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Research

JAMA Cardiology | Original Investigation

Characteristics and Outcomes of Adult Outpatients With


Heart Failure and Improved or Recovered Ejection Fraction
Andreas P. Kalogeropoulos, MD, MPH, PhD; Gregg C. Fonarow, MD; Vasiliki Georgiopoulou, MD, MPH, PhD;
Gregory Burkman, MD; Sarawut Siwamogsatham, MD; Akash Patel, MD; Song Li, MD;
Lampros Papadimitriou, MD, PhD; Javed Butler, MD, MPH, MBA

Editorial page 507


IMPORTANCE Heart failure (HF) guidelines recognize that a subset of patients with HF and Supplemental content at
preserved left ventricular ejection fraction (LVEF) previously had reduced LVEF but jamacardiology.com
experienced improvement or recovery in LVEF. However, data on these patients are limited.

OBJECTIVE To investigate the characteristics and outcomes of adult outpatients with HF and
improved or recovered ejection fraction (HFrecEF).

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study (inception period, January 1,
2012, to April 30, 2012) with 3-year follow-up at cardiology clinics (including HF subspecialty)
in an academic institution. The dates of the analysis were May 21, 2015, to August 10, 2015.
Participants were all outpatients 18 years or older who received care for a verified diagnosis of
HF not attributed to specific cardiomyopathies or other special causes during the inception
period.

EXPOSURES Type of HF at baseline, classified as HF with reduced ejection fraction (HFrEF)


(defined as current LVEF 40%), HF with preserved ejection fraction (HFpEF) (defined as
current and all previous LVEF reports >40%), and HF with recovered ejection fraction
(HFrecEF) (defined as current LVEF >40% but any previously documented LVEF 40%).

MAIN OUTCOMES AND MEASURES Mortality, hospitalization rates, and composite end points.

RESULTS The study cohort comprised 2166 participants. Their median age was 65 years,
41.4% (896 of 2166) were female, 48.7% (1055 of 2166) were white and 45.2% (1368 of
2166) black, and 63.2% (1368 of 2166) had coronary artery disease. Preserved (>40%) LVEF
at inception was present in 816 of 2166 (37.7%) patients. Of these patients, 350 of 2166
(16.2%) had previously reduced (40%) LVEF and were classified as having HFrecEF,
whereas 466 of 2166 (21.5%) had no previous reduced LVEF and were classified as having
HFpEF. The remaining 1350 (62.3%) patients were classified as having HFrEF. After 3 years,
age and sexadjusted mortality was 16.3% in patients with HFrEF, 13.2% in patients with
HFpEF, and 4.8% in patients with HFrecEF (P < .001 vs HFrEF or HFpEF). Compared with
patients with HFpEF and patients with HFrEF, patients with HFrecEF had fewer all-cause
(adjusted rate ratio [RR] vs HFpEF, 0.71; 95% CI, 0.55-0.91; P = .007), cardiovascular (RR,
0.50; 95% CI, 0.35-0.71; P < .001), and HF-related (RR, 0.48; 95% CI, 0.30-0.76; P = .002)
hospitalizations and were less likely to experience composite end points commonly used in
clinical trials (death or cardiovascular hospitalization and death or HF hospitalization).

CONCLUSIONS AND RELEVANCE Outpatients with HFrecEF have a different clinical course than
patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations, and
fewer composite end points. These patients may need to be investigated separately in
outcomes studies and clinical trials. Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Andreas P.
Kalogeropoulos, MD, MPH, PhD,
Division of Cardiology, Department of
Medicine, Emory University School of
Medicine, 1462 Clifton Rd NE,
JAMA Cardiol. 2016;1(5):510-518. doi:10.1001/jamacardio.2016.1325 Ste 535B, Atlanta, GA 30322
Published online July 6, 2016. (akaloge@emory.edu).

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Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

H
eart failure with preserved ejection fraction (HFpEF)
has been reported to account for almost half of all heart Key Points
failure (HF) cases.1-3 In most studies, the morbidity and
Question What are the outcomes of patients having heart failure
mortality of HFpEF were similar or comparable to those of HF (HF) with recovered ejection fraction (ie, HF with initially reduced
with reduced ejection fraction (HFrEF).1,2,4-7 Based on the epi- ejection fraction that has partially or fully recovered over time)?
demiological link of HFpEF to aging and age-related risk fac-
Findings In this cohort study of 2166 adult outpatients with HF,
tors and comorbid conditions, the prevalence of HFpEF is pro-
16.2% of patients were seen with recovered ejection fraction.
jected to rise.1,7 There is also growing evidence that HFpEF is After 3 years, these patients had significantly lower mortality
a diverse entity encompassing a wide range of structural and compared with patients having HF and permanently reduced or
clinical phenotypes.8-10 preserved ejection fraction, as well as significantly fewer
It has been recently recognized that a subset of patients hospitalizations.
with HFpEF previously had reduced left ventricular ejection Meaning Heart failure with recovered ejection fraction should be
fraction (LVEF) but had improvement or recovery in LVEF treated as a distinct entity for clinical and research purposes.
either by natural history or in response to therapy.11 Patients
with HF and recovered ejection fraction (HFrecEF) may be clini-
cally distinct from those with persistently preserved or re- judicated on the basis of individual review of medical rec-
duced LVEF. However, there are few reports that describe the ords. The ICD-9-CM codes were used for only cohort incep-
characteristics and outcomes of patients with HFrecEF,12,13 with tion. Case verification for HF and all further classification were
these limited data suggesting that such patients may have im- done by individual medical record review. The final analysis
proved outcomes compared with patients with persistent cohort consisted of 2166 patients. The Emory University In-
HFrEF or HFpEF,13 but further research is needed. Most im- stitutional Review Board approved the study. Because this was
portant, data on hospitalizations have not been reported to a retrospective study, no informed consent was required. The
date. institutional review board approved the use of data for the pur-
To enhance our understanding regarding the characteris- poses of this research.
tics and outcomes of patients with HFrecEF, we reviewed the
medical records of approximately 2500 outpatients with HF Classification of HF Cases
who received care in Emory Healthcare during a prespecified We classified patients as having (1) HFrEF (defined as current
window and collected 3-year follow-up data. Our primary hy- LVEF 40% regardless of previous LVEF assessments), (2)
pothesis was that patients having HFrecEF have lower mor- HFpEF (defined as current and all previous LVEF reports
tality compared with patients having HFpEF. >40%), or (3) HFrecEF (defined as current LVEF >40% but any
previously documented LVEF 40%). Patients with current pre-
served LVEF (>40%) but no previous documentation of LVEF
were assigned to HFpEF. We opted for a cutoff of 40% or less
Methods for HFrEF on the basis of the American guidelines suggesting
Study Population that this value is a reasonable definition of HFrEF.11 However,
We reviewed the medical records of 2507 adult (age 18 years) recognizing that there is a subset of patients with borderline
outpatients who received care associated with International LVEF, we classified cases using a greater than 50% cutoff in a
Classification of Diseases, Ninth Revision, Clinical Modifica- secondary analysis. For consistency, all LVEF assessments were
tion (ICD-9-CM) codes 402.X1, 404.X1, 404.X3, and 428.XX14 based on transthoracic echocardiography. When an LVEF range
between January 1, 2012, and April 30, 2012, in Emory Health- was reported, the mean value was assigned for analysis pur-
care by cardiologists. The inception time frame was selected poses (eg, for reported LVEF of 30%-35%, we assigned a value
to allow for at least 3 years of follow-up. Medical records were of 32.5%).
reviewed for symptoms, signs, and treatment of HF, as well as
the last reported LVEF, previous LVEF documentation, and spe- Baseline Characteristics and Conditions
cial causes of HF. The diagnosis of HF was verified in 2302 of Baseline demographic, anthropometric, and vital signs data
2507 patients (91.8%) based on physician documentation of were collected through the Emory Clinical Data Warehouse
symptoms, signs, and guideline-based treatment for HF. We from the index clinic visit record. Race was self-reported. For
excluded the following: (1) patients with specific cardiomy- laboratory values and medications, we extracted the last in-
opathies (eg, hypertrophic, stress induced, infiltrative, restric- formation available up to the index visit date. The presence
tive, or chemotherapy induced), (2) patients with HF due to of baseline chronic conditions was adjudicated according to
adult congenital heart disease, (3) recipients of heart trans- the latest (2014) algorithm proposed by the Chronic Condi-
plant or mechanical circulatory support, (4) patients with pri- tions Data Warehouse,15 which is used to analyze Medicare
mary right-sided disease (eg, right ventricular cardiomyo- data.
pathy or class I pulmonary arterial hypertension), and (5)
patients with primary valvular disease (eFigure in the Supple- Assessment and Classification of Outcomes
ment). We also excluded 7 patients who had no follow-up en- Outcomes data (death and hospitalizations) were collected
counters and 7 patients who had no quantitative LVEF data. through the Emory Clinical Data Warehouse up to April 30,
Special causes of HF and all other exclusion criteria were ad- 2015, providing for a minimum of 3 years of follow-up for each

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Research Original Investigation Heart Failure With Recovered vs Preserved Ejection Fraction

alive patient who continued to receive care in Emory Health- adjusted models based on associations with the exposure of
care. For patients who were alive for the last encounter but did interest (HF group), associations with outcomes, clinical
not continue to receive care in the system throughout the study interpretation, and previous work: age, sex, race (white,
period, the last encounter was considered the last date of fol- black, and other), body mass index, coronary artery disease,
low-up for analysis purposes. comorbid conditions (diabetes, depression, chronic lung
We classified hospitalizations based on the primary ICD- disease, chronic kidney disease, and atrial fibrillation),
9-CM codes using the Clinical Classifications Software, 2015 blood pressure, renal function, hemoglobin level, serum
version, as provided by the Healthcare Cost and Utilization Proj- sodium and potassium levels, and therapy with -blockers,
ect of the Agency for Healthcare Research and Quality.16 Hos- angiotensin-converting enzyme inhibitors or angiotensin
pitalizations with primary ICD-9-CM diagnoses mapping to receptor blockers, and loop diuretics. To evaluate for non-
Clinical Classifications Software category 7 (Diseases of the linear effects of covariates, we used restricted cubic splines.
circulatory system) were classified as cardiovascular. Hospi- We performed 2 sensitivity analyses. First, we repeated
talizations with primary codes 402.X1, 404.X1, 404.X3, and analyses using a greater than 50% cutoff for preserved
428.XX were classified as HF related. LVEF. Second, because outcomes in patients with HFrecEF
may reflect lead-time bias (ie, patients with HFrecEF had
End Points survived long enough for LVEF to recover), 18 we left-
We considered (1) time-to-event end points, including mor- truncated follow-up at 1 year and repeated time-to-event
tality and composite end points (death or first hospitalization analyses. Finally, we investigated for interactions of sex and
for any cause, death or first hospitalization for cardiovascu- race with HF groups for outcomes. We used a statistical
lar causes, and death or first HF-related hospitalization), and software program (Stata, version 14.0; StataCorp LP) for
(2) hospitalization rates over the entire follow-up period (all- analyses.
cause, cardiovascular, and HF-related hospitalizations). We in-
cluded estimates of composite end points because these val-
ues are frequently used in clinical trials.
Results
Statistical Analysis Study Population and HF Classification
Based on (1) an interim analysis for distribution of cases in Among the 2166 eligible patients with HF, 816 (37.7%) were seen
the first 400 eligible patients and (2) 1-year outcomes from with preserved LVEF (>40%) at the index visit. Of 816 pa-
our cohort and previous mortality data,13 we calculated that tients, 350 (42.9%) were classified as having HFrecEF (16.2%;
1900 eligible cases would provide 80% power to detect a 95% CI, 14.6%-17.8% of the cohort), and 466 (57.1%) were clas-
difference in mortality between the HFrecEF and HFpEF sified as having HFpEF (21.5%; 95% CI, 19.8%-23.3% of the co-
groups at 2-sided = .05 (primary hypothesis), allowing for hort). The remaining 1350 patients were classified as having
5% early loss to follow-up. We opted to focus on these 2 HFrEF (62.3%; 95% CI, 60.2%-64.4% of the cohort). The me-
groups because of similar LVEF at presentation and the dian time from the last reported LVEF was 182 days (25th to
potential of contamination of HFpEF studies with HFre- 75th percentile, 13-483 days) and did not differ between HF
cEF cases, which may have a different prognosis. Therefore, groups (P = .14 for difference). The median LVEFs were 55%
we opted to power the study for difference in mortality (25th to 75th percentile, 50%-60%) among patients with
between these 2 groups. Also, based on our preliminary HFpEF, 50% (25th to 75th percentile, 45%-55%) among pa-
data, the mortality gradient was smaller between HFpEF tients with HFrecEF (P < .001 vs HFpEF), and 25% (25th to 75th
and HFrecEF (vs HFrEF and HFrecEF). Therefore, we pow- percentile, 18%-33%) among patients with HFrEF. The me-
ered the study to detect the smaller mortality gradient reli- dian reduced LVEF among patients with HFrecEF before re-
ably. Because data review was done in calendar month covery was 25% (25th to 75th percentile, 18%-33%), and the
increments, the final sample size exceeded the required improvement in LVEF was observed over a median of 976 days
sample size. To compare characteristics between groups, we (25th to 75th percentile, 377-1797 days). Sixty-eight of 466
used the Kruskal-Wallis test for continuous variables and (14.6%) HFpEF cases with current preserved LVEF but no pre-
the Fisher 2 test for categorical variables. We used Cox pro- vious documentation of LVEF were categorized as HFpEF.
portional hazards models for mortality and composite time- The baseline characteristics of patients are listed in Table 1.
to-event end points. Because we detected nonproportional Patients with HFrecEF were (1) younger, with male predomi-
mortality between HF groups, we estimated hazard ratios nance compared with patients with HFpEF and with demo-
(HRs) separately for year 1 and years 2 to 3 based on an graphics closer to patients with HFrEF; (2) less likely to have
analysis with flexible parametric models showing that a coronary artery disease, diabetes, and kidney disease and had
knot at approximately 1 year best represented the time- lower systolic blood pressure compared with patients with
dependent component. There was no indication of nonpro- HFpEF; (3) more likely to be receiving an angiotensin-
portionality for other time-to-event end points. We used converting enzyme inhibitor or angiotensin receptor blocker
negative binomial regression to estimate rate ratios of hos- regimen and less likely to be taking loop diuretics, aspirin, or
pitalizations between HF groups. The rationale for these digoxin compared with the other 2 groups; and (4) less likely
models for hospitalization rates has been described to be recipients of implantable cardioverter-defibrillator or car-
previously. 17 We considered the following covariates in diac resynchronization therapy.

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Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

Table 1. Baseline Patient Characteristics


Overall HFrEF HFpEF HFrecEF
Variable (N = 2166) (n = 1350) (n = 466) (n = 350) P Value
Age, median (IQR), y 65 (54-75) 63 (51-72) 72 (62-82) 65 (55-74) <.001
Male sex, No. (%) 1270 (58.6) 887 (65.7) 201 (43.1) 182 (52.0) <.001
Race, No. (%)
White 1055 (48.7) 632 (46.8) 235 (50.4) 188 (53.7)
Black 979 (45.2) 619 (45.9) 208 (44.6) 152 (43.4) .006
Other 132 (6.1) 99 (7.3) 23 (4.9) 10 (2.9)
Body mass index, median (IQR)a 29 (25-35) 28 (25-34) 31 (26-38) 30 (25-34) <.001
Blood pressure, median (IQR), mm Hg
Systolic 124 (108-140) 119 (102-136) 135 (121-153) 129 (116-141) <.001
Diastolic 71 (63-80) 71 (63-79) 71 (62-80) 72 (64-80) .36
Current or former smoker, No. (%) 773 (35.7) 520 (38.5) 131 (28.1) 122 (34.9) <.001
History, No. (%)
Coronary artery disease 1368 (63.2) 883 (65.4) 290 (62.2) 195 (55.7) .004
Diabetes 716 (33.1) 414 (30.7) 196 (42.1) 106 (30.3) <.001
Hypertension 1556 (71.8) 902 (66.8) 400 (85.8) 254 (72.6) <.001
Cerebrovascular disease 167 (7.7) 104 (7.7) 39 (8.4) 24 (6.9) .74
Hyperlipidemia 1105 (51.0) 674 (49.9) 263 (56.4) 168 (48.0) .03
Atrial fibrillation 730 (33.7) 435 (32.2) 180 (38.6) 115 (32.9) .04
Chronic kidney disease 885 (40.9) 574 (42.5) 191 (41.0) 120 (34.3) .02
Chronic lung disease 352 (16.3) 208 (15.4) 99 (21.2) 45 (12.9) .003
Anemia 752 (34.7) 437 (32.4) 202 (43.3) 113 (32.3) <.001
Depression 348 (16.1) 200 (14.8) 98 (21.0) 50 (14.3) .005
Dementia 98 (4.3) 56 (4.2) 24 (5.2) 14 (4.0) .61
Laboratory values, median (IQR)
Hematocrit, % 37 (33-41) 38 (34-41) 36 (32-39) 37 (33-40) <.001
Hemoglobin level, g/dL 12 (11-14) 13 (11-14) 12 (11-13) 12 (11-14) <.001
White blood cell count, /L 6700 6700 6800 6700
.39
(5400-8400) (5300-8400) (5400-8700) (5400-8200)
Platelet count, /L 197 000 194 000 198 000 204 000
<.001
(158 000-242 000) (155 000-237 000) (163 000-245 000) (169 000-258 000)
Blood urea nitrogen level, mg/dL 20 (15-28) 20 (15-28) 21 (15-31) 17 (13-25) <.001
Creatinine level, mg/dL 1.2 (0.9-1.5) 1.2 (1.0-1.5) 1.2 (0.9-1.5) 1.1 (0.9-1.4) .001
Glucose level, mg/dL 104 (93-125) 104 (93-122) 107 (92-136) 103 (93-125) .13
Sodium level, mEq/L 138 (136-140) 138 (136-140) 139 (137-140) 139 (137-140) <.001
Potassium level, mEq/L 4.1 (3.9-4.5) 4.1 (3.9-4.5) 4.1 (3.8-4.5) 4.2 (3.9-4.5) .56
Therapy, No. (%)
Angiotensin-converting enzyme inhibitors 1584 (73.1) 1002 (74.2) 305 (65.5) 277 (79.1)
<.001
or angiotensin receptor blockers
-Blockers 1859 (85.8) 1180 (87.4) 369 (79.1) 310 (88.7) <.001
Loop diuretics 1545 (71.3) 973 (72.1) 357 (76.6) 215 (61.3) <.001
Thiazide diuretics 285 (13.2) 131 (9.7) 100 (21.4) 54 (15.4) <.001
Digoxin 293 (13.4) 212 (15.7) 41 (8.7) 40 (11.3) <.001
Nitrates 506 (23.3) 339 (25.1) 97 (20.9) 70 (20.1) .06
Hydralazine 516 (23.8) 348 (25.8) 89 (19.2) 79 (22.7) .02
Warfarin 643 (29.6) 435 (32.2) 118 (25.4) 90 (25.6) .005
Statins 1129 (52.1) 709 (52.5) 253 (54.3) 167 (47.7) .16
Aspirin 713 (32.9) 478 (35.4) 146 (31.4) 89 (25.3) .001
Implantable cardioverter-defibrillator 393 (18.1) 319 (23.6) 17 (3.6) 57 (16.3) <.001
Pacemaker 177 (8.2) 85 (6.3) 58 (12.4) 34 (9.7) <.001
Cardiac resynchronization therapy with 334 (15.4) 273 (20.2) 19 (4.1) 42 (12.0)
<.001
defibrillator capability
Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrecEF, proportion of 1.0, multiply by 0.01; hemoglobin level to grams per liter, multiply
heart failure with recovered ejection fraction; HFrEF, heart failure with reduced by 10.0; platelet count to 109/L, multiply by 1.0; potassium level to millimoles
ejection fraction; IQR, interquartile range. per liter, multiply by 1.0; sodium level to millimoles per liter, multiply by 1.0; and
SI conversion factors: To convert blood urea nitrogen level to millimoles per white blood cell count to 109/L, multiply by 0.001.
a
liter, multiply by 0.357; creatinine level to micromoles per liter, multiply by 88.4; Calculated as weight in kilograms divided by height in meters squared.
glucose level to millimoles per liter, multiply by 0.0555; hematocrit to

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Research Original Investigation Heart Failure With Recovered vs Preserved Ejection Fraction

Figure. Kaplan-Meier Curves, Adjusted for Age and Sex, Across the 3 Heart Failure Groups

A Death B Death or all-cause hospitalization

20 60 58.8%
HFrEF
HFpEF 16.3%
50

Cumulative Event Rate, %


52.7%
Cumulative Mortality, %

15 HFrecEF
40
41.4%
13.2%
10 30

20
5
4.8% 10

0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time, mo Time, mo
No. at risk No. at risk
HFpEF 466 444 412 385 349 310 243 HFpEF 466 360 293 247 212 176 122
HFrEf 1350 1224 1140 1057 962 869 678 HFrEf 1350 966 780 671 570 478 339
HFrecEF 350 331 312 298 289 277 211 HFrecEF 350 292 251 225 202 186 135

C Death or cardiovascular hospitalization D Death or heart failure hospitalization

60 60

Cumulative Event Rate, %


50 48.0% 50
Cumulative Event Rate, %

40.1%
40 40

37.2% 30 28.9%
30

20 20
17.4% 11.8%
10 10

0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time, mo Time, mo
No. at risk No. at risk
HFpEF 466 405 349 312 275 230 170 HFpEF 466 423 368 337 298 256 193
HFrEf 1350 1038 893 793 685 590 429 HFrEf 1350 1086 962 867 764 670 493
HFrecEF 350 317 289 271 258 244 185 HFrecEF 350 326 303 288 276 262 197

The stratified log-rank 22 was 15.0 (P < .001) for difference in mortality between HFrecEF, heart failure with recovered ejection fraction; and HFrEF, heart failure
groups. HFpEF indicates heart failure with preserved ejection fraction; with reduced ejection fraction.

Table 2. Heart Failure Category and Mortality Risk

Hazard Ratio (95% CI)


Age and Sex Adjusted Fully Adjusteda
Variable Year 1 P Value Years 2-3 P Value Year 1 P Value Years 2-3 P Value
HFrEF 1 [Reference] NA 1 [Reference] NA 1 [Reference] NA 1 [Reference] NA
HFpEF 0.76 (0.47-1.22) .25 0.94 (0.66-1.33) .71 0.86 (0.52-1.42) .56 1.04 (0.72-1.52) .83
HFrecEF 0.71 (0.40-1.26) .24 0.27 (0.14-0.52) <.001 0.91 (0.50-1.64) .75 0.35 (0.18-0.70) .003
Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrecEF, disease, chronic kidney disease, and atrial fibrillation), blood pressure, renal
heart failure with recovered ejection fraction; HFrEF, heart failure with reduced function, hemoglobin level, serum sodium and potassium levels, and therapy
ejection fraction; NA, not applicable. with -blockers, angiotensin-converting enzyme inhibitors or angiotensin
a
Adjusted for age, sex, race, body mass index, presence of coronary artery receptor blockers, and loop diuretics.
disease and relevant comorbid conditions (diabetes, depression, chronic lung

Mortality (log-rank 21 = 13.3, P < .001) (Figure, A). Age and sex
The median follow-up was 3.0 years (25th to 75th percentile, adjusted mortality did not differ significantly between the
1.9-3.2 years), with a total of 5367 patient-years. Death oc- HFrEF and HFpEF groups.
curred in 13.3% (288 of 2166) of the cohort. Age and sex Mortality in patients with HFrecEF decelerated after ap-
adjusted mortality at 1, 2, and 3 years was 5.0%, 9.4%, and proximately 1 year. Table 2 lists HRs separately for year 1 and
14.0%, respectively. Age and sexadjusted 3-year mortality was years 2 to 3, with patients with HFrEF as the reference. Dur-
4.8% in patients with HFrecEF vs 13.2% in patients with HFpEF ing year 1, mortality was not different between the 3 groups,
(log-rank 21 = 5.7, P = .02) and 16.3% in patients with HFrEF but patients with HFrecEF had lower mortality in years 2 to 3

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Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

Table 3. Heart Failure Category and Risk for Death or Hospitalization


Abbreviations: HFpEF, heart failure
Hazard Ratio (95% CI)
with preserved ejection fraction;
Variable Age and Sex Adjusted P Value Fully Adjusteda P Value HFrecEF, heart failure with recovered
Death or all-cause hospitalization ejection fraction; HFrEF, heart failure
with reduced ejection fraction;
HFrEF 1 [Reference] NA 1 [Reference] NA
NA, not applicable.
HFpEF 0.89 (0.77-1.04) .14 0.80 (0.67-0.94) .007 a
Adjusted for age, sex, race, body
HFrecEF 0.63 (0.52-0.75) <.001 0.72 (0.59-0.88) .001 mass index, presence of coronary
Death or cardiovascular hospitalization artery disease and relevant
comorbid conditions (diabetes,
HFrEF 1 [Reference] NA 1 [Reference] NA
depression, chronic lung disease,
HFpEF 0.74 (0.62-0.88) .001 0.70 (0.57-0.85) <.001 chronic kidney disease, and atrial
HFrecEF 0.34 (0.26-0.44) <.001 0.40 (0.31-0.53) <.001 fibrillation), blood pressure, renal
function, hemoglobin level, serum
Death or heart failure hospitalization
sodium and potassium levels, and
HFrEF 1 [Reference] NA 1 [Reference] NA therapy with -blockers,
HFpEF 0.72 (0.59-0.88) .001 0.73 (0.59-0.90) .004 angiotensin-converting enzyme
inhibitors or angiotensin receptor
HFrecEF 0.29 (0.21-0.39) <.001 0.38 (0.28-0.52) <.001
blockers, and loop diuretics.

Table 4. Hospitalization Rates Across Heart Failure Groups


Abbreviations: HFpEF, heart failure
Rate Ratio (95% CI)
Rate (95% CI) with preserved ejection fraction;
Variable per 100 Patient-years Age and Sex Adjusted P Value Fully Adjusteda P Value HFrecEF, heart failure with recovered
All-cause hospitalization ejection fraction; HFrEF, heart failure
with reduced ejection fraction;
HFrEF 84.9 (76.1-93.9) 1 [Reference] NA 1 [Reference] NA
NA, not applicable.
HFpEF 67.7 (57.8-77.6) 0.82 (0.67-1.01) .07 0.88 (0.72-1.07) .20 a
Adjusted for age, sex, race, body
HFrecEF 39.5 (30.0-49.0) 0.47 (0.38-0.59) <.001 0.62 (0.50-0.77) <.001 mass index, presence of coronary
Cardiovascular hospitalization artery disease and relevant
comorbid conditions (diabetes,
HFrEF 49.8 (43.9-55.7) 1 [Reference] NA 1 [Reference] NA
depression, chronic lung disease,
HFpEF 27.9 (22.9-32.9) 0.59 (0.45-0.76) <.001 0.68 (0.53-0.88) .003 chronic kidney disease, and atrial
HFrecEF 11.4 (7.5-15.3) 0.22 (0.16-0.30) <.001 0.34 (0.25-0.46) <.001 fibrillation), blood pressure, renal
function, hemoglobin level, serum
Heart failure hospitalization
sodium and potassium levels, and
HFrEF 39.6 (34.0-45.1) 1 [Reference] NA 1 [Reference] NA therapy with -blockers,
HFpEF 17.1 (13.2-21.0) 0.45 (0.33-0.62) <.001 0.54 (0.39-0.74) <.001 angiotensin-converting enzyme
inhibitors or angiotensin receptor
HFrecEF 6.1 (2.9-9.3) 0.14 (0.10-0.21) <.001 0.26 (0.17-0.38) <.001
blockers, and loop diuretics.

compared with patients with HFrEF or HFpEF. This finding per- not significant in fully adjusted models (HR, 0.91; 95% CI, 0.72-
sisted in fully adjusted models. The mean HR for mortality over 1.13; P = .38). However, death or cardiovascular hospitaliza-
the 3-year period in the HFrecEF group was 0.56 (95% CI, 0.34- tion (HR, 0.58; 95% CI, 0.43-0.78; P < .001) and death or HF
0.92; P = .02) vs HFpEF and 0.55 (95% CI, 0.35-0.87; P = .01) hospitalization (HR, 0.52; 95% CI, 0.37-0.74; P < .001) were less
vs HFrEF in adjusted models. Mortality did not differ in pa- likely in patients with HFrecEF vs HFpEF in adjusted models.
tients with HFpEF vs HFrEF (HR, 0.98; 95% CI, 0.71-1.35; There were no significant interactions of HF group with sex
P = .90) in adjusted models. There were no significant inter- or race for these end points.
actions of HF group with sex or race for mortality.
Hospitalization Rates
Composite End Points There were a total of 3813 hospitalizations (73.2 per 100 patient-
At 3 years, 55.2%, 41.1%, and 33.6% of patients met the com- years). Of this total, 1996 (52.3%) were for cardiovascular causes
posite end points of death or all-cause hospitalization, death inclusive of HF (38.3 per 100 patient-years), and 1501 (39.4%)
or cardiovascular hospitalization, and death or HF hospital- had specifically HF as the primary diagnosis (28.8 per 100 pa-
ization, respectively. Patients with HFrecEF were less likely to tient-years). Compared with patients with HFrEF, hospitaliza-
meet a composite end point compared with patients with either tions for cardiovascular causes and HF were less frequent in
HFrEF or HFpEF, and patients with HFpEF were less likely to patients with either HFrecEF or HFpEF, and this difference per-
meet a composite end point compared with patients with sisted in adjusted models (Table 4). However, all-cause hos-
HFrEF (Figure, B-D). These differences persisted in fully ad- pitalization rates did not differ significantly between pa-
justed models (Table 3). We list 1-year, 2-year, and 3-year es- tients with HFpEF and patients with HFrEF.
timates for these end points in eTable 1 in the Supplement. Patients having HFrecEF had less frequent hospitaliza-
Patients having HFrecEF were less likely to experience tions compared with patients having HFpEF. In fully ad-
death or hospitalization compared with patients having HFpEF justed models, the rate ratios for hospitalization of patients with
(HR, 0.70; 95% CI, 0.57-0.87; P = .001), but this difference was HFrecEF vs HFpEF were 0.71 (95% CI, 0.55-0.91; P = .007) for

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Research Original Investigation Heart Failure With Recovered vs Preserved Ejection Fraction

all-cause hospitalizations, 0.50 (95% CI, 0.35-0.71; P < .001) comes compared with patients with HFpEF or HFrEF, includ-
for cardiovascular hospitalizations, and 0.48 (95% CI, 0.30- ing lower mortality and fewer all-cause, cardiovascular, and
0.76; P = .002) for HF-related hospitalizations. There were no HF-related hospitalizations.
significant interactions of HF group with sex or race for hos- Use of -blockers, medications targeting the renin-
pitalization rates. angiotensin-aldosterone axis, and cardiac resynchronization
therapy led to improvement in LVEF in a substantial propor-
Alternative Definition of Preserved LVEF tion of patients with HFrEF.19-22 In the Improve the Use of Evi-
When LVEF exceeding 50% was used to define preserved LVEF, dence-Based Heart Failure Therapies in the Outpatient Setting22
486 of 2166 patients (22.4%) had preserved LVEF at the index registry, a performance improvement program aiming to in-
visit. Of 486 patients, 153 (31.5%) were classified as having crease use of guideline-directed medical therapy among HF
HFrecEF (7.1%; 95% CI, 6.0%-8.2% of the cohort) and 333 outpatients, the mean LVEF among approximately 4000 pa-
(68.5%) as having HFpEF (15.4%; 95% CI, 13.9%-17.0% of the tients increased from 25.8% at baseline to 32.3% at 24 months,
cohort). The remaining 1680 patients (77.6%; 95% CI, 75.7%- and 28.6% of patients had a greater than 10% improvement in
79.3% of the cohort) were classified as having HFrEF. ejection fraction. These data indicate that LVEF recovery is pos-
The mortality pattern across groups was similar to that ob- sible with guideline-directed treatment in a substantial pro-
served with the original definition (eTable 2 in the Supple- portion of patients with HFrEF. A previous study12 reported
ment). Patients with HFrecEF demonstrated lower rates of com- that two-thirds of referral patients seen with preserved LVEF
posite end points and hospitalizations compared with the other were actually HFrecEF cases, associated with a more benign
2 groups (eTable 3 and eTable 4 in the Supplement). The rela- clinical profile. In another referral cohort, 3 out of 5 patients
tive risk between patients with HFrEF and patients with HFpEF seen with LVEF of at least 50% were actually HFrecEF cases.13
for composite end points was not significant in adjusted mod- Because of its referral nature, that cohort was heavily skewed
els. Hospitalization rates for HF remained significantly lower toward HFrEF (84% of patients). However, despite concerns
in patients with HFpEF vs HFrEF. for survival bias in referral cohorts,18 the pattern of event rates
between HF groups reported in that study is similar to ours.13
Analysis Excluding Year 1 Events Despite a more inclusive approach in our study (all cardiol-
The HFrecEF outcomes may be differentially affected by ogy clinics vs HF specialist referrals),13 the academic medical
lead-time bias (ie, these patients survive long enough for center setting still introduces bias toward younger patients with
LVEF to recover before entering the study). Therefore, we more severe HF. However, in both studies, the mortality re-
left-truncated follow-up at 1 year and repeated time-to-event ported for HFrecEF is comparable to that of patients without
analyses. HF or LVEF impairment.23 We extend those observations by
The cohort now consisted of 1864 patients after exclud- providing relative risk estimates for mortality, hospitaliza-
ing those who died in year 1 (n = 109) or had no follow-up af- tions, and composite end points commonly used in clinical
ter year 1 (n = 193). Excluded patients (n = 302) were older and trials in the largest cohort of patients with HFrecEF reported
more likely to be white and smokers, had lower blood pres- to date. Notwithstanding the differences between these
sure and body mass index, and were more likely to have coro- cohorts, taken together these data indicate that patients with
nary artery disease and a worse comorbidity profile com- HFrecEF should be distinguished from those with HFpEF.
pared with those with more than 1 year of follow-up (eTable 5 There are several hypotheses regarding the more benign
in the Supplement). Patients with HFrecEF still demon- course of HFrecEF, despite the ongoing presence of symp-
strated lower mortality compared with patients with HFpEF toms and signs of HF. One potential explanation is partial re-
or HFrEF, lower rates of death or hospitalization (all-cause, car- verse remodeling with a more favorable neurohormonal
diovascular, and HF-related hospitalizations) compared with profile.13 In fact, some patients without scar may have achieved
patients with HFrEF, and lower rates of death or hospitaliza- near-normal left ventricular systolic function. In this aspect,
tion (cardiovascular and HF-related hospitalizations) com- it is notable that our patients with HFrecEF had lower preva-
pared with patients with HFpEF in adjusted models (eTable 6 lence of coronary artery disease, consistent with previous
in the Supplement). work.13,22 For example, the absence of prior myocardial in-
farction and nonischemic HF etiology were both associated
with a greater than 10% improvement in LVEF in the large
Improve Heart Failure Therapies in the Outpatient Setting
Discussion (IMPROVE HF) registry.22 Other comorbid conditions are also
In this retrospective, single-center cohort study from an aca- less frequent in HFrecEF compared with HFrEF. In turn, bet-
demic medical center, 42.9% (350 of 816) of outpatients with ter response to guideline-based treatment might be the result
HF who received cardiology care and had preserved LVEF of a more favorable structural profile early in the disease
(>40%) at presentation were actually cases with recovered ejec- process or genetic variability. Both have been shown to be
tion fraction (HFrecEF). Patients with HFrecEF were younger, the case in recipients of -blockers,24,25 renin-angiotensin-
predominantly male, and had lower prevalences of coronary aldosterone axis inhibitors,26,27 and cardiac resynchroniza-
artery disease, hypertension, diabetes, chronic lung disease, tion therapy.28,29 Lead-time bias might partially explain the
and atrial fibrillation compared with patients with HFpEF. more favorable outcomes in HFrecEF because these patients
These patients with HFrecEF had distinctly better 3-year out- may have survived long enough for LVEF to recover before

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Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

entering the study. In our study, the difference in outcomes the relative risk for hospitalization should be valid. We were
was still evident after excluding patients who died in year 1 or not able to comprehensively adjudicate causes of death; there-
had no follow-up after year 1. fore, we could not provide cause-specific data for mortality.
However, the retrospective design of our study did not al- The Emory Clinical Data Warehouse incorporates data on vi-
low us to provide insights into potential predictors of LVEF re- tal status from various sources (in-hospital death records, pa-
covery, including clinical and genetic characteristics. That tient communication, financial services, etc). Considering that
would require a different, longitudinal study design because we did not have institutional review board approval to con-
our present cross-sectional approach of HF group assign- tact patients and families and obtain death certificates and
ment does not allow us to causally link characteristics to LVEF other information on mode of death, adjudication of cause of
recovery. In addition, lead-time, referral, and ascertainment death would be possible for only the fraction of deaths that oc-
bias may have exaggerated the favorable outcomes among pa- curred in the hospital. Also, we did not measure neurohor-
tients with HFrecEF. An ideal study on the topic would pro- monal markers; therefore, we could not provide these patho-
spectively enroll patients with newly diagnosed HFrEF within physiological insights. Residual measured and unmeasured
a prespecified window of onset and regularly follow up these confounding may account for some of the findings. We did not
patients with echocardiography for recovery after guideline- study patients with previous transition from preserved to re-
directed medical and device therapy. A long-term extension duced LVEF status as a separate entity.30 All patients who had
of that study for outcomes among groups defined, for ex- reduced LVEF at the time of inception were classified as hav-
ample, by LVEF recovery after 6 or 12 months would inform ing HFrEF regardless of previous (reduced or preserved) LVEF.
us more definitively on the natural history and outcomes of We opted for this simple classification because pathophysiol-
LVEF response groups. ogy of HF converges once LVEF is reduced regardless of pre-
Our study has several limitations. Classification of HF cases vious LVEF status. Also, there is no current evidence that these
was based on clinically available echocardiographic data; there- patients should be treated differently depending on LVEF tra-
fore, misclassification may have occurred. A number of HFpEF jectory. Finally, to facilitate communication, we opted not to
cases did not have previous LVEF assessment. We opted to in- create a borderline LVEF category. Instead, we provide a sec-
clude these patients and classify them as HFpEF in the belief ondary analysis using LVEF greater than 50% as the cutoff for
that a patient is unlikely to have previous stage C HFrEF but HFpEF. Moreover, we recognize that small improvements in
no documentation of LVEF. Although such latent HFrecEF LVEF that still qualify as HFrecEF (eg, a change in LVEF from
cases are theoretically possible, they should be uncommon in 35% to 45%) have probably different prognostic implications
practice. Similarly, not all patients with reduced LVEF had re- than larger improvements.30 However, to quantify this ef-
peat LVEF assessments in prespecified time points. However, fect, a prospective, serial echocardiographic study to ensure
the median time from the last LVEF assessment to cohort in- consistent timing of LVEF measurements (because rate of im-
ception was similar between the groups, indicating that more provement could be an important factor) would be needed.
recent echocardiographic assessments are a less likely expla-
nation for ascertainment bias toward HFrecEF. Referral bias to-
ward more advanced HF (and therefore HFrEF) is likely be-
cause of the tertiary nature of the institution. Considering also
Conclusions
the single-center nature of our study, the findings may not be In an outpatient HF cohort receiving cardiology care in an aca-
generalizable to other settings. Hospitalizations were ascer- demic medical center, 42.9% (350 of 816) of patients seen with
tained from the Emory Clinical Data Warehouse. Therefore, LVEF exceeding 40% were patients with recovered rather than
hospitalization rates may have been underestimated because persistently preserved LVEF. These patients had more favor-
outside hospitalizations may have occurred. However, we did able 3-year outcomes, including all-cause mortality, com-
not observe any differential changes in hospitalization rates pared with patients with persistent HFpEF or HFrEF, imply-
across groups over time (eg, fewer hospitalizations in pa- ing that patients with HFrecEF should be investigated
tients with HFrecEF because patients improve), implying that separately in future outcomes studies and clinical trials.

ARTICLE INFORMATION Atlanta, Georgia (Burkman); currently with Acquisition, analysis, or interpretation of data:
Accepted for Publication: April 11, 2016. Department of Medicine, Faculty of Medicine, Kalogeropoulos, Burkman, Patel, Li, Papadimitriou,
Chulalongkorn University, Bangkok, Thailand Butler.
Published Online: July 6, 2016. (Siwamogsatham); currently with Division of Drafting of the manuscript: Kalogeropoulos,
doi:10.1001/jamacardio.2016.1325. Cardiology, Department of Medicine, Stony Brook Georgiopoulou, Burkman, Papadimitriou, Butler.
Author Affiliations: Division of Cardiology, School of Medicine, Stony Brook, New York Critical revision of the manuscript for important
Department of Medicine, Emory University School (Papadimitriou, Butler). intellectual content: Kalogeropoulos, Fonarow,
of Medicine, Atlanta, Georgia (Kalogeropoulos, Author Contributions: Dr Kalogeropoulos had full Georgiopoulou, Burkman, Siwamogsatham, Patel,
Georgiopoulou, Siwamogsatham, Papadimitriou, access to all the data in the study and takes Li, Butler.
Butler); AhmansonUCLA Cardiomyopathy Center, responsibility for the integrity of the data and the Statistical analysis: Kalogeropoulos.
Ronald ReaganUCLA Medical Center, University of accuracy of the data analysis. Administrative, technical, or material support:
California, Los Angeles (Fonarow); Associate Editor Study concept and design: Kalogeropoulos, Butler.
for Health Care Quality and Guidelines, JAMA Fonarow, Georgiopoulou, Siwamogsatham, Study supervision: Kalogeropoulos, Butler.
Cardiology (Fonarow, Patel, Li); Department of Papadimitriou, Butler. Conflict of Interest Disclosures: All authors have
Medicine, Emory University School of Medicine, completed and submitted the ICMJE Form for

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Research Original Investigation Heart Failure With Recovered vs Preserved Ejection Fraction

Disclosure of Potential Conflicts of Interest, and of the Treatment of Preserved Cardiac Function cardiomyopathy presenting with SCD-HeFT
none were reported. Heart Failure With an Aldosterone Antagonist trial. criteria? Am J Cardiol. 2012;109(5):729-735.
Disclaimer: Dr Fonarow is the Associate Editor for Circ Heart Fail. 2014;7(1):104-115. 21. de Groote P, Fertin M, Duva Pentiah A,
Health Care Quality and Guidelines, JAMA 11. Yancy CW, Jessup M, Bozkurt B, et al; Writing Gominne C, Lamblin N, Bauters C. Long-term
Cardiology, but was not involved in the editorial Committee Members; American College of functional and clinical follow-up of patients with
review or decision to accept the manuscript for Cardiology Foundation/American Heart Association heart failure with recovered left ventricular ejection
publications. Task Force on Practice Guidelines. 2013 ACCF/AHA fraction after -blocker therapy. Circ Heart Fail.
guideline for the management of heart failure: 2014;7(3):434-439.
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