Stroke and Heart Failure: Clinical Features, Access to Care, and Outcomes

ARTICLE IN PRESS

Stroke and Heart Failure: Clinical Features, Access to Care, and Outcomes Jitphapa Pongmoragot, MD,* Douglas S. Lee, MD, PhD,† Tai Hwan Park, MD, PhD,‡ Jiming Fang, PhD,§ Peter C. Austin, PhD,§ Gustavo Saposnik, MD, MSc, FAHA, FRCPC*‖ on behalf of the Investigators of the Registry of the Canadian Stroke Network and the University of Toronto Stroke Program for the Stroke Outcomes Research Canada (SORCan—www.sorcan.ca) Working Group

Background and Objectives: Limited information is known regarding acute ischemic stroke (AIS) and heart failure (HF). The aim of the study was to evaluate clinical characteristics, predisposing factors, and outcomes in AIS with HF. Methods: We included AIS patients admitted to the institutions participating in the Registry of the Canadian Stroke Network. HF was defined as history of pre-existing HF or pulmonary edema present at the time of arrival. The primary outcome was death or disability at discharge (modified Rankin Scale score >3). Secondary outcomes included disposition, death at 3 months and at 1 year, and 30-day hospital readmissions. Results: Among 12,396 patients, HF was found in 1124 (9.1%) patients. HF was associated with higher risk of death at 30 days (24.5% versus 11.2%, P < .0001), at 1 year (44.3% versus 20.6, P < .0001), and disability at discharge (70.4% versus 56%, P < .0001). In the multivariable analysis, HF was an independent predictor of death and disability (odds ratio 1.18, 95% confidence interval [CI] 1.011.37), death at 30 days (hazard ratio [HR] 1.22, 95% CI 1.05-1.41), and hospital readmissions (HR 1.32, 95% CI 1.05-1.65) at 30 days. The results were unaltered

From the *Stroke Outcomes Research Center, Division of Neurology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; †Peter Munk Cardiac Centre, Joint Department of Medical Imaging, Institute for Clinical Evaluative Science, IHPME, University Health Network, Toronto, Ontario, Canada; ‡Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea; §Department of Statistics, Institute of Clinical Evaluative Sciences (ICES), Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada; and ‖Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada. Received August 23, 2015; revision received November 17, 2015; accepted January 2, 2016. Grant support: This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the MOHLTC is intended or should be inferred. These data sets were held securely in a linked, deidentified form and were analyzed at the ICES. Dr. Austin was supported in part by a Career Investigator Award from the Heart and Stroke Foundation of Canada. Dr. Lee is supported by a clinician–scientist award from the Canadian Institutes of Health Research. Dr. Saposnik is supported by the Distinguished Clinician Scientist Award from Heart of Stroke Foundation of Canada following an open peer-review competition. Authors’ contributions: Dr. Pongmoragot drafted the manuscript and provided a critical review. Dr. Pongmoragot and Dr. Fang have access to the data to act as guarantors. Dr. Saposnik, Dr. Lee, Dr. Park, Dr. Fang, and Dr. Austin all contributed in the design, planning, and conduct of the study, and provided critical revisions to the manuscript.Address correspondence to Gustavo Saposnik, MD, MSc, FAHA, FRCPC, Stroke Outcomes Research Center, Department of Medicine, St. Michael’s Hospital, University of Toronto, 55 Queen St E, Toronto, Ontario M5C 1R6, Canada. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.01.013

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■

1

ARTICLE IN PRESS J. PONGMORAGOT ET AL.

2

when adjusting for pneumonia with the exception of death or disability at discharge. Conclusions: In this large cohort study, HF was observed in 9.1% of AIS patients. HF is an independent predictor of death and disability and hospital readmissions after stroke at 30 days. Key Words: Stroke—heart failure—quality of care—outcomes. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction Stroke is a major cause of death and disability worldwide. Some pre-existing medical conditions (e.g., atrial fibrillation [AF] and diabetes) directly influence stroke outcomes.1,2 Heart failure (HF) is a complex clinical syndrome that results from structural or functional impairment of ventricular filling or reduction in the ability of the ventricle to eject blood.3 The prevalence of HF is approximately 10 per 1000 after 65 years of age,4 increasing to over 80 per 1000 populations among those aged 85 years and older.5 HF carries high mortality with 1-year mortality of approximately 30%-45%.6 After the onset of HF, only 50% will survive in 5 years.7 Similarly, mortality is 2-fold higher in stroke patients with HF compared to those without HF.8-10 With the growth in the aging population, the increasing prevalence of stroke and HF in patients is expected. However, there is not much known about acute ischemic stroke (AIS) with HF. The aim of our study was to evaluate (1) clinical characteristics, predisposing factors, and outcomes in patients who have AIS with HF and (2) to determine if HF is an independent predictor of stroke outcomes.

Methods Study Population We identified consecutive patients aged 18 years old or older who were admitted with a diagnosis of ischemic stroke to participating institutions in the Registry of the Canadian Stroke Network (RCSN) between July 1, 2003, and June 30, 2008. Patients with missing Canadian Neurological Scale (CNS) scores (n = 304) and baseline glucose levels (n = 701) were excluded from the study. The study population and exclusions are shown in Figure 1.

Data Sources The RCSN is a large prospective quality monitoring stroke care registry that comprises acute stroke patients admitted to 11 stroke centers in Ontario, Canada. Details of the RCSN can be obtained from http://www.ices.on.ca/ Research/Research-programs/Cardiovascular/Ontario -Stroke-Registry and are published elsewhere.11 The poststroke mortality was obtained through linkages to the Ontario Registered Persons Database at the Institute for Clinical Evaluative Sciences. The Registered Persons

Figure 1. Study population. Abbreviations: CNS, Canadian Neurological Scale; RCSN, Registry of the Canadian Stroke Network.

Database was linked with the RCSN for capturing postdischarge mortality. Demographic data and clinical variables, including vascular risk factors, medical history of AF, and cardiac comorbidity, were recorded from clinical data. Stroke severity on admission was determined by the CNS score: mild (CNS score ≥ 8), moderate (CNS score 4-7), severe (CNS ≤ 4).12 We applied the iScore, a validated risk assessment tool, to estimate prognosis and outcomes in AIS with and without HF.2 Exposure HF was defined as a pre-existing history of HF or pulmonary edema present at the time of arrival documented in emergency room records/notes, history and physical exam, and physician’s admission notes. HF is one of the main variables captured in the RCSN.

ARTICLE IN PRESS STROKE AND HEART FAILURE: CLINICAL FEATURES, ACCESS TO CARE, AND OUTCOMES

Outcome Measures The primary outcome was death or disability at discharge, with disability defined as a modified Rankin scale (mRS) score equal to or greater than 3. Secondary outcomes included admission to the intensive care unit, discharge disposition, length of hospital stay (LOS), death at 3 months and at 1 year, and 30-day hospital readmissions. St. Michael’s Hospital review board and RCSN Publications Committee approvals were obtained. Statistical Analysis We used chi-square tests to compare categorical variables. Student’s t-test and Kruskal–Wallis test were used for means and medians of continuous variables, respectively. Multivariable logistic analysis adjusting for age, stroke severity, and comorbid conditions was used to determine the independent effect of HF on outcomes in patients with AIS. Survival analysis was conducted using Cox proportional hazard models. All the analyses were conducted with the use of SAS software (version 9.3; SAS Institute, Inc., Cary, NC). All reported P values are 2-sided.

Results Among 12,396 eligible patients with AIS, 1124 (9.1%) had HF. AIS with HF patients were older than AIS without HF patients (mean age 78.6 versus 71.4 years, P < .0001), with 53% occurring in those older than 80 years and more likely female (53.8% versus 46.9%, P < .0001) (Table 1). AIS with HF patients were more likely to have vascular risk factors including hypertension (80.2% versus 67%, P < .0001); diabetes mellitus (33.9% versus 24.7%, P < .0001); history of cardiac disease, including coronary artery disease (54.4% versus 20.8%, P < .0001); myocardial infarction (35.6% versus 13.3%, P < .0001); AF (43.1% versus 14.6%, P < .0001); valvular heart disease (12.9% versus 3.8%, P < .0001); and prior CABG surgery (17.7% versus 9.2%, P < .0001) compared to AIS without HF patients. The most common clinical presentation for AIS with HF was aphasia, visual field defect, and weakness. AIS with HF patients presented with more severe stroke (25.9% versus 14.1%, P < .0001), with the most likely stroke mechanism being cardioembolic (42% versus 21.3%, P < .0001). There was no difference in recombinant tissue plasminogen activator administration between AIS with HF and without HF. AIS with HF had higher iScore usually associated with an expected poorer outcome (Table 1).

Outcome Measures Overall, 1324 (10.7%) AIS patients died during hospital admission. Death and disability at discharge (mRS score ≥ 3) were significant higher in AIS with HF patients than in AIS without HF patients (70.4% versus 56%, P < .0001) (Table 2, Fig 2). Mortality rate at discharge

3

was higher in AIS with HF patients than in AIS without HF patients (21.4% versus 9.6%, P < .0001) (Table 2). AIS with HF patients had longer LOS (15.3 versus 12.6 days, P < .0001) than AIS without HF patients. There was no difference in the rate of admission to stroke unit or intensive care unit between AIS patients with and without HF. AIS patients with HF were more often discharged to a long-term care facility (18.1% versus 8.4%, P < .0001). Only approximately one third of AIS patients with HF were discharged home compared to nearly half for AIS patients without HF. Moreover, AIS patients with HF more often developed in-hospital complications including cardiac or respiratory arrest (8.4% versus 3.8%, P < .0001), myocardial infarction (3.6% versus 2.0%, P = .0009), and pneumonia (11.5% versus 5.5%, P < .0001) (Table 2). After discharge, AIS patients with HF had a higher readmission rate at 30 days (7.8% versus 6.3%, P = .046).

Multivariable Analysis HF (odds ratio 1.18, 95% confidence interval 1.011.37) was an independent predictor of poor outcome (mRS score 3-6) (Table 3) and lower survival at 30 days and 3 years (Fig 3, A,B). HF was also an independent predictor of 30-day readmissions after stroke hospital discharge (hazard ratio 1.32, 95% confidence interval 1.05-1.65). The addition of pneumonia in the adjusted analysis did not alter the results with the exception of the attenuation of the effect of HF for disability at discharge (Table 3). We also included an interaction term, “pneumonia × HF.” The interaction term was not significant for any of the outcomes (mRS score ≤2, P value for the interaction term .988; for 30-day mortality: P value for the interaction term .0733).

Discussion HF is a leading cause of hospital readmissions carrying high morbidity and mortality. The prevalence of HF increases with age. Hence, HF is expected to increase with the aging of the population. Previous studies revealed that HF is a common comorbid condition in stroke patients.1 However, limited information is available regarding presenting symptoms and outcomes in AIS with HF. In this large cohort study, HF was found in 9.1% of 12,396 AIS patients. HF among stroke patients was associated with higher disability and hospital readmissions and lower survival. One fifth of AIS with HF died during hospitalization. Only 50% of AIS patients with HF survived at 1 year. Thirty-day and 1-year mortality were double in AIS patients with HF compared to AIS patients without HF. In addition, AIS patients with HF had longer LOS and higher incidence of in-hospital complications.

ARTICLE IN PRESS J. PONGMORAGOT ET AL.

4

Table 1. Clinical characteristics of patients with and without heart failure Characteristics Age (years) Mean ± SD Younger than 60 60-79 80 or older Female Risk factors Hypertension Diabetes mellitus Hyperlipidemia Coronary artery disease Previous MI Atrial fibrillation or atrial flutter Previous PCI/PTCA/CABG Valvular heart disease Valve replacement Peripheral vascular disease Asthma or (COPD) Previous DVT/PE Cancer Renal dialysis Cirrhosis Current smoker (last 6 months) Preadmission medication Antiplatelet therapy Anticoagulant therapy Presenting stroke symptoms Aphasia Visual field defect Dysarthria Weakness Sensory Brainstem or cerebellar signs Seizures Vital signs on arrival Mean ± SD (n) Systolic BP Diastolic BP Stroke severity on admission Mild Moderate Severe Stroke subtype* Lacunar Cardioembolic Large-artery atherosclerosis Other Undetermined Laboratory on arrival Mean ± SD Hb INR Glucose Creatinine Thrombolysis therapy rtPA intravenous Medication at discharge Antiplatelet Anticoagulant for AF ACE inhibitor ARB Beta blocker Diuretic iScore 30 days Mean ± SD (n) iScore higher than 200 iScore 365 days Mean ± SD (n) iScore higher than 200

Total (n = 12,396) (%)

Stroke with HF (n = 1,124) (%)

Stroke without HF (n = 11,272) (%)

72.09 ± 13.8 2,279 (18.4) 5,863 (47.3) 4,254 (34.3) 5,888 (47.5)

78.62 ± 11.15 70 (6.2) 458 (40.7) 596 (53.0) 605 (53.8)

71.44 ± 13.87 2,209 (19.6) 5,405 (48.0) 3,658 (32.5) 5,283 (46.9)

8,452 (68.2) 3,169 (25.6) 4,332 (34.9) 2,961 (23.9) 1,894 (15.3) 2,128 (17.2) 1,231 (9.9) 568 (4.6) 243 (2) 789 (6.4) 1561 (12.6) 317 (2.6) 1,215 (9.8) 107 (.9) 62 (.5) 2,424 (19.6)

901 (80.2) 381 (33.9) 451 (40.1) 612 (54.4) 400 (35.6) 485 (43.1) 199 (17.7) 145 (12.9) 52 (4.6) 155 (13.8) 289 (25.7) 48 (4.3) 128 (11.4) 23 (2.0) 14 (1.2) 124 (11.0)

7,551 (67.0) 2,788 (24.7) 3,881 (34.4) 2,349 (20.8) 1,494 (13.3) 1,643 (14.6) 1,032 (9.2) 423 (3.8) 191 (1.7) 634 (5.6) 1,272 (11.3) 269 (2.4) 1,087 (9.6) 84 (.7) 48 (.4) 2,300 (20.4)

<.0001 <.0001 .0001 <.0001 <.0001 <.0001 <.0001 <.0001 <.0001 <.0001 <.0001 .0001 .0607 <.0001 .0002 <.0001

5,097 (41.1) 1,387 (11.2)

546 (48.6) 318 (28.3)

4,551 (40.4) 1,069 (9.5)

<.0001 <.0001

3,938 (31.8) 1,617 (13) 4,933 (39.8) 10,041 (81) 3,583 (28.9) 2,648 (21.4) 165 (1.3)

495 (44.0) 194 (17.3) 442 (39.3) 955 (85.0) 260 (23.1) 184 (16.4) 14 (1.2)

3,443 (30.5) 1,423 (12.6) 4,491 (39.8) 9,086 (80.6) 3,323 (29.5) 2,464 (21.9) 151 (1.3)

<.0001 <.0001 .7350 .0004 <.0001 <.0001 .7930

152.3 ± 29.07 79.99 ± 17.7

159.01 ± 30.03 83.5 ± 16.88

.0000 .0000 <.0001

8,081 (65.2) 2,440 (19.7) 1,875 (15.1)

583 (51.9) 250 (22.2) 291 (25.9)

7,498 (66.5) 2,190 (19.4) 1,584 (14.1)

2,095 (16.9) 2,870 (23.2) 1,859 (15) 346 (2.8) 4,928 (39.8)

147 (13.1) 472 (42.0) 131 (11.7) 21 (1.9) 343 (30.5)

1,948 (17.3) 2,398 (21.3) 1,728 (15.3) 325 (2.9) 4,585 (40.7)

158.4 ± 30.01 83.18 ± 16.98

P value <.0001

<.0001

<.0001

136.32 ± 18.86 1.14 ± .53 7.68 ± 3.37 101.77 ± 63.4

129.83 ± 19.5 1.3 ± .7 8.14 ± 3.3 122.87 ± 87.14

136.97 ± 18.68 1.12 ± .5 7.63 ± 3.38 99.66 ± 60.12

<.0001 <.0001 <.0001 <.0001 .0897

1681 (13.6)

171 (15.2)

1,510 (13.4)

8,646 (69.7) 2,393 (19.3) 4,831 (39) 1,114 (9) 3,403 (27.5) 2,823 (22.8)

592 (52.7) 357 (31.8) 419 (37.3) 109 (9.7) 469 (41.7) 478 (42.5)

8,054 (71.5) 2,036 (18.1) 4,412 (39.1) 1,005 (8.9) 2,934 (26) 2,345 (20.8)

<.0001 <.0001 .2218 .3823 <.0001 <.0001

166.83 ± 43 295 (26.2)

132.27 ± 40.43 762 (6.8)

<.0001 <.0001

141.59 ± 31.56 42 (3.7)

111.24 ± 30.17 69 (.6)

<.0001 <.0001

135.4 ± 41.86 1,057 (8.5) 113.99 ± 31.53 111 (.9)

Abbreviations: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin II receptor blockers; BP, blood pressure; CABG, coronary artery bypass surgery; COPD, chronic obstructive pulmonary disease; DVT, deep vein thrombosis; Hb, hemoglobin; HF, heart failure; INR, International normalized ratio; MI, myocardial infarction; PCI, percutaneous coronary intervention; PE, pulmonary embolism; PTCA, percutaneous transluminal coronary angioplasty; rtPA, recombinant tissue plasminogen activator; SD, standard deviation. P value less than .05 significant. *Information available: total ischemic stroke 12,098; stroke with HF 1114; stroke without HF 10,984.

ARTICLE IN PRESS STROKE AND HEART FAILURE: CLINICAL FEATURES, ACCESS TO CARE, AND OUTCOMES

5

Table 2. Outcome measures Total (n = 12,396) (%) Primary outcome Death or disability at discharge (mRS score ≥ 3) 7,103 (57.3) Secondary outcomes Admission to Stroke unit 5,525 (53.2) ICU 893 (8.6) Medical ward 2,059 (19.8) Other ward 1,904 (18.3) In-hospital complication (within 30 days of admission) Recurrent stroke (within 30 days of admission) 404 (3.3) Ischemic 283 of 404 (70) Hemorrhage 121 of 404 (30) Cardiac or respiratory arrest 434 (4.2) Myocardial infarct 270 (2.2) Atrial fibrillation (new onset) 671 (6.5) Pneumonia 744 (6) GI hemorrhage 164 (1.7) Deep vein thrombosis 95 (.8) Disposition Acute care facility 1,088 (9.8) Home 5,382 (48.6) Long-term care facility 1,016 (9.2) Rehabilitation facility 3,239 (29.3) Other 347 (3.1) Length of hospital stay Mean ± SD 12.83 ± 20.0 Stroke fatality At discharge 1,324 (10.7) 30 days 1,534 (12.4) 1 year 2,820 (22.7) 30 day hospital readmission 798 (6.4)

Stroke with HF (n = 1,124) (%)

Stroke without HF (n = 11,272) (%)

P value

791 (70.4)

6,312 (56.0)

<.0001

482 (49.8) 97 (10.0) 215 (22.2) 173 (17.9)

5,043 (53.6) 796 (8.5) 1,844 (19.6) 1,731(18.4)

.2303

44 (3.9) 31 of 44 (70.5) 13 of 44 (29.5) 81 (8.4) 40 (3.6) 64 (6.6) 129 (11.5) 24 (2.7) 7 (.6) 107 (12.1) 322 (36.4) 160 (18.1) 247 (27.9) 48 (5.4) 15.32 ± 24 240 (21.4) 275 (24.5) 498 (44.3) 88 (7.8)

360 (3.2) 252 of 360 (70.0) 108 of 360 (30.0) 353 (3.8) 230 (2.0) 607 (6.5) 615 (5.5) 140 (1.6) 88 (.8)

.1943 .9505 .9505 <.0001 .0009 .8291 <.0001 .0648 .5626

981 (9.6) 5,060 (49.7) 856 (8.4) 2,992 (29.4) 299 (2.9)

<.0001

12.58 ± 20

<.0001

1,084 (9.6) 1,259 (11.2) 2,322 (20.6) 710 (6.3)

<.0001 <.0001 <.0001 .0462

Abbreviations: GI, gastrointestinal; HF, heart failure; ICU, intensive care unit; mRS, modified Rankin Scale; SD, standard deviation. P value less than .05 significant.

In the multivariable analysis, HF was an independent predictor of disability at discharge (mRS score ≥3), 30day survival, and 30-day hospital readmissions after adjusting for age, stroke severity, and comorbid conditions. The effect of HF on disability at discharge was attenuated when the analysis was adjusted for pneumonia, but results remained unaltered for survival and hospital readmissions. The prevalence of HF in our stroke cohort was comparable with previous studies (9.5%-17.7%).9,10,13,14 Mortality was higher than reported in HF patients in the general population (3.8%,14 8.2%7). One-year mortality in AIS patients with HF was higher than that in HF patients in the general population (44.3% versus 30.5%-32.9%).7,15 The predictors of in-hospital mortality in HF in the general population include older age, low systolic blood pressure, higher respiratory rate, higher urea nitrogen level, and low sodium level.7,15 HF patients particularly with left ventricular systolic dysfunction have higher risk of

thrombosis and thromboembolic syndromes given that there is stasis of blood in cardiac akinesis or dyskinesis and systemic prothrombotic state.16 Our study found that the most common clinical presentations for AIS with HF were aphasia, visual field defect, and weakness, whereas the most common stroke mechanism was cardioembolic. Nearly half of AIS patients with HF had AF or atrial flutter. In AIS and AF patients, anticoagulation therapy has demonstrated reduction in thromboembolic event,17 and it is one of the most effective treatments for the prevention of a recurrent stroke.18 In our study, only one third of AIS patients with HF and AF were prescribed anticoagulants at discharge and one fifth in AIS patients without HF. In contrast to HF patients with reduced left ventricular ejection fraction who were in sinus rhythm, anticoagulation therapy did not show a reduction in the incident risk of stroke or death compared to aspirin.19 From the health policy perspective, HF represents the most common reason for hospitalization in patients older

ARTICLE IN PRESS J. PONGMORAGOT ET AL.

6 mR S 1

T otal

0

8.5

17.2

8.8

17.7

3

17.0

4

20.7

17.5

5

20.8

20.7

6

5.2 10.7

20.8

4.9 9.6

G roup

no HF

2

P<0.0001 p=0.000

HF 5.1 11.9

0.0

12.6

20.0

20.7

20.2

40.0

60.0

8.1

21.4

80.0

100.0

Figure 2. Functional outcomes at discharge according to the mRS score among AIS patients with and without HF. Abbreviations: AIS, acute ischemic stroke; HF, heart failure; mRS, modified Rankin Scale.

Table 3. Multivariable analysis: variables associated with death and disability Death or disability at discharge

30-day survival

30-day readmission

Variable

OR (95% CI)

HR (95% CI)

HR (95% CI)

Heart failure Age group (years) Ref younger than 60 60-79 80 or older Stroke severity on admission Mild Moderate Severe Comorbidities Hypertension Diabetes mellitus Atrial fibrillation Prior MI Heart failure in model also adjusted for pneumonia

1.18 (1.01-1.37)

1.22 (1.05-1.41)

1.32 (1.05-1.65)

1.0 1.49 (1.33-1.66) 2.42 (2.15-2.74)

1.0 1.55 (1.26-1.90) 2.71 (2.22-3.31)

1.0 1.30 (1.05-1.62) 1.60 (1.28-2.00)

1.0 6.08 (5.40-6.81) 21.3 (17.4-26.1)

1.0 4.33 (3.74-5.01) 11.6 (10.2-13.3)

1.11 (1.02-1.22) 1.31 (1.19-1.44) 1.25 (1.11-1.41)

NS NS 1.29 (1.15-1.44) 1.24 (1.09-1.41) 1.21 (1.04-1.44)

1.13 (.97-1.32)

1.0 NS NS 1.22 (1.04-1.44) NS NS NS 1.29 (1.03-1.62)

Abbreviations: CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; mRS, modified Rankin Scale; NS, nonsignificant; OR, odds ratio. Models adjusted for age, sex, stroke severity, and comorbidities (hypertension, diabetes, smoking, atrial fibrillation, and prior MI).

ARTICLE IN PRESS STROKE AND HEART FAILURE: CLINICAL FEATURES, ACCESS TO CARE, AND OUTCOMES

7

Figure 3. (A) Kaplan–Meier survival at 30 days in AIS. (B) Kaplan–Meier survival at 3 years in AIS patients with and without HF. Abbreviations: AIS, acute ischemic stroke; HF, heart failure.

than age 65 and also carries a high readmission rate.20 The readmission rate in the general population of HF patients ranged from 19% to 31%.20 In an effort to improve quality of care in HF patients, the American College of Cardiology Foundation/American Heart Association Task Force on Practice guideline3 and The Canadian Cardiovascular Society Heart Failure management guidelines were established. 21 Evidence-based practice guidelines (angiotensin-converting enzyme [ACE] inhibitor22,23 or angiotensin II receptor blockers, 24,25 beta blockers, 26,27 aldosterone receptor antagonists28) are recommended to reduce morbidity and mortality unless contraindicated. HF is considered a medical condition with potentially avoidable readmission. Previous studies of ACE inhibitors22,23 and beta blockers26 had proved in decreasing hospitalization. Recently, the Prospective Comparison

of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) with ACEI (Angiotensin-Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) study showed that angiotensin receptor–neprilysin inhibitor was superior to enalapril in reducing the risk of death and of hospitalization of HF.29 However, our study found that only approximately 40% of AIS patients with HF were prescribed ACE inhibitors or beta blockers at discharge. Together, our results suggest that there is an opportunity for improvement by optimizing the treatment of stroke patients with HF prior to discharge. Overall considering poor prognosis of AIS and HF, only 50% of AIS with HF survived at 1 year. This should raise attention as a major public health problem. Our study has practical clinical and health policy implications. For

ARTICLE IN PRESS J. PONGMORAGOT ET AL.

8

example, improvement awareness among clinicians is needed. In addition, early recognition signs and symptoms of HF, collaboration with cardiology service in the management, and adherence to HF guidelines may improve stroke outcome. Hospital managers, program directors, and policy makers can implement strategies for closer out-patient follow-up for AIS patients with HF to reduce readmissions, which may also contribute lowering healthcare costs. Further studies are necessary to evaluate these proposed health interventions and strategies. Some limitations in our study should be considered. First, we have no information of HF severity or titers of biomarkers (e.g., Trop I, B-type natriuretic peptide). Second, scarce information was available on the specific treatment received for the management of HF during stroke hospitalization. Third, we cannot rule out the possibility of residual confounding. Despite these limitations, our study comprises a large sample size of AIS patients (and over 1100 AIS patients with HF), including a wide variety of clinical factors and comorbid conditions with near complete follow-up assessment.

Conclusions HF is a common comorbid condition affecting stroke patients. Stroke patients with HF had a lower survival, longer hospitalization, higher disability, medical complications, and 30-day hospital readmissions. Our results may help increase the awareness of the impact of HF among stroke patients. Specific interventions (e.g., consultation with cardiology, integrated and programmed discharge, and close follow-up in stroke prevention clinics) targeting this high-risk group may improve access to specialized care and counseling for better patient and family adjustment post discharge, and may improve clinical outcomes.

References 1. Kaarisalo MM, Immonen-Räihä P, Marttila RJ, et al. Atrial fibrillation and stroke. Mortality and causes of death after the first acute ischemic stroke. Stroke 1997;28:311-315. 2. Saposnik G, Kapral MK, Liu Y, et al. IScore: a risk score to predict death early after hospitalization for an acute ischemic stroke. Circulation 2011;123:739-749. 3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2013;128:e240-e327. 4. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014;129:e28-e292. 5. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994-2003. Arch Intern Med 2008;168:418-424. 6. MacIntyre K, Capewell S, Stewart S, et al. Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995. Circulation 2000;102:1126-1131.

7. Lee DS, Austin PC, Rouleau JL, et al. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA 2003;290:25812587. 8. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292:344-350. 9. Divani AA, Vazquez G, Asadollahi M, et al. Nationwide frequency and association of heart failure on stroke outcomes in the United States. J Card Fail 2009;15:11-16. 10. Sharma JC, Fletcher S, Vassallo M, et al. Cardiovascular disease and outcome of acute stroke: influence of pre-existing cardiac failure. Eur J Heart Fail 2000;2:145-150. 11. Saposnik G, Fang J, O’Donnell M, et al. Escalating levels of access to in-hospital care and stroke mortality. Stroke 2008;39:2522-2530. 12. Côté R, Battista RN, Wolfson C, et al. The Canadian Neurological Scale: validation and reliability assessment. Neurology 1989;39:638-643. 13. Ois A, Gomis M, Cuadrado-Godia E, et al. Heart failure in acute ischemic stroke. J Neurol 2008;255:385-389. 14. Abraham WT, Fonarow GC, Albert NM, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol 2008;52:347356. 15. Aronson D, Mittleman MA, Burger AJ. Elevated blood urea nitrogen level as a predictor of mortality in patients admitted for decompensated heart failure. Am J Med 2004;116:466-473. 16. Freudenberger RS, Schumaecker MM, Homma S. What is the appropriate approach to prevention of thromboembolism in heart failure? Thromb Haemost 2010;103:489-495. 17. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-867. 18. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2014;45:2160-2236. 19. Lee M, Saver JL, Hong KS, et al. Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: a meta-analysis. Circ Heart Fail 2013;6:287292. 20. Epstein AM, Jha AK, Orav EJ. The relationship between hospital admission rates and rehospitalizations. N Engl J Med 2011;365:2287-2295. 21. McKelvie RS, Moe GW, Ezekowitz JA, et al. The 2012 Canadian Cardiovascular Society Heart Failure Management Guidelines update: focus on acute and chronic heart failure. Can J Cardiol 2013;29:168-181. 22. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293302. 23. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative group on ACE inhibitor trials. JAMA 1995;273:1450-1456. 24. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.

ARTICLE IN PRESS STROKE AND HEART FAILURE: CLINICAL FEATURES, ACCESS TO CARE, AND OUTCOMES 25. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759-766. 26. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-1658. 27. MERIT-HF study group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised

9

intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-2007. 28. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-1321. 29. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.