- Email: [email protected]
Comparison of Risk of Re-hospitalization, All-Cause Mortality, and Medical Care Resource Utilization in Patients With Heart Failure and Preserved Versus Reduced Ejection Fraction
Accepted Manuscript Comparison of Risk of Re-Hospitalization, All-Cause Mortality and Medical Care Resource Utilization in Patients with Heart Failure and Preserved versus Reduced Ejection Fraction Gregory A. Nichols, PhD, Kristi Reynolds, PhD, Teresa M. Kimes, MS, A. Gabriela Rosales, MS, Wing W. Chan, MS PII:
S0002-9149(15)01627-6
DOI:
10.1016/j.amjcard.2015.07.018
Reference:
AJC 21286
To appear in:
The American Journal of Cardiology
Received Date: 26 May 2015 Revised Date:
25 June 2015
Accepted Date: 3 July 2015
Please cite this article as: Nichols GA, Reynolds K, Kimes TM, Rosales AG, Chan WW, Comparison of Risk of Re-Hospitalization, All-Cause Mortality and Medical Care Resource Utilization in Patients with Heart Failure and Preserved versus Reduced Ejection Fraction, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.07.018. 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.
ACCEPTED MANUSCRIPT
Comparison of Risk of Re-Hospitalization, All-Cause Mortality and Medical Care Resource Utilization in Patients with Heart Failure and Preserved versus Reduced Ejection Fraction
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Short Title: Risk and Resource Use of HFrEF vs. HFpEF patients
Gregory A. Nichols, PhD1, Kristi Reynolds, PhD2, Teresa M. Kimes, MS1, A. Gabriela Rosales,
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MS1, Wing W. Chan, MS3
Kaiser Permanente Center for Health Research, Portland, Oregon
2
Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA
3
Novartis Pharmaceuticals Corporation, East Hanover, NJ
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1
Corresponding Author:
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Gregory A. Nichols, PhD Kaiser Permanente Center for Health Research 3800 N. Interstate Avenue Portland, OR 97227 Telephone: 503-335-6733 Email: [email protected]
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Abstract Because heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF) are different clinical entities with differing demographic characteristics, common HF outcomes
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may occur at different rates. Comparative outcomes studies have been equivocal, and studies comparing resource utilization are scant. We used an observational cohort design to study 6,513 patients hospitalized for HF who had an EF measured during the hospitalization and were
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discharged alive within 30 days. We excluded 677 patients with borderline EF values (41-49%) and categorized the remaining as HFrEF (EF <40%, n=2,205) and HFpEF (EF >50%, n=3,631).
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Patients were followed for up to one year for all-cause re-hospitalization and mortality and annualized medical resource utilization. HFrEF and HFpEF patients experienced similar adjusted incidence rates of re-hospitalization, but HFrEF patients had a 39% increased risk of mortality at 30 days (rate ratio 1.39, 95% CI 1.10-1.76) and 25% greater risk at 1 year (1.25,
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1.12-1.41). After adjustment for covariates, patients with HFpEF incurred significantly more annualized outpatient visits (21.5 vs. 20.1, p=0.002) and emergency room visits (3.24 vs. 2.94, p=0.002) than HFrEF patients, but absolute differences were small. High inpatient and
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pharmacy utilization did not differ. Our study suggests that whether a patient has HFrEF or HFpEF has little bearing on risk of re-hospitalization or inpatient resource utilization in the year
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following a HF hospitalization. Both groups experienced high mortality, but HFrEF patients had greater risk. In conclusion, from the standpoint of resource use, HF can be considered a single entity.
Key Words: heart failure, ejection fraction, resource utilization, re-hospitalization, mortality
2
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Heart Failure (HF) can have different etiologies with the most common distinction being drawn on the basis of ejection fraction (EF). In addition to poor left ventricular function, HF patients with reduced EF (HFrEF) tend to be younger and more likely to be men than HF patients with
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preserved ejection fraction (HFpEF).1;2 Because HFrEF and HFpEF are different clinical entities with differing demographic characteristics, it is reasonable to expect that common HF. Some studies report greater mortality,2-5 while others report similar or lower mortality among HFrEF
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compared with HFpEF patients.1;6 Similarly, rate of re-hospitalization was also been found to be higher among HFrEF patients in one study,4 but equal to that of HFpEF patients in another.2
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One study found medical costs over 5 years to be similar among HFpEF and HFrEF patients,7 but to our knowledge, no study has examined whether medical resource utilization differs between patients with HFrEF and HFpEF. We undertook the current study to compare risk of rehospitalization, all-cause mortality, and medical resource utilization for up to one year following
Methods
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discharge for a HF hospitalization.
We conducted a retrospective cohort study of members from Kaiser Permanente Southern
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California (KPSC), serving approximately 3.6 million individuals of Southern California and Kaiser Permanente Northwest (KPNW), serving approximately 480,000 individuals in the
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Portland, Oregon area. Virtually all medical care provided by KPSC and KPNW is captured in electronic databases, including inpatient admissions, outpatient visits, laboratory values and pharmaceutical dispensings. The KPNW Institutional Review Board (IRB) approved the study with a waiver of informed consent, and the KPSC IRB ceded oversight to KPNW. We identified all members of these two integrated health systems aged ≥18 years who had a hospitalization with a primary discharge diagnosis of heart failure (International
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Classification of Diseases, 9th Edition [ICD-9-CM] 428.xx) and were discharged alive between January 1, 2008 and December 31, 2011 and had no prior HF hospitalization in the preceding 12 months. Patients with <12 months of health plan membership prior to the index hospitalization
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were excluded. Of the approximately 19,000 potential patients who met these criteria, we
excluded 53 patients with length of stay greater than 30 days to avoid undue influence of these uncommon cases on the overall results.
SC
We limited our analyses to the 6,513 patients (34% of potential subjects) that had an echocardiogram during the index hospitalization. Because EF measurments are often imprecise
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or entered as free text, we implemented a computerized algorithm to categorize EF as reduced (EF <40%), borderline (EF 41-49%) or normal (EF >50%), and excluded the 677 patients who fell into the borderline category, resulting in a final analysis sample of 5,836. Baseline patient demographic characteristics, clinical risk factors and medical history
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were captured from electronic medical record (EMR) data during the 12 months prior to the index hospitalization. Medical history included prior diagnosis of HF and other comorbidities including coronary heart disease (ICD-9-CM 410.x-414.x), diabetes mellitus (ICD-9-CM
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250.xx), hypertension (ICD-9 code 401.x-405.x), and depression (ICD-9-CM code 296.2-296.8 and 311). We also characterized baseline kidney function using outpatient serum creatinine
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concentration values to estimate glomerular filtration rate (eGFR) using the Modification Diet in Renal Disease (MDRD) equation, defining chronic kidney disease as an eGFR < 60ml/min/1.73m2 or presence of a 585.x ICD-9-CM code. Our two clinical outcomes of interest were re-hospitalization for any reason and all-cause
mortality, each of which was assessed 30 days and 1 year following the discharge date of the index HF hospitalization. Re-hospitalizations were captured from the EMR. Deaths were
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identified from health plan databases, state death registries and Social Security Administration Death Master files. We collected inpatient, outpatient and pharmacy utilization for up to 12 months following
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the the index hospitalization, counting for each patient the total number of inpatient admissions, inpatient hospital days, emergency room visits, outpatient visits and pharmaceutical dispenses (in 30-day increments, e.g., a 90-day supply counted as 3 dispenses). Not all patients remained
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health plan members for the entire year of follow-up either due to mortality or disenrollment for
eligibility then multiplying by 12.
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other reasons, so we annualized each of these forms of utilization by dividing by months of
We compared baseline characteristics of patients with HFrEF vs. HFpEF using simple ttests for continuous variables and χ2 tests for dichotomous variables. To compare rates of rehospitalization and mortality, we used generalized linear models with Poisson errors and the
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natural log of person-time as an adjustment for unequal follow-up, including adjustments for covariates. We compared annualized medical utilization using generalized linear models weighted by months of eligibility. These models were also adjusted for covariates and included
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an indicator variable for mortality within one year. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC).
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Results
Of the 5,847 patients, 38% (n=2,205) had HFrEF and 62% (n=3,631) had HFpEF (Table
1). The crude prevalence of the four clinical outcomes of interest is compared in Table 2. The incidence of re-hospitalization was not statistically significantly different between HFrEF and HFpEF patients after adjustment for covariates at either 30 days or 1 year (Figure 1). However, Figure 2 shows that HFrEF patients had 39% greater adjusted mortality at 30 days. After
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adjustment for covariates including mortality, patients with HFpEF incurred significantly more annualized outpatient visits and emergency room visits compared with HFrEF patients, although the absolute differences were small (Table 3). Inpatient utilization and pharmaceutical dispenses
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were nearly identical and not statistically significantly different between the two groups. Discussion
In this observational cohort study of nearly 6,000 HF patients, we found that differences
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in demographic and clinical characteristics between HFrEF and HFpEF patients did not translate into meaningful differences in resource utilization. Our results suggest that the resources needed
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to manage HF patients are essentially the same for at least one year following HF hospitalization regardless of EF.
One recent study found that higher noncardiac comorbidity among patients with HFpEF was associated with higher non-HF hospitalizations, a finding that was offset by increased HF
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admissions among HFrEF patients.8 In our comparison of medical resource utilization between patients with HFrEF and HFpEF, we found no difference in inpatient (hospitalizations, hospital days) or pharmacy utilization, a finding consistent with a previous study comparing medical
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costs.7 Length of stay may be a proxy for HF severity, but was not clinically or statistically different between our two groups.9 One previous study used a medical claims database and found
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between 20 and 30 annual outpatient visits among all patients with at least one HF hospitalization, depending on age and recency of the qualifying hospitalization,10 a finding that is consistent with the data we report. There is no doubt that HF places a substantial burden on the health care system, and costs are expected to rise markedly over the next 25 years.11 Our data suggest that HFrEF and HFpEF require a similar amount of resources for chronic care. Nonetheless, HFpEF is itself a heterogeneous condition.12 Our data were not sufficiently granular
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to determine the extent to which varying pathophysiology within this group differentially impacts medical resource use. Most community-based studies reporting proportions of patients with preserved vs.
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reduced EF have consistently reported approximately 54% of HF patients to have reduced EF. For example, the Acute Decompensated Heart Failure (ADHERE) National Registry found that 46% of patients have evidence of mild or no impairment of systolic function.13 The EuroHeart
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Failure Survey (EHFS) project that spanned 24 countries also found slightly more HFrEF than HFpEF patients (54% vs. 46%),2 identical to the percentages reported among new-onset HF
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patients in the Framingham Heart Study.14 In contrast, we found a greater proportion of our study subjects (62%) had HFpEF. In-hospital mortality was 4% in ADHERE. Given the differences in survival between HFrEF and HFpEF patients we found, our requirement that patients survive the index hospitalization likely produced a different distribution than has been reported elsewhere.
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We required the index hospitalization have a primary diagnosis of HF, whereas ADHERE allowed secondary and tertiary diagnoses. EHFS included pharmacologic treatment for ventricular dysfunction in its definition of HF, which would necessarily increase the proportion
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with HFrEF, while Framingham excluded patients with pre-existing HF. We excluded patients with a HF hospitalization within the past year, but a significantly larger proportion of our HFrEF
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patients had a previous diagnosis of HF in their EMR.Most prior studies of mortality comparing HFrEF with HFpEF have reported greater mortality among HFrEF patients,2;3;15 with relative differences as high as two-fold.4;5 However, one study found equal mortality,1 while another reported lower mortality among HFrEF compared with HFpEF patients.6 Interestingly, a recent European study found that for a given level of B-type natriuretic peptide (BNP), mortality of patients with HFrEF did not differ from that of HFpEF.16 BNP and NT-proBNP were rarely
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measured in our data and not reported in the other studies. Follow-up time of these studies differed substantially, ranging from 12 weeks to 11 years, making direct comparisons difficult.
HFrEF is particularly high within 30 days.
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Our results, assessed at both 30 days and 1 year, suggest that increased risk of mortality among
Studies examining re-hospitalization of HFrEF compared with HFpEF patients are less common. Lenzen et al. found no difference in re-hospitalization rates at 12 weeks.2 The
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Candesartan in Heart failure: Reduction in Morbidity and mortality (CHARM) trials reported greater rates among HFrEF compared with HFpEF patients, but noted that time since last
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hospitalization was an important predictor of events.4 Our follow-up began immediately upon HF hospitalization discharge, so time since last hospitalization was equal between HFrEF and HFpEF patients.
Our study was strengthened by our ability to use comprehensive medical data for a large
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number of geographically and demographically diverse patients. The large initial sample also allowed us to select only patients who had an EF measured during the index hospitalization and to exclude patients with borderline values. This could also be viewed as a limitation, because our
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analysis sample consisted of only 34% of the potential study subjects. As an observational study, we acknowledge our results cannot be viewed as causal. We were unable to include
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important clinical variables such as BNP or NT-proBNP that could explain differences we both did and did not find.
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Funding: This study was funded by a contractual agreement between Kaiser Permanente Center for Health Research and Novartis Pharmaceuticals Corporation. By contract, the lead author
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(GAN) had final say on all content, interpretation, and decision to publish.
Disclosures: GAN has received grant funding from Novartis Pharmaceuticals, Merck & Co.,
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Inc., AstraZeneca, Boehringer-Ingelheim, and Incyte Corporation. KL has received grant
funding from Novartis Pharmaceuticals, Merck & Co., Inc., and AstraZeneca. AGR and TMK
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report no disclosures. WWC is an employee of Novartis Pharmaceuticals Corporation.
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(1) Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nikomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMA
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2006;296:2209-2216. (2) Lenzen MJ, Scholte op Reimer WJM, Boersma E, Vantrimpont PJMJ, Follath F,
Swedberg K, Cleland J, Komajda M. Differences between patients with a preserved and
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depressed left ventricular function: A report from the EuroHeart Failure Survey. Eur Heart J 2004;25:1214-1220.
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(3) McCullough PA, Khandelwal AK, McKinnon JE, Shenkman HJ, Pampati V, Nori D, Sullivan RA, Sandberg KR, Kaatz S. Outcomes and prognostic factors of systolic as compared with diastolic heart failure in urban America. CHF 2005;11:6-11. (4) Bello NA, Claggett B, Desai AS, McMurray JJV, Granger CB, Yusuf S, Swedberg K,
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Pfeffer MA, Solomon SD. Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart
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Fail 2014;7:590-595.
(5) Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart
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failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:19481955.
(6) Varadarajan P, Pai RG. Prognosis of congestive heart failure in patients with normal versus reduced ejection fractions: Results from a cohort of 2,258 hospitalized patients. Journal of Cardiac Failure 2003;9:107-112.
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(7) Liao L, Jollis JG, Anstrom KJ, Whellan DJ, Kitzman DW, Aurigemma GP, Mark DB, Schulman KA, Gottdiener JS. Costs for heart failue with normal vs reduced ejection
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fraction. Arch Intern Med 2006;166:112-118. (8) Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, Wehrens XHT, Deswal A. Impact of noncardiac comorbidities on morbidity and mortality in a
fraction. J Am Coll Cardiol 2012;59:998-1005.
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predominantly male population with heart failure and preserved versus reduced ejection
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(9) Reynolds K, Butler MG, Kimes TM, Rosales AG, Chan W, Nichols GA. Relation of acute heart failure hospital length of stay to subsequent readmission and all-cause mortality. Am J Cardiol 2015 doi:10.1016/j.amjcard.2015.04.052 (epub ahead of print). (10) Korves C, Eldar-Lissai A, McHale J, Lafeuille MH, Ong SH, Duh MS. Resource
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utilization and costs following hospitalization of patients with chronic heart failure in the US. Journal of Medical Economics 2012;15:925-937.
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(11) Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G,
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Orenstein D, Wilson PW, Woo YJ. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation
2011;123:933-944.
(12) Kitzman DW, Upadhya B. Heart failure with preserved ejection fraction: A heterogeneous disorder with multifactorial pathophysiology. J Am Coll Cardiol 2014;63:457-459.
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(13) Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP, for the ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure
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in the United States: Rationale, design, and preliminary observations from the first
100,000 cases in the acute decompensated heart failure national registry (ADHERE). Am
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Heart J 2005;149:209-216.
(14) Ho JE, Gona P, Pencina MJ, Tu JV, Austin PC, Vasan RS, Kannel WB, D'Agostino RB,
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Lee DS, Levy D. Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community. Eur Hear J 2012;33:1734-1741. (15) Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, Bakker SJ, Hillege HL, van Veldhuisen DJ, van Glist WH. Incidence and epidemiology of new onset
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heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J 2013;34:1424-1431. (16) van Veldhuisen DJ, Linssen GCM, Jaarsma T, van Glist WH, Hoes AW, Tijssen JGP,
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Paulus WJ, Voors AA, Hillege HL. B-Type natriuretic peptide and prognosis in heart
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failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013;61:1498-1506.
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Figure Legends
Figure 1. Incidence of re-hospitalization for any cause within 30 days and 1 year of index
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hospitalization for heart failure among patients with reduced vs. preserved ejection fraction. Incidence rates are adjusted for age, sex, race, smoking status, prior heart failure, coronary artery
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disease, diabetes, hypertension, chronic kidney disease, and depression.
Figure 2. Incidence of all-cause mortality within 30 days and 1 year of index hospitalization for
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heart failure among patients with reduced vs. preserved ejection fraction. Incidence rates are adjusted for age, sex, race, smoking status, prior heart failure, coronary artery disease, diabetes,
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hypertension, chronic kidney disease, and depression.
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Table 1. Characteristics of Study Sample with Reduced and Preserved Ejection Fraction.
Variable
HFrEF (n=2,205)
HFpEF (n=3,631)
Age (Years)
71.4 + 13.8
75.9 + 12.3
<0.001
Men
64%
45 %
<0.001
Hispanic
21%
20%
0.605
Non-Hispanic Black
19%
14%
<0.001
Non-Hispanic White/Other
60%
Current Smoker
11%
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P Value
<0.001
6%
<0.001
52%
45%
<0.001
40%
36%
<0.001
40%
49%
<0.001
51%
66%
<0.001
76%
90%
<0.001
19%
25%
<0.001
Systolic Blood Pressure (mmHg)
127 + 16
133 + 15
<0.001
Diastolic Blood Pressure (mmHg)
71 + 11
68 + 9
<0.001
Length of Stay of Index Hospitalization (Days)
4.0 + 3.2
3.8 + 3.2
0.064
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66%
Pre-existing Heart Failure Coronary Artery Disease Diabetes Mellitus Chronic Kidney Disease
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Depression
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Hypertension
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Table 2. Number (%) Study Outcomes among Subjects with Reduced and Preserved Ejection Fraction.
HFrEF (n=2,205)
HFpEF (n=3,631)
Within 30 Days
429 (20%)
688 (19%)
Within 1 Year
1,203 (55%)
2,107 (58%)
Within 30 Days
133 (6%)
187 (5%)
0.151
Within 1 Year
534 (24%)
836 (23%)
0.297
0.010
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All-Cause Mortality
0.633
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Re-Hospitalization
P Value
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Outcome
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Table 3. Adjusted Mean (SD) Annual Medical Resource Utilization among Patients with Reduced and Preserved Ejection Fraction
Medical Resource
HFrEF (n=2,205)
HFpEF (n=3,631)
Hospitalizations
2.02 + 2.61
2.02 + 2.58
Hospital Days
9.66 + 18.16
9.84 + 17.96
Outpatient Visits
20.1 + 17.1
21.5 + 16.9
Emergency Visits
2.94 + 4.20
3.24 + 3.67
0.002
Pharmaceutical Dispenses
96.5 + 46.6
96.6 + 46.1
0.936
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P Value 0.954
0.002
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0.704
1
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S0002-9149(15)01627-6
DOI:
10.1016/j.amjcard.2015.07.018
Reference:
AJC 21286
To appear in:
The American Journal of Cardiology
Received Date: 26 May 2015 Revised Date:
25 June 2015
Accepted Date: 3 July 2015
Please cite this article as: Nichols GA, Reynolds K, Kimes TM, Rosales AG, Chan WW, Comparison of Risk of Re-Hospitalization, All-Cause Mortality and Medical Care Resource Utilization in Patients with Heart Failure and Preserved versus Reduced Ejection Fraction, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.07.018. 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.
ACCEPTED MANUSCRIPT
Comparison of Risk of Re-Hospitalization, All-Cause Mortality and Medical Care Resource Utilization in Patients with Heart Failure and Preserved versus Reduced Ejection Fraction
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Short Title: Risk and Resource Use of HFrEF vs. HFpEF patients
Gregory A. Nichols, PhD1, Kristi Reynolds, PhD2, Teresa M. Kimes, MS1, A. Gabriela Rosales,
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MS1, Wing W. Chan, MS3
Kaiser Permanente Center for Health Research, Portland, Oregon
2
Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA
3
Novartis Pharmaceuticals Corporation, East Hanover, NJ
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1
Corresponding Author:
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Gregory A. Nichols, PhD Kaiser Permanente Center for Health Research 3800 N. Interstate Avenue Portland, OR 97227 Telephone: 503-335-6733 Email: [email protected]
1
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Abstract Because heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF) are different clinical entities with differing demographic characteristics, common HF outcomes
RI PT
may occur at different rates. Comparative outcomes studies have been equivocal, and studies comparing resource utilization are scant. We used an observational cohort design to study 6,513 patients hospitalized for HF who had an EF measured during the hospitalization and were
SC
discharged alive within 30 days. We excluded 677 patients with borderline EF values (41-49%) and categorized the remaining as HFrEF (EF <40%, n=2,205) and HFpEF (EF >50%, n=3,631).
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Patients were followed for up to one year for all-cause re-hospitalization and mortality and annualized medical resource utilization. HFrEF and HFpEF patients experienced similar adjusted incidence rates of re-hospitalization, but HFrEF patients had a 39% increased risk of mortality at 30 days (rate ratio 1.39, 95% CI 1.10-1.76) and 25% greater risk at 1 year (1.25,
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1.12-1.41). After adjustment for covariates, patients with HFpEF incurred significantly more annualized outpatient visits (21.5 vs. 20.1, p=0.002) and emergency room visits (3.24 vs. 2.94, p=0.002) than HFrEF patients, but absolute differences were small. High inpatient and
EP
pharmacy utilization did not differ. Our study suggests that whether a patient has HFrEF or HFpEF has little bearing on risk of re-hospitalization or inpatient resource utilization in the year
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following a HF hospitalization. Both groups experienced high mortality, but HFrEF patients had greater risk. In conclusion, from the standpoint of resource use, HF can be considered a single entity.
Key Words: heart failure, ejection fraction, resource utilization, re-hospitalization, mortality
2
ACCEPTED MANUSCRIPT
Heart Failure (HF) can have different etiologies with the most common distinction being drawn on the basis of ejection fraction (EF). In addition to poor left ventricular function, HF patients with reduced EF (HFrEF) tend to be younger and more likely to be men than HF patients with
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preserved ejection fraction (HFpEF).1;2 Because HFrEF and HFpEF are different clinical entities with differing demographic characteristics, it is reasonable to expect that common HF. Some studies report greater mortality,2-5 while others report similar or lower mortality among HFrEF
SC
compared with HFpEF patients.1;6 Similarly, rate of re-hospitalization was also been found to be higher among HFrEF patients in one study,4 but equal to that of HFpEF patients in another.2
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One study found medical costs over 5 years to be similar among HFpEF and HFrEF patients,7 but to our knowledge, no study has examined whether medical resource utilization differs between patients with HFrEF and HFpEF. We undertook the current study to compare risk of rehospitalization, all-cause mortality, and medical resource utilization for up to one year following
Methods
TE D
discharge for a HF hospitalization.
We conducted a retrospective cohort study of members from Kaiser Permanente Southern
EP
California (KPSC), serving approximately 3.6 million individuals of Southern California and Kaiser Permanente Northwest (KPNW), serving approximately 480,000 individuals in the
AC C
Portland, Oregon area. Virtually all medical care provided by KPSC and KPNW is captured in electronic databases, including inpatient admissions, outpatient visits, laboratory values and pharmaceutical dispensings. The KPNW Institutional Review Board (IRB) approved the study with a waiver of informed consent, and the KPSC IRB ceded oversight to KPNW. We identified all members of these two integrated health systems aged ≥18 years who had a hospitalization with a primary discharge diagnosis of heart failure (International
3
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Classification of Diseases, 9th Edition [ICD-9-CM] 428.xx) and were discharged alive between January 1, 2008 and December 31, 2011 and had no prior HF hospitalization in the preceding 12 months. Patients with <12 months of health plan membership prior to the index hospitalization
RI PT
were excluded. Of the approximately 19,000 potential patients who met these criteria, we
excluded 53 patients with length of stay greater than 30 days to avoid undue influence of these uncommon cases on the overall results.
SC
We limited our analyses to the 6,513 patients (34% of potential subjects) that had an echocardiogram during the index hospitalization. Because EF measurments are often imprecise
M AN U
or entered as free text, we implemented a computerized algorithm to categorize EF as reduced (EF <40%), borderline (EF 41-49%) or normal (EF >50%), and excluded the 677 patients who fell into the borderline category, resulting in a final analysis sample of 5,836. Baseline patient demographic characteristics, clinical risk factors and medical history
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were captured from electronic medical record (EMR) data during the 12 months prior to the index hospitalization. Medical history included prior diagnosis of HF and other comorbidities including coronary heart disease (ICD-9-CM 410.x-414.x), diabetes mellitus (ICD-9-CM
EP
250.xx), hypertension (ICD-9 code 401.x-405.x), and depression (ICD-9-CM code 296.2-296.8 and 311). We also characterized baseline kidney function using outpatient serum creatinine
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concentration values to estimate glomerular filtration rate (eGFR) using the Modification Diet in Renal Disease (MDRD) equation, defining chronic kidney disease as an eGFR < 60ml/min/1.73m2 or presence of a 585.x ICD-9-CM code. Our two clinical outcomes of interest were re-hospitalization for any reason and all-cause
mortality, each of which was assessed 30 days and 1 year following the discharge date of the index HF hospitalization. Re-hospitalizations were captured from the EMR. Deaths were
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identified from health plan databases, state death registries and Social Security Administration Death Master files. We collected inpatient, outpatient and pharmacy utilization for up to 12 months following
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the the index hospitalization, counting for each patient the total number of inpatient admissions, inpatient hospital days, emergency room visits, outpatient visits and pharmaceutical dispenses (in 30-day increments, e.g., a 90-day supply counted as 3 dispenses). Not all patients remained
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health plan members for the entire year of follow-up either due to mortality or disenrollment for
eligibility then multiplying by 12.
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other reasons, so we annualized each of these forms of utilization by dividing by months of
We compared baseline characteristics of patients with HFrEF vs. HFpEF using simple ttests for continuous variables and χ2 tests for dichotomous variables. To compare rates of rehospitalization and mortality, we used generalized linear models with Poisson errors and the
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natural log of person-time as an adjustment for unequal follow-up, including adjustments for covariates. We compared annualized medical utilization using generalized linear models weighted by months of eligibility. These models were also adjusted for covariates and included
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an indicator variable for mortality within one year. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC).
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Results
Of the 5,847 patients, 38% (n=2,205) had HFrEF and 62% (n=3,631) had HFpEF (Table
1). The crude prevalence of the four clinical outcomes of interest is compared in Table 2. The incidence of re-hospitalization was not statistically significantly different between HFrEF and HFpEF patients after adjustment for covariates at either 30 days or 1 year (Figure 1). However, Figure 2 shows that HFrEF patients had 39% greater adjusted mortality at 30 days. After
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adjustment for covariates including mortality, patients with HFpEF incurred significantly more annualized outpatient visits and emergency room visits compared with HFrEF patients, although the absolute differences were small (Table 3). Inpatient utilization and pharmaceutical dispenses
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were nearly identical and not statistically significantly different between the two groups. Discussion
In this observational cohort study of nearly 6,000 HF patients, we found that differences
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in demographic and clinical characteristics between HFrEF and HFpEF patients did not translate into meaningful differences in resource utilization. Our results suggest that the resources needed
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to manage HF patients are essentially the same for at least one year following HF hospitalization regardless of EF.
One recent study found that higher noncardiac comorbidity among patients with HFpEF was associated with higher non-HF hospitalizations, a finding that was offset by increased HF
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admissions among HFrEF patients.8 In our comparison of medical resource utilization between patients with HFrEF and HFpEF, we found no difference in inpatient (hospitalizations, hospital days) or pharmacy utilization, a finding consistent with a previous study comparing medical
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costs.7 Length of stay may be a proxy for HF severity, but was not clinically or statistically different between our two groups.9 One previous study used a medical claims database and found
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between 20 and 30 annual outpatient visits among all patients with at least one HF hospitalization, depending on age and recency of the qualifying hospitalization,10 a finding that is consistent with the data we report. There is no doubt that HF places a substantial burden on the health care system, and costs are expected to rise markedly over the next 25 years.11 Our data suggest that HFrEF and HFpEF require a similar amount of resources for chronic care. Nonetheless, HFpEF is itself a heterogeneous condition.12 Our data were not sufficiently granular
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to determine the extent to which varying pathophysiology within this group differentially impacts medical resource use. Most community-based studies reporting proportions of patients with preserved vs.
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reduced EF have consistently reported approximately 54% of HF patients to have reduced EF. For example, the Acute Decompensated Heart Failure (ADHERE) National Registry found that 46% of patients have evidence of mild or no impairment of systolic function.13 The EuroHeart
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Failure Survey (EHFS) project that spanned 24 countries also found slightly more HFrEF than HFpEF patients (54% vs. 46%),2 identical to the percentages reported among new-onset HF
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patients in the Framingham Heart Study.14 In contrast, we found a greater proportion of our study subjects (62%) had HFpEF. In-hospital mortality was 4% in ADHERE. Given the differences in survival between HFrEF and HFpEF patients we found, our requirement that patients survive the index hospitalization likely produced a different distribution than has been reported elsewhere.
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We required the index hospitalization have a primary diagnosis of HF, whereas ADHERE allowed secondary and tertiary diagnoses. EHFS included pharmacologic treatment for ventricular dysfunction in its definition of HF, which would necessarily increase the proportion
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with HFrEF, while Framingham excluded patients with pre-existing HF. We excluded patients with a HF hospitalization within the past year, but a significantly larger proportion of our HFrEF
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patients had a previous diagnosis of HF in their EMR.Most prior studies of mortality comparing HFrEF with HFpEF have reported greater mortality among HFrEF patients,2;3;15 with relative differences as high as two-fold.4;5 However, one study found equal mortality,1 while another reported lower mortality among HFrEF compared with HFpEF patients.6 Interestingly, a recent European study found that for a given level of B-type natriuretic peptide (BNP), mortality of patients with HFrEF did not differ from that of HFpEF.16 BNP and NT-proBNP were rarely
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measured in our data and not reported in the other studies. Follow-up time of these studies differed substantially, ranging from 12 weeks to 11 years, making direct comparisons difficult.
HFrEF is particularly high within 30 days.
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Our results, assessed at both 30 days and 1 year, suggest that increased risk of mortality among
Studies examining re-hospitalization of HFrEF compared with HFpEF patients are less common. Lenzen et al. found no difference in re-hospitalization rates at 12 weeks.2 The
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Candesartan in Heart failure: Reduction in Morbidity and mortality (CHARM) trials reported greater rates among HFrEF compared with HFpEF patients, but noted that time since last
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hospitalization was an important predictor of events.4 Our follow-up began immediately upon HF hospitalization discharge, so time since last hospitalization was equal between HFrEF and HFpEF patients.
Our study was strengthened by our ability to use comprehensive medical data for a large
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number of geographically and demographically diverse patients. The large initial sample also allowed us to select only patients who had an EF measured during the index hospitalization and to exclude patients with borderline values. This could also be viewed as a limitation, because our
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analysis sample consisted of only 34% of the potential study subjects. As an observational study, we acknowledge our results cannot be viewed as causal. We were unable to include
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important clinical variables such as BNP or NT-proBNP that could explain differences we both did and did not find.
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Funding: This study was funded by a contractual agreement between Kaiser Permanente Center for Health Research and Novartis Pharmaceuticals Corporation. By contract, the lead author
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(GAN) had final say on all content, interpretation, and decision to publish.
Disclosures: GAN has received grant funding from Novartis Pharmaceuticals, Merck & Co.,
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Inc., AstraZeneca, Boehringer-Ingelheim, and Incyte Corporation. KL has received grant
funding from Novartis Pharmaceuticals, Merck & Co., Inc., and AstraZeneca. AGR and TMK
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report no disclosures. WWC is an employee of Novartis Pharmaceuticals Corporation.
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(1) Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nikomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMA
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2006;296:2209-2216. (2) Lenzen MJ, Scholte op Reimer WJM, Boersma E, Vantrimpont PJMJ, Follath F,
Swedberg K, Cleland J, Komajda M. Differences between patients with a preserved and
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depressed left ventricular function: A report from the EuroHeart Failure Survey. Eur Heart J 2004;25:1214-1220.
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(3) McCullough PA, Khandelwal AK, McKinnon JE, Shenkman HJ, Pampati V, Nori D, Sullivan RA, Sandberg KR, Kaatz S. Outcomes and prognostic factors of systolic as compared with diastolic heart failure in urban America. CHF 2005;11:6-11. (4) Bello NA, Claggett B, Desai AS, McMurray JJV, Granger CB, Yusuf S, Swedberg K,
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Pfeffer MA, Solomon SD. Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart
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Fail 2014;7:590-595.
(5) Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart
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failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:19481955.
(6) Varadarajan P, Pai RG. Prognosis of congestive heart failure in patients with normal versus reduced ejection fractions: Results from a cohort of 2,258 hospitalized patients. Journal of Cardiac Failure 2003;9:107-112.
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(7) Liao L, Jollis JG, Anstrom KJ, Whellan DJ, Kitzman DW, Aurigemma GP, Mark DB, Schulman KA, Gottdiener JS. Costs for heart failue with normal vs reduced ejection
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fraction. Arch Intern Med 2006;166:112-118. (8) Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, Wehrens XHT, Deswal A. Impact of noncardiac comorbidities on morbidity and mortality in a
fraction. J Am Coll Cardiol 2012;59:998-1005.
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predominantly male population with heart failure and preserved versus reduced ejection
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(9) Reynolds K, Butler MG, Kimes TM, Rosales AG, Chan W, Nichols GA. Relation of acute heart failure hospital length of stay to subsequent readmission and all-cause mortality. Am J Cardiol 2015 doi:10.1016/j.amjcard.2015.04.052 (epub ahead of print). (10) Korves C, Eldar-Lissai A, McHale J, Lafeuille MH, Ong SH, Duh MS. Resource
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utilization and costs following hospitalization of patients with chronic heart failure in the US. Journal of Medical Economics 2012;15:925-937.
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(11) Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G,
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Orenstein D, Wilson PW, Woo YJ. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation
2011;123:933-944.
(12) Kitzman DW, Upadhya B. Heart failure with preserved ejection fraction: A heterogeneous disorder with multifactorial pathophysiology. J Am Coll Cardiol 2014;63:457-459.
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(13) Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP, for the ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure
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in the United States: Rationale, design, and preliminary observations from the first
100,000 cases in the acute decompensated heart failure national registry (ADHERE). Am
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Heart J 2005;149:209-216.
(14) Ho JE, Gona P, Pencina MJ, Tu JV, Austin PC, Vasan RS, Kannel WB, D'Agostino RB,
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Lee DS, Levy D. Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community. Eur Hear J 2012;33:1734-1741. (15) Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, Bakker SJ, Hillege HL, van Veldhuisen DJ, van Glist WH. Incidence and epidemiology of new onset
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heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J 2013;34:1424-1431. (16) van Veldhuisen DJ, Linssen GCM, Jaarsma T, van Glist WH, Hoes AW, Tijssen JGP,
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Paulus WJ, Voors AA, Hillege HL. B-Type natriuretic peptide and prognosis in heart
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failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013;61:1498-1506.
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Figure Legends
Figure 1. Incidence of re-hospitalization for any cause within 30 days and 1 year of index
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hospitalization for heart failure among patients with reduced vs. preserved ejection fraction. Incidence rates are adjusted for age, sex, race, smoking status, prior heart failure, coronary artery
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disease, diabetes, hypertension, chronic kidney disease, and depression.
Figure 2. Incidence of all-cause mortality within 30 days and 1 year of index hospitalization for
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heart failure among patients with reduced vs. preserved ejection fraction. Incidence rates are adjusted for age, sex, race, smoking status, prior heart failure, coronary artery disease, diabetes,
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hypertension, chronic kidney disease, and depression.
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Table 1. Characteristics of Study Sample with Reduced and Preserved Ejection Fraction.
Variable
HFrEF (n=2,205)
HFpEF (n=3,631)
Age (Years)
71.4 + 13.8
75.9 + 12.3
<0.001
Men
64%
45 %
<0.001
Hispanic
21%
20%
0.605
Non-Hispanic Black
19%
14%
<0.001
Non-Hispanic White/Other
60%
Current Smoker
11%
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P Value
<0.001
6%
<0.001
52%
45%
<0.001
40%
36%
<0.001
40%
49%
<0.001
51%
66%
<0.001
76%
90%
<0.001
19%
25%
<0.001
Systolic Blood Pressure (mmHg)
127 + 16
133 + 15
<0.001
Diastolic Blood Pressure (mmHg)
71 + 11
68 + 9
<0.001
Length of Stay of Index Hospitalization (Days)
4.0 + 3.2
3.8 + 3.2
0.064
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66%
Pre-existing Heart Failure Coronary Artery Disease Diabetes Mellitus Chronic Kidney Disease
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Depression
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Hypertension
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Table 2. Number (%) Study Outcomes among Subjects with Reduced and Preserved Ejection Fraction.
HFrEF (n=2,205)
HFpEF (n=3,631)
Within 30 Days
429 (20%)
688 (19%)
Within 1 Year
1,203 (55%)
2,107 (58%)
Within 30 Days
133 (6%)
187 (5%)
0.151
Within 1 Year
534 (24%)
836 (23%)
0.297
0.010
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All-Cause Mortality
0.633
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Re-Hospitalization
P Value
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Outcome
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Table 3. Adjusted Mean (SD) Annual Medical Resource Utilization among Patients with Reduced and Preserved Ejection Fraction
Medical Resource
HFrEF (n=2,205)
HFpEF (n=3,631)
Hospitalizations
2.02 + 2.61
2.02 + 2.58
Hospital Days
9.66 + 18.16
9.84 + 17.96
Outpatient Visits
20.1 + 17.1
21.5 + 16.9
Emergency Visits
2.94 + 4.20
3.24 + 3.67
0.002
Pharmaceutical Dispenses
96.5 + 46.6
96.6 + 46.1
0.936
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P Value 0.954
0.002
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0.704
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