key: cord-0900624-cx2urenk authors: Thoppil, Joby J.; Courtney, D. Mark; McDonald, Samuel; Kabrhel, Christopher; Nordenholz, Kristen E.; Camargo, Carlos A.; Kline, Jeffrey A. title: SARS-CoV-2 positivity in ambulatory symptomatic patients is not associated with increased venous or arterial thrombotic events in the subsequent thirty days date: 2022-01-17 journal: J Emerg Med DOI: 10.1016/j.jemermed.2021.12.020 sha: ed88208ea8c37b4c71ca48e7863a43cd5fc6da25 doc_id: 900624 cord_uid: cx2urenk Background COVID-19 has been associated with increased risk of thromboembolism in critically ill patients. Objectives We sought to examine the association of SARS-CoV-2 test positivity and subsequent acute vascular thrombosis, including venous thromboembolism (VTE) or arterial thrombosis (AT) in, a large nationwide registry of emergency department patients tested with a nucleic acid test for suspected SARS-CoV-2. Methods The RECOVER registry includes 155 emergency departments across the US. We performed a retrospective cohort study to produce odds ratios for COVID+ versus COVID- status as a predictor of 30 day VTE or AT, adjusting for age, biological sex, active cancer, intubation, hospital length of stay (LOS), and ICU care. Results Comparing 14,056 COVID+ patients with 12,995 COVID- patients, the overall 30-day prevalence of VTE events was 1.4% versus 1.3%, respectively (p=0.44, χ2). Multivariable analysis identified that testing positive for SAR-CoV-2 status was negatively associated with both VTE (OR 0.76, 95% CI: 0.61-0.94) and AT (0.51, 0.32-0.80), whereas intubation, ICU care, and age>=50 were positively associated with both VTE and AT. Conclusions In contrast to other reports, results from this large, heterogenous national sample of ED patients tested for SARS-CoV-2, showed no association between vascular thrombosis and COVID-19 test positivity. reports of the frequency of VTE was from hospitalized and ICU-level patients, or from autopsies. (2-4) (5) (6) In contrast to the above studies, a retrospective study performed across a multi-hospital health system in New York found the incidence of VTE in hospitalized patients to be as 1.09%. (7) Similarly, Cohen et. al. found a VTE rate in admitted patients of 2.9% and 4.9% in the ICU. (8) A retrospective cohort study of over 220,000 patients from Northern California tested for SARS-CoV-2 over a similar time as our study demonstrated an incidence of VTE of 0.8% in patients who tested positive for COVID. The authors also found the incidence of VTE increased with hospitalization as compared to those patients treated as an outpatient (4.8% vs 1.8%) (9). reporting no increased probability of PE diagnosis in COVID+ patients. (10) These more recent studies are similar in that they included patients with varying levels of illness (1, 2, 5, (7) (8) (9) (10) (11) (12) (13) . Fewer studies have reported on arterial thrombosis (AT) in acute COVID illness. Malas et al. identified 8 studies reporting increased risk of AT. (4) The overall AT rate within COVID+ patients was 2% and 5% in the ICU in their report which pooled myocardial infarction, cerebrovascular accidents, or acute limb ischemia as AT events. (4) Early signals from small studies in New York (14) and Wuhan (15) have reported acute ischemic stroke in context of hospitalized COVID positive patients. Reports from other groups are similar with a reported occurrence of stroke between 2.7% and 3.8% of patients. (4, 11) The published literature to date has focused on the incidence of thromboembolism in hospitalized and/or critically ill patients, however, the majority of people who carry the burden of acute COVID-19 infection globally are outpatients. Analysis of thromboembolic risk has focused mainly on specific cohorts of hospitalized COVID-19 patients and has not taken into account ambulatory COVID-19 patients with mild disease, which may have overestimated overall thromboembolic risk. (16) Therefore, we sought to examine the risk of vascular thrombosis (VTE and AT) in a large nationwide sample of COVID tested US ED patients. The REgistry of potential COVID-19 in Emergency Care (RECOVER) is a large observational clinical study of patients from 155 United States emergency departments (EDs) across 27 states. (17) Eligible subjects included ED patients with a SARS-COV-2 test during or 14 days prior to the index visit, from March -September 2020. The index visit from which data were abstracted came from the first ED visit that occurred within 14 days of SARS-COV-2 testing unless meeting specific exclusions (17) Exclusions included predefined circumstances where there was a lack of reasonable probability of being related to COVID-19 infection: (1) trauma, (2) alcohol or drug intoxication, (3) poisoning, (4) suicidality, (5) suspected rape or other domestic violence, (6) involuntary commitment, (7) other isolated chief complaints clearly not related to COVID-19 (e.g., suture removal), and (8) testing done purely for policy (e.g., any admitted patient), rather than testing based on clinical suspicion. Patients were enrolled from March-September 2020 with intent to enroll eligible patients consecutively. COVID+ disease status required a positive molecular reverse transcription polymerase chain reaction test performed on a nasopharyngeal swab, or positive serum antibody titer for SARS-CoV-2 within 30 days; all others were considered COVID negative. (17) Presenting symptoms and risk factors for all tested patients can be found in Table 1 of the protocol methodology already published. Initial unadjusted analysis of risk for VTE and AT outcomes based upon COVID status was tested with Chi-square analysis and univariate odds ratios with 95% confidence intervals. Subsequently, two multivariable logistic regression models were constructed (one for VTE one for AT) investigating COVID test status with adjustment for: age, biological sex, active cancer diagnosis at time of index visit, intubation, hospital length of stay (if admitted to hospital), and intensive care unit (ICU) stay within 30-days of index visit. Calculation of frequencies, Chi square values, unadjusted odds ratios, and multivariable logistic regression odds ratios were performed using SPSS. Though this was a registry where there was no a priori sample size calculation for this sub-analysis, we did a rough post-hoc estimate of power prior to the data analysis of this report. A sample size of 20,000 and a 50% positive rate for COVID, and 10% prevalence of VTE, allowed for adequate power to detect a minimum 0.8% difference in 30-day frequency of VTE and AT rates, based upon COVID status and 95% confidence interval testing. A 5% prevalence of VTE with similar sample size would allow for adequate power to detect a minimium 0.6% difference. As of December 2020, the registry contained 27,051 patients, including 14,056 cases who were COVID+ and 12,995 patients who were COVID-. The mean age was slightly older in the (Table 4 ) We then plotted incidence of VTE and AT against the WHO severity index in all tested patients. Incidence plots of VTE illustrate a trend of higher incidence of VTE in the severe disease category regardless of COVID status. (Figure 1A ) Incidence of plots of AT reveal a lower incidence of AT in Sars-CoV-2+ patients as compared to negative patients in all disease indices. CoV-2+ patients only and stratified the presence of VTE based on disease status and age deciles. As expected, frequency of VTE increased with age and disease severity similar to our multivariable analyses. (Figure 1C ). The results of this study did not find an increased risk of vascular thrombosis among COVID positive patients in this large, heterogenous nationwide sample of persons undergoing testing in the US acute care setting. After adjusting for variables commonly associated with VTE risk, COVID+ status was found to be negatively associated with the outcome of VTE. This was true despite the COVID+ cohort being 8 years older on average than the COVID-group. The findings of this study may impact care on several levels. First, the data emphasize the lack of evidence for empiric anticoagulation among non-critically ill patients with COVID+. Second, the data do not support efforts to perform routine diagnostic testing for vascular thrombosis shortly after COVID diagnosis. Third, this work provides justification for language that reassures non-critically ill COVID+ patients that they have a low risk of clotting. This study is unique in that it examines a large sample of emergency department patients with varying degrees of illness over a period of 7 months in both COVID+ and COVID-samples, allowing internal risk ratio estimations. Although a few papers have reported similar low risk of VTE after COVID diagnosis (8-10), these findings are in contrast to a majority of prior reports of increased VTE risk. (2-6, 13) Prior reports were retrospective studies of highly selected, small cohorts. (2) (3) (4) (5) (6) 13) The studies were early in the pandemic, possibly biased toward representing the severe spectrum of disease, and had short duration of follow up, different geographic locations, and lack of reference negative disease status. The findings from the adjusted model suggests a multifactorial, canonical explanation for the development of clinically evident vascular thrombosis in COVID+ patients. As could be expected from prior knowledge, the multivariable model in Table 2 showed that advanced age, cancer and immobility (associated with either intubation, the need for intensive care, or longer hospital length of stay) increased risk of VTE, whereas COVID+ status reduced risk. (16, 19, 20) With the exception of cancer and length of stay, Table 3 shows the same pattern for AT, including COVID+ status associated with significant risk reduction. These data provide a more comprehensive, quantitative assessment of vascular thrombosis risk in ambulatory COVID+ patients. (21) In our sample, only 15% of patients with COVID+ required intensive care, compared with higher rates in prior reports. (22) In a systematic review of four prospective studies objectively confirmed deep-vein thrombosis (DVT) rates varied from 13 to 31% in the ICU. (23) In one study, the rate of AT in all ICU patients approached 2%. (24) The obvious confounding effect is that severe COVID-19 infection is associated with intensive care which carries its own inherent risk of VTE from prolonged immobilization, indwelling central venous catheters, and hypoxemia. (16, 19, 20, 25) These studies, taken together with the present findings, suggest that critical illness alone is a primary determinant of vascular thrombosis in COVID+ patients, and therefore could inherently bias and inflate the prevalence of VTE and AT in COVID+ patients when no COVID-reference sample is included in analysis. The finding of a significant negative association between SARS-CoV-2 status and the development of vascular thrombosis on multivariable adjusted analysis was not an expected finding and could reflect an unmeasured potential confounding variable. However, this possibility is low, inasmuch as the E-value analysis (26, 27) for both VTE and AT revealed Evalues of 1.98 and 3.33, respectively. This would suggest a variable with an association as large as 1.98 for VTE and 3.33 for AT would be required to explain away the negative associations identified in this study. Because the majority of patients were ambulatory, the difference is probably not explained by antithrombotic treatment, nor by surveillance bias. One explanatory hypothesis centers on the development of a specific adaptive host response to SARS-CoV-2. In the normal host response to viral mediated sepsis, the coagulation cascade is activated to function as a host defense to limit the spread of virus. Many enveloped viruses in turn adapted to promote their own virulence by expressing host proteins that activate the coagulation cascade such as tissue factor (TF). SARS-CoV-2 and HSV have both been demonstrated to express TF on their viral capsid to increase infectivity. (28) (29) (30) Therefore, if the host response had previously adapted to prior non-SARS-CoV-2 coronavirus infection, this partial immunity could limit the activation of coagulation cascades as a means to combat infectivity of SARS-CoV-2. Further study is required to understand the pathophysiology of SARS-CoV-2 infection. The implication of high VTE incidence in COVID infection in early studies (1, 2, 5, 11) , raised the question of whether benefit of prophylactic anticoagulation outweighed the bleeding risk of anticoagulant therapy in critically ill patients. As a result, there was a call for clinical trials to evaluate the efficacy of prophylactic anticoagulation with patient outcomes in COVID disease. (2, 4, 31) In a retrospective cohort study of hospitalized patients, Cohen et. al. found that the use of prophylactic-dose anticoagulation, but not treatment-dose anticoagulation was associated with reduced VTE and mortality. (8) These findings suggest that standard of care prophylaxis in hospitalized patients is enough to reduce incidence of VTE, even in a COVID+ disease state. Ongoing randomized trials, ACTIV-4 and the COVID-19 outpatient thrombosis prevention trial, will only truly be able to determine whether prophylactic anticoagulation is associated with improved patient outcomes. Our study design was limited to the data collected retrospectively by the RECOVER registry. The sample is geographically, racially and ethnically diverse. The registry was restricted to ED patients who received SARS-CoV-2 diagnostic testing and we found the overall COVID disease prevalence during the seven-month period of data collection to approximate 50%. All patients deemed COVID-had a negative result of at least one RT-PCR test on a nasopharyngeal swab on the day of ED visit, and no evidence of infection for the subsequent 30 days. Thus, asymptomatic COVID patients or patients who were given a clinical diagnosis and who appeared well and therefore not tested and discharged from the ED were not included. Therefore, our findings cannot be generalized to asymptomatic or untested patients. We did not adjust for hierarchal effect by hospital because proportional numbers of patients were enrolled from each site by protocol. Another limitation is the potentially limited diagnostic sensitivity of molecular testing, making it possible that some small number of patients may have been misclassified with respect to COVID status. (32) Furthermore, at least early in the pandemic there was a selection bias due to limited testing capabilities. Molecular testing, however, is the most used and accurate test for disease status in reports and clinical care. (32) The electronic surveillance used in this study only considered those patients that had presented again to the same hospital system or to a hospital system sharing the same electronic medical record (EMR) e.g., EPIC, of the parent hospital system and therefore may miss those patients that may have presented to another hospital system not encompassed by the parent EMR or a rare outcome such as death. In conclusion, results from a national sample show no evidence of increased risk of vascular thrombosis associated with COVID-19 in a large, heterogenous sample of patients. Our study raises questions on the need for empirical anticoagulation in patients diagnosed with SARS-CoV-2 that currently underway randomnized clinical trial will be better suited to answer. Early pandemic data and literature have implicated an association of COVID-19 infection with increased risk of vascular thrombosis i.e., deep venous thrombosis, pulmonary embolism, stroke, myocardial infarction, etc. This has implications for possible prophylactic treatment to prevent the development of vascular thrombosis. This study attempts to indentify whether SARS-CoV-2 test positivity is associated with increased risk of vascular thrombosis. In contrast to the large body of literature, we found that COVID-19 illness alone is not associated with increased embolic risk. Consistent with the literature, age and critical illness in SARS-CoV-2 infected patients is more associated with embolic risk. How is patient care impacted? 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