key: cord-0956747-s3ap4g69 authors: Greene, Stephen J.; Lautsch, Dominik; Yang, Lingfeng; Tan, Xi; Brady, Joanne E. title: Prognostic Interplay Between COVID-19 and Heart Failure with Reduced Ejection Fraction date: 2022-05-18 journal: J Card Fail DOI: 10.1016/j.cardfail.2022.05.001 sha: f2b809ce0fde498739bad67de96dbd2c0cfbb4cd doc_id: 956747 cord_uid: s3ap4g69 BACKGROUND: : COVID-19 may negatively impact the prognosis of patients with chronic HFrEF, and vice versa. METHODS: : This study included two parallel analyses among US patients in the TriNetX health database who underwent PCR testing for SARS-CoV-2 as an inpatient or outpatient between January and September 2020. Analysis A included patients with a positive COVID-19 test, and compared patients with a history of worsening HFrEF (HF hospitalization or IV diuretic use in prior 12 months), HFrEF without worsening, and no prior HF. Analysis B included patients with history of HFrEF, and compared patients with positive vs. negative COVID-19 tests. Outcomes included mortality and worsening HF. In both analyses, pre-specified subgroup analyses stratified by inpatient vs. outpatient setting of COVID-19 test. RESULTS: : In Analysis A of 99,052 patients with a positive COVID-19 test, 514 (0.5%) and 524 (0.5%) patients had histories of worsening HFrEF and HFrEF without worsening, respectively. After adjustment, compared with non-HF patients, worsening HFrEF (risk ratio [RR] 1.42, 95% CI 1.10–1.83; p<0.001) and HFrEF without worsening (RR 1.33, 95% CI 0.96–1.84; p=0.06) were associated with higher 30-day mortality. Excess mortality risk tended to be pronounced among patients initially diagnosed with COVID-19 as outpatients (p for interaction 0.12 and 0.006, respectively). In Analysis B of 14,838 patients with HFrEF tested for COVID-19, 1,038 (7.0%) had positive tests. After adjustment, testing positive was associated with excess 30-day mortality risk (RR 1.67, 95% CI 1.38–2.02; p<0.001) and worsening HF (RR 1.33, 95% CI 1.17–1.51; p<0.001). Mortality risk was nominally more pronounced among patients presenting as outpatients (p for interaction 0.07). CONCLUSION: : In this large cohort of patients tested for COVID-19, among patients testing positive, a history of HFrEF with or without worsening was associated with excess mortality, particularly among patients diagnosed with COVID-19 as outpatients. Among patients with established HFrEF, compared with testing negative, testing positive for COVID-19 was independently associated with higher risk of death and worsening HF. Although Coronavirus Disease 2019 , which is caused by severe acute respiratory syndrome coronavirus-2 , is most recognized as a pathogen targeting the lungs and respiratory tract, cardiac manifestations and complications are common and contribute substantially to death and adverse outcomes. 1,2 In particular, patients with pre-existing heart failure (HF) have shown significant vulnerability to death and respiratory failure in the days to weeks following COVID-19 infection. 3, 4 As such, history of HF has been proposed as potentially useful for informing patient risk-stratification, and in guiding decisions for more aggressive patient surveillance or therapy. 3 Nonetheless, many facets of the relationship between COVID-19 and HF remain unclear. 5, 6 For example, it is unknown if poor clinical outcomes with COVID-19 among HF patients are driven by a subset of higher risk HF patients, including those with recent HF hospitalization or outpatient clinical worsening. Likewise, it is unknown whether excess risk of death among HF patients with COVID-19 is concentrated among patients who present with severe COVID-19 symptoms prompting inpatient diagnosis and hospitalization, or if significant clinical risk extends to milder initial presentations of COVID-19 diagnosed as an outpatient. In addition, while multiple studies have assessed associations between COVID-19 and HF in terms of in-hospital and 30-day outcomes, longer-term clinical consequences and prognostic implications remain poorly characterized, including associations with downstream HF-specific endpoints, such as hospitalizations for worsening HF. 3, 4, 7 In this context, the objectives of the current study were to leverage a large, longitudinal, real-world dataset of patients tested for SARS-CoV-2 to characterize 1) associations between history of HF with reduced ejection fraction (HFrEF) with vs. without a recent worsening heart failure event and clinical outcomes among patients diagnosed with COVID-19; 2) the prognostic implications of testing positive vs. negative for COVID-19 among patients with HFrEF; and 3) the interaction between HFrEF, clinical outcomes, and the location of initial COVID-19 presentation in the inpatient vs. outpatient setting. This study utilized a de-identified patient dataset from the TriNetX Dataworks USA Network (Cambridge, MA). TriNetX is a global health research database that contains de-identified data sourced and continuously updated from electronic medical records (EMR) . Clinical organizations, such as hospitals or integrated delivery networks, own all rights, consents, and approvals on transferring data to TriNetX. The current study utilized data from the United States (US), including data from >37 healthcare organizations responsible for the care of >58 million US patients. Patients with a variety of health insurance coverage were included (i.e., private insurance, Medicare, Medicaid, and no insurance). Data include longitudinal outpatient and inhospital data, and encompass patient demographics, medical diagnoses, laboratory test results, outpatient visits, hospitalizations, and mortality. TriNetX, LLC is compliant with the Health Insurance Portability and Accountability Act (HIPAA), the US federal law which protects the privacy and security of healthcare data, and any additional data privacy regulations applicable to the contributing healthcare organizations. TriNetX is certified to the ISO 27001:2013 standard and maintains an Information Security Management System to ensure the protection of the healthcare data it has access to and to meet the requirements of the HIPAA Security Rule. Any data displayed on the TriNetX Platform in aggregate form, or any patient level data provided in a data set generated by the TriNetX Platform, only contains de-identified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data is de-identified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. Because this study used only de-identified patient records and did not involve the collection, use, or transmittal of individually identifiable data, this study was exempted from Institutional Review Board approval. This retrospective observational study included adult patients age ≥18 years who had received ≥1 polymerase chain reaction (PCR) test for SARS-CoV-2 between January 1, 2020, and September 30, 2020; had EMR data for the 12 months prior to the index COVID-19 PCR test; and had both inpatient and outpatient EMR records accessible. Patients were included if they had either a diagnosis of HFrEF, or no prior HF diagnosis, as determined by International Classification of Diseases-10 th Revision (ICD-10) codes during the 12 months before COVID-19 testing). To be defined as having a history of HFrEF, a patient was required to have either one inpatient diagnosis for HFrEF, two outpatient diagnoses for HFrEF on two different dates, or one outpatient diagnoses for HFrEF plus one outpatient diagnosis for any HF on two different dates (Supplemental Table 1 ). Given established differences in patient profile, pathophysiology, and outcomes among patients with HFrEF versus HF with preserved ejection fraction (HFpEF), patients with any diagnosis of HFpEF (ICD-10: I50.3X) were pre-specified for exclusion so as to focus specifically on the HFrEF phenotype. For all analyses, date of the PCR test for SARS-CoV-2 was considered the index date and study baseline. For patients with multiple positive PCR tests for COVID-19, the first positive test was used as the index test. For purposes of analysis, patients with both positive and negative tests were considered positive for COVID-19 with the date of the positive test considered the index date. From this overall study population, two sets of analyses involving two distinct cohorts were pre-specified. Analysis A was designed to assess the clinical implications of prior history of HFrEF with vs. without a worsening heart failure event (WHFE) among patients newly diagnosed with COVID-19. Only patients with a positive PCR test for SARS-CoV-2 were included. Patients were then categorized into one of three mutually exclusive groups defined by their history of HF during the 12 months prior to the positive COVID-19 test: 1) worsening HFrEF, defined as a hospitalization for HF or receipt of intravenous (IV) diuretics (either inpatient or outpatient) in the prior 12 months, 2) HFrEF, without worsening, and 3) no history of HF. Analysis B was designed to assess the clinical implications of COVID-19 among the subset of patients with a history of HFrEF. Patients with HFrEF who tested positive for COVID-19 were compared with patients who tested negative. In both analyses A and B, patients were included regardless of whether their COVID-19 test was in the setting of a hospitalization or in the outpatient setting. For Analysis A among patients with COVID-19, pre-specified study endpoints included 1) 30day all-cause mortality, 2) 90-day all-cause mortality, and 3) composite of all-cause mortality or hospitalization. For Analysis B among patients with HFrEF, endpoints included 1) 30-day allcause mortality, 2) 90-day all-cause mortality, and 3) worsening HF, defined as a hospitalization for HF or receipt of IV diuretics (either inpatient or outpatient). Hospitalization for HF was defined as an inpatient claim with primary diagnosis of HF, and IV diuretic use was defined by relevant procedure codes (Supplemental Table 2 ). For both analyses (A and B), baseline characteristics were described for each patient group. To assess associations between patient group and each outcome, three levels of statistical modeling were employed in all analyses to account for potential confounders: unadjusted, base adjustment (accounting for demographics and comorbidities), and comprehensive adjustment (base adjustment plus adjustment for inpatient vs. outpatient status at time of index test for COVID-19). Pre-specified covariates in the base adjusted model included age, gender, race, ethnicity, and past medical history (asthma, type 2 diabetes mellitus, chronic obstructive pulmonary disease, hypertension, coronary artery disease, history of thrombosis, coronary revascularization, myocardial infarction, obesity, chronic kidney disease, peripheral arterial disease, vascular disease, moderate/severe liver disease, metastatic solid tumor, and atrial or ventricular tachyarrhythmia) (Supplemental Table 3 ). For all endpoints (30-day mortality, 90-day mortality, composite all-cause mortality or all-cause hospitalization, worsening HF), unadjusted and adjusted log linear models (Poisson distribution, with a log link and a robust error variance) were used to estimate relative risk. Recognizing that the location of COVID-19 testing (in-hospital vs. outpatient) may suggest significant differences in health status at time of testing, and that the prognostic interplay between HFrEF and COVID-19 may differ based on the clinical severity of the initial suspected or confirmed COVID-19 presentation, associations with study endpoints were stratified by inpatient vs. outpatient location of COVID-19 testing. Thus, in Analyses A, associations between prior HF history and study endpoints were assessed separately among patients testing positive for COVID-19 during inpatient and outpatient settings. Likewise, in Analysis B, associations between testing positive vs. negative for COVID-19 were separately assessed among patients being tested for COVID-19 as inpatients vs. outpatients. Inpatient location was defined as an associated inpatient encounter at the time of testing. To capture patients being tested in the emergency department or ambulatory setting and directly admitted to the hospital, inpatient location was also defined as a test in the emergency department or ambulatory setting with an associated inpatient encounter within three days. Outpatient location was defined as testing performed in the emergency department or ambulatory setting without an inpatient encounter within three days. In both Analyses A and B, interaction p-values were calculated to assess for a differential association between patient group and clinical outcome by the location of COVID-19 testing. Statistical analyses were performed with SAS 9.4 (SAS Institute, Cary, NC), and twotailed p-value of 0.05 was considered statistically significant. Between January 1, 2020, and September 30, 2020, there were 1,548,747 unique US patients who received ≥1 PCR test for SARS-CoV-2. After excluding patients who did not have at least 1 encounter in EMR during the 12 months prior to testing, were <18 years old, had a known diagnosis of HFpEF, and died on the date of COVID-19 testing, the final study population included 1,016,453 (65.6%) adults who underwent PCR testing for SARS-CoV-2. Of this sample, 99,052 (9.7%) of patients had a positive PCR test, and 14,838 (1.5%) patients had a history of HFrEF (Figure 1) . Among 99,052 patients with a positive PCR test for SARS-CoV-2, 514 (0.5%) had a history of worsening HFrEF, 524 (0.5%) had a history of HFrEF without worsening, and 98,014 (99.0%) patients had no prior history of HF ( Comparing patients with HFrEF with vs. without a history of worsening, patients were generally similar in terms of demographics, but those with worsening HFrEF tended to have higher rates of cardiac and non-cardiac comorbidities. Compared with HFrEF without worsening, patients with worsening HFrEF tended to have lower lymphocyte percentage, serum hemoglobin, and serum albumin, but generally had similar serum creatinine. Rates of 30-day and 90-day mortality were lowest among patients without HF (1.4% and 1.6%), intermediate among patients with HFrEF without worsening (8.0% and 9.0%), and highest among patients with worsening HFrEF (15.6% and 16.5%) ( Table 5 ). In stratified analyses accounting for inpatient vs. outpatient testing for COVID-19, the association between prior HF status and each clinical outcome differed significantly by location of COVID-19 diagnosis ( Figure 3A) . For each endpoint, excess risk associated with HFrEF (with or without worsening) was driven by patients who were diagnosed with COVID-19 as outpatients. In the subset of patients diagnosed with COVID-19 during a hospitalization, although HFrEF were both associated with substantially higher unadjusted event rates, there was no independent association with mortality or composite outcomes after adjustment for potential confounders. Among 14,838 patients with HFrEF who underwent testing for COVID-19, 1,038 (7.0%) patients tested positive and 13,800 (93.0%) tested negative ( Table 3) . Irrespective of test result, patients were generally similar with regards to age, gender, comorbidities, and laboratory findings. However, patients testing positive were more likely to be Black or of Hispanic ethnicity, and less likely to be White. Rates of 30-day and 90-day mortality were higher among HFrEF patients who tested positive for COVID-19 (11.8% and 12.7%) than among HFrEF patients who tested negative (7.2% and 8.5%) ( Figure 1 ). Although not reaching formal statistical significance, there were borderline statistical interactions whereby the relationship between testing positive for COVID-19 and 30-day and 90day mortality differed for patients who presented to the inpatient vs. outpatient setting ( Figure 3B ). Although a positive COVID-19 test was independently associated with excess risk of death across both locations, the magnitude of excess risk was higher among patients tested as an outpatient. In contrast, for the worsening HF endpoint, the higher clinical risk with a positive COVID-19 test was consistent irrespective of inpatient vs. outpatient testing. In this large cohort of US adults tested for COVID-19 in the ambulatory and hospitalized setting, there are several notable findings. First, among patients testing positive for COVID-19, patients with worsening HFrEF represent a particularly high-risk subset, and were more likely to require hospitalization at time of COVID-19 diagnosis. However, although unadjusted rates of mortality and hospitalization were markedly higher among patients with HFrEF, after comprehensive risk adjustment for potential confounders, neither a history of worsening HFrEF nor a history of HFrEF without worsening were consistently associated with worse clinical outcomes in the setting of concurrent COVID-19. Second, among patients with HFrEF, relative to patients who tested negative, a diagnosis of COVID-19 was independently associated with substantially heightened risk of mortality and subsequent worsening HF. Third, these data highlight the importance of the presenting clinical setting on the interplay between COVID-19 and HFrEF. Specifically, among patients with COVID-19, a history of stable or worsening HFrEF carried independent prognostic value predominantly when COVID-19 was diagnosed as an outpatient, and less so when patients were hospitalized for COVID-19. Likewise, among patients with established HFrEF who received COVID-19 testing, the relative increase risk of death with a positive test was highest among patients diagnosed in the ambulatory setting. To our knowledge, we present the first large-scale analysis evaluating the bidirectional prognostic interplay between COVID-19 and HFrEF. In this regard, several strengths and novel features of this analysis warrant consideration. First, we examined a unique population tested for COVID-19 in either the inpatient or outpatient setting, allowing a unique comparison of the prognostic interplay of testing and diagnosis of COVID-19 among patients initially receiving inhospital vs. ambulatory care. Although prior studies have near exclusively centered on patients hospitalized or presenting to the emergency department who are likely to be highly symptomatic, comparatively little is known regarding the implications of ambulatory COVID-19 testing for HFrEF patients, or the anticipated clinical course for patients who are diagnosed with COVID-19 yet initially with milder symptoms not requiring hospitalization. 3, 4, [7] [8] [9] [10] Second, in a large population of >1 million patients tested for SARS-CoV-2 in the US in 2020, we report both the overall test positivity rate (9.7%) and the test positivity rate among patients with established HFrEF (7.0%). Although potentially subject to confounding and requiring further validation, the lower test positivity rate among patients with HFrEF does not suggest patients with HFrEF as being particularly vulnerable to acquiring COVID-19. Third, while prior studies have examined clinical outcomes among patients with HF and COVID-19, comparator groups have generally been loosely defined as HF patients without In contrast, by exclusively studying a population that underwent PCR testing, the present analysis offers a more secure control group of patients confirmed to be COVID-19-negative. Likewise, given that all patients receiving a test presumably had some degree of new or worsening symptoms or clinical suspicion compatible with active COVID-19 infection, the current study may better address potential confounding by indication stemming from the decision to test for COVID-19. Fourth, recognizing that clinical risk may vary within the broad HFrEF population, the current study sub-categorized patients into those with vs. without a recent worsening HF episode (i.e., HF hospitalization or IV diuretic administration). In doing so, the results highlight that although a graded relationship in unadjusted clinical event rates was observed, the incremental and independent prognostic value of a worsening HF event seen in prior analyses may not necessarily extend to the setting of active COVID-19 infection. 11, 12 Lastly, to the best of our knowledge, this analysis is the first to evaluate the association between COVID-19 and longer-term HF-specific outcomes in clinical practice. Among patients with established HFrEF, compared with testing negative, a diagnosis of COVID-19 was independently associated with a 33% greater risk of a worsening HF event over median follow-up 3.5 months. These data highlight the potential impact of COVID-19 on HFrEF disease progression even after recovery from acute infection, and are consistent with other data suggesting the potential for longer-term cardiac consequences of the disease. 13, 14 Prior analyses have documented high rates of in-hospital mortality among patients with a history of HF hospitalized for COVID-19. For example, an analysis from New York City studying an early and particularly severe phase of the pandemic through June 2020 reported exceptionally high event rates for patients hospitalized for COVID-19, with in-hospital mortality of 40.0% and 24.9% for patients with and without history of HF, respectively. 3 High event rates were also reported in a more recent analysis by Bhatt et al. that extended through September 2020, with in-hospital mortality of 24.2% among patients hospitalized for COVID-19 with a history of HF, compared with a mortality rate of 14.2% among non-HF patients. 4 In the current analysis, among the subset with inpatient diagnoses of COVID-19, we observed lower, albeit still markedly elevated, rates of 30-day mortality. Specifically, 30-day mortality was 19.0% and 12.7% for hospitalized patients with histories of worsening HF and HF without worsening, respectively, as compared with 7.9% for non-HF patients. Compared with the study by Bhatt et al. examining a similar timeframe, reasons for lower mortality among hospitalized patients in the present study are unclear but could be related to 1) exclusion of patients with HFpEF, 2) differences in COVID-19 definition based on PCR results as opposed to diagnoses codes, 3) differences in case-mix for primary clinical reasons for hospitalization (i.e., hospitalized for primary or secondary diagnosis of COVID-19 in prior study, vs. diagnosed with COVID-19 during hospitalization in current study). The low rate of mortality we observed among US patients diagnosed with COVID-19 in the ambulatory setting is notable. Indeed, we found risks of 90-day mortality among ambulatory non-HF patients of <1%. However, among patients with HFrEF, the adjusted relative risk of death compared with non-HF patients was particularly high when patients with HFrEF were diagnosed with COVID-19 as outpatients. Among patients diagnosed with COVID-19 as inpatients, differences in adjusted mortality risk between HFrEF and non-HF patients were less pronounced. Although future analyses are needed to confirm the results of this subgroup analysis, these findings may speak to the ability of a history of HF to drive prognosis among patients presenting with mild or no COVID-19 symptoms. By comparison, it is possible that patients hospitalized with severe COVID-19 symptoms may have outcomes more strongly determined by the infection itself, and that HFrEF may have lesser prognostic importance after rigorously accounting for confounding risk factors and clinical markers of severe illness. The results for patients with HFrEF who test positive vs. negative for COVID-19 warrant mention. Although prior studies have supported adverse outcomes relative to HF patients without COVID-19, the current analysis exclusively examining patients receiving testing may more strongly support the independent prognostic consequences of COVID-19, as compared with other cardiorespiratory processes that may mimic COVID-19 symptoms. Likewise, similar to analysis A, analysis B found statistically significant interactions for mortality by the location of COVID-19 testing. Despite lower absolute risks, relative risk of mortality with COVID-19 was particularly high among patients with HFrEF tested in the outpatient setting. Limitations of this analysis should be noted. First, this retrospective observational analysis cannot definitively prove cause-effect relationships, and residual or unmeasured confounding may remain. Likewise, data on vital signs, laboratory tests, examination findings, symptoms of HF and/or COVID-19, medications, and procedures were not available, and thus could not be included as covariates in adjusted models. Moreover, this study cannot decipher the reason patients presented for COVID-19 testing (e.g., symptoms of COVID-19, close contact to confirmed case, requirement for inpatient hospitalization). Inpatient vs. outpatient location of COVID-19 testing was added to models as a potential surrogate of clinical severity at presentation, but this may not necessarily capture the complete clinical risk reflected by vital signs and objective clinical characteristics. Second, data on location of COVID-19 testing were not available for all patients in this sample. We cannot exclude the potential of selection bias among patients with available data. Third, history of HFrEF was defined by administrative coding and some degree of misclassification may have occurred. Fourth, despite sampling >1 million patients tested for COVID-19, the proportions and absolute numbers of patients with HFrEF without worsening and worsening HFrEF were modest. In the setting of some outcome results having marginal p-values and wide confidence intervals, a larger sample of HFrEF patients may have provided more statistical power and precision for risk estimates. Fifth, given established differences in pathophysiology and clinical profile, this analysis excluded patients with HFpEF and focused solely on those with HFrEF. The degree to which the current findings for HFrEF extend to patients with HFpEF requires future dedicated study in that population. Sixth, the current study pre-specified exclusion of patients who died on the day of COVID-19 testing to ensure all patients were alive at the beginning of the study and had at least some period of follow-up. Nonetheless, this may have introduced a bias, and the current findings should be interpreted in this context. Lastly, the study period included patients in the early pandemic period in 2020 prior to availability of vaccines. The degree to which these findings generalize to patients vaccinated with COVID-19, or to the more recent omicron variant of SARS-CoV-2 is unclear. In this large US cohort of patients tested for COVID-19 in the inpatient or outpatient setting, among patients testing positive, a history of HFrEF (with or without recent clinical worsening) was not independently associated with excess risk of mortality and hospitalization. However, this association varied by location of COVID-19 testing, with HFrEF associated with substantial clinical risk among patients tested for COVID-19 as outpatient. Among patients with histories of HFrEF, compared with testing negative, a positive test for COVID-19 was independently associated with higher risk of death and worsening HF, with interaction testing identifying a nominal trend towards higher mortality risk being driven by patients tested for COVID-19 as outpatients. These findings support the strong prognostic interplay between COVID-19 and Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19) Prognostic Impact of Prior Heart Failure in Patients Hospitalized With COVID-19 Clinical Outcomes in Patients With Heart Failure Hospitalized With COVID-19 COVID-19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19 Outcomes of coronavirus disease-2019 among veterans with pre-existing diagnosis of heart failure Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study Task Force for the management of C-otESoC. ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2-care pathways, treatment, and follow-up Influence of previous heart failure hospitalization Efficacy of Sacubitril/Valsartan Relative to a Age (years) Worsening HFrEF Worsening HFrEF All-cause Mortality or Hospitalization ‡ No Prior HF 12 Adjusted for age, sex, race, ethnicity, asthma, type 2 diabetes mellitus, chronic obstructive pulmonary disease, hypertension, coronary artery disease, history of thrombosis, coronary revascularization, myocardial infarction, obesity, chronic kidney disease, peripheral artery disease, vascular disease, moderate/severe liver disease, metastatic cancer, and atrial fibrillation/atrial or ventricular tachyarrhythmia †Includes covariates in base adjusted model, with addition of location of COVID-19 test/diagnosis (i.e., inpatient or outpatient or unknown) IQR) follow-up was 48 (2-144) days Abbreviations: CI, confidence interval Race/ethnicity 900 and 12277 patients with available data in the positive test and negative test groups, respectively. §There were 895 and 11703 patients with available data in the positive test and negative test groups, respectively. ||There were 561 and 7801 patients with available data in the positive test and negative test groups COPD, chronic obstructive pulmonary disease heart failure with reduced ejection fraction Adjusted for age, sex, race, ethnicity, asthma, type 2 diabetes mellitus, chronic obstructive pulmonary disease, hypertension, coronary artery disease, history of thrombosis, coronary revascularization, myocardial infarction, obesity, chronic kidney disease, peripheral artery disease, vascular disease, moderate/severe liver disease, metastatic cancer, and atrial fibrillation/atrial or ventricular tachyarrhythmia †Includes covariates in base adjusted model, with addition of location of COVID-19 test/diagnosis (i.e., inpatient or outpatient or Abbreviations: CI, confidence interval HFrEF, heart failure with reduced ejection fraction The authors would like to thank Dr. Amy Puenpatom for statistical and study design consultation.