Study Design
This is a retrospective study of all patients tested for severe acute respiratory syndrome coronavirus 2 at four hospitals of Lahey Heath in Massachusetts. Patients were determined to have cancer if they had any solid or hematologic malignancy. Patients were determined to have CVD if they had a history of coronary artery disease, cardiomyopathy, congestive heart failure, moderate to severe valvular heart disease, or ischemic stroke. The data were extracted from the electronic medical record for both hospitalized and ambulatory patients.

Study Endpoints
The co-primary endpoints of this study were to assess COVID-19-associated severe disease (composite of need for mechanical ventilation, shock, or death) in patients with cancer compared with those without cancer, and in patients with both cancer and CVD compared to those with either diagnosis alone.

Secondary endpoints included death, shock, need for mechanical ventilation, need for supplemental oxygen, arrhythmia, venous thromboembolism, encephalopathy, abnormal troponin level, and length of stay in patients with cancer compared with those without cancer and in patients with both cancer and CVD compared with those with either diagnosis alone.

Results
In this study, of 21,217 subjects tested, the incidence of COVID-19 infection was 11.7% for the entire cohort, 8.6% for patients with cancer, 13.2% for patients with CVD, and 9.3% for patients with both cancer and CVD.

In the entire cohort of patients with COVID-19, a total of 11% developed severe disease over a median of 22 days (range = 20-29 days). Cancer was identified as an independent predictor of severe disease along with advanced age, male sex, smoking history, diabetes, and use of beta-blockers. Patients with a history of cancer were at significantly higher risk of COVID-19-associated severe disease (hazard ratio [HR] 2.02; 95% confidence interval [CI], 1.53-2.68; p < 0.001) and had a shorter median time to severe disease (11 [range = 10-30] vs. 23 [range = 21-30] days; p < 0.001) compared to patients without cancer. Interestingly, even after the exclusion of patients with active/recent cancer, those with a history of remote cancer also had a higher incidence of severe disease compared to those without cancer (24.4% vs. 11%; p < 0.05).

Patients with COVID-19 and cancer were hospitalized more frequently. Although the need for mechanical ventilation and supplemental oxygen did not differ between those with and without cancer, shock (8% vs. 4%; p = 0.011), mortality (25% vs. 8%; p < 0.001), arrhythmia (16% vs. 5%; p < 0.001), venous thromboembolism (10% vs. 3%; p < 0.001), and encephalopathy (13% vs. 8%; p = 0.019) were significantly higher in patients with cancer than in those without cancer.

Most importantly, although CVD alone was not found to be an independent predictor of COVID-19-associated severe disease, possibly due to collinearity with other risk factors including cancer, those with both cancer and CVD were at higher risk of developing severe disease than those with cancer (HR 1.86; 95% CI, 1.11-3.10; p = 0.018) or CVD (HR 1.79; 95% CI, 1.21-2.66; p = 0.004) alone. Mortality was also significantly higher in patients with COVID-19 and both cancer and comorbid CVD than those with cancer (35% vs. 17%; p = 0.004) or CVD (35% vs. 21%; p = 0.009) alone and also had a higher frequency of arrhythmias and encephalopathy.

Perspective
Evolving evidence shows that older people and people with multiple comorbidities are at a higher risk of COVID-19-associated adverse outcomes.^1-3 However, not all comorbid conditions carry similar risks of adverse outcomes when affected by COVID-19. It is possible that patients with multiple comorbidities may not have as high a risk of adverse outcomes as other patients with a single comorbid condition. Alternatively, some comorbidities may have a synergistic effect when present in the same patient, leading to exponentially worse outcomes with COVID-19 infections.

As we get into the worst phase of the pandemic, it is very important to recognize which comorbid conditions are associated with poorer COVID-19 outcomes to appropriately prioritize the allocation of resources and even early vaccination.

Patients with CVD, such as coronary artery disease or heart failure, as well as risk factors for CVD (such as hypertension, diabetes, and obesity), have reported increased severity of COVID-19 infection.^3,4 Furthermore, COVID-19 itself has been shown to have myriad effects on the cardiovascular system, thereby exacerbating the severity of viral illness in those patients with and without diagnosed CVD.⁵

In the absence of CVD, patients with cancer and concurrent COVID-19 infections have also been shown to have poor outcomes,^1,6 due in part to their compromised host defenses and the sequelae of antineoplastic treatment (namely, leukopenia, disruption in barriers to infection, and shifts in microbial flora). Several studies have shown that patients with COVID-19 and a history of cancer have two- to threefold increased risk of mortality than patients without cancer.^7,8 The study by Ganatra et al. also shows that patients with a history of cancer and COVID-19 are at an increased risk of serious complications including shock, arrhythmia, venous thromboembolism, and encephalopathy, as well as longer lengths of stay than patients without cancer.² Although a few other registries had demonstrated COVID-19-associated adverse outcomes in patients with cancer, the study by Ganatra et al. also demonstrates cancer as an independent risk factor for such adverse outcomes in a multivariate regression analysis even after adjusting for other known confounders.²

Although it has been shown that cancer and CVD individually are risk factors for poor outcomes in patients with COVID-19, this study demonstrated that patients affected by both cancer and CVD are at a significantly higher risk of mortality and serious morbidities such as hospitalization, need for mechanical ventilation, and shock, compared to those with either cancer or CVD alone.²

Considering evolving evidence, patients with cancer and comorbid CVD represent one of the highest risk cohorts. These findings have important public health implications. Patients undergoing potentially cardiotoxic antineoplastic therapy, especially those with underlying CVD, are recommended to have periodic screening during treatment with potentially cardiotoxic cancer therapies. Given their increased risk of having adverse outcomes with COVID-19, the frequency of such surveillance should be individualized on a case-by-case basis. Telehealth and home health services should be utilized for such patients and should be strongly considered in areas of high viral transmission.

At least three vaccines have been successfully developed and approved in record-breaking time,⁹ with more vaccines on horizon, but the reality is that these vaccines will not be available widely at the outset as production continues to ramp up to meet the required demand. Thus, each country will have to decide how it prioritizes the limited number of vaccines; given evolving evidence, patients afflicted with a dual diagnosis of cancer and CVD should be prioritized for vaccination beyond the highest risk group, including frontline health care workers and residents in long-term care facilities.

Even among patients with cancer or CVD, the risk of COVID-19-associated adverse outcomes may vary on a case-by-case basis. For example, patients with lung cancer or hematological cancers and those actively undergoing antineoplastic therapy are likely at a higher risk for adverse outcomes. Similarly, the mortality risk was higher in patients with frank CVD rather than just risk factors for CVD.¹⁰ Therefore, the decision of how to prioritize vaccination in this heterogeneous population of patients is complex and requires a more thoughtful approach until the vaccines are widely available.

References

1. Ganatra S, Hammond SP, Nohria A. The Novel Coronavirus Disease (COVID-19) Threat for Patients With Cardiovascular Disease and Cancer. JACC CardioOncol 2020;2:350-5.
2. Ganatra S, Dani SS, Redd R, et al. Outcomes of COVID-19 in Patients With a History of Cancer and Comorbid Cardiovascular Disease. J Natl Compr Canc Netw 2020;Nov 3:[Epub ahead of print].
3. 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.
4. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020;382:1708-20.
5. Ganatra S, Dani SS, Shah S, et al. Management of Cardiovascular Disease During Coronavirus Disease (COVID-19) Pandemic. Trends Cardiovasc Med 2020;30:315-25.
6. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet 2020;395:1907-18.
7. Meng Y, Lu W, Guo E, et al. Cancer history is an independent risk factor for mortality in hospitalized COVID-19 patients: a propensity score-matched analysis. J Hematol Oncol 2020;13:75.
8. Mehta V, Goel S, Kabarriti R, et al. Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System. Cancer Discov 2020;10:935-41.
9. Ball P. The lightning-fast quest for COVID vaccines—and what it means for other diseases (Nature.com). December 18, 2020. Available at  https://www.nature.com/articles/d41586-020-03626-1. Accessed January 17, 2021.
10. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) (WHO Global website). February 16-24, 2020. Available at https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf. Accessed March 9, 2020.

Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, COVID-19 Hub, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension, Smoking

Keywords: COVID-19, Coronavirus, severe acute respiratory syndrome coronavirus 2, Cardiotoxicity, Retrospective Studies, Coronary Artery Disease, Electronic Health Records, Venous Thromboembolism, Troponin, Public Health, Pandemics, Respiration, Artificial, Brain Ischemia, Stroke, Heart Failure, Cardiovascular System, Diabetes Mellitus, Risk Factors, Hypertension, Cardiomyopathies, Neoplasms, Arrhythmias, Cardiac, Telemedicine, Heart Valve Diseases, Registries, Leukopenia, Antineoplastic Agents, Obesity, Hematologic Neoplasms, Regression Analysis, Hospitals, Vaccination, Resource Allocation, Smoking, Oxygen

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