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Emergency department cardiovascular disease encounters and associated mortality in patients with cancer: A study of 20.6 million records from the USA

Open AccessPublished:June 22, 2022DOI:https://doi.org/10.1016/j.ijcard.2022.06.053

      Highlights

      • Out of over 20 million ED encounters with CVD, 3.4% were in patients with cancer.
      • In patients with cancer the most common CVDs was DVT/PE.
      • Patients with cancer presenting with CVD were at higher risk of adverse outcomes.
      • Cancer was associated with higher risk of mortality in almost all CVD categories.

      Abstract

      Background

      there is limited data on Emergency department (ED) cardiovascular disease (CVD) presentations and outcomes amongst cancer patients.

      Objectives

      The present study aimed to describe the clinical characteristics, prevalence, and clinical outcomes of the most common cardiovascular ED admissions in patients with cancer.

      Methods

      All ED encounters with a primary CVD diagnosis from the US Nationwide Emergency Department Sample between January 2016 to December 2018 were stratified by cancer type as well as metastatic status. Multivariable logistic regression was performed to determine the adjusted odds ratios of in-hospital mortality in different groups.

      Results

      From a total of 20,737,247 ED encounters with a primary CVD diagnosis, cancer was present in 3.4%. In patients with cancer the most common CVDs were DVT/PE (20%), hypertensive heart or kidney disease (14.7%), and AF/flutter (11.2%). The distribution of CVDs varied by cancer type, with AF/flutter most common in patients with lung cancer, AMI most common in patients with prostate cancer, heart failure most common in those with haematological malignancies, and patients with colorectal cancer having the greatest frequency of DVT/PE. Cancer status was independently associated with significantly higher risk of mortality in almost all CVD categories, consistent across all the cancer types, amongst which lung cancer patients had the highest risk of mortality across all CVD categories, except intracranial haemorrhage and hypertensive crisis.

      Conclusions

      Cardiovascular presentations to the ED varied by cancer subtype. Across all cancer subtypes, patients presenting with cardiovascular presentations carried a significantly increased risk of mortality compared to patients with no cancer.

      Keywords

      1. Introduction

      Cancer and cardiovascular diseases (CVD) are the leading causes of morbidity and mortality worldwide [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]. Patients with cancer are at high cardiovascular risk, due to shared risk factors, chemo-radiotherapy related cardiotoxicity, and pathophysiologic processes associated with the underlying malignancy itself [
      • Ambrus J.L.
      • Ambrus C.M.
      • Mink I.B.
      • Pickren J.W.
      Causes of death in cancer patients.
      ]. Therapeutic advances have improved the life expectancy of cancer patients through reducing the risk of death from malignancy. As patients with cancer survive to older ages, CVDs are increasingly recognised as an important cause of morbidity and mortality [
      • Kobo O.
      • Khattak S.
      • Lopez-Mattei J.
      • et al.
      Trends in cardiovascular mortality of cancer patients in the US over two decades 1999-2019.
      ].
      Up to 10% of in-hospital stays in patients with cancer are attributed to CVD, with significant variations in the CVD admission diagnoses across different cancer sites [
      • Kobo O.
      • Brown S.-A.
      • Nafee T.
      • et al.
      Impact of malignancy on in-hospital mortality, stratified by the cause of admission: an analysis of 67 million patients from the National Inpatient Sample.
      ].
      The emergency department (ED) is the first point of contact for potentially serious and life-threatening CVDs. Although patients may be hospitalised from the ED, some may be treated and discharged, whilst others may not survive beyond the initial ED encounter. As such, hospital inpatient statistics alone do not provide a complete picture of cardiovascular presentations. To understand the full spectrum of cardiovascular healthcare needs of patients with cancer, it is essential that we consider the type, frequency, and outcomes from ED encounters. The present study aimed to describe the clinical characteristics, prevalence, and outcomes of the most common cardiovascular ED admissions in patients with cancer.

      2. Methods

      2.1 Data source

      We used the Nationwide Emergency Department Sample (NEDS), developed by the Healthcare Cost and Utilisation Project (HCUP) and sponsored by the Agency for Healthcare Research and Quality (AHRQ) [
      ]. The NEDS produces probabilistically accurate national estimates of hospital-owned ED encounters in the United States (US). Weighted, NEDS data estimate roughly 145 million nationally representative ED visits, comprised of discharge data from 989 hospitals located in 40 states and the District of Columbia. ED diagnoses are recorded using standardised International Classification of Disease (ICD) codes, which from 2016 onwards are based on the tenth revision (ICD-10). Patient demographics, mortality outcomes, discharge status, and charges for all patients are also captured for each encounter.

      2.2 Study population

      We analysed all ED encounters in adults (≥18 years) with any CVD listed as the primary diagnosis from the NEDS survey between January 2016 to December 2018. CVDs were grouped into the following categories: hypertensive heart or chronic kidney disease, essential hypertension, AF or atrial flutter, AMI, ischemic stroke, heart failure(HF), deep vein thrombosis(DVT) or pulmonary embolism(PE), hypertensive crisis, cardiac arrest, intracranial haemorrhage, supraventricular tachycardia(SVT). We identified patients with record of any cancer, which we then stratified by cancer type (haematological, lung, colorectal, prostate, breast, other). CVD categories and cancer types were assigned using ICD-10 codes provided in Table S1. Information on patient demographics was extracted for each encounter including age, sex, admission day (weekday or weekend), expected primary payer, and median household income according to ZIP code. Encounters with missing data for age, sex, weekend admission, or mortality status were excluded (Supplementary Fig. 1).

      2.3 Statistical analysis

      Statistical analysis was performed on IBM SPSS version 26. Continuous variables are presented as median (25th percentile, 75th percentile), due to skewed data. Categorical data are presented as frequencies and percentages. Categorical variables were compared using Pearson's chi square test, while continuous variables were compared using Kruskal-Wallis test. Sampling weights were used to calculate the estimated total discharges using methods specified by AHRQ [
      ].
      We first calculated the proportion of admissions attributed to each CVD category by cancer type (any malignancy, haematological, lung, colorectal, prostate, breast, ‘other’ malignancy). We examined overall ED and in-hospital mortality rates stratified by primary CVD diagnosis and cancer type (haematological, lung, colorectal, prostate, breast, or ‘other’ malignancy). Then, we estimated the association of cancer diagnosis with mortality (in ED or in-hospital) using fully adjusted multivariable logistic regression models, separately by CVD category and cancer type. Each cancer type (haematological, breast, prostate, lung, colon, other) was entered separately as the exposure of interest with the comparator cohort being encounters without any record of cancer; mortality was set as the model outcome. Modelled covariates included: region of hospital, location/teaching status of hospital, age, sex, weekend admission, primary expected payer, smoking status, previous AMI, valvular heart disease, previous cerebrovascular accident, dementia, hypertension, dyslipidaemia, obesity, thrombocytopenia, anaemia, chronic lung disease, coagulopathy, diabetes mellitus, liver disease, peripheral vascular disorders, chronic renal failure. In secondary analyses, we considered destination of discharge from ED, stratified by CVD category and cancer type.

      3. Results

      3.1 Baseline characteristics

      A total of 20,737,247 primary cardiovascular ED encounters were included in the study; of these, 707,585 (3.4%) had a recorded cancer diagnosis (Table 1). Haematological malignancy was the most common cancer type (178,987, 0.9%), followed by lung (119,263, 0.6%), colorectal (103,224, 0.5%), prostate (69,703, 0.3%) and breast (56,471, 0.3%) malignancies.
      Table 1Patient characteristic.
      Malignancy type
      HaematologicalLungColorectalProstateBreastOther malignancyAny MalignancyNo malignancy
      Number of weighted records, %178,987

      0.9%
      119,263

      0.6%
      103,224

      0.5%
      69,703

      0.3%
      56,471

      0.3%
      179,937

      0.9%
      707,585

      3.4%
      19,929,661

      96.6%
      Age (years), median (IQR) [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      74 (65,82)71 (63,78)69 (61, 78)77 (70,84)71 (61,80)71 (62,80)72 (63,81)67 (54,78)
      Females, % [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      43.0%46.2%40.4%0%98.5%49.0%44.9%48.8%
      Hospital Location [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      Northeast21.0%20.5%21%21%20.7%20.3%20.7%16.9%
      Midwest23.7%25.6%22.8%23.2%23.3%22.9%23.6%22.6%
      South37.6%39.6%37.9%35.1%37.9%37.5%37.8%42.6%
      West17.6%14.3%18.2%20.7%18.2%19.2%17.9%17.9%
      Hospital Location/ teaching Status [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      Metropolitan non-teaching24.0%24.4%23.5%24.4%23.4%22.6%23.6%26.1%
      Metropolitan teaching65.5%63.1%65.9%64.6%65.9%67.5%65.6%58.6%
      Non-metropolitan10.5%12.5%10.5%11.1%10.7%9.9%10.8%15.2%
      Weekend Admission [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      23.7%22.6%22.8%23.6%22.9%23%23.1%24.6%
      Median ZIP income [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1st quartile25.5%29.9%28.7%27.8%28.4%26.8%27.5%33.3%
      2nd quartile24.9%27.3%25.7%25.1%25.3%25.5%25.6%27.2%
      3rd quartile24.5%23.4%23.4%24%23.2%24.3%23.9%21.6%
      4th quartile25%19.4%22.2%23.1%23.2%23.5%23.0%17.9%
      Expected Primary Payer [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      Medicare75.9%70.9%64.6%81.2%67.2%67.1%71.0%56.2%
      Medicaid5.2%8.5%9.5%3/6%9%8.2%7.3%12.1%
      Private15.7%16.9%21.5%12%23.1%20.7%18.1%22.3%
      Uninsured1.4%1.5%1.9%1%1.3%1.9%1.6%6.6%
      No charge0.1%0.10.1%0.1%0.1%0.1%0.1%0.4%
      Other1.6%2.1%2.3%2.1%1.2%1.9%1.9%2.5%
      Comorbidities
      Previous MI [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      10.3%9.8%8.2%12.3%6.1%8.6%9.3%8.9%
      Cerebrovascular disease [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      5.9%5.9%5%7.2%5.3%6.5%6%5.7%
      Heart failure [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      46.6%32.1%27.1%40%34.4%30.8%35.7%30.9%
      Valvular disease [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      15.6%9%8.6%14.1%11.8%10.5%11.7%8.8%
      Atrial fibrillation/flutter [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      40%35.8%27.1%37.2%28.9%29.3%33.5%26%
      Hypertension [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      76.5%68.7%68%80.5%71.8%71.1%72.6%75.6%
      Dyslipidaemia [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      45.7%42%36.9%51.2%39%40.5%42.5%37.4%
      Diabetes Mellitus [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      31.7%26.1%34%31.9%29.7%28.8%30.2%30.2%
      Smoking [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      36.5%66.5%40.3%42.2%29.7%39.5%42.9%34.9%
      Peripheral vascular disease [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      7.7%9.3%5.7%8.8%5.4%6.5%7.3%5.6%
      Chronic lung disease [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      23.9%50.6%19.3%20.9%20.8%21.3%26.5%18.7%
      Chronic renal failure [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      33.8%17.7%18.5%30.9%18.9%25%25.1%20.7%
      Obesity [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      11.5%7.6%9.2%9.8%14.8%11.6%10.6%12.6%
      Anaemia [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      39.9%21.7%41%32.7%28.9%34%35.8%15.1%
      Thrombocytopenia [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      13.4%7.2%10.1%6.7%5%7.1%8.9%2.5%
      Coagulopathy [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      2.9%4.1%5.9%2.6%2.9%3.7%3.7%1.2%
      Dementia [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      6%4.4%3.7%8.9%5.6%5%5.4%5.1%
      Chronic Liver Disease [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.2%0.8%5.6%0.9%0.9%1%1.7%0.7%
      ED and In-hospital outcomes
      Total ED and inpatient charge, median (IQR) [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      37,440 (20,898, 70,862)37,860 (21,568, 70,195)38,080 (21,510, 72,254)37,560 (20,860, 71,536)34,041 (19,532, 61,603)38,482 (21,342, 72,446)37,571 (21,085, 70,658)37,398 (20,723, 71,004)
      LOS (days), median, (IQR)
      For patients admitted to hospital.
      [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      4 (2,6)4 (2,7)4 (2,7)3 (2,6)3 (2,6)4 (2,7)4 (2,6)3 (2,5)
      Overall Mortality^ [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      5.2%8.9%8.1%4.9%4.4%6.2%6.4%3.7%
      ^ ED and in-hospital mortality.
      1 p value for any malignancy vs no malignancy <0.0001; 2 p value differences between cancer types <0.0001.
      low asterisk For patients admitted to hospital.
      Compared with individuals without cancer, patients with cancer were older (median age 72 years vs. 76 years), more commonly males, had Medicare insurance, and presented to metropolitan teaching hospitals. They tended to be multimorbid with increased frequency of HF, AF, chronic lung and liver diseases, anaemia, thrombocytopenia, and coagulopathy, but with a lower prevalence of obesity.
      Amongst the specific cancer types, patients with prostate cancer were, the oldest (median 77 years) and had the highest prevalence of previous AMI (12.3%) cerebrovascular disease (7.2%), hypertension (80.5%), and dementia (8.9%). Patients with haematological malignancies had the greatest burden of pre-existing HF (46.6%), valvular heart disease (15.6%), and chronic renal failure (33.8%). Patients with colorectal cancer were the youngest (median 69 years), with a lower prevalence of HF (27.1%), cerebrovascular disease (5.0%), hypertension (68%), dyslipidaemia (36.9%) compared to the other cancer groups (Table 1).

      3.2 Primary CVD diagnoses by cancer status and cancer type

      Baseline characteristics of patients with specific causes of admission are presented in supplementary Tables 2–8. The distribution of primary CVD diagnoses by cancer status and type is summarised in Table 2, Fig. 1, and Supplementary fig. 2. The most common cardiovascular cause of ED admission amongst patients without cancer was hypertensive heart or kidney disease (14.4%), followed by essential hypertension (13.7%), and AF/flutter (9.9%). Amongst patients with cancer the most common CVD diagnosis was DVT/PE (20%), followed by hypertensive heart or kidney disease (14.7%), and AF/flutter (11.2%).
      Table 2Prevalence of the cardiovascular admission diagnoses and associated total ED and in-hospital mortality based on malignancy.
      Malignancy type
      HaematologicalLungColorectalProstateBreastOther

      Malignancy
      Any

      Malignancy
      No

      Malignancy
      Number of weighted records, %178,987

      0.9%
      119,263

      0.6%
      103,224

      0.5%
      69,703

      0.3%
      56,471

      0.3%
      179,937

      0.9%
      707,585

      3.4%
      19,929,661

      96.6%
      Hypertensive heart or chronic kidney disease, 14.4%

      (N = 2,978,453)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      20.6%11.1%10.5%17.2%14.5%13%14.7%14.4%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      3.8%5%4.1%3.5%3%3.9%3.9%1.7%
      Essential (primary) hypertension, 13.3%

      (N = 2,750,217)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.9%1.2%2%3%4%2.7%2.3%13.7%
      Mortality<0.1%<0.1%<0.1%<0.1%<0.1%0.2%0.1%<0.1%
      Atrial Fibrillation/ Flutter, 10%

      (N = 2,056,294)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      12.7%14.1%9.1%10.6%11.1%9.3%11.2%9.9%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.7%3.2%3.0%1.6%1.8%1.9%2.2%0.4%
      Acute Myocardial infarction, 8.9%

      (N = 1,829,582)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      8.2%8.1%6.8%10.7%6.1%7.3%7.8%8.9%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      6.7%11.7%11.2%5.8%6%7.9%8.3%4.1%
      Ischemic stroke, 8.1% (N = 1,662,442)Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      7.7%10.7%9.6%10%8.1%9.5%9.2%8%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      4.7%9.3%8.9%3.6%4.7%6.4%6.6%2.7%
      Heart Failure, 7.4%

      (N = 1,524,789)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      11%6.7%5.2%8.4%8.4%6.3%7.8%7.4%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      4.8%4.7%3.5%3.7%2.9%3.9%4.2%1.7%
      DVT/PE, 6.7%

      (N = 1,387,342)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      11.8%21.9%28.1%12.2%22.7%24.3%20%6.3%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      2.9%5.5%3.9%2.2%2.5%3.4%3.6%1%
      Hypertensive Crisis, 2.8%

      (N = 573,542)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.2%0.6%1.1%1.3%1.7%1.4%1.2%2.8%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      <0.1%1.1%1%0.8%0.5%0.6%0.5%0.1%
      Cardiac Arrest, 2.4%

      (N = 495,406)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.5%3.3%3.3%1.5%1.6%2.1%2.2%2.4%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      87.2%90.5%90.8%85.7%88.8%88.9%89.2%87.8%
      Intracranial Haemorrhage, 2.2%

      (N = 460,816)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      2.7%2.6%2.1%3%2.1%4.7%3.1%2.2%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      24.9%17.1%23.4%22.7%13.8%16.5%19.6%13.2%
      Supraventricular Tachycardia, 1.9%

      (N = 395,098)
      Prevalence [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.3%1.8%1.6%1.6%2%1.4%1.5%1.9%
      Mortality [
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]
      1.8%2.3%0.7%0.5%0.4%0.8%1.2%0.1%
      1 p value for any malignancy vs no malignancy <0.0001; 2 p value differences between cancer types <0.0001.
      Fig. 1
      Fig. 1Overview of the cardiovascular ED admission diagnoses for patients with malignancy, by malignancy type.
      DVT: deep vein thrombosis, PE: pulmonary embolism, SVT: supraventricular tachycardia. *p Value <0.001.
      The proportion of CVD admission attributed to DVT/PE was greater amongst individuals with any cancer compared to those without cancer (20% vs 6.3%). This was consistent across all the cancer types, and most notable amongst those with colorectal (28.1%), breast (22.7%), and lung (21.9%) cancer.
      Attendance for primary diagnosis of hypertensive heart disease or chronic kidney disease featured prominently for both patients with (14.7%) and without (14.4%) cancer, being most common in patients with haematological (20.6%) and prostate (17.2%), and breast (14.5%) cancers. The proportion of attendances attributed to “hypertensive crisis” was slightly more common amongst those with (2.8%) than those without (1.2%) cancer.
      AF/flutter appeared more commonly amongst those with cancer (11.2%) compared with those without cancer (9.9%), being most common in patients with lung cancer (14.1%).
      Intracranial haemorrhage and ischaemic strokes occurred more commonly amongst cancer patients, however these differences were small. The proportion of admissions attributed to AMI and cardiac arrests were comparable amongst those with and without cancer; however, within the cancer subtypes, those with prostate cancer had the greatest proportion of AMI (10.7% vs 8.9% amongst those without cancer). HF was most common in patients with haematological cancers (11%), appearing more commonly than in those without cancer (7.4%) and in the cancer cohorts combined (7.8%).

      3.3 Mortality

      Patients with cancer had higher unadjusted rates of all-cause mortality compared with the no-cancer group (6.4% vs. 3.7%, p < 0.001) Amongst the cancer subgroups, lung cancer carried the highest rate of all-cause mortality (8.9%), followed by colorectal cancer (8.1%), cancer of other causes (6.2%), haematological (5.2%), prostate (4.9%) and breast (4.4%) cancer (Table 1).
      When accounting for the specific principal diagnoses, the unadjusted rates of all-cause mortality were higher in patients with cancer across all selected cardiovascular admission diagnoses (P < 0.001), except in patients with haematological malignancies who had the lowest mortality following presentation with hypertensive crisis (<0.1% vs 0.1%–1.1%) and cardiac arrest (87.2% vs 87.8%–90.8%). As expected, admission with cardiac arrest was associated with the highest mortality rate across all cancers (87.2%–90.8%), followed by intracranial haemorrhage (13.2%–24.9%). Table 2.
      Amongst the cancer subtypes, patients with lung cancer had the highest in hospital (in ED and during admission as inpatient) mortality for acute MI (11.7%), ischemic stroke (9.3%), DVT/PE (5.5%) hypertensive heart or kidney disease (5%), atrial fibrillation/flutter (3.2%), SVT (2.3%), and hypertensive crisis (1.1%). The highest mortality of patients presenting with intracranial haemorrhage was observed in patients with haematological cancers. The lowest mortality of AMI (5.8%) and ischemic stroke (3.6%), DVT/PE (2.2%) atrial fibrillation/ flutter (1.6%) was observed in patients with prostate cancer. Finally, the lowest mortality rates associated with the primary diagnoses of intracranial haemorrhage (13.8%) and HF (2.9%) were observed in the breast cancer group (Table 2).
      Following adjustment for differences in baseline covariates, the adjusted odds of in hospital mortality were significantly increased for most of the acute CV causes for ED presentation in all cancers. Presentation with AF/flutter (aOR 2.22–5.23), hypertensive heart or kidney disease (aOR 1.33–2.57), HF (aOR1.5–2.55), and DVT/PE (aOR 1.58–4.53) were associated with an increased odds of all-cause mortality in all cancer groups. SVT was associated with highest aOR for mortality amongst patients with lung (aOR 8.17, 95% CI 5,88–11.34) and haematological malignancies (aOR 3.9, 95% CI 2.76–5.52).
      Cardiac arrest, AMI, ischemic, and haemorrhagic stroke, were associated with increased odds of mortality amongst most cancer types. The exceptions are prostate cancer which was associated with lower odds of mortality after cardiac arrest (aOR 0.83, 95%CI 0.7–0.99), and similar odds of mortality after AMI (aOR 0.94, 95% CI 0.85–1.03) and ischemic stroke (aOR 0.9, 95% CI 0.79–1.02); and breast cancer which was associated with similar odds of mortality after intracranial haemorrhage (aOR 0.93, 95% CI (0.78–1.09) Table 3.
      Table 3Adjusted odds of total (ED and inpatient) mortality in different malignancy types and selected cardiovascular admission diagnoses
      Reference group is group without any malignancy.Note: Binomial multivariable logistic regression analysis. adjusted for: region of hospital, location/teaching status of hospital, age, sex, weekend admission, primary expected payer, smoking status, previous myocardial infarction, valvular heart disease, previous cerebrovascular accident, dementia, dyslipidemia, obesity, thrombocytopenia and other comorbidities (anemias, chronic lung disease, coagulopathy, diabetes mellitus, liver disease, peripheral vascular disorders, chronic renal failure).
      HaematologicalLungColorectalProstateBreastOther
      Malignancy
      Hypertensive heart or chronic kidney disease1.592.571.931.331.681.88
      aOR (95%CI), p value(1.5–1.68)(2.37–2.78)(1.75–2.13)(1.21–1.47)(1.48–1.92)(1.76–2.01)
      P < 0.0012P < 0.0012P < 0.0012P < 0.0012P < 0.0012<0.0012
      Atrial Fibrillation/Flutter2.225.23 (4.76–5.75)4.552.33.423.11
      aOR (95%CI), p value(1.99–2.47)P < 0.0012(4.02–5.16)(1.91–2.78)(2.82–4.14)(2.77–3.48)
      P < 0.0012P < 0.0012P < 0.0012P < 0.0012P < 0.0012
      Acute Myocardial infarction1.092.652.180.941.131.46
      aOR (95%CI), p value(1.01–1.16)(2.49–2.83)(2.02–2.35)(0.85–1.03)(0.98–1.3)(1.37–1.56)
      P = 0.022P < 0.0012P < 0.0012P = 0.22P = 0.12P < 0.0012
      Ischemic stroke1.21 (1.12–1.32)2.86 (2.69–3.05)2.36 (2.19–2.54)0.9 (0.79–1.02)1.41 (1.23–1.62)1.88 (1.76–2)
      aOR (95%CI), p valueP < 0.0012P < 0.0012P < 0.0012P = 0.12P < 0.0012P < 0.0012
      Heart Failure2.12.551.691.51.631.88
      aOR (95%CI), p value(1.96–2.25)(2.29–2.83)(1.56–1.96) P < 0.0012(1.31–1.72)(1.37–1.93)(1.7–2.07) P < 0.0012
      P < 0.0012P < 0.0012P < 0.0012P < 0.0012
      DVT/PE2.04 (1.88–2.22)4.533.061.582.1 (1.87–2.36)2.79
      aOR (95%CI), p valueP < 0.0012(4.27–4.81) P < 0.0012(2.86–3.26)(1.36–1.83)P < 0.0012(2.64–2.95)
      P < 0.0012P < 0.0012P < 0.0012
      Hypertensive CrisisN/A14.415.82.773.743.11
      aOR (95%CI), p value(2.03–9.57)(3.15–10.7)(1.31–5.8)(1.52–9.23)(1.18–5.33)
      P < 0.0012P < 0.0012P = 0.0082P = 0.0042P < 0.0012
      Cardiac Arrest1.11.461.370.831.241.22
      aOR (95%CI), p value(0.98–1.25)(1.31–1.63)(1.22–1.54)(0.7–0.99)(1–1.52)(1.01–1.35)
      1.2

      P = 0.092
      P < 0.0012P < 0.0012P = 0.042P = 0.0472P < 0.0012
      Intracranial Haemorrhage1.761.231.71.690.931.28
      aOR (95%CI), p value(1.65–1.88)(1.11–1.35)(1.54–1.88)(1.52–1.8)(0.78–1.09)(1.2–1.35)
      P < 0.0012P < 0.0012P < 0.0012P < 0.0012P = 0.372P < 0.0012
      Supraventricular Tachycardia3.98.171.730.993.192.14
      aOR (95%CI), p value(2.76–5.52)(5.88–11.34)(0.9–3.32)(0.39–2.49)(1.3–7.83)(1.32–3.46)
      P < 0.0012P < 0.0012P = 0.12P = 0.982P = 0.012P = 0.0022
      1N/A due to small numbers. 2 Hosmer and Lemeshow test p value>0.05.
      Abbreviations: aOR – adjusted Odds Ratios; CI – Confidence Interval.
      low asterisk Reference group is group without any malignancy.Note: Binomial multivariable logistic regression analysis. adjusted for: region of hospital, location/teaching status of hospital, age, sex, weekend admission, primary expected payer, smoking status, previous myocardial infarction, valvular heart disease, previous cerebrovascular accident, dementia, dyslipidemia, obesity, thrombocytopenia and other comorbidities (anemias, chronic lung disease, coagulopathy, diabetes mellitus, liver disease, peripheral vascular disorders, chronic renal failure).

      3.4 Destination of discharge from ED

      supplementary fig. 3 and supplementary table 9 presents the destination of discharge of patients from ED. Compared to patients without cancer, those with cancer were more likely to be admitted to the hospital (76.7% vs 49.8%), and less likely to be discharged home (16.4% vs 39.4%). Amongst different cancer types, patients with lung cancer were most likely to be admitted to the hospital (79%) and patients with breast cancer were least likely to be admitted (71.6%). Only 12.9% of lung cancer patients were discharged home. While the ED mortality rate was higher amongst patients with colorectal (3.1%) or lung (2.8%) compared to patients with no cancer (2.2%) it was lower amongst patients in other cancer groups (1.2%–1.8%).

      4. Discussion

      We evaluated over 20 million ED encounters with a primary CVD diagnosis and considered the distribution of CVDs and subsequent mortality outcomes by cancer status and cancer type. A total of 3.4% of ED encounters were in patients with cancer. The most common CVDs in patients without cancer were hypertensive heart or kidney disease (14.4%), essential hypertension (13.7%), and AF/flutter (9.9%). Whilst, in patients with cancer the most common CVDs were DVT/PE (20%), hypertensive heart or kidney disease (14.7%), AF/flutter (11.2%), and ischemic stroke (9.2%). The distribution of CVDs varied by cancer type, with AF/flutter most common in patients with lung cancer, AMI most common in patients with prostate cancer, HF most common in those with haematological malignancies, and DVT/PE in patients with colorectal cancer. Patients with cancer presenting with an emergency CVD encounter were at higher risk of adverse outcomes compared with those without cancer. Cancer status was independently associated with significantly higher risk of mortality in almost all CVD categories, consistent across all the cancer types, amongst which lung cancer patients had the highest risk of mortality across all CVD categories, except intracranial haemorrhage and hypertensive crisis.
      Previous epidemiologic studies have characterised the rates and utilisation patterns of EDs by patients with cancer [
      • Oatley M.
      • Fry M.
      • Mullen L.
      A cross-sectional study of the clinical characteristics of cancer patients presenting to one tertiary referral emergency department.
      ,
      • Rivera D.R.
      • Gallicchio L.
      • Brown J.
      • Liu B.
      • Kyriacou D.N.
      • Shelburne N.
      Trends in adult cancer-related emergency department utilization: an analysis of data from the nationwide emergency department sample.
      ,
      • Caterino J.M.
      • Adler D.
      • Durham D.D.
      • et al.
      Analysis of diagnoses, symptoms, medications, and admissions among patients with cancer presenting to emergency departments.
      ,
      • Vandyk A.D.
      • Harrison M.B.
      • Macartney G.
      • Ross-White A.
      • Stacey D.
      Emergency department visits for symptoms experienced by oncology patients: a systematic review.
      ,
      • Peyrony O.
      • Fontaine J.-P.
      • Beaune S.
      • et al.
      EPICANCER-Cancer patients presenting to the emergency Departments in France: a prospective Nationwide study.
      ,
      • Gallaway M.S.
      • Idaikkadar N.
      • Tai E.
      • et al.
      Emergency department visits among people with cancer: frequency, symptoms, and characteristics.
      ,
      • Mayer D.K.
      • Travers D.
      • Wyss A.
      • Leak A.
      • Waller A.
      Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina.
      ,
      • Lee S.Y.
      • Ro Y.S.
      • Do Shin S.
      • Moon S.
      Epidemiologic trends in cancer-related emergency department utilization in Korea from 2015 to 2019.
      ] However, these studies have not specifically looked in granular detail at cardiovascular data. Whilst those that have systematically examined CVD diagnoses have focussed on in-hospital admissions [
      • Matetic A.
      • Mohamed M.
      • Miller R.J.H.
      • et al.
      Impact of cancer diagnosis on causes and outcomes of 5.9 million US patients with cardiovascular admissions.
      ] or mortality data. Thus, there is limited data on ED CVD presentations and outcomes amongst cancer patients. Our study presents a dedicated analysis of primary CVD ED encounters, extending existing literature and providing novel insights into the full spectrum of cardiovascular healthcare needs of patients with cancer.
      Our findings indicate that patients with haematologic, lung, and colorectal cancers are the top three cancer types attending ED with a primary CVD diagnosis, whilst patients with breast and prostate cancer were less frequently encountered. Previous studies examining ED attendances without specificity to CVD have reported a slightly different distribution of cancer types. In an analysis of 37,760 ED visits by patient with cancer in North Carolina, Mayer et al. identified patients with lung, breast, prostate, and colorectal cancers as the most common cancer types encountered [
      • Mayer D.K.
      • Travers D.
      • Wyss A.
      • Leak A.
      • Waller A.
      Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina.
      ]. Consistent with these findings, Gallaway et al. [
      • Gallaway M.S.
      • Idaikkadar N.
      • Tai E.
      • et al.
      Emergency department visits among people with cancer: frequency, symptoms, and characteristics.
      ] also showed that lung, breast, colorectal, and prostate are the most commonly encountered cancer types in ED. Lee et al. [
      • Lee S.Y.
      • Ro Y.S.
      • Do Shin S.
      • Moon S.
      Epidemiologic trends in cancer-related emergency department utilization in Korea from 2015 to 2019.
      ] presented a nationwide analysis of ED use amongst cancer patients in Korea. They identified lung, liver, and colorectal cancer as the most common cancers. Thus, it appears that lung and colorectal cancers are frequent attenders of the ED for both CVD and non-CVD diagnoses. However, whilst breast cancer patients were featured highly in unselected analyses of ED presentations [
      • Gallaway M.S.
      • Idaikkadar N.
      • Tai E.
      • et al.
      Emergency department visits among people with cancer: frequency, symptoms, and characteristics.
      ,
      • Mayer D.K.
      • Travers D.
      • Wyss A.
      • Leak A.
      • Waller A.
      Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina.
      ] they were less commonly encountered in our analysis. This suggests that breast cancer patients are high users of ED services, but that this is most often for non-CVD illnesses. Indeed, in an earlier analysis of unselected ED visits by cancer patients using the NEDS database, Rivera et al. [
      • Rivera D.R.
      • Gallicchio L.
      • Brown J.
      • Liu B.
      • Kyriacou D.N.
      • Shelburne N.
      Trends in adult cancer-related emergency department utilization: an analysis of data from the nationwide emergency department sample.
      ] reported breast [14.9%], prostate [11.3%], and lung [10.3%] cancer as the most common cancer presenting to ED. The most common primary reasons for visits were pneumonia (4.5%), nonspecific chest pain (3.7%), and urinary tract infection (3.2%). These observations indicate differential ED usage for CVD diagnoses by cancer type, which is distinct from patterns of unselected ED utilisation.
      We found that 76.4% of cancer patients presenting to ED with a CVD required hospitalisation, which was significantly greater than individuals without cancer. Rivera et al. [
      • Rivera D.R.
      • Gallicchio L.
      • Brown J.
      • Liu B.
      • Kyriacou D.N.
      • Shelburne N.
      Trends in adult cancer-related emergency department utilization: an analysis of data from the nationwide emergency department sample.
      ] report association of cancer-related ED visits with significantly higher inpatient admission rate than non–cancer-related ED visits (59.7% vs 16.3%). These admission rates for cancer patients presenting to ED are reasonably consistent across the literature, with Mayer et al. [
      • Mayer D.K.
      • Travers D.
      • Wyss A.
      • Leak A.
      • Waller A.
      Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina.
      ] reporting a rate of 63.2%, Lee et al. [
      • Lee S.Y.
      • Ro Y.S.
      • Do Shin S.
      • Moon S.
      Epidemiologic trends in cancer-related emergency department utilization in Korea from 2015 to 2019.
      ] a rate of 54.8%, and in a nationwide study from France, Peyroni et al. [
      • Peyrony O.
      • Fontaine J.-P.
      • Beaune S.
      • et al.
      EPICANCER-Cancer patients presenting to the emergency Departments in France: a prospective Nationwide study.
      ] report a hospitalisation rate of 64.9%. Thus, overall cancer patients presenting to the ED have high likelihood of requiring hospitalisation; however, our findings suggest that this risk is greatly increased in patients presenting with a primary CVD diagnosis.
      In our study of ED CVD visits, a greater proportion of cancer patients died (ED and in-hospital) compared with those without cancer (6.4% vs 3.7). Lee et al. [
      • Lee S.Y.
      • Ro Y.S.
      • Do Shin S.
      • Moon S.
      Epidemiologic trends in cancer-related emergency department utilization in Korea from 2015 to 2019.
      ] and Peyroni et al. [
      • Peyrony O.
      • Fontaine J.-P.
      • Beaune S.
      • et al.
      EPICANCER-Cancer patients presenting to the emergency Departments in France: a prospective Nationwide study.
      ] report higher mortality rates, than in our study, of 9.5% and 13.4%, respectively. The absence of CVD-specific data in these studies preclude direct comparison with our results, particularly given the great heterogeneity in clinical status of cancer patients and the wide range of illnesses with which they may present.
      Our findings suggest that cancer status appeared to be significantly associated with mortality independent of a wide range demographic and clinical factors, this appeared broadly consistently across all cancer types and CVD subtypes. We found that the risk of death to be most augmented in patients with lung cancer. Patients with lung cancer had over 8-fold and over 5-fold greater adjusted risk of death after an ED encounter with SVT and AF/flutter, respectively, and over 4-fold risk of death after encounter with DVT/PE or hypertensive crisis. The association between AF and lung cancer is multifactorial with smoking status, pre-existing chronic lung disease, pulmonary hypertension, mass affect from atrial structures radiotherapy, and subclinical metastatic disease all implicated [
      • Grymonprez M.
      • Vakaet V.
      • Kavousi M.
      • et al.
      Chronic obstructive pulmonary disease and the development of atrial fibrillation.
      ,
      • Wanamaker B.
      • Cascino T.
      • McLaughlin V.
      • Oral H.
      • Latchamsetty R.
      • Siontis K.C.
      Atrial arrhythmias in pulmonary hypertension: pathogenesis, prognosis and management.
      ,
      • Bandyopadhyay D.
      • Ball S.
      • Hajra A.
      • et al.
      Impact of atrial fibrillation in patients with lung cancer: insights from national inpatient sample.
      ,
      • Yang X.
      • Li X.
      • Yuan M.
      • et al.
      Anticancer therapy-induced atrial fibrillation: electrophysiology and related mechanisms.
      ]. This is particularly important as AF is challenging from an anticoagulation perspective as patients with cancer are at both an increased risk of VTE and bleeding, both as progression of the disease and medications associated with treatment [
      • Barish R.
      • Gates E.
      • Barac A.
      Trastuzumab-induced cardiomyopathy.
      ]. Historically, patients with AF or VTE and cancer were managed with low molecular weight heparin (LMWH) or warfarin [
      • Mosarla R.C.
      • Vaduganathan M.
      • Qamar A.
      • Moslehi J.
      • Piazza G.
      • Giugliano R.P.
      Anticoagulation strategies in patients with cancer: JACC review topic of the week.
      ]. More recently, direct oral anticoagulants (DOACs) therapies have been shown to be non-inferior with easier dosing strategies than LMWH or warfarin, even amongst patients with cancer-related VTE [
      • Elbadawi A.
      • Shnoda M.
      • Mahmoud K.
      • Elgendy I.Y.
      Efficacy and safety of direct oral anticoagulants vs. low molecular weight heparin for cancer-related venous thromboembolism: a meta-analysis of randomized trials.
      ].
      The most common CVD amongst those with cancer was DVT/PE, being over 3-fold more frequent amongst those with cancer compared with those without (20% vs 6.3%). The greater risk of venous thromboembolism amongst cancer patients is widely reported and our findings are consistent with previous population-based studies [
      • Cohen A.T.
      • Katholing A.
      • Rietbrock S.
      • Bamber L.
      • Martinez C.
      Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study.
      ,
      • Stein P.D.
      • Beemath A.
      • Meyers F.A.
      • Skaf E.
      • Sanchez J.
      • Olson R.E.
      Incidence of venous thromboembolism in patients hospitalized with cancer.
      ]. Malignancies activate the coagulation cascade and enhance prothrombotic properties of host cells, in addition to known risk factors of thrombosis including chemotherapy and immobilisation [
      • Abdol Razak N.B.
      • Jones G.
      • Bhandari M.
      • Berndt M.C.
      • Metharom P.
      Cancer-associated thrombosis: an overview of mechanisms, risk factors, and treatment.
      ]. Cancer patients have been shown to have a 5–7 fold increase of developing VTE [
      • Agnelli G.
      • Verso M.
      Management of venous thromboembolism in patients with cancer.
      ,
      • Blom J.W.
      • Doggen C.J.M.
      • Osanto S.
      • Rosendaal F.R.
      Malignancies, prothrombotic mutations, and the risk of venous thrombosis.
      ], and for those patients who develop VTE with cancer, they have a significantly worse prognosis compared to cancer patients without VTE [
      • Karimi M.
      • Cohan N.
      Cancer-associated thrombosis.
      ]. In our analysis, DVT/PE was more common in those with colorectal (28.1%), breast (22.7%), and lung cancer (21.9%); these findings are consistent with previous reports [
      • Cohen A.T.
      • Katholing A.
      • Rietbrock S.
      • Bamber L.
      • Martinez C.
      Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study.
      ,
      • Lee L.H.
      • Nagarajan C.
      • Tan C.W.
      • Ng H.J.
      Epidemiology of cancer-associated thrombosis in Asia: a systematic review.
      ]. The augmented risk of VTE in patients with these cancers is likely complicated with requirement for major surgeries, which as well as further increasing the risk of VTE may also be associated with interruptions to anticoagulation. Such scenarios are challenging and require careful risk balance evaluations. There are also suggestions that distinct pathophysiology of these cancers may further predispose to VTE. For example, in colorectal cancer tissue factor is abnormally expressed on tumour cells [
      • Seto S.
      • Onodera H.
      • Kaido T.
      • et al.
      Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis.
      ] and colorectal cancer patients with high serum tissue levels have been shown to have significantly increased risk of recurrent VTE whilst on anticoagulation [
      • Khorana A.A.
      • Kamphuisen P.W.
      • Meyer G.
      • et al.
      Tissue factor as a predictor of recurrent venous thromboembolism in malignancy: biomarker analyses of the CATCH trial.
      ]. Thus, whilst VTE risk is elevated amongst cancer patients, the risk is not uniform across cancer types with a multitude of treatment and cancer-specific mechanisms playing a role in cancer-associated thrombosis.
      Interestingly, we found that attendances for severe manifestations of hypertension (e.g., end-organ damage or crisis) appeared prominent amongst across the whole sample of patients presenting with CVD, with comparable distribution amongst cancer and non-cancer patients. However, many more admissions were attributed to essential hypertension amongst those without cancer (13.7%), than those with cancer (2.3%). This may reflect different referral and service use patterns amongst cancer patients. As patients with cancer have greater healthcare contact through multiple sources, they may be less likely to present to the ED with problems that could be managed in other settings.
      Haematological malignancies were most common in patients with HF, with breast cancer the least frequent compared to other cancer subgroups. Breast cancer, specifically with the use of Herceptin has been associated with cardiotoxicity and HF [
      • Johnstone C.
      • Rich S.E.
      Bleeding in cancer patients and its treatment: a review.
      ], whilst haematological malignancies have been implicated in HF due to the use of anthracyclines which have been shown to be cardiotoxic but are often used to treat both solid and haematological cancers [
      • Swain S.M.
      • Whaley F.S.
      • Ewer M.S.
      Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.
      ]. However, surveillance strategies do differ by cancer subtype with increasingly frequent monitoring by echocardiogram or cardiac magnetic resonance imaging in breast cancer, which may in part reflect the reduced rates of HF in this group [
      • Di Lisi D.
      • Bonura F.
      • Macaione F.
      • et al.
      Chemotherapy-induced cardiotoxicity: role of the conventional echocardiography and the tissue Doppler.
      ,
      • Davis C.C.
      • Zelnak A.
      • Eley J.W.
      • Goldstein D.A.
      • Switchenko J.M.
      • McKibbin T.
      Clinical utility of routine cardiac monitoring in breast cancer patients receiving Trastuzumab.
      ]. The frequency of haematological malignancy was also highest in patients with AMI. This is likely a reflection of their prothrombotic state. Additionally, patients with CLL tended to be male, older and the higher prevalence of AMI increased with age.

      4.1 Strengths and limitations

      In this study we utilised the NEDS database to evaluate a large sample of nationally representative record of ED visits with diagnoses recorded using ICD-10 codes. Of course, administrative datasets that utilise ICD-10 coding also have several limitations, including risk of misdiagnoses, miscoding, or coding omissions. However, this is an unlikely source of bias in our study as it is unlikely that the rates of such errors are differential across patients. As we were reliant on ICD-10 codes, the granularity of our diagnoses was limited by the predefined disease categories. However, the as ICD-10 codes are used in routine health records internationally, their use permits wider generalisability of our findings and allows for comparison across other cohorts. Additionally, due to limitations of the NEDS dataset, we were unable to evaluate the influence of factors such as chemo-radiotherapy, haematological and blood biochemistry indices, stage of cancer, how long patients have been diagnosed with cancer in relation to the index admission, or whether there are ceilings of care in place that limit the management and therefore determine clinical outcomes. Although we were able to reliably ascertain fact of death, we were unable to consider cause-specific mortality. Finally, the NEDS includes in-hospital events and does not provide long-term outcomes. As with other observational studies of this nature, it is possible that our results could be affected by confounding. We have tried to mitigate for this by adjusting for the appropriate variables in our multivariate models. Finally, our analysis is largely descriptive and is not used to test hypotheses.

      5. Conclusions

      In this analysis of ED encounters, patients with cancer tended to be older and increasingly multimorbid. Cardiovascular presentations to the ED varied by cancer subtype with lung cancer being increasingly prevalent with AF, colorectal cancer with VTE and haematological malignancies with HF and AMI. Across all cancer subtypes, cancer patients presenting with cardiovascular presentations carried a significantly increased risk of mortality. They were more likely to be admitted to hospital. Recognition of their increased risk factor profile is likely to influence management of this high risk heterogenous group of patients by physicians in the ED.

      Funding

      ZR-E recognizes the National Institute for Health Research (NIHR) Integrated Academic Training programme which supports her Academic Clinical Lectureship post and was also supported by British Heart Foundation Clinical Research Training Fellowship No. FS/17/81/33318.
      The remaining authors have nothing to disclose.

      Declaration of Competing Interest

      Giuseppe Biondi-Zoccai has consulted for Cardionovum, Innovheart, Meditrial, Opsens Medical, and Replycare.

      Acknowledgements

      None.

      Appendix A. Supplementary data

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