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Research Article| Volume 192, P7-15, April 01, 2023

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Association of Frailty Status on the Causes and Outcomes of Patients Admitted With Cardiovascular Disease

Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.amjcard.2022.12.029
      Data are limited about the contemporary association between frailty and the causes and outcomes of patients admitted with cardiovascular diseases (CVD). Using the US National Inpatient Sample, CVD admissions of interest (acute myocardial infarction, ischemic stroke, atrial fibrillation (AF), heart failure, pulmonary embolism, cardiac arrest, and hemorrhagic stroke) were stratified by Hospital Frailty Risk Score (HFRS). Logistic regression was used to determine adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of in-hospital mortality among different groups with frailty. The study included 9,317,398 hospitalizations. Of these, 5,573,033 (59.8%) had a low HFRS (<5); 3,422,700 (36.7%) had an intermediate HFRS (5 to 15); and 321,665 (3.5%) had a high HFRS (>15). Ischemic stroke was the most common admission for the groups with high risk (75.4%), whereas acute myocardial infarction was the most common admission for the group with low risk (36.9%). Compared with the group with low risk, patients with high risk had increased mortality across the most CVD admissions, except in patients admitted for cardiac arrest and hemorrhagic stroke (p <0.001). The strongest association with all-cause mortality was shown among patients with high risk admitted for AF (aOR 6.75, 95% CI 6.51 to 7.00, and aOR 17.69, 95% CI 16.08 to 19.45) compared with their counterparts with low risk. In conclusion, patients with CVD admissions have varying frailty risk according to cardiovascular cause of admission, with ischemic stroke being the most common among groups with frailty and high risk. Increased frailty is associated with all-cause mortality in patients with most CVD admissions, except for cardiac arrest and hemorrhagic stroke, with the strongest association seen in patients admitted with AF.

      Graphical Abstract

      Frailty is defined as an impairment of multiple systems resulting in an increased vulnerability to stress, leading to an increased risk of adverse outcomes such as hospitalizations and mortality, and is strongly associated with age.
      • Xue QL.
      The frailty syndrome: definition and natural history.
      With the growing numbers of the older population, the proportion living with frailty in society and across healthcare systems is increasing.
      • Ramsay SE
      • Arianayagam DS
      • Whincup PH
      • Lennon LT
      • Cryer J
      • Papacosta AO
      • Iliffe S
      • Wannamethee SG.
      Cardiovascular risk profile and frailty in a population-based study of older British men.
      Similarly, the numbers of patients living with cardiovascular (CV) disease (CVD) are increasing, particularly given an improved survivorship in patients with acute or chronic CVD.
      • Vasan RS
      • Enserro DM
      • Xanthakis V
      • Beiser AS
      • Seshadri S.
      Temporal trends in the remaining lifetime risk of cardiovascular disease among middle-aged adults across 6 decades: the Framingham study.
      The relation between frailty and CVD is bidirectional.
      • Chung KJNC
      • Wilkinson C
      • Veerasamy M
      • Kunadian V.
      Frailty scores and their utility in older patients with cardiovascular disease.
      CVD is associated with a threefold increase in frailty, and frailty is independently associated with an increased mortality from CVD.
      • Newman AB
      • Gottdiener JS
      • McBurnie MA
      • Hirsch CH
      • Kop WJ
      • Tracy R
      • Walston JD
      Fried LP, Cardiovascular Health Study Research Group. Associations of subclinical cardiovascular disease with frailty.
      ,
      • Afilalo J
      • Karunananthan S
      • Eisenberg MJ
      • Alexander KP
      • Bergman H.
      Role of frailty in patients with cardiovascular disease.
      A recent meta-analysis including 31,343 patients with CVD reported that the prevalence of frailty was 17.9% and was associated with an increased risk of heart failure (HF).
      • Veronese N
      • Cereda E
      • Stubbs B
      • Solmi M
      • Luchini C
      • Manzato E
      • Sergi G
      • Manu P
      • Harris T
      • Fontana L
      • Strandberg T
      • Amieva H
      • Dumurgier J
      • Elbaz A
      • Tzourio C
      • Eicholzer M
      • Rohrmann S
      • Moretti C
      • D'Ascenzo F
      • Quadri G
      • Polidoro A
      • Lourenço RA
      • Moreira VG
      • Sanchis J
      • Scotti V
      • Maggi S
      • Correll CU
      Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis.
      Previous studies have attempted to understand the underlying mechanisms linking older age and adverse CVD outcomes, with common mechanisms implicated being inflammation, concomitant risk factors, and co-morbidity burden.
      • Ramsay SE
      • Arianayagam DS
      • Whincup PH
      • Lennon LT
      • Cryer J
      • Papacosta AO
      • Iliffe S
      • Wannamethee SG.
      Cardiovascular risk profile and frailty in a population-based study of older British men.
      However, there are few data investigating whether CVD admissions vary by frailty status and whether frailty is associated with in-hospital outcomes in patients admitted with acute CVD conditions. Knowledge of the specific causes of CVD admissions and their outcomes in relation to frailty status is fundamental in planning healthcare services around the growing needs of the population living with frailty. Therefore, the aim of this study was to describe the prevalence, clinical characteristics, and in-hospital mortality of patients with the CVD admissions of interest based on their frailty status, as measured by the Hospital Frailty Risk Score (HFRS).

      Methods

      The National Inpatient Sample (NIS) is the largest available database of US hospitalizations developed for the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality.

      Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUP). Available at: https://www.ahrq.gov/data/hcup/index.html. Accessed on 01/09/2023.

      The NIS contains anonymized data on diagnoses and procedures from >7 million hospitalizations annually, representing a 20% stratified sample of all discharges from US community hospitals, excluding rehabilitation and long-term acute care hospitals.

      Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUP). Available at: https://www.ahrq.gov/data/hcup/index.html. Accessed on 01/09/2023.

      The HFRS was developed by Gilbert et al
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      to establish whether older patients at risk of adverse outcomes could be identified using routinely collected healthcare data. Briefly, a cohort of older patients (aged >74 years) hospitalized with diagnoses associated with frailty was identified.
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      The HFRS was then created by grouping the patients identified according to their International Classification of Diseases (ICD) Tenth Revision codes into 3 groups: low risk (HFRS <5), intermediate risk (HFRS 5 to 15), and high risk (HFRS >15).
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      The score was then validated using a local and national United Kingdom cohort.
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      Each component of the HFRS and the associated weighting is outlined in Supplementary Appendix 1.
      Using ICD Tenth Revision codes (Supplementary Table 1), all adult discharge records with a principal diagnosis of an acute CVD admission between October 2015 and December 2019 were identified. This sample was further filtered by focusing on the 7 CVD admissions of interest: acute myocardial infarction (AMI), atrial fibrillation/flutter (AF), ischemic stroke, HF, pulmonary embolism (PE), cardiac arrest, and hemorrhagic stroke. The sample was further stratified according to their frailty status measured by the HFRS into 3 groups: low risk (HFRS <5), intermediate risk (HFRS 5 to 15), and high risk (HFRS >15), as defined by Gilbert et al.
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      Cases were excluded owing to missing data for the following variables: age, gender, elective admission, in-hospital mortality, primary expected payer, total charges, and length of stay. These cases accounted for no more than 1.0% of the original dataset. Cases not pertaining to 1 of the 7 diagnoses of interest were also excluded (Supplementary Figure 1). This observational study was appraised according to the Strengthening The Reporting of OBservational Studies in Epidemiology recommendations (Supplementary Appendix 2).
      Continuous variables such as age, length of stay, and total charges were summarized using median and interquartile range. Categorical variables were compared using the chi-square test and summarized as percentages (%). Multivariable logistic regression was performed to determine the adjusted odds ratio (aOR) for all-cause mortality. Regression was adjusted for the following variables: age, gender, race, weekend admission, primary expected payer, median household income, bed size of hospital, region of hospital, location/teaching status of hospital, smoking status, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass graft, dyslipidemia, and Elixhauser co-morbidities (anemias, coagulopathy, diabetes mellitus, liver disease, metastatic cancer, peripheral vascular disorders, and chronic renal failure). Results were presented as aORs with 95% confidence intervals (CIs). Results were determined significant at the level of p <0.05. All statistical analyses were weighted and performed using SPSS version 27 (IBM Corp, Armonk, New York).

      IBM. SPSS Statistics for Macintosh. version 27.0 Armonk, NY: IBM Corp. https://www.ibm.com/support/pages/how-cite-ibm-spss-statistics-or-earlier-versions-spss.

      Results

      A total of 9,317,398 discharges had 1 of the 7 CVD diagnoses of interest (AMI, ischemic stroke, AF, HF, PE, and hemorrhagic stroke) (Supplementary Figure 1). Overall, 5,573,033 discharges (59.8%) had an HFRS of <5; 3,422,700 (36.7%) had an HFRS of 5 to 15; and 321,665 (3.5%) had an HFRS of >15 (Table 1).
      Table 1Patient characteristics for all cardiovascular admissions according to HFRS
      CharacteristicsHospital Frailty Risk ScoreOverall p Value
      Low <5 (59.8%)Intermediate 5–15 (36.7%)High >15 (3.5%)
      Number of weighted discharges5,573,0333,422,700321,665<0.001
      Age (years), median (IQR)68 (58, 78)73 (62, 82)75 (63,84)<0.001
      Female sex43.0%49.7%54.1%<0.001
      Ethnicity<0.001
      White74.8%70.4%65.0%
      Black12.3%15.6%19.2%
      Hispanic7.6%8.0%8.8%
      Other5.3%6.0%7.0%
      Weekend admission23.4%25.3%26.3%<0.001
      Primary expected payer<0.001
      Medicare58.9%70.5%72.4%
      Medicaid9.5%8.7%9.6%
      Private insurance24.6%15.4%13.1%
      Self-pay4.2%3.1%3.0%
      No charge0.4%0.2%0.2%
      Other2.6%2.1%1.8%
      Median household income (percentile)<0.001
      0-25th29.8%31.0%31.2%
      26th–50th27.1%26.4%25.5%
      51st-75th24.0%23.7%23.7%
      76th–100th19.1%18.8%19.6%
      Homelessness0.5%0.4%0.4%<0.001
      Comorbidities
      Atrial fibrillation38.1%32.3%30.9%<0.001
      Dyslipidemia52.5%53.7%54.2%<0.001
      Thrombocytopenia3.4%5.6%6.0%<0.001
      Smoking9.6%8.1%8.6%<0.001
      Previous AMI10.8%10.3%7.4%<0.001
      Previous PCI11.8%9.7%6.2%<0.001
      Previous CABG8.5%8.5%5.9%<0.001
      Anemias12.7%22.6%23.5%<0.001
      Congestive heart failure43.743.6%29.4%<0.001
      Valvular disease7.2%6.8%3.9%<0.001
      Hypertension61.7%61.6%71.5%<0.001
      Peripheral vascular disorders6.6%9.1%8.6%<0.001
      Coagulopathy4.8%8.2%9.2%<0.001
      Diabetes Mellitus26.9%28.4%21.5%<0.001
      Liver disease2.7%4.0%2.9%<0.001
      Chronic renal failure14.8%32.4%32.6%<0.001
      Bed size of hospital<0.001
      Small19.5%17.2%13.0%
      Medium30.0%28.9%25.6%
      Large50.5%53.9%61.4%
      Hospital region<0.001
      Northeast19.2%17.4%15.0%
      Midwest22.3%22.6%25.4%
      South41.1%41.3%40.6%
      West17.4%18.8%19.0%
      Location/teaching status of hospital<0.001
      Rural10.1%8.1%4.5%
      Urban non-teaching24.0%21.4%15.5%
      Urban teaching65.9%70.5%80.0%
      Length of stay (days), median (IQR)3 (2, 4)4 (2, 7)7 (4, 13)<0.001
      Total charges (USD), median (IQR)35,715 (18,233, 71,510)45,681 (25,231, 91,144)77,672 (40,321, 162,236)<0.001
      All-cause in-hospital mortality2.2%7.6%10.3%<0.001
      AMI = acute myocardial infarction; CABG = coronary artery bypass graft; IQR = interquartile range; PCI = percutaneous coronary intervention; USD = US dollar.
      Patients with an HFRS >15 were more likely to be older (median age 75 vs 73 years for HFRS 5-to- 15 group and 68 years for HFRS <5 group) and female (54.1% vs 48.7% for HFRS 5-to-15 group and 43.0% for HFRS <5 group) and to have a higher prevalence of hypertension, coagulopathy, and thrombocytopaenia, in addition to a lower prevalence of previous AMI, previous percutaneous coronary intervention, previous coronary artery bypass graft, HF, and diabetes, than were patients with an HFRS <5 and HFRS 5 to 15 (p <0.001 for all) (Table 1).
      The most common cause of admission was AMI (28.7%), followed by ischemic stroke (23.8%), AF (21.0%), HF (16.2%), hemorrhagic stroke (5.9%), PE (4.0%), and cardiac arrest (0.4%). The cohort admitted with ischemic stroke had the highest proportion of patients with an HFRS >15 (10.8%), followed by hemorrhagic stroke and cardiac arrest (9.1% and 2.5%). Similarly, cohorts admitted with cardiac arrest had the highest proportion of patients with an HFRS 5 to 15 (70.4%), followed by ischemic stroke and hemorrhagic stroke (66.9% and 54.9%, respectively). The cohort admitted with AF had the highest proportion of patients with an HFRS <5, followed by AMI and PE (80.3% vs 76.7% and 74.1%) (Figure 1, Supplementary Table 2-8 ).
      Figure 1
      Figure 1Distribution of each HFRS category within each of the selected cardiovascular admission causes.
      The most common cause of CVD admission in the HFRS <5 cohort was AMI (36.9%), followed by AF (28.2%) and HF (17.4%). Ischemic stroke was the most common CVD admission for the HFRS 5-to-15 group (43.3%), followed by AMI (17.8%) and HF (15.6%). Similarly, ischemic stroke was the most common CVD admission for the HFRS of >15 groups (75.4%), followed by hemorrhagic stroke (15.5%) and AMI (4.3%) (Figure 2).
      Figure 2
      Figure 2Distribution of selected cardiovascular admission causes within each HFRS category.
      Patients with HFRS >15 had higher unadjusted rates of all-cause mortality than did their counterparts with lower frailty (10.3% vs 7.6 for HFRS 5-to-15 group and 2.2% for HFRS <5 group, p <0.001). Increased unadjusted rates of all-cause mortality for patients with high-risk frailty were also observed in patients admitted with AMI, ischemic stroke, AF, HF, and PE but not for patients admitted with cardiac arrest or hemorrhagic stroke (all p <0.001) (Supplementary Figure 2, Table 2).
      Table 2Prevalence of the cardiovascular admission diagnoses and associated in-hospital deaths based on HFRS
      Admission diagnosisHospital Frailty Risk ScoreOverall P-value
      Low <5 (59.8%)Intermediate 5-15 (36.7%)High >15 (3.5%)
      Acute myocardial infarction (n = 2,677,890)Prevalence36.9%17.8%4.3%<0.001
      In-hospital mortality2.2%12.7%15.4%<0.001
      Ischemic stroke (n = 2,217,925)Prevalence8.9%43.3%75.4%<0.001
      In-hospital mortality2.0%3.8%8.9%<0.001
      Atrial fibrillation/flutter (n = 1,959,699)Prevalence28.2%11.1%2.2%<0.001
      In-hospital mortality0.3%2.9%8.0%<0.001
      Heart failure (n = 1,511,459)Prevalence17.4%15.6%2.6%<0.001
      In-hospital mortality1.7%5.4%12.3%<0.001
      Pulmonary embolism (n = 375,940)Prevalence5.0%2.8%0.7%<0.001
      In-hospital mortality1.4%8.5%10.6%<0.001
      Cardiac arrest (n = 28,790)Prevalence0.1%0.6%0.2%<0.001
      In-hospital mortality71.7%74.0%55.2%<0.001
      Hemorrhagic stroke (n = 545,695)Prevalence3.5%8.8%15.5%<0.001
      In-hospital mortality17.8%20.7%15.0%<0.001
      HFRS = Hospital Frailty Risk Score.
      On adjustment for baseline covariates, increasing frailty risk was associated with increased odds of all-cause mortality. Patients with an HFRS of 5 to 15 or HFRS >15 admitted for AF had the highest odds of all-cause mortality (aOR 17.69, 95% CI 16.08 to 19.45 for HFRS >15 group, aOR 6.75, 95% CI 6.51 to 7.00 for HFRS 5-to-15 group). Increased odds of mortality were observed with worsening frailty status across a broad range of different CV causes for admission. The HFRS >15 group was associated with in an increased odds of mortality for patients admitted with AMI, ischemic stroke, HF, and PE admission diagnoses (p <0.001). Interestingly, a decreased odds of mortality in the HFRS >15 group was observed in patients admitted for cardiac arrest and hemorrhagic stroke only (aOR 0.46, 95% CI 0.39 to 0.55 for patients with cardiac arrest with an HFRS >15, aOR 0.86, 95% CI 0.83 to 0.88 for patients with hemorrhagic stroke with an HFRS >15) (Figure 3, Table 3).
      Figure 3
      Figure 3Adjusted mortality rates for different frailty risk category and selected cardiovascular admission causes. Reference group is low HFRS score <5 for each CVD admission diagnosis.
      Multivariable logistic regression model adjusted for age, gender, race, weekend admission, elective admission, primary expected payer, median household income, hospital bed size, region and teaching status, thrombocytopenia, previous PCI, previous AMI, previous CABG, anemia, coagulopathies, liver disease, metastatic disease, and peripheral vascular disease. CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention.
      Table 3Adjusted odds of mortality in different HFRS categories and selected cardiovascular admission diagnoses
      Admission diagnosisHospital Frailty Risk Score
      Intermediate 5–15 (36.7%)High >15 (3.5%)
      aORp ValueaORp Value
      Acute myocardial infarction (n = 2,677,890)4.95 [4.86–5.02]<0.0015.67 [5.39–5.96]<0.001
      Ischemic stroke (n = 2,217,925)1.88 [1.84–1.92]<0.0014.31 [4.20–4.43]<0.001
      Atrial fibrillation/flutter (n = 1,959,699)6.75 [6.51–7.00]<0.00117.69 [16.08–19.45]<0.001
      Heart failure (n =1,511,459)3.15 [3.08–3.22]<0.0017.01 [6.52–7.53]<0.001
      Pulmonary embolism (n = 375,940)5.58 [5.34–5.82]<0.0017.09 [6.14–8.18]<0.001
      Cardiac arrest (n = 28,790)1.12 [1.05–1.20]<0.0010.46 [0.39–0.55]<0.001
      Hemorrhagic stroke (n = 545,695)1.21 [1.20–1.23]<0.0010.86 [0.83–0.88]<0.001
      Reference group is low HFRS score <5 for each CVD admission diagnosis. Multivariable logistic regression model adjusted for age, sex, race, weekend admission, elective admission, primary expected payer, median household income, hospital bed size, region and teaching status, thrombocytopenia, previous PCI, previous AMI, previous CABG, anemia, coagulopathies, liver disease, metastatic disease, peripheral vascular disease.
      aOR = adjusted odds ratio; CI = confidence interval; HFRS = Hospital Frailty Risk Score.

      Discussion

      To the best of our knowledge, this is the first study to examine the prevalence, clinical characteristics, and in-hospital mortality of patients admitted with a broad range of acute CV presentations on a nationwide scale based on their frailty status. We report several important findings. Firstly, we report the most common CVD admissions across frailty categories, with AMI being the most common in patients with a low frailty score, and ischemic stroke being the most common in patients with an intermediate and high frailty score. Secondly, we report important frailty-based differences in baseline characteristics across patients with different CVD admission diagnoses. Finally, patients with an intermediate and high frailty score had increased all-cause mortality compared with their counterparts with lower risk across most CVD admission diagnoses, except in cardiac arrest and hemorrhagic stroke categories.
      The association between frailty and CVD has been widely explored in the literature.
      • Ramsay SE
      • Arianayagam DS
      • Whincup PH
      • Lennon LT
      • Cryer J
      • Papacosta AO
      • Iliffe S
      • Wannamethee SG.
      Cardiovascular risk profile and frailty in a population-based study of older British men.
      ,
      • Chung KJNC
      • Wilkinson C
      • Veerasamy M
      • Kunadian V.
      Frailty scores and their utility in older patients with cardiovascular disease.
      • Newman AB
      • Gottdiener JS
      • McBurnie MA
      • Hirsch CH
      • Kop WJ
      • Tracy R
      • Walston JD
      Fried LP, Cardiovascular Health Study Research Group. Associations of subclinical cardiovascular disease with frailty.
      • Afilalo J
      • Karunananthan S
      • Eisenberg MJ
      • Alexander KP
      • Bergman H.
      Role of frailty in patients with cardiovascular disease.
      • Veronese N
      • Cereda E
      • Stubbs B
      • Solmi M
      • Luchini C
      • Manzato E
      • Sergi G
      • Manu P
      • Harris T
      • Fontana L
      • Strandberg T
      • Amieva H
      • Dumurgier J
      • Elbaz A
      • Tzourio C
      • Eicholzer M
      • Rohrmann S
      • Moretti C
      • D'Ascenzo F
      • Quadri G
      • Polidoro A
      • Lourenço RA
      • Moreira VG
      • Sanchis J
      • Scotti V
      • Maggi S
      • Correll CU
      Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis.
      Frailty has been shown to be a predictor of incident CVD.
      • Afilalo J
      • Karunananthan S
      • Eisenberg MJ
      • Alexander KP
      • Bergman H.
      Role of frailty in patients with cardiovascular disease.
      ,
      • Newman AB
      • Simonsick EM
      • Naydeck BL
      • Boudreau RM
      • Kritchevsky SB
      • Nevitt MC
      • Pahor M
      • Satterfield S
      • Brach JS
      • Studenski SA
      • Harris TB.
      Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability.
      CVD is associated with a threefold increase in prevalent frailty, and frailty increases odds of CVD by 35%.
      • Afilalo J
      • Karunananthan S
      • Eisenberg MJ
      • Alexander KP
      • Bergman H.
      Role of frailty in patients with cardiovascular disease.
      This relation is believed to be due to similar underlying biological pathways.
      • Afilalo J
      • Karunananthan S
      • Eisenberg MJ
      • Alexander KP
      • Bergman H.
      Role of frailty in patients with cardiovascular disease.
      CVD and frailty share similar biomarkers such as interleukin 6 and high levels of factor VIII, d-dimer, fibrinogen, and C-reactive protein.
      • Walston J
      • McBurnie MA
      • Newman A
      • Tracy RP
      • Kop WJ
      • Hirsch CH
      • Gottdiener J
      Fried LP, Cardiovascular Health Study. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the cardiovascular Health Study.
      • Di Napoli M
      • Papa F
      Villa Pini Stroke Data Bank Investigators. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients.
      • Patterson CC
      • Blankenberg S
      • Ben-Shlomo Y
      • Heslop L
      • Bayer A
      • Lowe G
      • Zeller T
      • Gallacher J
      • Young I
      • Yarnell J.
      Which biomarkers are predictive specifically for cardiovascular or for non-cardiovascular mortality in men? Evidence from the Caerphilly prospective study (CaPS).
      The pathways in conjunction with low physical activity and poor nutrition could lead to decreased physiological reserves and increased susceptibility to stress, leading to frailty.
      • Damluji AA
      • Huang J
      • Bandeen-Roche K
      • Forman DE
      • Gerstenblith G
      • Moscucci M
      • Resar JR
      • Varadhan R
      • Walston JD
      • Segal JB.
      Frailty among older adults with acute myocardial infarction and outcomes from percutaneous coronary interventions.
      In addition, these factors can lead to a prothrombotic state and increased levels of inflammation, leading to increased risk of CV events and adverse outcomes.
      • Walston J
      • McBurnie MA
      • Newman A
      • Tracy RP
      • Kop WJ
      • Hirsch CH
      • Gottdiener J
      Fried LP, Cardiovascular Health Study. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the cardiovascular Health Study.
      • Di Napoli M
      • Papa F
      Villa Pini Stroke Data Bank Investigators. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients.
      • Patterson CC
      • Blankenberg S
      • Ben-Shlomo Y
      • Heslop L
      • Bayer A
      • Lowe G
      • Zeller T
      • Gallacher J
      • Young I
      • Yarnell J.
      Which biomarkers are predictive specifically for cardiovascular or for non-cardiovascular mortality in men? Evidence from the Caerphilly prospective study (CaPS).
      The HFRS was nationally validated using a cohort of >1 million patients in the United Kingdom, of whom 37.6% had an intermediate risk of frailty and 20% had a high risk of frailty.
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
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      ,
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      and up to 40.9% in studies using the HFRS.
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      Hospital Frailty Risk Score and adverse health outcomes: evidence from longitudinal record linkage cardiac data.
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      • Valsdottir LR
      • Shen C
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      • Yeh RW.
      Association of frailty with 30-day outcomes for acute myocardial infarction, heart failure, and pneumonia among elderly adults.
      Variable prevalence of frailty in the literature could be partially explained by differences in the cohorts studied but also and importantly by differences in definitions used and what is considered to represent frailty, with studies using definitions derived from Rockwood et al,
      • Rockwood K
      • Song X
      • MacKnight C
      • Bergman H
      • Hogan DB
      • McDowell I
      • Mitnitski A.
      A global clinical measure of fitness and frailty in elderly people.
      Fried et al,
      • Fried LP
      • Tangen CM
      • Walston J
      • Newman AB
      • Hirsch C
      • Gottdiener J
      • Seeman T
      • Tracy R
      • Kop WJ
      • Burke G
      • McBurnie MA
      Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype.
      and Gill et al.
      • Veronese N
      • Cereda E
      • Stubbs B
      • Solmi M
      • Luchini C
      • Manzato E
      • Sergi G
      • Manu P
      • Harris T
      • Fontana L
      • Strandberg T
      • Amieva H
      • Dumurgier J
      • Elbaz A
      • Tzourio C
      • Eicholzer M
      • Rohrmann S
      • Moretti C
      • D'Ascenzo F
      • Quadri G
      • Polidoro A
      • Lourenço RA
      • Moreira VG
      • Sanchis J
      • Scotti V
      • Maggi S
      • Correll CU
      Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis.
      ,
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      ,
      • Fried LP
      • Tangen CM
      • Walston J
      • Newman AB
      • Hirsch C
      • Gottdiener J
      • Seeman T
      • Tracy R
      • Kop WJ
      • Burke G
      • McBurnie MA
      Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype.
      ,
      • Rockwood K
      • Song X
      • MacKnight C
      • Bergman H
      • Hogan DB
      • McDowell I
      • Mitnitski A.
      A global clinical measure of fitness and frailty in elderly people.
      ,
      • Gill TM
      • Baker DI
      • Gottschalk M
      • Peduzzi PN
      • Allore H
      • Byers A.
      A program to prevent functional decline in physically frail, elderly persons who live at home.
      There is a challenge to defining frailty because there is no standardized measurement, but the HFRS represents a potentially advantageous option owing to its dependence on the widely available ICD coding system.
      • Aguayo GA
      • Donneau AF
      • Vaillant MT
      • Schritz A
      • Franco OH
      • Stranges S
      • Malisoux L
      • Guillaume M
      • Witte DR.
      Agreement between 35 published frailty scores in the general population.
      The HFRS follows the deficit model (combining impairments) and has been validated against the Rockwood and Fried scores; however, it can be quite challenging for clinicians to calculate because of a lack of automated computation.
      • Kwok CS
      • Zieroth S
      • Van Spall HGC
      • Helliwell T
      • Clarson L
      • Mohamed M
      • Mallen C
      • Duckett S
      • Mamas MA.
      The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure.
      Similarly to other studies, we observed that patients with increasing frailty are likely to be older and female, and to have longer hospital stays and total costs.
      • Ramsay SE
      • Arianayagam DS
      • Whincup PH
      • Lennon LT
      • Cryer J
      • Papacosta AO
      • Iliffe S
      • Wannamethee SG.
      Cardiovascular risk profile and frailty in a population-based study of older British men.
      ,
      • Newman AB
      • Gottdiener JS
      • McBurnie MA
      • Hirsch CH
      • Kop WJ
      • Tracy R
      • Walston JD
      Fried LP, Cardiovascular Health Study Research Group. Associations of subclinical cardiovascular disease with frailty.
      ,
      • Veronese N
      • Cereda E
      • Stubbs B
      • Solmi M
      • Luchini C
      • Manzato E
      • Sergi G
      • Manu P
      • Harris T
      • Fontana L
      • Strandberg T
      • Amieva H
      • Dumurgier J
      • Elbaz A
      • Tzourio C
      • Eicholzer M
      • Rohrmann S
      • Moretti C
      • D'Ascenzo F
      • Quadri G
      • Polidoro A
      • Lourenço RA
      • Moreira VG
      • Sanchis J
      • Scotti V
      • Maggi S
      • Correll CU
      Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis.
      ,
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      ,
      • Kundi H
      • Wadhera RK
      • Strom JB
      • Valsdottir LR
      • Shen C
      • Kazi DS
      • Yeh RW.
      Association of frailty with 30-day outcomes for acute myocardial infarction, heart failure, and pneumonia among elderly adults.
      ,
      • Kwok CS
      • Zieroth S
      • Van Spall HGC
      • Helliwell T
      • Clarson L
      • Mohamed M
      • Mallen C
      • Duckett S
      • Mamas MA.
      The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure.
      This study found important variations in frailty status across different CVD admissions. Among patients with intermediate or high frailty risk, the most prevalent CVD admission was acute ischemic stroke. This may be explained by the inclusion of the sequelae of stroke in the HFRS, but other contributors, such as older age, which increases the risk of both stroke and frailty, with 70% of strokes occurring after the age of 65, are also important.
      • Kelly-Hayes M.
      Influence of age and health behaviors on stroke risk: lessons from longitudinal studies.
      AF has been reported to be prevalent in 15% of the population with frailty, although we report an interesting pattern of a decreasing proportion of AF admission with increasing frailty.
      • Orkaby AR
      • Kornej J
      • Lubitz SA
      • McManus DD
      • Travison TG
      • Sherer JA
      • Trinquart L
      • Murabito JM
      • Benjamin EJ
      • Preis SR.
      Association between frailty and atrial fibrillation in older adults: the Framingham heart study offspring cohort.
      Again, this could be mediated by varying definitions of frailty because the previous study used scores devised by Fried et al
      • Fried LP
      • Tangen CM
      • Walston J
      • Newman AB
      • Hirsch C
      • Gottdiener J
      • Seeman T
      • Tracy R
      • Kop WJ
      • Burke G
      • McBurnie MA
      Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype.
      and Rockwood et al.
      • Rockwood K
      • Song X
      • MacKnight C
      • Bergman H
      • Hogan DB
      • McDowell I
      • Mitnitski A.
      A global clinical measure of fitness and frailty in elderly people.
      Studies using the HFRS indicated a similar distribution of frailty status to this study among patients with AF, with most patients at low risk of frailty and only a small percentage at high risk of frailty.
      • Orlandi M
      • Dover DC
      • Sandhu RK
      • Hawkins NM
      • Kaul P
      • McAlister FA.
      The introduction of direct oral anticoagulants has not resolved treatment gaps for frail patients with nonvalvular atrial fibrillation.
      This study shows admission for HF decreases with increasing frailty yet is still common, with >3 in 10 patients admitted with HF at intermediate or high risk of frailty. Our findings are supported by other studies that show intermediate or high risk of frailty is present in up to 1 in 5 patients hospitalized with HF and is associated with a longer length of stay and increased total charges.
      • Kwok CS
      • Zieroth S
      • Van Spall HGC
      • Helliwell T
      • Clarson L
      • Mohamed M
      • Mallen C
      • Duckett S
      • Mamas MA.
      The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure.
      ,
      • McAlister FA
      • Savu A
      • Ezekowitz JA
      • Armstrong PW
      • Kaul P.
      The Hospital Frailty Risk Score in patients with heart failure is strongly associated with outcomes but less so with pharmacotherapy.
      This could be explained by an increased number of co-morbidities in the population with HF, with a high prevalence of dyslipidemia, anemia, and hypertension.
      • Kwok CS
      • Zieroth S
      • Van Spall HGC
      • Helliwell T
      • Clarson L
      • Mohamed M
      • Mallen C
      • Duckett S
      • Mamas MA.
      The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure.
      This agrees with multiple studies that showed patients with increased HFRS have a higher Charlson co-morbidity score, in line with the HFRS being based on the total co-morbidity burden of patients.
      • Gilbert T
      • Neuburger J
      • Kraindler J
      • Keeble E
      • Smith P
      • Ariti C
      • Arora S
      • Street A
      • Parker S
      • Roberts HC
      • Bardsley M
      • Conroy S.
      Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.
      ,
      • Kundi H
      • Wadhera RK
      • Strom JB
      • Valsdottir LR
      • Shen C
      • Kazi DS
      • Yeh RW.
      Association of frailty with 30-day outcomes for acute myocardial infarction, heart failure, and pneumonia among elderly adults.
      ,
      • Kwok CS
      • Zieroth S
      • Van Spall HGC
      • Helliwell T
      • Clarson L
      • Mohamed M
      • Mallen C
      • Duckett S
      • Mamas MA.
      The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure.
      There are no studies describing the prevalence of PE, cardiac arrest, and hemorrhagic stroke among patients with frailty who are hospitalized.
      Interestingly, AF was a rare cause of admission in the high-risk group but was associated with the worst prognosis in these patients. The association between AF and mortality has been reported in multiple studies because the prevalence of AF increases with age and co-morbidity burden, and increases the risk of stroke and its associated complications.
      • Guo Q
      • Du X
      • Ma CS.
      Atrial fibrillation and frailty.
      ,
      • Benjamin EJ
      • Wolf PA
      • D'Agostino RB
      • Silbershatz H
      • Kannel WB
      • Levy D
      Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.
      Studies have suggested that patients with frailty also have a larger left atrial volume, which is one of the main cardiac abnormalities linked to the development of AF and systolic dysfunction.
      • Villani ER
      • Tummolo AM
      • Palmer K
      • Gravina EM
      • Vetrano DL
      • Bernabei R
      • Onder G
      • Acampora N.
      Frailty and atrial fibrillation: a systematic review.
      Furthermore, patients with incident AF are commonly on anticoagulant medications, which increases risk of bleeding and further complications such as hemorrhage.
      • Guo Q
      • Du X
      • Ma CS.
      Atrial fibrillation and frailty.
      However, studies report that patients with AF and increasing frailty are less likely to be treated with oral anticoagulants, which can lead to increased likelihood of downstream thrombotic events and poorer outcomes.
      • Orlandi M
      • Dover DC
      • Sandhu RK
      • Hawkins NM
      • Kaul P
      • McAlister FA.
      The introduction of direct oral anticoagulants has not resolved treatment gaps for frail patients with nonvalvular atrial fibrillation.
      ,
      • Villani ER
      • Tummolo AM
      • Palmer K
      • Gravina EM
      • Vetrano DL
      • Bernabei R
      • Onder G
      • Acampora N.
      Frailty and atrial fibrillation: a systematic review.
      We report that HF was independently associated with higher odds of mortality with increasing frailty, as seen in other studies.
      • Kwok CS
      • Zieroth S
      • Van Spall HGC
      • Helliwell T
      • Clarson L
      • Mohamed M
      • Mallen C
      • Duckett S
      • Mamas MA.
      The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure.
      ,
      • McAlister FA
      • Savu A
      • Ezekowitz JA
      • Armstrong PW
      • Kaul P.
      The Hospital Frailty Risk Score in patients with heart failure is strongly associated with outcomes but less so with pharmacotherapy.
      Our findings of cardiac arrest and hemorrhagic stroke, although different to the other CVD admissions of interest, could have several explanations. These conditions have substantial mortality per se, with little modification by HFRS. This analysis encompassed only patients who were admitted owing to cardiac arrest, leading to potential selection bias, so it is possible that many of the patients with frailty did not survive to admission, and only those with the most favorable prognosis survived to admission. It is possible that the poor outcomes in these patient groups occur independently of frailty status.
      • Kochanek KD
      • Xu J
      • Arias E.
      Mortality in the United States, 2019.
      ,
      • Andersen LW
      • Holmberg MJ
      • Berg KM
      • Donnino MW
      • Granfeldt A.
      In-hospital cardiac arrest: a review.
      There are important clinical implications of this study. This study indicates that patients with intermediate-to-high frailty risk represent a substantial portion of the population admitted for CVD and raises the importance of frailty assessment by cardiologists. A co-existence of frailty and CVD is becoming even more important owing to an aging population with higher morbidity burden. Patients with frailty admitted with CVD have higher mortality rates and burden the healthcare system, and knowledge of the trends in CVD admission is fundamental to improve the outcomes of this clinically at-risk population. This study may support the early identification and management of CVD in patients with frailty, particular in primary care, although whether this would affect acute admissions is not known.
      This study has several limitations inherent to the use of the NIS database. Firstly, coded data for the NIS could be subject to selection bias because of inaccurate coding or missing data. Secondly, detailed clinical information such as pharmacological treatment that can mediate outcomes could not be investigated because it was not available from the NIS. The impact of differential pharmacological management in the population with frailty on outcomes may be an area for further research. Thirdly, because this is an observational study, confounding bias could not be fully eliminated despite the broad scope of conditions covered by the NIS, and therefore, causality between frailty, CVD admission, and mortality cannot be proved. Finally, the NIS only captures information on in-hospital events, and therefore, a more detailed analysis of longitudinal outcomes could not be assessed.
      • Khera R
      • Krumholz HM.
      With great power comes great responsibility: big data research from the National Inpatient Sample.
      In conclusion, the causes of CVD admission vary with frailty status, with AMI being the most common in patients with a low risk of frailty, whereas ischemic stroke is the most common in patients with intermediate or high risk of frailty. Increasing frailty in patients admitted for AMI, ischemic stroke, AF, HF, and PE is associated with an increased all-cause mortality. Future, more granular studies are necessary to guide care and improve the CVD outcomes in patients with frailty in an ever-aging population.

      Disclosures

      The authors have no conflicts of interest to declare.

      Appendix. Supplementary materials

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