Impact of cancer and cardiovascular disease on in-hospital outcomes of COVID-19 patients: results from the american heart association COVID-19 cardiovascular disease registry

The novel coronavirus Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the ongoing and relentless global Coronavirus Disease 2019 (COVID-19) pandemic, and was the leading cause of death in the United States in 2020 (US) [1, 2]. Underlying cardiovascular disease (CVD) risk factors and CVD are important prognosticators of clinical outcomes in hospitalized patients with COVID-19 [3]. Patients with COVID-19 who have pre-existing malignancy and those undergoing cancer-specific therapy are disproportionately affected and represent a population at risk for worse outcomes [3‐6]. However, data on the impact of COVID-19 in patients with a history of prior or active cancer who also have underlying or acquired CVD from cancer-related treatments—the cardio-oncology population—is limited. Furthermore, it is important to investigate the safety of recent use of cancer therapies as observational studies early in the pandemic suggested that COVID-19 patients with cancer who are immunosuppressed as a result of their underlying active cytoreduction therapies may have increased mortality and intensive care needs compared to those without cancer [7]. Although the direct impact of COVID-19 on cardio-oncology patients has not been evaluated in clinical trials, prior studies have shown that both CVD patients and cancer patients do have an increased risk for cardiac injury, which in of itself is an independent predictor of mortality in COVID-19 [8, 9]. As oncologists and cardio-oncologists weigh the risk and benefits of initiating versus delaying or continuing versus stopping cancer-related therapies in light of the ongoing pandemic, it is critical to understand the impact of COVID-19 in the cancer population, and particularly among those with concomitant CVD.

This large multicenter AHA COVID-19 CVD registry-based analysis highlights several important points regarding hospitalized adult cancer patients with symptomatic COVID-19. First, a history of cancer was found to be a significant predictor of in-hospital mortality, with its largest effect being in patients who were younger with lower BMIs and had a history of smoking. The higher rates of mortality seem to be driven by severe disease complications. Second, cancer patients who received recent chemotherapy in the prior 2 weeks to admission had increased in-hospital mortality compared with those without recent cancer-related therapy. Finally, cancer patients with concomitant pre-existing CVD had similar rates of in-hospital mortality to those cancer patients without CVD. However, CVD risk factors of age, male gender, BMI, hypertension, diabetes, and smoking were significant predictors in adjusted models.

In 2020, COVID-19, heart disease, and malignant neoplasms have been the leading causes of death in the US [2]. As COVID-19 rates have exponentially increased since March 2020, the interplay between these 3 entities has become increasingly important. Small studies from China at the onset of the pandemic indicated that higher proportions of patients with a history of cancer had severe in-hospital complications and in-hospital mortality as compared to those without a history of cancer, prompting suggestions that intentional postponement of adjuvant chemotherapy or elective surgery should be considered [7, 11]. With respect to cancer therapies, a small prospective cohort study reported no significant association between use of cytotoxic chemotherapy or other anticancer treatment and mortality in the setting of COVID-19 [12]. A larger cohort study from the COVID-19 and Cancer Consortium similarly reported that cancer patients receiving anticancer therapies did not have higher rates of mortality, although the presence of cancer itself, whether stable/improving or progressive was independently associated with 30-day mortality [13]. However, specific CVD risk factors such as hypertension and obesity, previously shown to be associated with in-hospital mortality were not adjusted for [14, 15]. More recently, as the pandemic has continued to unfold, there has been more interest in evaluating risk in those with concomitant CVD and history of cancer. For example, in a retrospective study by Ganatra et al. of 2,476 patients from 4 Massachusetts-based hospitals patients with a history of both CVD (N = 414) and cancer (N = 195) had a higher short-term mortality as compared to either cancer or CVD alone [16]. In addition, history of cancer was predictive of severe disease complications, while pre-existing CVD was not.

In the present study, history of cancer was a robust predictor of in-hospital mortality among hospitalized symptomatic adult COVID-19 patients. Given older age and obesity have previously been shown to be associated with mortality in the setting of COVID-19, it is not surprising that the most predominant effect of history of cancer on mortality we observed was in younger patients with lower BMIs. The increased mortality appears to be driven by increased severe disease complications in patients with history of cancer, particularly in those with a history of smoking, independent of prior pulmonary disease. Additionally, while male gender was unsurprisingly associated with higher MACE in those without cancer history, females with a history of cancer exhibited higher rates of MACE. However, interpretation is limited for MACE given the overall low event rate. Other factors that may also explain the increased mortality rate observed in cancer patients compared with non-cancer patients include: 1) residual confounding due to unaccounted for differences between cancer and non-cancer patients, such as use of vasoactive medications and code status; and 2) inadequate power to detect a difference in venous thromboembolism (VTE) given low event rates.

Venous thromboembolism (VTE) has been of particular interest in COVID-19 patients with underlying cancer given the perceived elevated risk of VTE from both the hypercoagulable/inflammatory milieu of COVID-19 and cancer itself. Data has shown that elevated D-dimers levels are independently associated with thrombotic events, and subsequently those with thrombotic events have higher all-cause mortality [17]. However, the prevalence of VTE in COVID-19 cancer patients is not clear. Ganatra et al. reported VTE in 10% of cancer patients admitted with COVID-19, whereas we observed VTE in only 3% of cancer patients with COVID-19 [16]. This may be an underestimation given other smaller studies suggest higher rates even in those without a history of cancer [18], and may be a reflection of low rates of systematic surveillance and suspicion without confirmation in critically ill patients.

To the best of our knowledge, this AHA COVID-19 registry-based study is the largest multicenter prospective analysis to date to evaluate the effect of recent use of cancer-related therapy in hospitalized symptomatic COVID-19 patients. In contrast to prior studies, among cancer patients, we observed a strong independent association of cancer-specific therapy with in-hospital mortality. Importantly, cancer patients with underlying CVD did not have higher in-hospital mortality rates compared with those without CVD. Taken together, these findings suggest that oncologists and cardio-oncologists alike should discuss with their patients the optimal timing for and possible delay of cancer-related therapy in areas where COVID-19 viral transmission is high and hospital resources are limited, but that the presence of CVD should not be a major determinant of therapy in the cardio-oncology population. However, this be balanced with the need of urgent therapy based on cancer type and cancer status. Multiple societal documents have similarly discussed the need to potentially curtailing the frequency of cardiotoxicity surveillance for selected patients [19‐21].

This study has important limitations. First, the AHA CVD COVID-19 registry does not provide granular data regarding the type of cancer, status of cancer (relapse, remission, etc.), or cancer-specific therapies that patients are receiving to allow for stratification of cancer severity. Second, the initial registry data did not include information regarding code status and advanced directives, which may be disproportionately high in those with cancer and thus possibly impact in-hospital outcomes. Third, these data only pertain to in-hospital outcomes and thus post-discharge outcomes are not known. Lastly, the voluntary hospital participation in the registry is weighted toward urban academically affiliated institutions, and so the results may not be generalizable; however, we adjusted for site-specific clustering of outcomes to address this issue.

In summary, in the large national AHA COVID-19 CVD registry, history of cancer is a significant predictor of in-hospital mortality. Notably, among cancer patients, those with underlying CVD had similar outcomes to those without CVD, while recent use of cancer-related therapy was significantly associated with in hospital mortality. Further studies focusing on malignancy type and specific treatments, and their interactions with concomitant CVD and CVD risk factors, are warranted to identify vulnerable subgroups of the cancer population that may benefit from aggressive interventions during the COVID-19 pandemic including earlier prioritization for vaccine initiation.