intermediate (1) dose prophylactic anticoagulation with each outcome. Follow up time was measured from time of hospital admission until death, symptomatic VTE, discharge, or 28 days. Major bleeding events were defined using ISTH criteria 5 .

All analyses were performed in R version 4.0.3 (https://www.r-project.org). Variables were compared with Student t-tests, Wilcoxon, ANOVA, or Kruskal-Wallis tests, as appropriate. Bleeding rates were compared with Pearson Chi-squared statistic. KM analyses were performed using the survival R package; curves were compared using log-rank tests, and p-values were considered significant if below a Bonferroni-adjusted threshold. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals.

Proportional hazard assumptions were assessed by Schoenfeld residual plots and tests. Retrospective studies comparing therapeutic to standard dose heparin prophylaxis have yielded conflicting results for mortality, with several reports of elevated bleeding rates in those on therapeutic anticoagulation 7-9 . The ACTIV-4a trial 10 , comparing therapeutic to standard dose prophylaxis, was halted in critically-ill patients as there was no improvement in the endpoint of organ dysfunction at 21 days; however, a recent press release indicates benefit in moderately-ill hospitalized patients, though results of other endpoints, such J o u r n a l P r e -p r o o f as bleeding, are not yet available 11 . The INSPIRATION randomized trial of intermediate versus standard dose prophylaxis results were published after we submitted our work, and also found no difference in mortality and thrombotic outcomes, however event rates were very low in comparison to other reported rates 12 . Recent data suggest that VTE events are still high in the second wave despite lower mortality 13 . Given the continued urgency and remaining uncertainty about optimal treatment, we utilized a propensity score- J o u r n a l P r e -p r o o f 

Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave

Impact of high dose prophylactic anticoagulation in critically ill patients with COVID-19 pneumonia

An inflammatory cytokine signature predicts COVID-19 severity and survival

Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia

Table 1: Characteristics of participants matched on age, sex, body-mass index, DVT history, ferritin, creatinine, partial thromboplastin time, history of hematologic malignancy, and total length of hospital stay