key: cord-1046644-qwsd45oe authors: Meena, Richard A.; Sharifpour, Milad; Gaddh, Manila; Cui, Xiangqin; Xie, Yue; Di, Mengyu; Brewster, Luke P.; Duwayri, Yazan; Alabi, Olamide title: COVID-19 Associated Venous Thromboembolism Portends Worse Survival date: 2021-08-09 journal: Semin Vasc Surg DOI: 10.1053/j.semvascsurg.2021.08.001 sha: 0493a1408824539124c7e2918b06df6b19d5db50 doc_id: 1046644 cord_uid: qwsd45oe Background: Patients with Coronavirus Disease 2019 (COVID-19) seem to be at high risk for venous thromboembolism (VTE) development, but there is a paucity of data exploring both the natural history of COVID-19 associated VTE and the risk for poor outcomes after VTE development. This investigation aims to explore the relationship between COVID-19 associated VTE development and mortality. Methods: A prospectively maintained registry of patients over 18 years of age admitted for COVID-19 related illnesses within an academic healthcare network between March and September 2020 was reviewed. Codes from the tenth revision of the International Classification of Diseases (ICD-10) for VTE were collected. The charts of those patients with an ICD-10 code for VTE were manually reviewed to confirm VTE diagnosis. Results: 2552 patients were admitted with COVID-19 related illnesses. 126 (4.9%) patients developed a VTE. A disproportionate percentage of patients of Black race developed a VTE (70.9% VTE versus 57.8% non-VTE, p=0.012). A higher proportion of patients with VTE expired during their index hospitalization (22.8% VTE versus 8.4% non-VTE, p<0.001). On multivariable logistic regression analysis, VTE was independently associated with mortality (OR 3.17; 95% CI, 1.9 to 5.2; p<0.001). Hispanic/Latinx ethnicity was associated with decreased mortality (OR 0.45; 95% CI, 0.21 to 1.00; p=0.049). Discussion: Hospitalized patients of Black race with COVID-19 were more prone to VTE development, and patients with COVID-19 who developed in-hospital VTE roughly nearly threefold higher odds of mortality. Further emphasis should be placed on optimizing COVID-19 anticoagulation protocols to reduce mortality in this high-risk cohort. Background: Patients with Coronavirus Disease 2019 (COVID- 19) seem to be at high risk for venous thromboembolism (VTE) development, but there is a paucity of data exploring both the natural history of COVID-19 associated VTE and the risk for poor outcomes after VTE development. This investigation aims to explore the relationship between COVID-19 associated VTE development and mortality. Methods: A prospectively maintained registry of patients over 18 years of age admitted for COVID-19 related illnesses within an academic healthcare network between March and September 2020 was reviewed. Codes from the tenth revision of the International Classification of Diseases (ICD-10) for VTE were collected. The charts of those patients with an ICD-10 code for VTE were manually reviewed to confirm VTE diagnosis. Results: 2552 patients were admitted with COVID-19 related illnesses. 126 (4.9%) patients developed a VTE. A disproportionate percentage of patients of Black race developed a VTE (70.9% VTE versus 57.8% non-VTE, p=0.012). A higher proportion of patients with VTE expired during their index hospitalization (22.8% VTE versus 8.4% non-VTE, p<0.001). On multivariable logistic regression analysis, VTE was independently associated with mortality (OR 3.17; 95% CI, 1.9 to 5.2; p<0.001). Hispanic/Latinx ethnicity was associated with decreased mortality (OR 0.45; 95% CI, 0.21 to 1.00; p=0.049). Discussion: Hospitalized patients of Black race with COVID-19 were more prone to VTE development, and patients with COVID-19 who developed in-hospital VTE roughly nearly threefold higher odds of mortality. Further emphasis should be placed on optimizing COVID-19 anticoagulation protocols to reduce mortality in this high-risk cohort. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus Disease 2019 , emerged in December 2019 and quickly developed into a global pandemic. Disease severity can range from asymptomatic clinical presentations to multi-organ system failure and death. As investigators study this complex virus, certain characteristics of COVID-19 infection appear to place patients at higher risk for complications and death. One aspect of COVID-19 that has garnered increased attention is its associated hypercoagulable state; many investigators have reported higher than expected rates of arterial and venous thromboembolic events (VTE) [1] [2] [3] [4] . Since hospitalized patients with COVID-19 seem to be at high risk for VTE, various healthcare institutions supported early anticoagulation strategies in hospitalized patients, albeit with sparse data to guide these protocols [5] [6] [7] [8] . There is a paucity of published data regarding both the natural history of COVID-19 associated VTE and the risk for poor outcomes with VTE development. Thus, our primary goal was to estimate the incidence of VTE in our large academic healthcare network. In addition, we aimed to explore the relationship between COVID-19 associated VTE and mortality. This study was approved by our institution's Institutional Review Board (IRB #00000601). All patients over 18 years of age who were admitted to one of four hospitals within our large academic healthcare network between March 4, 2020, and September 13, 2020, for COVID-19 related illnesses were identified from a prospectively maintained database within the institution's Corporate Data Warehouse (CDW). This administrative database houses demographic patient information that was utilized for analysis, including but not limited to age, birth sex, race, ethnicity, insurance status, high-risk comorbidities as identified by the Centers for Disease Control and Prevention (CDC), hospital length of stay, and in-hospital mortality. Codes from the tenth revision of the International Classification of Diseases (ICD-10) were used to capture incident VTE development. Any patient requiring care within an intensive care unit (ICU) during any part of their hospital stay were included in the ICU cohort. Any patient not treated within an ICU during their hospital stay were included in the ward cohort. Vulnerable populations including prisoners, pregnant women, and minors were excluded from the study. While reviewing the initial dataset, it was noted that the use of ICD-10 codes for VTE provided many false positives for in-hospital VTE development. Therefore, to validate VTE events, we manually reviewed all COVID-19 admissions with a documented ICD-10 code for VTE to obtain a more accurate in-hospital VTE incidence. Patients were defined as having an inhospital VTE based on the following criteria: 1) radiographic findings confirming VTE diagnosis, and 2) documentation of high clinical suspicion for VTE per the physician of record. While 114 (90.5%) of the 126 patients with VTE were diagnosed by radiographic findings, only 12 (9.5%) of 126 patients in the VTE cohort were diagnosed by high clinical suspicion (Fig 1) . COVID-19 admissions within the study period with ICD-10 codes for VTE without either radiographic evidence of, or high clinical suspicion for, VTE were included in the overall analysis within the non-VTE cohort. Statistical analysis was completed using R programming (The R Project for Statistical Computing, Vienna, Austria) and SAS (SAS Institute, Cary, NC). Chi-square tests and analysis of variance (ANOVA) tests were used to assess categorical variables, while t-tests were used to analyze continuous variables. Logistic regression models were used to perform univariable and multivariable analyses for the outcomes of both development of VTE and mortality. Between March 4, 2020, and September 13, 2020, 2552 patients were admitted with a COVID-19 related illness to one of four hospitals within an academic healthcare network. 126 (4.9%) were diagnosed with a VTE during their index hospital stay. While roughly one-third of all (Table 3) . Of note, Hispanic/Latinx ethnicity (OR 0.45; 95% CI: 0.21 to 1.00; p=0.049) was associated with decreased odds of mortality (Fig 2) . Current studies report higher than anticipated rates of VTE development in patients with COVID-19. Prior to the COVID-19 pandemic, VTE rates for critically ill patients ranged from 5 to 15% [9] [10] [11] . For those patients with COVID-19 requiring ICU admission, early publications reported VTE rates ranging from 20% to 69% [3] [4] [12] [13] [14] . To date, VTE development among ward patients with COVID-19 has not been well characterized [15] . Additionally, a paucity of data exists regarding the risk factors for increased VTE development in patients with COVID-19. Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTAC) trial. All of the aforementioned trials were stopped early in COVID-19 ICU patients given concern for potential harm of anticoagulation in this population. However, in non-ICU patients, findings suggest that full-dose anticoagulation may improve patient outcomes such as a decreased need for end-organ support including mechanical ventilation [17] . While several of the early studies evaluating VTE in this patient population analyzed the impact of heparin use on mortality, few studies have explored the relationship between VTE and mortality, itself [18] [19] [20] [21] . Clearly defining such a relationship could alter decision-making paradigms in the management of this high-risk patient population. In our multicenter academic healthcare network, 2552 patients were admitted with COVID-19 over a six-month period. 126 of these 2552 patients, roughly one in every 20, were diagnosed with a VTE. While ICD-10 codes were used for data abstraction to define those who had VTE during their index COVID-19 hospital encounter, manual chart review was completed to confirm the VTE diagnosis. Roughly 67% of these 2552 patients did not require ICU level of care ("ward cohort"). . Although a disproportionate percentage of patients in the VTE cohort were Black (70.9%) compared to the non-VTE cohort (57.8%), there were no statistically significant differences in median age, birth sex, or ethnicity between the VTE and non-VTE cohorts. Patients in the VTE cohort had higher mean D-dimer (9184.9 versus 2812.9) and CRP (125.7 versus 88.9) levels. Those who developed VTE during their index COVID-19 hospital encounter also stayed in the hospital on average 5 days longer than those who did not develop VTE. Patients in the VTE cohort had significantly higher mortality rates, with an absolute difference in mortality of 14.4%. On multivariable analysis, VTE was found to be independently associated with mortality, with an adjusted odds ratio of 3.17. In reviewing our experience, we noted three things. First, our in-hospital COVID-19 VTE rate (4.9%) is comparable to or lower than that in other centers [10] [11] [12] [13] . Our institution employed tiered anticoagulation protocols shortly after the first known COVID-19 hospitalizations in our state and this may in part account for our low COVID-19 associated VTE incidence rates. Second, our COVID-19 related death rates are lower than those reported in many of the large reviews [22, 23] . These lower mortality rates are also reflected in published data from our institution's critical care team, who postulated that the delayed inception and peak of COVID-19 cases in our state may have allowed our institution to establish more consensus-driven clinical protocols prior to the influx of admissions [24] . Third, despite these lower mortality rates within our institution, we found that VTE development was independently associated with mortality. This finding suggests a need for targeted anticoagulation strategies for high-risk patients in this population. Historically, based on large population studies, patients who develop VTE have a 30-day mortality rate of 3.0%, far exceeding the 30-day mortality rate for patients who do not develop a VTE: 0.4% [25] . Clearly, VTE complicates other pre-existing comorbidities and puts patients at increased risk for mortality. In our cohort, patients with COVID-19 who developed a VTE had an in-hospital mortality rate of 22.8%, compared to an in-hospital mortality rate of 8.4% for patients with COVID-19 who did not develop a VTE. Even in an at-risk population with evidence of increased hypercoagulability, VTE drastically alters mortality rates, stressing the importance of prophylaxis, early diagnosis, and rapid treatment. Although there is the potential for bleeding complications with anticoagulation, studies have demonstrated that therapeutic anticoagulation is achievable in COVID-19 patients with low bleeding rates [20, 26] . Of the 126 patients with COVID-19 who developed VTE in our healthcare network, five had documented bleeding complications. Four of these patients were able to resume anticoagulation prior to discharge. Two additional patients exhibited symptomatology similar to disseminated intravascular coagulation; these presentations were attributed to COVID-19 coagulopathy, rather than to anticoagulation therapy. Considering the high rate of mortality in patients with COVID-19 who develop VTE, early anticoagulation strategies in high-risk patients may be lifesaving. We found an independent association of ICU admission and pre-hospitalization history of CHF with VTE development. In our study, any patient requiring care within an ICU during their hospital stay were included in the ICU cohort. A temporal relationship cannot be established as VTE development may have occurred at any point during a patient's hospitalization, and not all patients were admitted directly to the ICU upon presentation to the hospital. Patients requiring ICU admission were inherently more sick; consequently, it is feasible that VTE development may have occurred as a sequela of their critical illness. However, it is also feasible that VTE development itself contributed to or represented a marker of clinically significant critical illness in the COVID-19 patient, considering the association between VTE occurrence and mortality in this COVID-19 cohort. Our reported sample size allowed for a more comprehensive analysis of risk factors for VTE and mortality than a single center review; however, a multi-institutional analysis is needed to confirm our findings. Also, our study is a retrospective chart review, which poses its own limitations given variability in chart documentation. Additionally, as is the current standard of care in our institution, routine surveillance for VTE was not performed. Our VTE rates may represent an underestimation of the overall incidence of VTE in this patient population. As aforementioned, tiered anticoagulation protocols were implemented within the first month of COVID-19 hospitalizations in our state, which could have theoretically altered the normal pathophysiologic course of the virus and further underestimated the overall untreated incidence of VTE in patients with COVID-19. Well known risk factors for VTE such as history of malignancy, tobacco use, and cerebrovascular disease were not associated with increased rates of VTE in our cohort. This may in part be due to the early and aggressive implementation of anticoagulation protocols in our institution. In addition to VTE rates and the impact of VTE on mortality, our descriptive analysis also builds upon other important findings published in the current literature. Early studies at the beginning of the pandemic showed increased rates of COVID-19 infection, hospitalization, and death among patients of Black race [27, 28] . Our study demonstrates that Black patients appear to have disproportionately higher rates of incident VTE, as well. If Black patients with COVID-19 are more prone to VTE development and if there is an independent association between VTE and COVID-19 mortality, further investigation should be aimed toward determining if early anticoagulation strategies should be further refined to improve the management of high-risk subgroups who remain at disproportionately higher risk of negative sequelae or death with COVID-19 infection. Interestingly, while more patients of Black race developed VTE, Black race was not found to be independently associated with mortality when adjusting for other covariates of interest. Also of note, Hispanic/Latinx ethnicity was associated with decreased odds of mortality; however, the upper limit of the 95% confidence interval was 1.00 (odds ratio 0.45; 95% confidence interval: 0.21 to 1.00). Our study included only 258 patients who identified as Hispanic/Latinx, or 10.1% of the total study population. A larger sample size would improve our ability to discern if there is in fact an association between Hispanic/Latinx ethnicity and improved survival in this COVID-19 cohort. In conclusion, patients of Black race who are diagnosed with COVID-19 are more prone to VTE development and patients with COVID-19 who develop VTE during their hospital stay have nearly threefold increased odds of mortality. Further emphasis should be placed on understanding which COVID-19 patients are at increased risk of VTE development and, thus, developing models for prophylactic and therapeutic anticoagulation protocols as an effort to reduce mortality in this high-risk cohort. : Fig 1. 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