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Comparison of Outcomes in Patients With COVID-19 and Thrombosis Versus Those Without Thrombosis

      The occurrence of venous thromboembolisms in patients with COVID-19 has been established. We sought to evaluate the clinical impact of thrombosis in patients with COVID-19 over the span of the pandemic to date. We analyzed patients with COVID-19 with a diagnosis of thrombosis who presented to the MedStar Health system (11 hospitals in Washington, District of Columbia, and Maryland) during the pandemic (March 1, 2020, to March 31, 2021). We compared the clinical course and outcomes based on the presence or absence of thrombosis and then, specifically, the presence of cardiac thrombosis. The cohort included 11,537 patients who were admitted for COVID-19. Of these patients, 1,248 had noncardiac thrombotic events and 1,009 had cardiac thrombosis (myocardial infarction) during their hospital admission. Of the noncardiac thrombotic events, 562 (45.0%) were pulmonary embolisms, 480 (38.5%) were deep venous thromboembolisms, and 347 (27.8%) were strokes. In the thrombosis arm, the mean age of the cohort was 64.5 ± 15.3 years, 53.3% were men, and the majority were African-American (64.9%). Patients with thrombosis tended to be older with more co-morbidities. The in-hospital mortality rate was significantly higher (16.0%) in patients with COVID-19 with concomitant non-cardiac thrombosis than in those without thrombosis (7.9%, p <0.001) but lower than in patients with COVID-19 with cardiac thrombosis (24.7%, p <0.001). In conclusion, patients with COVID-19 with thrombosis, especially cardiac thrombosis, are at higher risk for in-hospital mortality. However, this prognosis is not as grim as for patients with COVID-19 and cardiac thrombosis. Efforts should be focused on early recognition, evaluation, and intensifying antithrombotic management for these patients.
      Patients infected with SARS-CoV-2, which causes COVID-19, can develop cardiac damage,
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      In addition, the direct effects of the virus and the indirect effects of the infection predispose these patients to thrombotic events. A combination of the disseminated intravascular coagulation and the severe inflammatory response, critical illness, and underlying traditional risk factors may all predispose a patient to thrombotic events.
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      Furthermore, therapies for treating COVID-19 may have adverse drug-drug interactions with antiplatelet agents and anticoagulants. In the present study, we describe our health care system's experience with COVID-19 patients with thrombosis (stroke and venous thromboembolism [VTE]) in comparison with patients with COVID-19 without VTE in terms of characteristics and clinical outcomes. In addition, we compared these patients with patients with COVID-19 with cardiac thrombosis (myocardial infarction).

      Methods

      We analyzed patients with COVID-19 who presented to the MedStar Health system (11 hospitals in Washington, District of Columbia, and Maryland) during the pandemic era. The pandemic era was identified as the period from March 1, 2020, through March 31, 2021. A positive test result for the infection was based on polymerase chain reaction testing and the patient presenting with respiratory symptoms and/or having chest x-ray or computed tomography findings.
      Evaluating for a thromboembolism was not standardized and was done at the discretion of the provider. A diagnosis was made by an imaging modality, including lower-extremity venous duplex for deep VTE and computed tomography or ventilation or perfusion lung scan for a 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 supported by an imaging modality. The final diagnosis and inclusion in our analysis was based on the hospital-stay International Classification of Diseases, Tenth Revision (ICD-10).
      For the cardiac thrombosis cohort, patients were identified by the ICD-10 codes for the diagnosis of STEMI or NSTEMI. Next, the measurement of troponin levels was not standardized and was conducted at the discretion of the provider. The troponin value that was recorded is the peak level measured during the hospitalization. In our analysis, we included cardiac troponin I (upper limit of normal of 0.03 ng/ml) or high-sensitivity cardiac troponin (upper limit of normal of 30 ng/ml), which are common troponin markers collected in our health care system that were measured for 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.
      The baseline characteristics and co-morbidities were collected for all patients. In this analysis, co-morbidities were identified using the ICD-10 codes. Laboratory data and the use of ventilation were compared between the 2 groups. The primary end point 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 SDs were used to describe the study population. Student t test or analysis of variance was used to compare the mean values of normally distributed data. Cox-regression method was used to evaluate risk factors for the primary outcome. Two-tailed Fisher's exact test or chi-square test was used to compare categorical variables. The odds ratio for in-hospital mortality and ventilation requirement was estimated from a multivariate logistic regression. Statistical significance was considered to be p <0.05. All analyses were done in SAS version 9.4 (SAS Institute, Cary, North Carolina). One author (B.C.C.) has full access to all the data in the study and takes full responsibility for its integrity and the data analysis.

      Results

      This study included 11,537 patients with COVID-19 who were admitted during the pandemic. Of these patients, 1,248 (10.8%) had noncardiac thrombotic events (stroke or VTE) during their hospital admission and 1,009 (8.7%) had cardiac thrombosis (myocardial infarction). Of the noncardiac thrombotic events, 562 (45.0%) were pulmonary embolisms, 480 (38.5%) were deep VTEs, and 347 (27.8%) were strokes. The baseline characteristics are displayed in Table 1. In the non-cardiac thrombosis cohort, the majority of patients were men (53.3%) with a mean age of 64.5 ± 15.3 years. Patients with COVID-19 with non-cardiac thrombosis tended to have a higher rate of co-morbidities than patients with COVID-19 without thrombosis. However, the rate of co-morbidities in the non-cardiac thrombosis cohort was lower than in patients with COVID-19 with cardiac thrombosis, except for those with a history of stroke.
      Table 1Baseline characteristics of patients with COVID-19 overall, thrombosis present, cardiac thrombosis only, and those without thrombosis
      Overall (N = 11,537)Non-Cardiac Thrombosis
      Venothromboembolism and Pulmonary Embolism.
      (N = 1,248)
      Cardiac Thrombosis
      ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction.
      (N = 1,009)
      No Thrombosis (N = 9,280)p Value
      Demographics
       Age ± SD (years)61.21 +/- 17.6864.48 +/- 15.3470.2 +/- 14.0859.79 +/- 17.98<0.001
       Male48.7%53.3%53.4%47.65<0.001
      Ethnicity
       White26.3%24.5%26.9%26.5%0.294
       Black58.0%64.9%64.5%56.4%<0.001
       Asian1.3%0.9%1.5%1.4%0.350
       Native American0.2%0.0%0.1%0.2%0.157
       Other14.1%9.7%6.9%15.5%<0.001
      Co-Morbidities
       Active malignancy8.0%9.5%9.7%7.6%0.008
       Heart disease27.3%33.3%64.3%22.4%<0.001
       Diabetes mellitus33.8%45.5%35.0%32.4%<0.001
       Kidney disease8.9%9.4%20.2%7.7%<0.001
       Liver disease4.1%5.3%5.9%3.7%<0.001
       Lung disease36.7%34.2%47.1%35.9%<0.001
      low asterisk Venothromboembolism and Pulmonary Embolism.
      low asterisk ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction.
      During their hospital admissions, the white blood cell count and concentration of creatinine, C-reactive protein, lactate dehydrogenase, and ferritin were significantly higher in patients with thrombosis than in patients without thrombosis. However, these laboratory values and those of troponin and N-terminal prohormone B-type natriuretic peptide were significantly higher in the cardiac thrombosis arm than in the non-cardiac thrombosis and no-thrombosis cohorts. Laboratory data are displayed in Table 2.
      Table 2Laboratory data of patients with COVID-19 overall, thrombosis present, cardiac thrombosis only, and those without thrombosis
      VariableOverall (N = 11,537)Non-Cardiac Thrombosis
      Venothromboembolism and Pulmonary Embolism.
      (N = 1,248)
      Cardiac Thrombosis
      ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction.
      (N = 1,009)
      No Thrombosis (N = 9,280)p Value
      Maximum troponin-I (ng/mL)0.59 +/- 6.320.64 +/- 4.974.1 +/- 17.420.09 +/- 1.63<0.001
      Maximum high-sensitivity troponin (ng/mL)310.7 +/- 2824.62784.65 +/- 5604.181,590.25 +/- 6145.0377.93 +/- 539.01<0.001
      N-terminal-pro-hormone BNP (ng/L)5,321.95 +/- 20,010.594,754.7 +/- 14,685.1515,151.82 +/- 34,976.653,630.63 +/- 16,015.69<0.001
      Maximum creatinine (mg/dL)2.08 +/- 2.52.5 +/- 2.713.51 +/- 3.621.88 +/- 2.27<0.001
      Maximum white blood cell (K/µL)8.94 +/- 8.8810.2 +/- 6.6210.17 +/- 8.838.68 +/- 9.09<0.001
      C-reactive protein (mg/dL)69.89 +/- 54.4278.68 +/- 54.2285.4 +/- 61.5 (394)67.04 +/- 53.18 (<0.001
      Lactate dehydrogenase (U/L)420.73 +/- 299.6420.73 +/- 299.6553.76 +/- 538.32397.74 +/- 247.57<0.001
      Ferritin (ng/mL)1,071.99 +/- 2,409.211,337.77 +/- 2,456.671,967.09 +/- 4,165.481,967.09 +/- 4,165.48<0.001
      BNP = B-type natriuretic peptide.
      low asterisk Venothromboembolism and Pulmonary Embolism.
      low asterisk ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction.
      Our primary end point, in-hospital mortality (Figure 1), was significantly higher (16.0%) in patients with COVID-19 with non-cardiac thrombosis than in those without a thrombotic event (7.9%, p <0.001) but was lower than in patients with COVID-19 with cardiac thrombosis (24.7%, p <0.001). With regard to our secondary end points, patients with COVID-19 with non-cardiac thrombosis required ventilation (28.2%) at a higher rate than patients with COVID-19 with cardiac thrombosis (26.8%) or those without thrombosis (9.7%). Primary and secondary end point data are displayed in Table 3.
      Figure 1
      Figure 1Overall in-hospital outcomes for patients with COVID-19, those with thrombosis present, with cardiac thrombosis only, and those without thrombosis.
      Table 3Primary and secondary outcomes. In-hospital mortality and ventilator requirement of patients with COVID-19 during the pandemic era overall, with thrombosis present, cardiac thrombosis only, and those without thrombosis
      VariableOverall (N = 11,537)Non-Cardiac Thrombosis
      Venothromboembolism and Pulmonary Embolism.
      (N = 1,248)
      Cardiac Thrombosis
      ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction.
      (N = 1,009)
      No Thrombosis (N = 9,280)p Value
      Overall In-Hospital Mortality10.2%16.0%24.7%7.9%<0.001
      Ventilator Requirement13.2%28.2%26.8%9.7%<0.001
      low asterisk Venothromboembolism and Pulmonary Embolism.
      low asterisk ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction.
      Finally, the odds ratio for in-hospital mortality (area under the receiver operator characteristic curve of 0.85) and ventilation requirement (area under the receiver operator characteristic curve of 0.84) was estimated from a multivariate logistic regression and the results are presented in Table 4. Thrombosis versus no thrombosis appeared to be significant for in-hospital mortality, whereas thrombosis versus no thrombosis and then cardiac thrombosis versus noncardiac thrombosis appeared to be significant for ventilation requirement.
      Table 4Adjusted in-hospital mortality in patients with COVID-19. Adjusted odds ratios of thrombosis versus no thrombosis and cardiac thrombosis versus non-cardiac thrombosis, adjusting for inflammatory markers
      In-hospital mortalityOdds Ratio95% confidence interval
      Thrombosis versus no thrombosis0.680.50 – 0.93
      Cardiac thrombosis versus non-cardiac thrombosis1.190.80 – 1.77
      Creatinine1.081.04 – 1.11
      C-reactive protein1.011.01 – 1.01
      Lactate dDehydrogenase1.001.00 – 1.00
      Ferritin1.001.00 – 1.00
      Ventilation requirementOdds Ratio95% Confidence Interval
      Thrombosis versus no thrombosis0.320.25 – 0.42
      Cardiac thrombosis versus non-cardiac thrombosis0.630.44 – 0.89
      Creatinine1.101.07 – 1.14
      C-reactive protein1.011.04 – 1.08
      Lactate dehydrogenase1.001.00 -1.00
      Ferritin1.001.00 – 1.00

      Discussion

      The primary findings of our analysis suggest that patients with COVID-19 with concomitant non-cardiac thrombosis have a significantly increased risk of mortality when compared with patients with COVID-19 without thrombosis but not as high of a risk as patients with COVID-19 with cardiac thrombosis. Patients with COVID-19 with non-cardiac thrombosis tended to require ventilation at a higher rate than patients with COVID-19 with cardiac thrombosis and those without any thrombosis.
      There are multiple factors that contribute to the development of thrombosis in patients with COVID-19. First, patient risk factors include acute critical illness, being bedridden, active infection or sepsis, underlying liver or kidney disease, or the presence of a malignancy.
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      • Balekian AA
      • Klein RC
      • Le H
      • Schulman S
      • Murad MH
      Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      Finally, our analysis demonstrates that myocardial infarction in patients with COVID-19 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 an angiography. Later in the pandemic, providers may have been aware of the increasing evidence that troponin elevations are seen in patients with COVID-19 without obstructive coronary artery disease and, thus, chose to forgo invasive testing. Particular attention has been directed toward the management of acute coronary syndrome during the COVID-19 pandemic. In patients with STEMI or NSTEMI with high-risk features in which the etiology of their acute myocardial infarction is suspected to be true plaque rupture and not myocarditis or stress-induced cardiomyopathy in the setting of SARS-CoV-2 infection, our cardiac catheterization laboratory implemented procedures to ensure the safety of medical personnel during primary percutaneous coronary intervention. Per the guidelines recommended by the American College of Cardiology's Intervention Council and the Society for Cardiovascular Angiography and Interventions,
      • Welt FGP
      • Shah PB
      • Aronow HD
      • Bortnick AE
      • Henry TD
      • Sherwood MW
      • Young MN
      • Davidson LJ
      • Kadavath S
      • Mahmud E
      • Kirtane AJ
      American College of Cardiology's Interventional Council, Society for Cardiovascular Angiography Interventions
      Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from the ACC's interventional council and SCAI.
      we trained everyone in the catheterization laboratory on proper personal protective equipment use, designated 1 laboratory for patients with COVID-19 or those who were under investigation, and performed extensive cleaning after each procedure. We also implemented new treatment and risk stratification algorithms, utilizing noninvasive diagnostic testing such as echocardiography and cardiac magnetic resonance imaging in patients with low-risk features, to ensure that only high-risk patients with COVID-19 with suspected plaque rupture were brought to the catheterization laboratory.
      • Yerasi C
      • Case BC
      • Forrestal BJ
      • Chezar-Azerrad C
      • Hashim H
      • Ben-Dor I
      • Satler LF
      • Mintz GS
      • Waksman R
      Treatment of ST-segment elevation myocardial infarction During COVID-19 pandemic.
      There are limitations to our study. First, the analysis is retrospective and relies on the ICD-10 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 completely separate those with obstructive coronary artery disease from those with other etiologies of myocardial injury (e.g., myocarditis or stress-induced cardiomyopathy).
      • Khalid N
      • Chen Y
      • Case BC
      • Shlofmitz E
      • Wermers JP
      • Rogers T
      • Ben-Dor I
      • Waksman R
      COVID-19 (SARS-CoV-2) and the heart - an ominous association.
      Furthermore, although we captured whether patients were diagnosed, we did not capture the treatment strategy (pharmacologic, mechanical, and so on). Finally, our data captured patients in the Mid-Atlantic region of the United States where the pandemic had the greatest impact in March 2020 and April 2020. Our findings may not represent the broader United States outcome data.
      In conclusion, our analysis suggests that patients with COVID-19 with non-cardiac thrombosis are at higher risk for in-hospital mortality. However, this prognosis is not as grim as for patients with cardiac thrombosis. Efforts should focus on early recognition, evaluation, and intensifying care of these patients.

      Disclosures

      Dr. Rogers reports serving as a proctor and consultant for Medtronic and Edwards Lifesciences, serving on the advisory board for Medtronic, and holding equity interest in Transmural Systems. Dr. Waksman reports serving as an advisory board member for Amgen, Boston Scientific, Cardioset, Cardiovascular Systems Inc., Medtronic, Philips, and Pi-Cardia Ltd.; serving as a consultant for Amgen, Biotronik, Boston Scientific, Cardioset, Cardiovascular Systems Inc., Medtronic, Philips, and Pi-Cardia Ltd.; receiving grant support from AstraZeneca, Biotronik, Boson Scientific, and Chieisi; serving on the speakers bureau for AstraZeneca and Chiesi; and being an investor in MedAlliance. The remaining authors have no conflicts of interest to disclose.

      Acknowledgment

      A special acknowledgment to Jason Wermers, MS, for assistance in preparing this manuscript.

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