Outcomes and Worsening Renal Function in Patients Hospitalized With Heart Failure With Preserved Ejection Fraction

Accepted Manuscript Outcomes and Worsening Renal Function in Patients Hospitalized with Heart Failure with Preserved Ejection Fraction Kavita Sharma, MD, Terence Hill, MD, Morgan Grams, MD, PhD, Natalie R. Daya, MPH, Allison G. Hays, MD, Derek Fine, MD, David R. Thiemann, MD, Robert G. Weiss, MD, Ryan J. Tedford, MD, David A. Kass, MD, Steven P. Schulman, MD, Stuart D. Russell, MD PII:

S0002-9149(15)01846-9

DOI:

10.1016/j.amjcard.2015.08.019

Reference:

AJC 21370

To appear in:

The American Journal of Cardiology

Received Date: 2 June 2015 Revised Date:

4 August 2015

Accepted Date: 18 August 2015

Please cite this article as: Sharma K, Hill T, Grams M, Daya NR, Hays AG, Fine D, Thiemann DR, Weiss RG, Tedford RJ, Kass DA, Schulman SP, Russell SD, Outcomes and Worsening Renal Function in Patients Hospitalized with Heart Failure with Preserved Ejection Fraction, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.08.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Outcomes and Worsening Renal Function in Patients Hospitalized with Heart Failure with Preserved Ejection Fraction Kavita Sharma, MDa, Terence Hill, MDa, Morgan Grams, MD, PhDb, Natalie R. Daya, MPHb,

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Allison G. Hays, MDa, Derek Fine, MDb, David R. Thiemann, MDa, Robert G. Weiss, MDa,

Ryan J. Tedford, MDa, David A. Kass, MDa, Steven P. Schulman, MDa, Stuart D. Russell, MDa Department of Medicine, Divisions of Cardiologya and Nephrologyb,

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The Johns Hopkins Hospital, Baltimore, MD 21287

Address for Correspondence:

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Running Title: HFpEF Hospitalization Outcomes and Worsening Renal Function

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Stuart D. Russell, MD The Johns Hopkins Hospital Sheikh Zayed Tower 7E Rm 7125S-B3 1800 Orleans Street Baltimore, MD 21287 410-955-5708 443-287-3180 (fax) Email address: [email protected]

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Abstract: Heart failure with preserved ejection fraction (HFpEF) has been described as a disease of elderly individuals with female predominance and hypertension. Our clinical experience suggests HFpEF patients

hospital morbidity.

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from an urban population are far more heterogeneous, with greater comorbidities, and significant inThere are limited data on the hospitalization course and outcomes in acute

decompensated HFpEF. Hospitalizations for acute heart failure at our institution from 7/2011-6/2012

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were identified by ICD-9 codes and physician review for left ventricular ejection fraction (LVEF) ≥ 50% and were reviewed for patient characteristics and clinical outcomes. Worsening renal function (WRF) was

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defined as creatinine increase of ≥ 0.3 mg/dL by 72 hours after admission. Hospital readmission and mortality data were captured from electronic medical records and the Social Security Death Index. Of 434 heart failure admissions, 206 (47%) HFpEF patients were identified. WRF developed in 40%, the highest reported in HFpEF to date, and was associated with higher blood pressure and lower volume of diuresis. Compared to prior reports, hospitalized HFpEF patients were younger (mean age 63.2 ± 13.6 years),

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predominantly black (74%), and had more frequent and severe comorbidities: hypertension (89%), diabetes (56%), and chronic kidney disease (55%). There were no significant differences in 1-month or 12-month outcomes by sex, race, or WRF. In conclusion, we found hospitalized HFpEF patients from an

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urban population develop a high rate of WRF, are younger than prior cohorts, often black, and have greater comorbidities than previously described.

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Keywords: heart failure with preserved ejection fraction; worsening renal function; epidemiology; outcomes

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Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all hospitalized heart failure today, with clinical outcomes similar to heart failure with reduced ejection fraction (HFrEF) and no proven therapies to date.1-3 HFpEF has generally been described as a disease of elderly, predominantly

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female patients, with hypertensive heart disease from predominantly Caucasian cohorts.2,4 There are limited data on the population of HFpEF patients that present with acute heart failure, the treatments they receive, and their hospitalization course.5,6 In particular, worsening renal function (WRF) has been associated with poor outcomes in HFrEF; however, to our knowledge there is only a single report of WRF

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outcomes in hospitalized HFpEF.7 In contrast to prior observational studies, our clinical experience with

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hospitalized HFpEF patients from an urban population has been that these patients are younger, racially diverse, with more comorbidities than previously described. To investigate this experience, we reviewed hospitalizations of HFpEF patients with acute heart failure with the following objectives: 1. To describe the baseline characteristics and comorbidities of hospitalized urban HFpEF patients; and 2. To examine

Methods

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the hospitalization course and clinical outcomes of HFpEF patients.

Patients hospitalized for acute heart failure on the Osler Internal Medicine services at The Johns Hopkins Hospital between July 2011 and June 2012 were identified by the primary discharge diagnosis

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code 428 according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Of these patients, records of those with left ventricular ejection fraction (LVEF)

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measurement of ≥ 50% within one year prior to admission and without any suspected interval clinical event to suggest a decline in LVEF were reviewed. The diagnosis of heart failure was confirmed by Framingham criteria.8 If a patient was admitted more than once for heart failure within the study period, only data from the first admission were included for analysis. This study was approved by The Johns Hopkins Institutional Review Board.

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Patients were excluded if they presented with active ischemic heart disease, primary hypertrophic or other cardiomyopathy (e.g. active myocarditis, hypertrophic obstructive cardiomyopathy, severe valvular disease, restrictive or constrictive cardiomyopathy, including known amyloidosis, sarcoidosis, or

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hemochromatosis), complex congenital heart disease, constrictive pericarditis, or severe primary pulmonary hypertension. Patients with end-stage renal disease, defined as requiring dialysis, or with estimated glomerular filtration rate (eGFR) ≤ 15 mL/min/1.73m2, determined by the Chronic Kidney

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Disease Epidemiology Collaboration (CKD- EPI) equation were included in the overall study, however were not included in the analysis of renal outcomes, nor were they considered at risk for worsening renal

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function.9

eGFR (mL/min/1.73m2) was calculated using the CKD-EPI equation (GFR = 141 X min (serum creatinine/κ,1)α X max (serum creatinine/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159 [if black], where κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of serum creatinine/κ or 1, and max indicates the maximum of serum creatinine/κ or 1 (serum

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creatinine, mg/dL).9 CKD was defined as eGFR < 60 mL/min/1.73m2 at presentation. WRF was defined as a rise in serum creatinine by ≥ 0.3 mg/dL from admission to within 72 hours of admission.10 All patients included in the study had undergone a clinically indicated comprehensive 2-

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dimensional echocardiography study with standard Doppler imaging during their index hospitalization, or within one year prior to the index hospitalization. Standard echocardiographic views were obtained

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according to American Society of Echocardiography guidelines.11 LV mass was defined as: (LV mass = 0.8(1.04 [(Dd + PW + VS)3 – (Dd)3] + 0.6g, where Dd = diastolic dimension, PW = posterior wall thickness, and VS = septal thickness.11 Left ventricular (LV) hypertrophy was defined by 2 criteria: 1) LV mass/height2.7 with gender-specific reference values of at least 46.7 g/m2.7 in women and at least 49.2 g/m2.7 in men to define LV hypertrophy; and 2) LV mass/body surface area, with cut points of 116 g/m2 in men and 104 g/m2 in women to identify LV hypertrophy independently of obesity.12 Early diastolic medial and lateral mitral annular tissue velocity (e′), E/A ratio of mitral inflow velocity, and the ratio of 4

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the early transmitral flow velocity (E) to e′ (E/e′) were used to estimate LV relaxation and LV filling pressure. Pulmonary artery systolic pressure was calculated from the peak tricuspid regurgitant velocity and the estimated right atrial pressure using the simplified Bernoulli equation.

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Hospital readmission data were acquired through review of the Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center electronic medical record systems. One-year mortality data was captured from review of the Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center

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electronic medical record systems, as well as linkage to the Social Security Death Index.

Summary statistics are presented as mean and standard deviation or median and interquartile

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range for continuous variables and percentages for categorical variables. Comparisons of demographics, comorbidities, and risk factors for HFpEF were made by sex, race, and WRF status using t-tests (for continuous variables) and chi-square tests (for categorical variables). Hospital readmission and mortality status over the year following discharge was analyzed by sex, race, and WRF status, using Cox

Results

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proportional hazards regression.

Of 434 patients hospitalized for heart failure during the study period on the Osler Internal

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Medicine services at our institution, 206 (47%) met the pre-defined criteria for HFpEF. The baseline characteristics of hospitalized HFpEF patients are summarized in Table 1. The mean age was 63 years ±

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14 years, ranging from 31 to 91 years, with a female predominance at 62% of the cohort. Seventy four percent of patients were black. Comorbidities were common, particularly hypertension (89%), diabetes (56%), and CKD (55%), with 22 patients classified as end-stage renal disease at the time of admission. Just over half of the patients had been hospitalized before their index admission for heart failure. On admission, mean systolic blood pressure was 150 mmHg ± 33 mmHg and mean diastolic blood was 76 mmHg ± 18 mmHg. The mean body mass index (BMI) was 37.3 kg/m2 ± 12.6 kg/m2, mean eGFR was 62 mL/min/1.73m2 ± 35 mL/min/1.73m2, and mean creatinine was 1.6 mg/dl ± 1.1 mg/dl. 5

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Medication use prior to hospitalization included diuretics (74%), angiotensin converting enzymeinhibitors (ACE-I, 43%), beta-blockers (56%), statins (50%), and nitrates (12%). Echocardiographic findings showed normal LV dimensions, increased LVM and left ventricular mass index (LVMI), and

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impaired relaxation: LV end-diastolic diameter 4.6 cm ± 0.7cm; LV end-systolic diameter 3.1 cm ± 0.7 cm; E/E’ 16.2 ± 10.7; E/A 1.3 ± 0.7; LVM 230.5 gm ± 85gm (range 92.6 gm to 635.0 gm); LVMI 105.3 gm/m2 ± 34.7 gm/m2. LVH was noted in 69% of patients based on pre-specified echocardiographic

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criteria.

The hospital course and clinical outcomes for hospitalized HFpEF patients are summarized in

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Table 2. WRF developed in 40% of patients within 72 hours of hospitalization, with 2% requiring new initiation of dialysis during the index admission. The mean change in creatinine was 0.3 mg/dL ± 0.3 mg/dL (range -0.1 mg/dL to 2.0 mg/dL); mean fluid removed during the hospitalization was 5.6 L ± 8.1 L (range -5.8 L to 56.8 L); and mean weight loss was 4.6 kg ± 8.2 kg (range -9.6 kg to 60.7 kg). Intravenous diuretics were administered in 98% of patients; the mean dose of furosemide administered at a time was

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83 mg. Fourteen percent of patients received a thiazide diuretic in addition to a loop diuretic. Of note, 28% percent of patients received intravenous contrast for computed tomography studies on initial evaluation in the Emergency Department to evaluate for pulmonary embolism as a cause of dyspnea;

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none of these studies were diagnostic of pulmonary embolism. Thirty seven percent of HFpEF patients were readmitted to our hospital system in the year following their index admission; 9% were readmitted

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within 30-days post-discharge. Two patients died during their index hospitalization; mortality at one year of the cohort was 13%.

Women on average were three years older than men, with a mean age of 64 years in women.

Eighty one percent of women were black, compared to 61% of men. Women had lower LVM indices (205.4 g versus 270.9 g, p < 0.001; 99.6 g/m2 versus 114.5 g/m2, p< 0.001), and lower hemoglobin compared to men (10.7 g/dL versus 11.6 g/dL, p< 0.01). There were no differences in heart failure admission-free survival or mortality by sex at one year (Figure 1). 6

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Blacks had higher blood pressure on admission (systolic blood pressure 155 mmHg versus 137 mmHg, p <0.001), higher rate of diabetes (60% versus 44%, p=0.05) and higher LVM indices (109 g/m2 versus 95 g/m2, p=0.011), lower rate of atrial fibrillation (21% versus 35%, p=0.04), and were more likely

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to be anemic than non-blacks (hemoglobin of 10.8 g/dL versus 11.7 g/dL, p=0.002). Black HFpEF patients had significantly shorter length of stay compared to non-blacks (5.4 days versus 9.8 days, p=0.003). There were no significant differences in heart failure admission-free survival or mortality by

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race at one year (Figure 2).

There were no differences in the risk of development of WRF by age, sex, race, or CKD status. In

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addition, the administration of intravenous contrast for computed tomography studies did not affect the risk of development of WRF. Higher systolic blood pressure (odds ratio (OR) per 10mmHg higher, 1.15, 95% CI: 1.04-1.26, p=0.006) and higher diastolic blood pressure (OR per 10mmHg higher, 1.30, 95% CI: 1.05-1.60, p=0.02) were associated with significantly higher risk of WRF. In addition, WRF was associated with less fluid removal adjusted for body surface area (2.1L/m2 versus 3.1 L/m2, p = 0.034).

Discussion

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There were no differences in 30-day or one-year outcomes in those that developed WRF (Figure 3).

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Classically described as a disease of elderly, hypertensive, predominantly women, HFpEF has largely been characterized from relatively homogenous population-based studies.1,2 In this study of

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patients hospitalized with acute HFpEF from an urban population, we report the highest rate of WRF to date in HFpEF patients hospitalized for acute heart failure. In addition, we found that HFpEF patients are younger, with more blacks, and higher rates and severity of comorbidities. HFpEF is now well-recognized to be as common as HFrEF and perhaps more prevalent in the

inpatient hospital setting.2-4 There are a multitude of proposed cardiac- and non-cardiac mechanisms of HFpEF, and it is increasingly being recognized that categorizing patients into phenotypic (and perhaps genotypic) subtypes is likely needed to better understand mechanisms of disease and better target 7

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therapies for individual patients.13,14 In order to do so, we need an accurate representation of HFpEF from diverse patient populations to better understand differences in demographics, comorbidities, and risk factors that influence clinical outcomes.

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We found a high rate of WRF in hospitalized HFpEF patients at 40%, compared to the 12% incidence of WRF in the only other study that has examined renal outcomes in hospitalized HFpEF.7 In the outpatient setting, WRF has been reported in up to 6% of HFpEF patients.15 The development of WRF

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in the setting of acute and chronic heart failure has been reported to be associated with poor prognosis and worse outcomes.10,16,17 Specifically, WRF in the setting of heart failure has been associated with higher

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rates of hypertension, coronary disease, diabetes, and higher 3-month and 5-month mortality when compared to those who do not develop WRF.10,16 Interestingly, although CKD is typically a predictor of WRF, we did not observe that CKD was associated with higher rate of WRF. The mechanisms for development of WRF in the setting of acute heart failure in HFpEF are

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unclear; however, there are a few possible considerations. First, volume shifts in the renal and splanchnic circulatory beds in the setting of acute congestion and treatment with diuretics may result in impaired renovascular perfusion.18 Second, we observed that relatively higher blood pressure on admission was significantly associated with higher risk of WRF. Patients who are markedly hypertensive on admission

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may have impaired renal autoregulation and are more susceptible to WRF in the setting of receiving antihypertensive agents in hospital.19 Third, we observed that less fluid removal was associated with higher

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risk of WRF, which may reflect renovascular congestion that is present in acute HFpEF leading to WRF. Alternatively, it is possible that care providers may slow down diuresis (or stop altogether) in the setting of WRF development. Ultimately, we did not observe any significant difference in outcomes at one year in those who developed WRF; however, the detection of any difference in clinical outcomes may have been limited by our study size.

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Our study findings suggest the characteristics of HFpEF patients are evolving. Age and agingrelated myocardial and vascular changes have long been thought to be at the core of mechanisms which drive the development of concentric remodeling, impaired diastolic function, and vascular stiffness in

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HFpEF, particularly in women.20 However, in comparison to other population studies of HFpEF patients in which the average age is well over 70 years, we found that hospitalized HFpEF patients are younger by nearly a decade.2,4 Yet, our patients had higher rates of hypertension, diabetes, the highest BMI, and the highest rate of CKD of any prior observational study, suggesting that alternative mechanisms from aging

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are at play in the development of HFpEF.1-5 Perhaps these other comorbidities, which certainly place

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different stressors on the heart, are responsible for the earlier presentation. In addition, compared to a prior report of high prevalence of LV hypertrophy in HFpEF patients with elevated LV mass indices (mean 81± 23g/m2.7), we found much less LV hypertrophy in our cohort, also suggestive that alternative mechanisms to aging-related hypertensive heart disease are responsible for the development of HFpEF.5 Targeting preventive efforts towards younger patients who are at risk for disease development will be

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imperative in this growing population.

To our knowledge, the black predominance seen in this study is the highest of any prior observational cohort or clinical trial population, which have had rates of 2 to 30%.3-5,21,22 The obvious

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explanation for this finding is that our institution serves an urban population which is enriched with blacks; however, other single- and multi-center observational studies from urban medical centers have not It is well-established in the HFrEF literature that blacks

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reported as many blacks with HFpEF.5,6

compared to other race groups are at increased risk of developing heart failure; we suspect HFpEF is under recognized and underreported in blacks and clearly blacks are significantly underrepresented in clinical trials.21-24 A greater understanding of differences in HFpEF by race is needed as blacks may have unique underlying pathophysiologic mechanisms that lead to HFpEF development and effect response to therapies. And, based on lessons learned from HFrEF, there may be therapies that particularly benefit blacks with HFpEF.25-27

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Little is understood as to what role gender plays in the development, clinical manifestations, and outcomes in HFpEF.28 Women constituted 62% of our cohort, were an average 3 years older than men, with trends towards higher rates hypertension, diabetes, and CKD, higher mean blood pressure, and lower

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mean GFR (non-statistically significant). Earlier studies have reported up to 70% of HFpEF patients being women, with more coronary artery disease and atrial fibrillation, however less hypertension, diabetes, and CKD than we observed, with no comparisons of gender differences.3-5 Gender differences in

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HFpEF need to be studied on a larger scale with continued efforts for clinical trials to adequately represent both women and men.

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We observed overall higher rates and severity of comorbidities, particularly of hypertension, diabetes, CKD, and obesity in younger patients compared to prior reports of hospitalized HFpEF.2-5 Our lower observed rates of coronary artery disease (17%), and less LV hypertrophy (69%) suggest that these traditional risk factors are not solely responsible for the development of HFpEF in our population. Comorbidities may impact outcomes as well in HFpEF, as some HFpEF clinical trials have shown that

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non-HF cardiovascular disease and non-cardiac comorbidities are the underlying cause of significant morbidity and mortality in hospitalized HFpEF patients.29,30 The findings of this study should be considered in the context of several limitations. This is a

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single-center, retrospective review of patients with HFpEF hospitalized with acute heart failure. The data collected are limited by what was reported in the medical record that we were able to extract. We were

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also limited in that readmission data was primarily abstracted from our institution’s electronic medical record which may not have reflected hospitalizations at other institutions. Finally, these data do not imply cause-and-effect relationships, as this was a retrospective analysis. However, this is still the largest study of HFpEF patients from an urban population admitted with an acute exacerbation of heart failure and demonstrates a high incidence of WRF. Disclosures

The authors have no conflicts of interest or funding to disclose.

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Figure Titles and Legends

Figure 1. One-year Heart Failure Readmission Free- and Overall Survival in Heart Failure with Preserved

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Ejection Fraction by Gender

Caption: Kaplan-Meier curves for heart failure readmission-free survival (1A) and one-year survival (1B)

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by gender.

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Figure 2. One-year Heart Failure Readmission Free- and Overall Survival in Heart Failure with Preserved Ejection Fraction by Race

Caption: Kaplan-Meier curves for heart failure readmission-free survival (2A) and one-year survival (2B)

TE D

by race.

Figure 3. One-year Heart Failure Readmission Free- and Overall Survival in Heart Failure with Preserved

EP

Ejection Fraction by Worsening Renal Function Status Caption: Kaplan-Meier curves for heart failure readmission-free survival (3A) and one-year survival (3B)

AC C

by worsening renal function status.

16

ACCEPTED MANUSCRIPT

Table 1. Clinical Characteristics and Hospitalization Course for Heart Failure with Preserved Ejection Fraction (n=206)

Women

62%

Black

74%

Hypertension

89%

Diabetes mellitus

56%

Atrial fibrillation

25%

Coronary artery disease

18%

Estimated glomerular filtration rate < 60

55%

mL/min/1.73m

2

11%

Any prior heart failure hospitalization

55%

I

TE D

End-stage renal disease

NYHA Functional Classes

13%

II

EP

43%

III

AC C

V

2

26% 18%

Body mass index(kg/m )

37.3 ± 12.6

Systolic blood pressure (mmHg)

150 ± 34

Diastolic blood pressure (mmHg)

76 ± 18

Estimated glomerular filtration rate

62 ± 35

2

(mL/min/1.73m ) Sodium (mEq/L)

SC

63 ± 14

M AN U

Age (years)

RI PT

Variables

140 ± 3.5

1.6 ± 1.1

Hemoglobin (g/dL)

11.0 ± 2.0

Albumin (g/dL)

3.8 ± 0.5

Troponin I (ng/mL)

0.1 ± 0.1

Medication Use 43%

Angiotensin receptor blocker

12%

Diuretic

74%

Beta-blocker

56%

Aldosterone antagonist

6%

Nitrates

12%

Digoxin

3%

Statin

50%

Aspirin

56%

TE D

M AN U

ACE inhibitor

Echocardiographic Characteristics E', cm/s

7.3 ± 2.7

E/E'

16.2 ± 10.7

EP

E/A

1.3 ± 0.7 4.2 ± 0.9

LV end-diastolic diameter (cm)

4.6 ± 0.7

LV end-systolic diameter (cm)

3.1 ± 0.7

LV mass (g)

231 ± 85

AC C

LA systolic diameter (cm)

2

LV mass/body surface area (g/m ) 2.7

LV mass/Height

SC

Creatinine(mg/dL)

RI PT

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2.7

(g/m )

Intraventricular septal diameter (cm)

105 ± 35 56 ± 19 1.3 ± 0.3

1.2 ± 0.3

LV hypertrophy

69%

Left bundle branch block

2%

Right ventricular systolic pressure (mmHg)

48 ± 16

Hospitalization Course and Outcomes 98%

Furosemide dose(mg)

83 ± 47

Thiazide given

14%

IV contrast received

28%

Fluid removed (mL)

5622 ± 8116

Weight loss (kg)

4.6 ± 8.2

Change in creatinine (mg/dL)

0.3 ± 0.3

Development of WRF

40%

Incident hemodialysis

2%

In-patient death 1-year mortality

TE D

Length of Stay (days)

M AN U

Diuretic given

SC

LV posterior wall diameter (cm)

RI PT

ACCEPTED MANUSCRIPT

6.6 ± 9.2 1%

13%

EP

Variables presented as mean ± standard deviation or %; Coronary artery disease defined as any coronary

AC C

disease history mention in medical record; NYHA = New York Heart Association; ACE-I = angiotensin converting enzyme; LA = left atrial; LV = left ventricular. LV hypertrophy defined as 1) LV mass/height2.7 with gender-specific partition values of 46.7 g/m2.7 in women and 49.2 g/m2.7 in men to define LV hypertrophy, or 2) LV mass/body surface area, with cut points of 116 g/m2 in men and 104 g/m2 in women to define LV hypertrophy.

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Table 2. Clinical Characteristics, Hospital Course, and Outcomes of Hospitalized Heart Failure with Preserved Ejection Fraction by Gender, Race, and Worsening Renal Function Status By Gender

Course and

By Race

Male

Female

p-value

38%

62%

Age (years)

61

64

Women

…

…

Black

63%

80%

0.005

Hypertension

87%

90%

0.6

Diabetes

49%

60%

0.1

Atrial

31%

21%

0.1

46%

60%

0.1

Non-black

Black

By WRF Status p-value

Outcomes

Estimated

glomerular filtration rate <

2

mL/min/1.73m

Body mass

EP

60

LV hypertrophy

62

46%

68%

…

…

0.1

0.005

Yes WRF

p-value

53%

36%

63

65

0.4

59%

68%

0.2

69%

77%

0.2

SC

66

No WRF

83%

91%

0.1

85%

92%

0.2

44%

60%

0.05

54%

59%

0.5

35%

21%

0.039

28%

23%

0.5

49%

57%

0.3

51%

59%

0.3

TE D

fibrillation

74%

M AN U

0.1

26%

RI PT

Clinical

71%

0.4

57%

73%

0.033

66%

73%

0.3

38

0.4

38

37

0.5

39

37

0.3

147

152

0.3

137

155

<0.001

143

158

0.003

79

75

0.1

69

79

<0.001

73

78

0.019

65%

AC C

36

2

index (kg/m ) Systolic

blood

pressure (mmHg)

Diastolic blood pressure

ACCEPTED MANUSCRIPT

(mmHg) Maximum Lasix

80

85

0.5

86

82

0.6

78

88

0.1

3

7

0.2

9

4

0.1

6

5

0.9

60

71

0.1

61

69

0.3

2638

2523

0.8

3036

2395

0.2

27%

29%

0.8

35%

44%

0.2

6.8

6.4

0.8

9%

9%

38%

37%

Continuous

Lasix dose (mg) Intermittent

Fluid

removed/body

(mL)

contrast given Development

Length of Stay

(days) HF readmission

3173

2106

0.034

0.002

30%

27%

0.6

33%

43%

0.2

…

…

…

9.8

5.4

0.003

7.1

6.5

0.7

9%

0.9

9%

8%

0.8

0.8

35%

38%

0.7

33%

41%

0.3

53%

0.2

46%

61%

0.1

52%

57%

0.6

11%

0.2

19%

11%

0.2

13%

14%

0.9

AC C

63%

22%

9%

EP

in 1 year Any

0.5

0.9

within 30 days HF readmission

70

44%

TE D

of WRF

M AN U

surface area

Intravenous

75

SC

Lasix dose (mg)

RI PT

dose (mg)

readmission

within 1 year 1-year

17%

mortality

Variables presented as mean or %; WRF = worsening renal function; LV = left ventricular; LV hypertrophy defined as 1) LV mass/height2.7 with gender-specific partition values of 46.7 g/m2.7 in women and 49.2

ACCEPTED MANUSCRIPT

g/m2.7 in men to define LV hypertrophy, or 2) LV mass/body surface area, with cut points of 116 g/m2 in

AC C

EP

TE D

M AN U

SC

RI PT

men and 104 g/m2 in women to define LV hypertrophy; HF = heart failure

ACCEPTED MANUSCRIPT

Figure 1.

M AN U

SC

RI PT

1A.

AC C

EP

TE D

1B.

ACCEPTED MANUSCRIPT

Figure 2.

M AN U

SC

RI PT

2A.

AC C

EP

TE D

2B.

ACCEPTED MANUSCRIPT

Figure 3.

M AN U

SC

RI PT

3A.

No WRF

AC C

EP

TE D

3B.

WRF

1