The Yale COVID-19 Cardiovascular Registry

Quick Takes

  • Hospitalized patients with coronavirus disease 2019 (COVID-19) had high prevalence of cardiovascular risk factors and conditions.
  • In-hospital risk of death was 14%, and in-hospital risk of composite major adverse cardiovascular events (MACE) was 23%.
  • Poor prognostic markers included older age, pre-existing cardiovascular disease, respiratory failure, altered mental status, and higher troponin T concentrations at admission.

Introduction

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global pandemic. As of January 10, 2021, more than 90 million worldwide cases had been reported, and ~1.9 million deaths had been attributed to this entity.1 The condition has received considerable attention in the cardiovascular community because persons with established cardiovascular disease or a high burden of cardiovascular risk factors seem to be particularly vulnerable during infection.2-6 The infection itself may also increase the risk of a variety of cardiovascular events and complications.7,8

The Yale COVID-19 Cardiovascular Registry

The Yale COVID-19 Cardiovascular Registry is an ongoing registry comprising data from adult patients who are admitted (or transferred) to Yale New Haven Hospital with a positive SARS-CoV-2 test.9 Patients could be included in cases of SARS-CoV-2 infection detected by a reverse-transcriptase polymerase chain reaction assay or high-throughput sequencing or if they were discharged with a diagnosis of COVID-19 using the International Classification of Diseases, Tenth Revision code, U07.1.

Study data were collected through manual chart review. We obtained information related to demographics (including prevalent cardiovascular risk factors, conditions, and medications), presenting symptoms, vital signs, laboratory test results at admission, imaging findings, electrocardiograms, and in-hospital events (including cardiovascular and COVID-19-specific medication use, supportive measures, ICU admission, cardiovascular events, other pertinent clinical events, and mortality).

The primary endpoint was in-hospital death. The main secondary endpoint was in-hospital MACE (a composite of type 1 or 2 myocardial infarction, stroke, new acute decompensated heart failure or cardiogenic shock, venous thromboembolism, new-onset ventricular arrhythmia, new-onset atrial fibrillation or flutter, pericardial effusion or cardiac tamponade, or aborted cardiac arrest). Cardiac events were adjudicated by experienced physicians.

Clinical Presentation and Laboratory Findings

The current study results were derived from 586 COVID-19-positive patients who were admitted between March 1 and May 31, 2020, and who had a final disposition (i.e., either in-hospital death or survival to hospital discharge). The median age was 67 years, 47% were female, and 49% identified as Non-Hispanic White, 31% identified as Non-Hispanic Black, and 16% identified as Hispanic. Prior clinical cardiovascular disease was reported in 37%, and 60% had hypertension, 40% had diabetes mellitus, and 39% had hyperlipidemia. With respect to antihypertensive medications, 33% were receiving angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers, 30% were on beta-blockers, and 28% were on diuretics.

The median time from symptom onset to admission was 4 days, and the median length of hospital stay was 13 days. In descending order, the most common presenting symptoms were cough (59%), fever or chills (59%), dyspnea (55%), and fatigue or malaise (34%). Laboratory findings stratified for mortality status are presented in Table 1.

Table 1: Laboratory Findings at Admission in Patients With COVID-19 Who Survived and Did Not Survive to Hospital Discharge

Laboratory Study Survived to Hospital Discharge
(n = 504)
Did Not Survive to Hospital Discharge
(n = 82)
P-value for Difference
Hematology (n = 545)      
  Hemoglobin (g/dl) 13.0 (11.5-14.1) 12.4 (10.6-13.7) 0.03
  White blood cell count (per mm3) 6.4 (4.9-8.4) 7.45 (5.5-11.5) 0.005
  Absolute lymphocyte count (per mm3) (n = 529) 1.0 (0.7-1.4) 0.8 (0.5-1.1) <0.001
  Absolute neutrophil count (per mm3) (n = 535) 4.6 (3.1-6.5) 5.8 (3.9-9.6) <0.001
  Platelet count (per mm3) 204 (161-262) 164 (127-232) 0.002
Renal (n = 549)      
  Creatinine (mg/dl) 1.0 (0.8-1.4) 1.4 (1.0-2.1) <0.001
Liver (n = 497)      
  Alanine aminotransferase (units/l) 26 (19-44) 26.5 (20-42) 0.76
  Aspartate aminotransferase (units/l) 41 (30-63) 53.5 (37-79) 0.002
  Lactate dehydrogenase (units/l) (n = 293) 304 (245-439) 358 (285-439) 0.16
  Total bilirubin (mcmol/l) (n = 485) 0.4 (0.3-0.6) 0.5 (0.4-0.8) 0.002
  Albumin (g/dl) (n = 481) 3.7 (3.3-4.0) 3.4 (3.0-3.8) <0.001
  International normalized ratio (n = 511) 0.99 (0.93-1.06) 1.06 (0.99-1.12) <0.001
Inflammation      
  High-sensitivity C-reactive protein (mg/l) (n = 512) 68 (18-139) 119 (52-161) <0.001
  Procalcitonin (ng/ml) (n = 517) 0.12 (0.06-0.28) 0.29 (0.12-0.94) <0.001
  Ferritin (ng/ml) (n = 503) 499 (222-1012) 623 (368-1470) 0.02
  D-dimer (mg/l) (n = 498) 0.99 (0.56-1.79) 1.56 (0.82-2.90) <0.001
  Fibrinogen (mg/dl) (n = 488) 511 (383-617) 531 (405-619) 0.70
Circulatory      
  Troponin T (ng/ml) (n = 504) <0.01 (<0.01 to <0.01) 0.03 (<0.01 to 0.08) <0.001
  N-terminal prohormone of B-type
natriuretic peptide (pg/ml) (n = 335)
223 (68-848) 2775 (613-8401) <0.001

Morbidity and Mortality

In all, 82 (14%) patients died in-hospital, 196 (33%) were admitted to the intensive care unit, and 111 (19%) required mechanical ventilation. The risk of in-hospital death was 8% among those not admitted to the intensive care unit and 26% among those admitted to the intensive care unit. A total of 135 (23%) patients experienced in-hospital MACE (Table 2).

Table 2: Cardiovascular Events in Patients With COVID-19

Endpoint All patients
(n = 586)
MACE (%) 135 (23%)
Ischemic  
  Type 1 myocardial infarction 3 (1%)
  Type 2 myocardial infarction 44 (8%)
  Isolated myocardial injury 64 (11%)
  Stroke 11 (2%)
Heart Failure  
  New acute decompensated heart failure 31 (5%)
  Worsening acute decompensated heart failure 35 (6%)
  Cardiogenic shock 12 (2%)
  Myocarditis 0
  Stress (takotsubo) cardiomyopathy 4 (1%)
Arrhythmia  
  New-onset atrial fibrillation or atrial flutter 46 (8%)
  New-onset ventricular arrhythmia 19 (3%)
Venous  
  Pulmonary embolism or deep vein thrombosis 34 (6%)
Other  
  Pericardial effusion or cardiac tamponade 5 (1%)
  Aborted cardiac arrest 21 (4%)

Predictors of mortality in a multivariable logistic regression model adjusted for demographic characteristics, clinical presentation, and laboratory findings were age (odds ratio [OR] 1.28 per 5 years; 95% confidence interval [CI], 1.13-1.45; p < 0.001), prior ventricular arrythmias (OR 18.97; 95% CI, 3.68-97.88; p < 0.001), use of P2Y12 receptor inhibitors (OR 7.91; 95% CI, 1.64-38.17; p = 0.01), C-reactive protein (OR 1.81 per standard deviation [SD]; 95% CI, 1.18-2.78; p = 0.007), albumin (OR 0.64 per SD; 95% CI, 0.47-0.86; p = 0.003), and troponin T (OR 1.84 per SD; 95% CI, 1.39-2.46; p < 0.001).

In a similarly adjusted multivariable logistic regression model, predictors of MACE were altered mental status at presentation (OR 2.94; 95% CI, 1.38-6.24; p = 0.005), respiratory rate (OR 1.31 per 5 bpm; 95% CI, 1.05-1.65; p = 0.02), absolute lymphocyte count (OR 0.66 per SD; 95% CI, 0.50-0.87; p = 0.003), total bilirubin (OR 1.39 per SD; 95% CI, 1.05-1.84; p = 0.02), albumin (OR 0.65 per SD; 95% CI, 0.49-0.85; p = 0.002), and troponin T (OR 1.85 per SD; 95% CI, 1.43-2.39; p < 0.001).

First and Second Waves

Several treatment advances were made as the pandemic progressed, including studies showing benefits of dexamethasone, tocilizumab, and, to some extent, remdesivir. We found that patients admitted during the so-called "second wave" (between October 1 and December 31, 2020) had a significantly lower rate of in-hospital mortality at 9% (34 deaths/386 admissions) compared with 14% during the initial wave (p = 0.006).

Conclusions

The individuals in our study presented in a similar fashion to in-hospital patients described in earlier reports of COVID-19.2-6,10 Our overall conclusions also support prior studies that proposed cardiovascular disease as being an adverse risk marker.2-6,11 Similar inferences can be drawn for various biomarkers, particularly cardiac troponin.7,8,12-14 Still, our study stands out given its fairly large sample size, data collection through manual review of electronic health records, and event adjudication.15 Overall cardiovascular event rates were high but lower than initially thought after events were adjudicated. Major limitations include the observational design, use of a composite cardiovascular endpoint, and the limited power for assessing individual cardiovascular outcomes.

Several questions remain unanswered, most of which pertain to optimal management of patients with elevations of certain biomarkers (e.g., D-dimer and troponin). Although some institutions have adopted biomarker-guided algorithms, the evidence for these strategies remains unclear, and we have yet to examine whether these interventions have affected patient prognosis positively at our institution. It is also unknown whether any specific measures are available in the acute setting to lower the higher risk among patients with pre-existing cardiovascular disease. Nevertheless, our findings in the context of a global pandemic may be used as an incentive to optimize management of cardiovascular risk factors and known cardiovascular disease.

Acknowledgements

The authors would like to thank Maxwell Eder, Justin Pacor, Jakob Park, Zaniar Ghazizadeh, Alex Heard, Ana Sofia Cruz-Solbes, Roozbeh Nikooie, Chad Gier, Zain V. Ahmed, James V. Freeman, Judith Meadows, Kim G. E. Smolderen, Rachel Lampert, Eric J. Velazquez, and Tariq Ahmad for their invaluable contributions to the study.

References

  1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 2020;20:533-4.
  2. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020;382:1708-20.
  3. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
  4. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62.
  5. Gao C, Cai Y, Zhang K, et al. Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study. Eur Heart J 2020;41:2058-66.
  6. Inciardi RM, Adamo M, Lupi L, et al. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy. Eur Heart J 2020;41:1821-9.
  7. Shi S, Qin M, Shen B, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802-10.
  8. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020;5:811-8.
  9. Pareek M, Singh A, Vadlamani L, et al. Relation of Cardiovascular Risk Factors to Mortality and Cardiovascular Events in Hospitalized Patients With Coronavirus Disease 2019 (from the Yale COVID-19 Cardiovascular Registry). Am J Cardiol 2021;Feb 1:[Epub ahead of print].
  10. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-13.
  11. Lai PH, Lancet EA, Weiden MD, et al. Characteristics Associated With Out-of-Hospital Cardiac Arrests and Resuscitations During the Novel Coronavirus Disease 2019 Pandemic in New York City. JAMA Cardiol 2020;5:1154-63
  12. Lala A, Johnson KW, Januzzi JL, et al. Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection. J Am Coll Cardiol 2020;76:533-46.
  13. Shi S, Qin M, Cai Y, et al. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J 2020;41:2070-9.
  14. Basso C, Leone O, Rizzo S, et al. Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur Heart J 2020;41:3827-35.
  15. Bensley RP, Yoshida S, Lo RC, et al. Accuracy of administrative data versus clinical data to evaluate carotid endarterectomy and carotid stenting. J Vasc Surg 2013;58:412-9.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Pericardial Disease, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension, Noninvasive Imaging

Keywords: COVID-19, Coronavirus, Coronavirus Infections, severe acute respiratory syndrome coronavirus 2, Cardiovascular Diseases, Antihypertensive Agents, Hospital Mortality, Patient Discharge, Troponin T, C-Reactive Protein, Purinergic P2Y Receptor Antagonists, Shock, Cardiogenic, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Logistic Models, Cardiac Tamponade, African Americans, Pericardial Effusion, Hyperlipidemias, International Classification of Diseases, Venous Thromboembolism, Albumins, Bilirubin, Respiratory Rate, Pandemics, Atrial Fibrillation, Reverse Transcriptase Polymerase Chain Reaction, Confidence Intervals, Laboratories, Risk Factors, Stroke, Heart Failure, Diabetes Mellitus, Hypertension, Registries, Heart Arrest, Dyspnea, Hospitals, Lymphocyte Count, Fatigue, High-Throughput Nucleotide Sequencing, Intensive Care Units, Electrocardiography, Dexamethasone, Reference Standards


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