key: cord-0853940-937d3hwp
authors: Giannis, Dimitrios; Allen, Steven L.; Tsang, James; Flint, Sarah; Pinhasov, Tamir; Williams, Stephanie; Tan, Gary; Thakur, Richa; Leung, Christian; Snyder, Matthew; Bhatia, Chirag; Garrett, David; Cotte, Christina; Isaacs, Shelby; Gugerty, Emma; Davidson, Anne; Marder, Galina S.; Schnitzer, Austin; Goldberg, Bradley; McGinn, Thomas; Davidson, Karina W.; Barish, Mathew A; Qiu, Michael; Zhang, Meng; Goldin, Mark; Matsagkas, Miltiadis; Arnaoutoglou, Eleni; Spyropoulos, Alex C.; Manoharan, Mohanambal; Meyers, Kerry; Ghiuzeli, Christina; Jou, Erin; De Oleo, Ivan Ramirez; Gitlin, Jordan
title: Post-Discharge Thromboembolic Outcomes and Mortality of Hospitalized COVID-19 Patients: The CORE-19 Registry
date: 2021-04-09
journal: Blood
DOI: 10.1182/blood.2020010529
sha: a36440960cd0058c4b1977be5697b8e281351153
doc_id: 853940
cord_uid: 937d3hwp

Thromboembolic events including venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality from sub-clinical thrombotic events occur frequently in COVID-19 inpatients. Whether the risk extends post-discharge has been controversial. Our prospective registry included consecutive COVID-19 patients hospitalized within our multihospital system from March 1st - May 31st 2020. We captured demographics, comorbidities, laboratory parameters, medications, post-discharge thromboprophylaxis, and 90-day outcomes. Data from electronic health records, health informatics exchange, a radiology database, and telephonic follow-up were merged. The primary outcome was a composite of adjudicated VTE, ATE, and all-cause mortality (ACM). The principal safety outcome was major bleeding (MB). Among 4,906 patients (53.7% male) mean age was 61.7 years. Comorbidities included hypertension (38.6%), diabetes (25.1%), obesity (18.9%), and cancer history (13.1%). Post-discharge thromboprophylaxis was prescribed in 13.2%. VTE rate was 1.55%, ATE 1.71%, ΑCM 4.83%, and MB 1.73%. The composite primary outcome rate was 7.13% and was significantly associated with advanced age (OR: 3.66, 95%CI: 2.84-4.71), prior VTE (OR: 2.99, 95%CI: 2.00-4.47), ICU stay (OR: 2.22, 95%CI: 1.78-2.93), chronic kidney disease (CKD) (OR: 2.10, 95%CI: 1.47-3.0), peripheral arterial disease (OR: 2.04, 95%CI: 1.10-3.80), carotid occlusive disease (OR: 2.02, 95%CI: 1.30-3.14), IMPROVE-DD VTE score ≥4 (OR: 1.51, 95%CI: 1.06-2.14), and coronary artery disease (OR: 1.50, 95%CI: 1.04-2.17). Post-discharge anticoagulation was significantly associated with reducing the primary outcome (OR: 0.54, 95%CI: 0.47-0.81). Post-discharge VTE, ATE, and ACM occur frequently following COVID-19 hospitalization. Advanced age, cardiovascular risk factors, CKD, IMPROVE–DD VTE score ≥4, and ICU stay increase risk. Post-discharge anticoagulation reduced risk by 46%.

 In our registry, the 90 day post-discharge venous and arterial thromboembolism and all-cause mortality rates were 1.55%, 1.71%, and 4.83%

 Anticoagulants at discharge, mostly in prophylactic doses, were associated with a 46% decrease in the composite endpoint of major TE or ACM

The coronavirus disease 2019 (COVID- 19) pandemic has been associated with significant morbidity and mortality globally. Importantly, elevated rates of macrovessel thrombotic events, including venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE), and arterial thromboembolism (ATE), such as stroke and myocardial infarction (MI), have been described, especially in sick and critically ill hospitalized patients. [1] [2] [3] [4] In addition, postmortem studies suggest that approximately 60% and up to 100% of patients have unsuspected VTE or pulmonary arterial thrombosis at the time of death, with pulmonary microthrombi suggesting in situ fatal PE as an important contributor to death. 5, 6 There are limited and conflicting data on the rates of thromboembolic events and death in the post-discharge period for hospitalized COVID-19 patients with previous studies limited by small sample sizes, retrospective designs, and non-standardized follow-up. 7, 8 Antithrombotic guidelines for extended postdischarge thromboprophylaxis for COVID-19 patients are also conflicting, suggesting either no routine thromboprophylaxis or an individualized approach to thromboprophylaxis using individual thrombotic and bleeding risk factors. [9] [10] [11] There have been few previous efforts to assess predictors of thrombosis or death in the post-discharge period for hospitalized COVID-19 patients, which represent a subset of medically ill patients. 12 ]. Previous data from randomized trials suggest an elevated rate of major and fatal thromboembolic events in high risk medicallyill patients (including those with pneumonia and sepsis) within six weeks of hospital discharge, with a significant 28% to 38% risk reduction using extended thromboprophylaxis. 13, 14 To overcome the current knowledge gap in post-discharge rates of VTE, ATE, death, and major complications in hospitalized COVID-19 patients, we undertook an investigator-initiated, multicenter, prospective registry named CORE-19 as part of our health system's COVID- 19 Research Consortium. Our second aim was to assess clinical and laboratory risk factors, as well as relevant medications including anticoagulants, to predict risk of thromboembolic disease or death in the post-discharge period.

This study is a prospective registry of consecutive patients diagnosed with COVID-19 infection within the Northwell Health System. The Northwell Health Institutional Review Board (IRB) approved our study (IRB #20-0363) and, as described in ICH guidelines for Good Clinical Practice (GCP), provided regulatory oversight. The study was performed with waiver of informed consent. in the absence of other likely mechanisms. Death was determined by telephonic patient calls. The principal safety outcome was major bleeding (MB) using ISTH criteria. 17 Secondary outcomes included re-hospitalization (with or without ICU admission), congestive heart failure exacerbation, atrial fibrillation/flutter, interstitial lung disease, myocarditis, and acute respiratory distress syndrome using standardized definitions.

Our dedicated team of 35 abstractors attempted to contact discharged patients via at least three phone calls on different days and times to obtain one set of data elements during the study period using a standardized and structured questionnaire. All study data were aggregated and systematically stored in a unified repository (data mart) developed by the Center for Research Informatics and Innovation. Our database includes data extracted through automatic extracttransform-load (ETL) processes that query and transfer data from radiology databases, EHRs (through identification of ICD-9 and ICD-10 codes) and the HIE and REDCap sources. The unified repository resides in an instance of MS SQL server database and uses a common data model (CDM) that ensures semantic interoperability between data originating from disparate sources and accurate interpretation of statistical analyses.

The team of abstractors called the patients and entered any postdischarge outcomes in the standardized REDCap questionnaire. Subsequently, in the population of respondents, the demographic characteristics, all available diagnoses, comorbidities, VTE risk factors, laboratory values (highest values during index hospitalization), medications including in-hospital and postdischarge thromboprophylaxis and post-discharge events were captured through automatic ETL processes that extracted data from radiology images, EHRs, and HIE. All post-discharge outcomes that were captured manually through phone calls (in REDCap) or through automatic ETL processes were pooled in a common file that was then used by the abstractors to manually screen the patients' charts and confirm or reject the presence of an outcome. The postdischarge outcomes were adjudicated by two abstractors and any disagreements were resolved by a third experienced abstractor (A.C.S).

Data were summarized using descriptive statistics. Categorical variables were summarized using frequencies and percentages; continuous variables were summarized using mean and standard deviation. Logistic regression analyses were performed to assess the association between independent variables and the composite outcome consisting of VTE or ATE or ACM (yes or no). Univariate analyses were performed first, followed by multivariate analyses. In the final logistic regression model, the following variables were included regardless of their univariate P values: age, body mass index (BMI), IMPROVE-DD VTE score, use of anticoagulants or antiplatelet agents, D-dimer > 4 -6 X ULN or > 6 X ULN, history of VTE, coronary artery disease, history of peripheral arterial disease, history of carotid occlusive disease, congestive heart failure, chronic renal disease, race, and ICU admission. Variables with univariate P-values of less than 0.2 were also included into the final model if selected through backward selection process. Results were reported as adjusted odds ratios (ORs) with 95% confidence intervals (CIs).

All statistical analyses were conducted using SAS 9.4 (Cary, NC). A twotailed p-value < 0.05 was considered statistically significant.

From a total of 11,249 adult non-obstetric/non-gynecologic hospitalized patients with COVID-19 (March 1 st -May 31 st , 2020), 3,081 died in-hospital. We thus identified 8,168 eligible patients, of whom we contacted 8,034 patients. Our abstractors were able to capture the outcomes of 4,906 unique patients (61% response rate) at a mean follow-up of 92.0 ± 13.8 days ( Table 1) . The cohort had a mean age of 61.7±17.5 years, was male predominant (53.7%), and consisted of 36.6% White, 21.4% African American/Black, 8.1% Asian patients, and 29.6% of patients in an "Other" category who did not self-identify race.

Main comorbidities included hypertension in 38.6%, diabetes mellitus in 25.1%, BMI> 35 kg/m 2 in 18.9%, intensive care unit (ICU) admission at index hospitalization in 11.8%, coronary artery disease in 6.9%, heart failure in 4.5%, atrial fibrillation in 6.5%, history of ischemic stroke in 3.6%, history of carotid occlusive disease in 3.7%, peripheral arterial disease in 1.7%, history of bleeding in 8.9%, chronic renal disease in 6.8%, chronic lung disease in 7.3%, chronic liver disease in 1.0%, and thyroid disease in 7.2%.

Main comorbidities associated with increased risk for VTE included a personal history of VTE in 10.8%, known thrombophilia in 1.4%, cancer in 13.1%, autoimmune disease in 2.1%, family history of VTE in 1.4%, and paraplegia or hemiplegia in 0.4%.

The population characteristics and main comorbidities of 3,262 patients that were eligible and did not respond to follow-up phone calls or were not contacted are summarized in Appendix 1. There did not appear to be major differences in demographic characteristics and comorbidities between the group of patients for whom follow-up was available and this group.

In-hospital laboratory parameters included mild leukocytosis (WBC: 11.0±6.7 K/uL), mildly increased serum creatinine (1.8±2.5 mg/dL), elevated Troponin I Table 2 ).

In-hospital medications included IL-6 antagonists (tocilizumab or sarilumab) in 56.3%, hydroxychloroquine in 55.6%, statins in 30.6%, glucocorticoids in 27.1%, aspirin in 21.9%, other antiplatelet agents in 5.7%, famotidine in 14.3%, antibiotics in 10.5%, IL-1 antagonist (anakinra) in 6.0%, and antivirals in 2.0% (Table 3) .

At index hospitalization, thromboprophylaxis consisted of prophylactic enoxaparin in 53.6%, treatment dose enoxaparin in 5.5%, subcutaneous prophylactic unfractionated heparin in 20.1%, intravenous treatment dose unfractionated heparin in 4.7%, prophylactic apixaban in 6.3%, treatment dose apixaban in 1.1%, prophylactic rivaroxaban in 2.3%, treatment dose rivaroxaban in 1.0%, and treatment dose warfarin in 1.6% (Table 3, Supplemental Table) .

Post-discharge thromboprophylaxis was prescribed in 12.7% of the population and consisted of prophylactic dose rivaroxaban in 6.9%, prophylactic dose apixaban in 3.7%, and prophylactic dose enoxaparin in 1.3%. The rate of post-discharge thromboprophylaxis in patients with an IMPROVE-DD VTE score of 4 or more was 21.5% compared to patients with an IMPROVE-DD VTE score less than 4 who had a post-discharge thromboprophylaxis rate of 9.7% (p <.0001). 

Multivariate analysis showed significant association between VTE, ATE or ACM It is by now well-recognized that COVID-19 induces a prothrombotic state resulting from interactions between the immune, inflammatory, and coagulation systems in sick, hospitalized patients that lead to a multifold increased risk of inhospital VTE and ATE. 4, 18 In addition, autopsy data in hospitalized patients with COVID-19 suggested that ~60% and up to 100% of thrombotic events including PE and pulmonary arterial thrombosis may not be suspected before death, indicating that thrombotic mechanisms play a major role in mortality. 5, 6 As such, major thrombotic events and death may represent competing risks in these patients.

Our study found that hospitalized COVID-19 patients had a post-discharge ΑCM rate of nearly 5%; an ATE rate of 1.71% that included stroke, MI, non-MI coronary revascularization, major adverse limb event, and systemic embolism ; a 14 VTE rate of 1.55% of which more than half of events included PE, with a composite primary outcome rate of 7.13% in the 90-day period post-discharge.

These rates are higher than previous reports of post-discharge thrombotic events in hospitalized COVID-19 patients, with absolute VTE rates of 0.2% to 0.98% seen in three studies of 1529,1877 and 102 patients, respectively, while results of another small study of 163 patients were more in line with our findings, suggesting a cumulative incidence of arterial and venous thrombosis of 2.5% (95% CI 0.8% to 7.6%) at 30 days. 7, 8, 12, 19 The reasons for these discrepant results may include the small sample sizes, retrospective designs, a shorter observation period, or lack of systematic follow-up and uniform data collection seen in previous studies compared to our prospective registry design. In addition, our results suggest at least a four-fold increased risk of major thromboembolic events and death in the post-discharge period in COVID-19 patients compared to untreated hospitalized medically-ill patients (including those with sepsis and pneumonia) in the pre-COVID-19 era, with event rates of ~ 1.77%. 13 Our study also found that approximately one in six patients were re-hospitalized in the immediate post-discharge period, which is in accordance with a previous large study in COVID-19 patients during the 60-days post-discharge (19.9%) 20 and comparable with 30-day readmission rates in patients with pneumonia (17.8%) 21 The post-discharge MB rate of 1.73% seen in our study was higher than in a previous report of post-discharge MB of 0.7% (95% CI 0.1% -5.1%) seen in hospitalized COVID-19 patients. 8 However, this study included a small sample size and retrospective design, which may have underestimated results. In addition, our MB rate is multifold higher than previous rates of MB of ~0.2% seen in contemporary studies of extended post-discharge thromboprophylaxis of hospitalized medically-ill patients prior to the COVID-19 era. 13 Of the 85 patients with MB in our study, only 17.6% were prescribed post-discharge anticoagulants.

These data suggest that although the majority of MB occurred in the patient population not prescribed post-discharge anticoagulants, a clinically important relationship between post-discharge anticoagulation and MB cannot be ruled out.

An important bleeding diathesis in hospitalized COVID-19 patients also cannot be excluded, although the rates of thrombotic events (and presumably unrecognized thrombotic events leading to death) are at least 2 or more fold higher than MB events.

Our study found that advanced age > 75 years, cardiovascular risk factors (personal history of VTE, coronary artery disease, carotid occlusive disease, peripheral arterial disease), CKD, an IMPROVE-DD VTE score ≥ 4, and ICU stay were all significantly associated with post-discharge major thromboembolic events and death, with ORs of ~2.0 to 3.66, while "Other" race in patients who did not self-identify race appeared protective, with an OR of 0.68. Advanced age, history of cardiovascular disease, and ICU level of care have been consistently associated with poor outcomes and increased thrombotic events and mortality in hospitalized COVID-19 patients. 3, 22, 23 CKD has also been associated with increased risk of thrombotic events and mortality in COVID-19 patients. 24, 25 The IMPROVE VTE score has been extensively validated in medically ill patients, 26 and addition of an elevated D-dimer > 2X ULN to improve model discrimination has identified medically ill patients (including those with pneumonia and sepsis) with a nearly 3-fold increased risk for VTE. 27 Consistent reports support that an elevated D-dimer -which may reflect the hyperinflammatory state and cytokine storm that leads to thromboinflammation -especially more than four or six times the upper limit of normal is a strong predictor of mortality and thrombosis in COVID-19 inpatients. 2, 28 In our study, a D-dimer of more than six-fold the upper limit of normal was predictive of our primary outcome in the univariate analysis, but lost significance in the multivariate analysis. However, the IMPROVE-DD VTE score which incorporates elevated D-dimer, was a significant predictor of post-discharge cardiovascular events and death, with an OR of 1.5 in the multivariate analysis. More recently, the IMPROVE-DD VTE score has been validated in hospitalized COVID-19 patients, with patients with a score of ≥ 4 having a high risk of thrombosis. 16 An important observation in our study is that anticoagulants (either LMWH or a DOAC), mainly at prophylactic-doses and prescribed at hospital discharge, was significantly associated with a reduction of the composite outcome of ATE, VTE, or ACM by 46% in hospitalized COVID-19 patients. ACM represented the key component of our composite outcome. Previous autopsy-based studies in hospitalized COVID-19 patients revealed that unsuspected ante-mortem thrombotic events such as in-situ PE and pulmonary arterial thrombi may play a key role in subsequent death. [4] [5] [6] 18 Our health system policy at the time of our study advocated for extended anticoagulant thromboprophylaxis for 30 days after hospitalization in high-risk hospitalized COVID-19 patients. 29 Previous high quality data from randomized trials in high risk hospitalized medically ill patients (including those with sepsis/pneumonia, an IMPROVE VTE score of ≥ 4, and elevated D-dimers) revealed a 28% to 38% risk reduction for major and fatal thromboembolic events (including ATE and VTE) using extended post hospital discharge thromboprophylaxis with a direct oral anticoagulant (DOAC). 13, 14 Antithrombotic guidelines and hospital protocols in hospitalized COVID-19 patients diverge on this topic, with some suggesting extended thromboprophylaxis in high-risk COVID-19 patients, 10, 18, 29, 30 while others do not advocate for extended thromboprophylaxis. 9, 11, 31 Our findings support extended thromboprophylaxis with an anticoagulant (either LMWH or preferably a DOAC due to oral route of administration) in high risk COVID-19 patients at low bleeding risk at the time of discharge, especially as the majority of post-discharge MB events in our study (82.4%) occurred in patients not on post-discharge anticoagulants. High risk criteria include advanced age > 75 years, the presence of cardiovascular risk factors (personal history of VTE, coronary artery disease, carotid occlusive disease, peripheral arterial disease), CKD, an IMPROVE-DD VTE score ≥ 4, or an ICU stay.

Our study has several strengths and limitations. Our prospective registry design and large sample size of consecutive and diverse patients hospitalized with COVID-19 within a multihospital health system reinforces the generalizability of our findings. In addition, the use of a standardized data collection instrument and unified datamart, reflects the high integrity of data collection, while use of adjudicated outcomes using chart review reflects the high quality of outcomes capture. Another potential strength when interpreting study results is the well-defined criteria for post-discharge thromboprophylaxis. Limitations include the lack of a comparator group, the potential introduction of hidden bias with our study's 61% response rate, the inability to capture medication adherence including omission of anticoagulant use, and the inability to undergo further statistical analyses of less frequent cardiovascular complications with multivariate analyses. Another study limitation when interpreting results is the relatively small subgroup of patients who received post-discharge thromboprophylaxis.

In conclusion, our prospective multihospital registry of 4,906 adult hospitalized COVID-19 patients followed for a mean of 92 days reveals that VTE, ATE, and ACM occur with a higher frequency during this post-discharge period than previously reported. Key predictors of post-discharge thromboembolic events and death include advanced age, cardiovascular risk factors, CKD, an IMPROVE-DD VTE score ≥ 4, and ICU stay. The use of post-discharge anticoagulants, mostly at prophylactic-doses, was associated with a reduction of the risk of major thromboembolic events and death by 46%. Well-conducted randomized trials of the efficacy and safety of extended post-discharge thromboprophylaxis in hospitalized COVID-19 patients are needed. 

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience

Thrombosis in hospitalized patients with COVID-19 in a New York City health system

Weitz Jeffrey I. Hospitalized COVID-19 patients and venous thromboembolism

Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series

Autopsy findings and venous thromboembolism in patients with COVID-19: A Prospective Cohort Study

Postdischarge venous thromboembolism following hospital admission with COVID-19

Postdischarge thrombosis and hemorrhage in patients with COVID-19

Prevention, Diagnosis, and Treatment of VTE in Patients With COVID-19

Scientific and Standardization Committee Communication: Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID-19

ASH Guidelines on Use of Anticoagulation in Patients with COVID-19

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study

Post-Discharge Prophylaxis With Rivaroxaban Reduces Fatal and Major Thromboembolic Events in Medically Ill Patients

Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy

The IMPROVEDD VTE Risk Score: Incorporation of D-Dimer into the IMPROVE Score to Improve Venous Thromboembolism Risk Stratification

Validation of the IMPROVE-DD risk assessment model for venous thromboembolism among hospitalized patients with COVID-19

Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up

Incidence of Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalisation

Readmission and Death After Initial Hospital Discharge Among Patients With COVID-19 in a Large Multihospital System

Hospital nursing and 30-day readmissions among Medicare patients with heart failure, acute myocardial infarction, and pneumonia

Pulmonary embolism in patients with COVID-19: Awareness of an increased prevalence

Regardless of age, obesity and hypertension increase risks with COVID-19

Prognosis of COVID-19 in Patients with Liver and Kidney Diseases: An Early Systematic Review and Meta-Analysis

COVID-19 and cardiovascular diseases

American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients

Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Emergence of Institutional Antithrombotic Protocols for Coronavirus

Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine

Antithrombotic Therapy in Patients with COVID-19

*Highest value during initial hospitalization SD: Standard Deviation N: Number of patients with available laboratory parameter value WBC: White Blood Cell count Hb: Hemoglobin Hct: Hematocrit PLT: Platelet count TnI: Troponin I TnT: Troponin T IL-6: Interleukin 6 CRP: C-reactive protein LDH: Lactate dehydrogenase MPL: M phospholipids GPL: G phospholipids β2GP1: Beta-2-Glycoprotein 1

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