key: cord-278536-b4eyegx5
authors: Piazza, Gregory; Campia, Umberto; Hurwitz, Shelley; Snyder, Julia E.; Rizzo, Samantha M.; Pfeferman, Mariana B.; Morrison, Ruth B.; Leiva, Orly; Fanikos, John; Nauffal, Victor; Almarzooq, Zaid; Goldhaber, Samuel Z.
title: Registry of Arterial and Venous Thromboembolic Complications in Patients With COVID-19
date: 2020-11-03
journal: J Am Coll Cardiol
DOI: 10.1016/j.jacc.2020.08.070
sha: 
doc_id: 278536
cord_uid: b4eyegx5

BACKGROUND: Cardiovascular complications, including myocardial infarction, ischemic stroke, and pulmonary embolism, represent an important source of adverse outcomes in coronavirus disease-2019 (COVID-19). OBJECTIVES: To assess the frequency of arterial and venous thromboembolic disease, risk factors, prevention and management patterns, and outcomes in patients with COVID-19, the authors designed a multicenter, observational cohort study. METHODS: We analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through our Mass General Brigham integrated health network. The total cohort was analyzed by site of care: intensive care (n = 170); hospitalized nonintensive care (n = 229); and outpatient (n = 715). The primary study outcome was a composite of adjudicated major arterial or venous thromboembolism. RESULTS: Patients with COVID-19 were 22.3% Hispanic/Latinx and 44.2% non-White. Cardiovascular risk factors of hypertension (35.8%), hyperlipidemia (28.6%), and diabetes (18.0%) were common. Prophylactic anticoagulation was prescribed in 89.4% of patients with COVID-19 in the intensive care cohort and 84.7% of those in the hospitalized nonintensive care setting. Frequencies of major arterial or venous thromboembolism, major cardiovascular adverse events, and symptomatic venous thromboembolism were highest in the intensive care cohort (35.3%, 45.9%, and 27.0 %, respectively) followed by the hospitalized nonintensive care cohort (2.6%, 6.1%, and 2.2%, respectively) and the outpatient cohort (0% for all). CONCLUSIONS: Major arterial or venous thromboembolism, major adverse cardiovascular events, and symptomatic venous thromboembolism occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high utilization rate of thromboprophylaxis.

C oronavirus disease-2019 (COVID- 19) , caused by severe acute respiratory syndrome-coronavirus-2, has emerged as a devastating global public health crisis. Whereas the morbidity and mortality associated with COVID-19 are usually attributed to acute respiratory distress syndrome (ARDS) and end-organ failure, cardiovascular complications, including myocardial infarction (MI), ischemic stroke, and pulmonary embolism (PE), also cause disability and death in these patients (1) (2) (3) . An increased frequency of arterial and venous thrombosis was observed early in the COVID-19 pandemic and has been attributed to systemic inflammation, immobility, and a prothrombotic milieu (4, 5) . Venous thromboembolism (VTE) is now recognized as among the predominant cardiovascular hazards in patients with COVID-19 (4, (6) (7) (8) (9) (10) . The frequency of VTE is highest in the intensive care unit (ICU) setting and has ranged from 25%, when symptomatic disease is considered, to 69%, when surveillance venous ultrasonography is performed (4, (6) (7) (8) . A high prevalence of in situ microthrombosis suspected to be due to endothelial injury from direct viral infection has also been described (11) (12) (13) . Quantifying the risk of cardiovascular complications in the heterogeneous population of patients with COVID-19 has been hampered by reports of limited sample size, restriction of assessments to the ICU setting, variable outcome definitions, and differing thromboprophylaxis patterns. Antithrombotic therapy has been recommended for hospitalized patients with to prevent thromboembolic cardiovascular events (1, (14) (15) (16) ; however, a subset of patients appears to experience arterial and venous events despite standard thromboprophylaxis.

To assess frequency of arterial and venous throm- Thromboembolism in COVID-19

The study population was analyzed as a total cohort Figure 1 ). All-cause 30-day mortality was 5.7% in the overall cohort of patients with COVID-19. The most frequent cause of death was Values are n (%), median (interquartile range), or mean AE SD. Dashes indicate data were not available. *Patient was a resident at an assisted living facility and was diagnosed with COVID-19 as an outpatient. When she developed ARDS, she was transitioned to palliative care without hospitalization. †Patient experienced acute respiratory failure while hospitalized in the non-intensive care setting, was initiated on mechanical ventilation, but was ultimately transitioned to comfort measures. ‡Patient presented to the emergency department with hypotension that resolved with intravenous fluid. §Laboratory reference values: LDH ¼ 110 to 210 U/l; lactate ¼ 0.5 to 2.0 mmol/l; NT-proBNP ¼ 0 to 1,800 pg/ml; high-sensitivity cardiac troponin T ¼ 0 to 9 ng/l; D-dimer < 500 ng/ml; high-sensitivity CRP ¼ 0 to 3 mg/l; high-sensitivity IL-6 < 5.00 pg/ml. Tables 1 and 2 . Among patients with COVID-19 in the hospitalized non-ICU cohort, the frequency of death at 30 days was 6.7%. All deaths occurred during the hospitalization, and 80% were due to sepsis.

OUTPATIENTS WITH COVID-19. The mean age was 44.8 years in 715 patients with COVID-19 who were not hospitalized ( Table 1) . Patients with COVID-19 in the outpatient cohort were more likely to be female (60.6%), and were 18.6% Hispanic/Latinx and 43.1% non-White. Cardiovascular risk factors of hypertension (24.5%), hyperlipidemia (20.8%), and diabetes (9.4%) were common ( Table 2) . The most common symptoms of COVID-19 were cough (72.2%), fever (64.3%), and myalgias (54.7%) ( Table 3) . COVID-19associated pneumonia was the most common complication (37.8%). Prophylactic anticoagulation was rare in the outpatient cohort. The outpatient cohort had a low risk of major arterial or VTE events, major adverse cardiovascular events, and symptomatic VTE ( ¼ 170) . Among those admitted to the non-ICU setting (n ¼ 229), the frequency of major arterial or venous thromboembolism, major adverse cardiovascular events, and symptomatic VTE was also elevated but lower than for those with critical illness. The increased frequency of thromboembolic complications occurred in the context of a relative high rate of thromboprophylaxis prescription. Outpatients (n ¼ 715) were considered to be low risk for major arterial or venous thromboembolism, major adverse cardiovascular events, and symptomatic VTE.

Piazza et al. Although we obtained 30-day follow-up data on 96% of subjects in the total study population, we were unable to obtain follow-up for 40 outpatients, and, therefore, we are likely to have underestimated 30-day outcomes in this cohort. We were also unable to assess microvascular thrombosis, particularly in the pulmonary circulation, which has emerged as an important concern in COVID-19. We were not able to obtain data regarding medication adherence to antiplatelet, antithrombotic, statin, and insulin therapy prior to the diagnosis of COVID-19. We were also unable to determine the rationale for omission of thromboprophylaxis. Finally, a limited sample size precluded more extensive statistical assessment of less frequent cardiovascular complications and development of larger multivariable models. We anticipate a greater ability to discern important associations with subsequent analyses of this rapidly growing registry. 

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