key: cord-0737604-e7hjhyrz authors: Ionescu, Filip; Jaiyesimi, Ishmael; Petrescu, Ioana; Lawler, Patrick R; Castillo, Edward; Munoz‐Maldonado, Yolanda; Imam, Zaid; Narasimhan, Mangala; Abbas, Amr E.; Konde, Anish; Nair, Girish B. title: Association of anticoagulation dose and survival in hospitalized COVID‐19 patients: A retrospective propensity score‐weighted analysis date: 2020-11-04 journal: Eur J Haematol DOI: 10.1111/ejh.13533 sha: baddea7bf08c0f66db1f1e631a80ceaf655333bf doc_id: 737604 cord_uid: e7hjhyrz BACKGROUND: Hypercoagulability may contribute to COVID‐19 pathogenicity. The role of anticoagulation (AC) at therapeutic (tAC) or prophylactic doses (pAC) is unclear. OBJECTIVES: We evaluated the impact on survival of different AC doses in COVID‐19 patients. METHODS: Retrospective, multi‐center cohort study of consecutive COVID‐19 patients hospitalized between March 13 and May 5, 2020. RESULTS: A total of 3480 patients were included (mean age, 64.5 years [17.0]; 51.5% female; 52.1% black and 40.6% white). 18.5% (n = 642) required intensive care unit (ICU) stay. 60.9% received pAC (n = 2121), 28.7% received ≥3 days of tAC (n = 998), and 10.4% (n = 361) received no AC. Propensity score (PS) weighted Kaplan‐Meier plot demonstrated different 25‐day survival probability in the tAC and pAC groups (57.5% vs 50.7%). In a PS–weighted multivariate proportional hazards model, AC was associated with reduced risk of death at prophylactic (hazard ratio [HR] 0.35 [95% confidence interval {CI} 0.22‐0.54]) and therapeutic doses (HR 0.14 [95% CI 0.05‐0.23]) compared to no AC. Major bleeding occurred more frequently in tAC patients (81 [8.1%]) compared to no AC (20 [5.5%]) or pAC (46 [2.2%]) subjects. CONCLUSIONS: Higher doses of AC were associated with lower mortality in hospitalized COVID‐19 patients. Prospective evaluation of efficacy and risk of AC in COVID‐19 is warranted. dysfunction, 2 as well as a markedly abnormal coagulation profile on thromboelastography suggestive of hypercoagulability in the context of severe systemic inflammation. 3, 4 Furthermore, marked elevations in D-dimer level and markers of endothelial dysfunction (von Willebrand factor antigen, soluble thrombomodulin) have been correlated with worse outcomes. 2, 5, 6 One case series of critically ill COVID-19 patients reported a high incidence of thrombotic complications (31%) 7 and numerous autopsy case series have described pulmonary and other visceral microthromboses suggesting that coagulation abnormalities are not simply an epiphenomenon but are likely major pathogenic components. [8] [9] [10] [11] A small number of retrospective studies have observed that thromboprophylactic-dose anticoagulation is associated with improved outcomes in patients with COVID-19, but a growing body of evidence suggests a possible advantage with using more intense regimens. Our group found a dose-and duration-dependent delay in death in a cohort of 127 deceased patients with severe COVID- 19. 12 Others have also explored the effect of AC in a large cohort of hospitalized COVID-19 patients and found superior outcomes for those treated with tAC, but the comparison group consisted of patients who either received pAC or no AC, and no conclusions could be reached regarding optimal dosing. 13 Notably, in critically ill patients, a significant association with improved survival in subjects treated with tAC compared to pAC was observed. 14 A subsequent analysis of the same cohort again found superior outcomes with the use of AC, but a direct comparison between tAC and pAC failed to show a significant difference. 11 There is a lack of large observational data examining outcomes among patients with COVID-19 receiving tAC compared with pAC or no AC and available results are conflicting. We hypothesized that tAC and pAC may be associated with improved outcomes in a dose-dependent manner relative to no AC among hospitalized patients with COVID-19. We further hypothesized that these associations may be strongest among critically ill patients receiving mechanical ventilation. We also sought to determine the risk of major bleeding. Accordingly, we performed an observational cohort study in the largest hospital network in Southeast Michigan, USA, examining survival relative to anticoagulation dose in hospitalized patients with COVID-19. We conducted a retrospective analysis of a large cohort of consecutive COVID-19 patients hospitalized within the largest academic healthcare system comprised of eight hospitals located in Southeast Michigan, USA. Patients aged 18 years or older who tested positive for SARS-CoV-2 on nucleic amplification testing of nasopharyngeal secretions between March 13, 2020, and May 5, 2020, were retrospectively identified from electronic medical records. To ensure the main reason for hospitalization was COVID-19, subjects who had tested positive for SARS-CoV-2 prior to the admission date or after the third day of hospitalization were excluded. Data were obtained automatically from electronic records. The study was approved by the Institutional Review Board (IRB # 2020-125). In the absence of evidence-based criteria for initiating AC in COVID-19 patients, our institution published internal recommendations for the use of tAC for disease requiring mechanical ventilation, worsening kidney failure and/or a D-dimer >6-fold the upper limit of normal (>3000 ng/ mL fibrinogen-equivalent-units), but tAC could also be initiated at the discretion of the clinician and as salvage therapy. The recommended duration of tAC was 5 days based on expert consensus, but treatment could be extended in the presence of a clear indication or by clinician choice. Therapeutic anticoagulation was defined as a minimum 3-day course of either: (a) intravenous unfractionated heparin (UFH) with at least one documented activated partial thromboplastin time in the anticoagulation range (≥45 seconds); (b) subcutaneous enoxaparin at doses of 1 mg/kg twice daily or 1.5 mg/kg once daily (while allowing for dose adjustment based on creatinine clearance); (c) intravenous argatroban infusion; (d) subcutaneous fondaparinux at doses of 5-10 mg once daily (weight-based dosing); or (e) oral anticoagulants (warfarin, apixaban, rivaroxaban, dabigatran) prescribed prior to and continued throughout hospitalization. Prophylactic anticoagulation (pAC) was defined as one of the following administrations on most days of hospitalization: 1) subcutaneous injection of UFH at doses of 5000 units twice or three times daily; subcutaneous enoxaparin injection at doses of 30-40 mg once daily; or 3) subcutaneous fondaparinux at a dose of 2.5 mg once daily. Patients who received therapeutic anticoagulation for less than 3 days were also included in the pAC group. Because many patients transitioned between anticoagulants depending on ability to ingest oral medication and the safety profile of the drug, the specific anticoagulant agent administered in the most doses was considered the primary anticoagulant for a given patient. Immunosuppressive corticosteroid therapy was defined as at least one dose of greater than 15 mg methylprednisolone or equivalent dose of other corticosteroid. For the purposes of Novelty Statements 1. We retrospectively compared survival of patients treated with different anticoagulation doses in a large cohort. 2. Higher doses of anticoagulation were associated with prolonged survival, especially in critically ill patients, but this larger effect size came at the cost of excess nondisabling bleeding. 3. Anticoagulation may be considered in the treatment of hospitalized COVID-19 patients, but prospective studies are required to further assess the benefit and bleeding risk. analysis, intensive care unit (ICU) stay was defined as need for mechanical ventilation to maintain adequate oxygenation. Table 1 using the method of false discovery rate of Benjamini, Hochberg and Yekutieli. 15 Multivariate Cox regression was used to evaluate the survival time of COVID-19 patients compared between those who received tAC, Pac, and no AC. Time zero was the time of admission and patients were right-censored at the time of discharge or at the end of the study period if they remained hospitalized. Propensity score (PS) weights were used as a summary adjustment variable to address the issue of possible bias introduced by the retrospective nature of the study. This approach was preferred to PS matching to preserve the sample size. The PS was calculated using a logistic regression model with categorical AC group as dependent variable and it was adjusted for the following covariables: age (years), sex, Table 1 . [16.9] in the pAC and 55.0 [21.7] in the no AC groups), with a higher frequency of common comorbid conditions. Rates of therapeutic interventions are presented in Table 1 . In-hospital mortality among the groups was statistically different (11.4% for no AC, 10.8% for pAC and 23.6% for tAC; P < .001). Median survival times were 25 days for pAC and 30 days for tAC. Major bleeding events defined by composite criteria occurred in 147 subjects: 81 (8.1%) patients treated with tAC compared to 20 (5.5%) among those who received no AC and 46 (2.3%) in those who received pAC ( The biological basis for the potential benefit of anticoagulation in COVID-19 is derived from reports of hypercoagulability and endothelial dysfunction 2,6,17-19 with resulting formation of micro-and macrothrombi. 8, 9, 20 Ours is among the first and the largest studies to evaluate the effect of AC on survival in COVID-19. Our main findings are as follows: 1) both prophylactic and therapeutic AC were associated with decreased mortality in COVID-19; 2) patients receiving therapeutic doses had higher survival probability compared to those receiving prophylactic doses, and the greatest effect was observed in critically ill patients; and 3) major bleeding events occurred more frequently in patients receiving tAC. Our study population was derived from a large US cohort ( Hypercoagulability is emerging as an important component of COVID-19 pathogenicity and evidence for the beneficial effect of anticoagulation on survival is increasing. We report a statistically significant association between anticoagulant treatment and decreased mortality in a large US cohort of COVID-19 patients. The effect of anticoagulation appears to be dose-dependent, with a stepwise increase in survival benefit observed with the use of prophylactic regimens and a three-day course of therapeutic anticoagulation compared to no anticoagulation. The greatest impact is seen primarily in patients with critical illness, but benefit was also observed in hospitalized non-ICU patients. Bleeding was more frequent with the use of therapeutic anticoagulation, but the prevalence of disabling intracranial bleed was similar which may tip the risk-benefit discussion in the favor of anticoagulation. Prospective, randomized controlled trials are required to establish the true effect of tAC on survival and to identify patients with COVID-19 most likely to benefit from this intervention. Ionescu F performed literature search, designed the study, analyzed and processed the data, provided figures, and wrote, critically revised, and finally approved the manuscript. Jaiyesimi I, Lawler PR, Abbas AE, Konde A, Narasimhan M, and Castillo E critically revised and finally approved the manuscript. Petrescu I wrote, critically revised, and finally approved the manuscript. Munoz-Maldonado Y analyzed the data, provided figures, and critically revised and finally approved the manuscript. Imam Z processed the data and critically revised and finally approved the study. Nair GB literature search, designed the study, analyzed and processed the data, and wrote, critically revised, and finally approved the manuscript. Raw data were generated within the Beaumont Health System. Derived data supporting the findings of this study are available from the corresponding author, GBN, on request. 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R package version 1.6. Accessed Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Coagulopathy and antiphospholipid antibodies in patients with Covid-19 COVID-19 and its implications for thrombosis and anticoagulation Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline Additional supporting information may be found online in the Supporting Information section Association of anticoagulation dose and survival in hospitalized COVID-19 patients: A retrospective propensity score-weighted analysis