key: cord-0892786-aszmde46
authors: Case, Brian C.; Abramowitz, Jonathan; Shea, Corey; Rappaport, Hank; Medranda, Giorgio A.; Yerasi, Charan; Forrestal, Brian J.; Chezar-Azerrad, Chava; Zhang, Cheng; Satler, Lowell F.; Ben-Dor, Itsik; Hashim, Hayder; Rogers, Toby; Weintraub, William S.; Waksman, Ron
title: Comparison of Outcomes in Patients with COVID-19 and Thrombosis vs. Those Without Thrombosis: COVID-19 Patients with Thrombosis and Outcomes
date: 2021-08-28
journal: Am J Cardiol
DOI: 10.1016/j.amjcard.2021.08.038
sha: a41b31b690dc168ce676ceb876d12b78831d29c0
doc_id: 892786
cord_uid: aszmde46

Venous thromboembolism (VTE) in coronavirus disease 2019 (COVID-19) has been established. We sought to evaluate the clinical impact of thrombosis in COVID-19-positive patients over the span of the pandemic to date. We analyzed COVID-19-positive patients with the diagnosis of thrombosis who presented to the MedStar Health system (11 hospitals in Washington, DC, and Maryland) during the pandemic (March 1, 2020 – March 31, 2021). We compared clinical course and outcomes based on the presence or absence of thrombosis and then, specifically, cardiac thrombosis. The cohort included 11,537 COVID-19-positive admitted patients. Of these patients, 1,248 had non-cardiac thrombotic events and 1,009 had cardiac thrombosis (myocardial infarction) during their hospital admission. Of the non-cardiac thrombotic events, 562 (45.0%) were pulmonary embolism, 480 (38.5%) were deep venous thromboembolism, and 347 (27.8%) were stroke. In the thrombosis arm, the cohort's mean age was 64.5 ± 15.3 years, 53.3% were men, and a majority were African American (64.9%). Patients with thrombosis tended to be older, with more co-morbidities. In-hospital mortality was significantly higher (16.0%) in COVID-19-positive patients with concomitant thrombosis versus those without thrombosis (7.9%; p <0.001) but lower than in COVID-19-positive patients with cardiac thrombosis (24.7%; p <0.001). In conclusion, COVID-19 patients with thrombosis are at higher risk for in-hospital mortality. However, this prognosis is not as grim as cardiac thrombosis. Efforts should focus on early recognition, evaluation, and intensifying antithrombotic management of these patients.

Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in coronavirus disease 2019 (COVID- 19) , can develop cardiac damage 1,2 and the overall prevalence is high in hospitalized patients 3 . Furthermore, patients with known cardiovascular disease are at an increased risk of developing COVID-19, including in a more severe form 4 . Given these concerning findings, guidelines reinforced primary percutaneous coronary intervention as the standard of care for ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) in patients with high-risk features 5, 6 . In addition, the direct effects of the virus, as well as indirect effects of the infection, predispose these patients to thrombotic events. A combination of disseminated intravascular coagulation (DIC), along with the severe inflammatory response, critical illness, and underlying traditional risk factors may all predispose a patient to thrombotic events 7, 8 . Furthermore, therapies for treating COVID-19 may have adverse drug-drug interactions with antiplatelet agents and anticoagulants. In the present study, we describe our healthcare system's experience of COVID-19 patients with thrombosis (stroke and venous thromboembolism [VTE] ) as compared to COVID-19 patients without VTE in terms of characteristics and clinical outcomes. In addition, we compared these patients to COVID-19 patients with cardiac thrombosis (myocardial infarction).

We analyzed COVID-19-positive patients who presented to the MedStar Health system (11 hospitals in Washington, DC, and Maryland) during the pandemic era. The "pandemic era" was identified as March 1, 2020, through March 31, 2021. The positive test for the infection was based on polymerase chain reaction testing and the patient having respiratory symptoms and/or chest x-ray or computed tomography findings.

Evaluating for thromboembolism was not standardized and was at the discretion of the provider. Diagnosis was made by an imaging modality: lower extremity venous duplex for deep VTE and computed tomography or ventilation/perfusion lung scan for pulmonary embolism. The presence of D-dimer alone did not qualify as a diagnosis of VTE. For stroke, the diagnosis was made on the basis of clinical symptoms of a stroke and imaging modality. The final diagnosis, and inclusion in our analysis, was based on the hospital-stay International Classification of Diseases, Tenth Revision.

For the cardiac thrombosis cohort, patients were identified by the International Classification of Diseases, Tenth Revision, for the diagnosis of STEMI or NSTEMI. Next, the drawing of troponins was not standardized and was at the discretion of the provider. The troponin value recorded is the peak value during the hospitalization. In our analysis, we included cardiac troponin I (upper limit of normal 0.03 ng/mL) or high-sensitivity cardiac troponin (upper limit of normal 30 ng/mL), which are common troponin markers collected in our healthcare system that were used in all patients in this analysis. Investigators identified significant presence of troponin I as an elevation>1 ng/mL or high-sensitivity troponin >30 ng/mL. Baseline characteristics and co-morbidities were collected for all patients. In this analysis, co-morbidities were identified using International Classification of Diseases, Tenth

Revision. Laboratory data and use of ventilation were compared between the 2 groups. The primary endpoint was in-hospital mortality. The study was conducted in accordance with the Declaration of Helsinki and was approved by our institutional review board.

Descriptive statistics such as frequencies, means, and standard deviations were used to describe the study population. Student's t-test or analysis of variance was used to compare mean values of normally distributed data. Cox-regression methods was used to evaluate risk factors for the primary outcome. Two-tailed Fisher's exact test or chi-squared test was used to compare categorical variables. Odds ratio with respect to in-hospital mortality and ventilation requirement was estimated from a multivariate logistic regression. Statistical significance was considered to be a p-value <0.05. All analyses were done in SAS 9.4. One author (BCC) has full access to all the data in the study and takes full responsibility for its integrity and the data analysis.

This study included 11,537 COVID-19-positive admitted patients during the pandemic.

Of these patients, 1,248 (10.8%) had non-cardiac thrombosis (stroke or VTE) diagnosis during their hospital admission, and 1,009 (8.7%) had cardiac thrombosis (myocardial infarction). Of the non-cardiac thrombotic events, 562 (45.0%) were pulmonary embolism, 480 (38.5%) were deep VTE, and 347 (27.8%) were stroke. Baseline characteristics are displayed in Table 1 . In the thrombosis cohort, the majority of patients were men (53.3%) with a mean age of 64.5 ± 15.3 years. COVID-19 patients with thrombosis tended to have a higher rate of co-morbidities than COVID-19 patients without thrombosis. However, the rate of co-morbidities was lower than in patients with COVID-19 and cardiac thrombosis, except for prior history of stroke.

During their hospital admissions, white blood cell count, creatinine, C-reactive protein, lactate dehydrogenase, and ferritin were all significantly higher in the thrombosis cohort than in patients without thrombosis. However, these laboratory values, along with troponin and Nterminal-pro-hormone B-type natriuretic peptide, were significantly higher in the cardiac thrombosis arm than in the thrombosis cohort and no-thrombosis cohort. Laboratory data are displayed in Table 2 .

Our primary endpoint, in-hospital mortality (Figure 1 ), was significantly higher (16.0%) in COVID-19 patients with thrombosis than in those without a thrombotic event (7.9%; p<0.001) but was lower than in COVID-19-positive patients with cardiac thrombosis (24.7%, p <0.001).

With regard to our secondary endpoints, COVID-19-positive patients with thrombosis required ventilation (28.2%) at a higher rate than COVID-19 patients with cardiac thrombosis (26.8%) or those without thrombosis (9.7%). Primary and secondary endpoint data are displayed in Table 3 .

Finally, odds ratio with respect to in-hospital mortality (receiver operator characteristic curve 0.85) and ventilation requirement (receiver operator characteristic curve 0.84) was estimated from a multivariate logistic regression and results are in Table 4 .Thombosis versus no thrombosis appeared to be significant in terms of in-hospital mortality, while thrombosis versus no thrombosis, and then cardiac thrombosis versus non-cardiac thrombosis, appeared to be significant for ventilation requirement.

The primary findings of our analysis suggest that COVID-19-positive patients with concomitant thrombosis have a significantly increased risk of mortality as compared to COVID-19-positve patients without thrombosis, but not as high as COVID-19 patients with cardiac thrombosis. COVID-19 patients with thrombosis tended to require ventilation at a higher rate than patients with COVID-19 and cardiac thrombosis and those patients without any thrombosis.

There are multiple factors that contribute to a COVID-19 patient developing thrombosis.

First, patient risk factors include acute, critical illness, being bedridden, active infection/sepsis, underlying liver/kidney disease, or presence of a malignancy [9] [10] [11] [12] . In our analysis, co-morbidities were all significantly higher in the thrombosis cohort than in those patients without thrombosis.

Second, the infection itself results in an inflammatory response with lymphopenia, elevated fibrinogen and increased inflammatory markers/cytokines. Furthermore, SARS-CoV-2 infection leads to further superimposed infections 9, 13 . Again, these findings were demonstrated to be higher in our analysis with increased white blood cell count, creatinine, C-reactive protein, lactate dehydrogenase, and ferritin in the thrombosis arm. This reiterates the importance of checking these markers, as they may help predict outcomes and guide treatment.

The combination of patient risk factors, and the infection itself, results in intravascular coagulopathy leading to myocardial injury and pulmonary microthrombi. These abnormalities ultimately result in VTE, myocardial infarction, hyperinflammation, and, in some cases, disseminated intravascular coagulation 14, 15 . Furthermore, there is the concept of "thromboinflammation," which is thrombosis leading to more inflammatory activation. This phenomenon can be challenging to treat and has been seen in COVID-19 patients 16 . As outlined by our analysis, patients with thrombosis carry a worse prognosis than those patients without thrombosis. However, myocardial infarction in COVID-19 patients carried the worst prognosis.

One way to ensure favorable outcome is rapid disease awareness and early admission of the patient to the hospital for treatment therapy, especially with respect to anticoagulation and antithrombotic therapy. Throughout the course of the COVID-19 pandemic, treatment strategies have evolved significantly as guidelines have changed and clinical knowledge has improved. In the early stages of the pandemic, standard of care was initially supportive, including the use of supplemental oxygen, prone positioning 17,18 , conservative fluid management 19 , prophylactic antibiotics, management of co-morbidities, avoiding mechanical ventilation whenever possible, and a variety of antithrombotic management protocols. More recently, the use of corticosteroids, in particular dexamethasone, is recommended in COVID-19 patients who require supplemental oxygen or mechanical ventilation to decrease all-cause mortality 20, 21 . Other treatment strategies include convalescent plasma infusions 22 . Finally, in October 2020, the antiviral medication remdesivir received Emergency Use Authorization from the US Food and Drug Administration, as it was shown to be superior to placebo at reducing time to recovery in those hospitalized with COVID-19 23 , although more recent data on remdesivir may not support this finding as strongly 24 .

For patients hospitalized with COVD-19, pharmacological VTE prophylaxis should be initiated unless contraindicated. In addition, three large international clinical trials conducted by the National Institutes of Health suggest that full-dose anticoagulation improved outcomes for patients hospitalized with moderate COVID-19 (need for ventilation and reduction in mortality) 25 . This may be a treatment strategy for critically ill patients. Parenteral anticoagulation is recommended in most cases in which anticoagulant therapy is needed for known thrombotic disease. Unfractionated heparin can be used in the setting of anticipated procedures or in patients with deteriorating renal function. If no urgent procedures are anticipated, low-molecular-weight heparin is a reasonable alternative 26 .

Finally, our analysis has demonstrated that myocardial infarction in COVID-19 patients is a concern. Early in the pandemic, providers may have been more likely to regard elevated troponins as a marker of obstructive coronary artery disease and recommend angiography. Later There are limitations to our study. First, the analysis is retrospective and relies on International Classification of Diseases, Tenth Revision codes to identify the patient population.

Inclusion in our analysis depended only on a positive COVID-19 test and a diagnosis of a thrombotic event as reported by the provider. In addition, STEMI or NSTEMI patients' coronary angiographic findings were not fully captured in our analysis. Analysis of these data would have allowed us to more completely separate those with obstructive CAD from those with other etiologies of myocardial injury (e.g., myocarditis or stress-induced cardiomyopathy) 28 .Further, while we captured whether patients were diagnosed, we did not capture treatment strategy (pharmacological, mechanical, etc.). Finally, our data captured patients in the Mid-Atlantic region of the US, where the pandemic was most impactful in March and April 2020. Our findings may not represent the broader US outcome data.

In conclusion, our analysis suggests that COVID-19 patients with thrombosis are at higher risk for in-hospital mortality. However, this prognosis is not as grim as cardiac thrombosis. Efforts should focus on early recognition, evaluation, and intensifying care of these patients.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 

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Special acknowledgment to Jason Wermers for assistance in preparing this manuscript.