Trends in Prevalence and Outcome of Heart Failure with Preserved Ejection Fraction
Theophilus E. Owan, M.D., David O. Hodge, M.S., Regina M. Herges, B.S., Steven J. Jacobsen, M.D., Ph.D., Veronique L. Roger, M.D., M.P.H., and Margaret M. Redfield, M.D.
Background The prevalence of heart failure with preserved ejectionfraction may be changing as a result of changes in populationdemographics and in the prevalence and treatment of risk factorsfor heart failure. Changes in the prevalence of heart failurewith preserved ejection fraction may contribute to changes inthe natural history of heart failure. We performed a study todefine secular trends in the prevalence of heart failure withpreserved ejection fraction among patients at a single institutionover a 15-year period.
Methods We studied all consecutive patients hospitalized withdecompensated heart failure at Mayo Clinic Hospitals in OlmstedCounty, Minnesota, from 1987 through 2001. We classified patientsas having either preserved or reduced ejection fraction. Thepatients were also classified as community patients (OlmstedCounty residents) or referral patients. Secular trends in thetype of heart failure, associated cardiovascular disease, andsurvival were defined.
Results A total of 6076 patients with heart failure were dischargedover the 15-year period; data on ejection fraction were availablefor 4596 of these patients (76 percent). Of these, 53 percenthad a reduced ejection fraction and 47 percent had a preservedejection fraction. The proportion of patients with the diagnosisof heart failure with preserved ejection fraction increasedover time and was significantly higher among community patientsthan among referral patients (55 percent vs. 45 percent). Theprevalence rates of hypertension, atrial fibrillation, and diabetesamong patients with heart failure increased significantly overtime. Survival was slightly better among patients with preservedejection fraction (adjusted hazard ratio for death, 0.96; P=0.01).Survival improved over time for those with reduced ejectionfraction but not for those with preserved ejection fraction.
Conclusions The prevalence of heart failure with preserved ejectionfraction increased over a 15-year period, while the rate ofdeath from this disorder remained unchanged. These trends underscorethe importance of this growing public health problem.
Although the incidence of heart failure has remained stablein recent decades, the likelihood of survival after a diagnosisof heart failure has increased,1,2 suggesting that the profileof heart failure may be changing. Such changes may be due toshifts in population demographics, changes in the prevalenceof risk factors for heart failure, and the evolution of therapeuticstrategies for heart failure.3 The overall profile of heartfailure may also be influenced by changes in the prevalenceof heart failure with preserved ejection fraction.
We performed a study to define secular trends in the prevalenceof heart failure with preserved ejection fraction among patientsadmitted for decompensated heart failure at a single institutionover a 15-year period. We hypothesized that the prevalence ofheart failure with preserved ejection fraction has increasedover time. We also investigated whether patterns of the prevalenceof heart failure were associated with changes in the types ofcardiovascular disease among patients with heart failure. Finally,we examined whether changes in survival rate over the 15-yearperiod differed between patients with preserved ejection fractionand those with reduced ejection fraction.
Methods
Study Setting
The Mayo Clinic hospitals are located in Olmsted County, Minnesota,and serve patients from the community and those referred fromother sites. The institution maintains an integrated medical-recordsystem of all encounters that identifies each patient with aunique number.4 This system served as the basis for our retrospectiveanalysis of data on patients hospitalized for heart failure.Study funding was provided by the Miami Heart Research Instituteand the National Institutes of Health. The study was approvedby the institutional review board of the Mayo Foundation; becausethe study involved only the review of records obtained as apart of routine medical care, no patient consent was required.
Identification of Patients
The Mayo Integrated Computer System identified all consecutivepatients admitted to Mayo Clinic hospitals in Rochester, Minnesota,between January 1, 1987, and December 31, 2001, who were dischargedwith a code 428 diagnosis according to the International Classificationof Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).2The list of patients with this diagnosis was matched with thelist of patients discharged with a diagnosis-related-group (DRG)code 127 diagnosis. Only patients discharged with both ICD code428 and DRG code 127 were considered for inclusion in the study.If a patient was admitted more than once for heart failure duringthe study period, only the data from the first admission wereanalyzed. We validated the frequency with which such patientsmet the modified Framingham criteria for heart failure5 or theclinical criterion (diagnosis of heart failure recorded on thechart by the attending physician) during the index hospitalizationby manually abstracting data from the charts of a random sampleof 135 patients.
Data Extraction
All data were extracted electronically. Data were collectedon the age, date of birth, sex, home address, admission date,body weight, and height of the patients. During the study, theproportion of patients for whom data on height and weight wereelectronically available increased from 9 percent in the firstfive years to 31 percent in the second five years to 83 percentin the last five years. Data on coexisting cardiovascular conditionsin each patient were also extracted with the use of all relevantICD codes. Data on serum creatinine and blood hemoglobin levelswere extracted from the Mayo Laboratory Information System.Data on ejection fraction and the presence of valve diseasethat was more than moderate (aortic or mitral stenosis or regurgitation)were extracted from the Mayo echocardiographic database.6 Thefinal study cohort consisted of patients meeting the above criteriawho had undergone echocardiography within 30 days before orafter hospitalization.
Definition of Covariates
Patients with an ejection fraction of 50 percent or higher wereclassified as having heart failure with preserved ejection fraction,whereas those with an ejection fraction of less than 50 percentwere classified as having heart failure with reduced ejectionfraction.7,8,9 Obesity was defined by a body-mass index (theweight in kilograms divided by the square of the height in meters)of 30 or more. The patients were classified as community patients(residents of Olmsted County) or referral patients on the basisof their ZIP Code of residence.
Mortality Data
Survival status was initially determined from the Mayo Clinicregistration database, as previously described.2 For patientswith no record of death in the registration database, informationon vital status and mortality was queried with the use of ACCURINT,an institutionally approved Web-based resource and locationservice.
Statistical Analysis
To identify changes over time, we constructed simple linearregression models with the year of admission as the independentvariable. We report Pearson's correlation coefficients and Pvalues. Differences between groups were tested by the two-samplet-test for continuous variables and the chi-square test forcategorical variables. We used a regression model to adjustfor the effect of age on the differences in baseline characteristicsbetween patients with preserved ejection fraction and thosewith reduced ejection fraction. We estimated the overall survivalby the Kaplan–Meier method and tested for differencesin survival between groups or times by the log-rank test. Coxproportional-hazards regression was used to adjust for the effectof differences in baseline characteristics on survival. We didnot adjust for body-mass index in this analysis because completedata on this variable were not available.
Results
A total of 6076 patients with ICD code 428 and DRG code 127were discharged from 1987 through 2001. Echocardiographic assessmentof ejection fraction within 30 days was available for 4596 patients(76 percent), who constituted the study population. The proportionof patients undergoing echocardiography did not change significantlyover time (P=0.10). Ninety-five percent of the charts sampledfor validation of the diagnosis of heart failure met the Framinghamcriteria, and 99 percent met either the clinical or the Framinghamcriteria. More than 97 percent of the patients were white.
Patient Characteristics and Ejection Fraction
Patients with preserved ejection fraction were older, were morelikely to be female, had a higher mean body-mass index, weremore likely to be obese, and had lower hemoglobin than thosewith reduced ejection fraction (Table 1). Overall, the prevalenceof preserved ejection fraction among all patients with a dischargediagnosis of heart failure was 49 percent among patients 65years of age or older and 40 percent among those under 65 yearsof age (P=0.004).
Table 1. Characteristics of Patients with Heart Failure and Preserved or Reduced Ejection Fraction.
The prevalence rates of hypertension and atrial fibrillationwere higher and the prevalence rates of coronary artery diseaseand valve disease were lower among patients with preserved ejectionfraction than among those with reduced ejection fraction. Thesedifferences remained significant after adjustment for the agedifference between the two groups (Table 1). The serum creatininelevel on admission and the prevalence of diabetes were similarin the two groups of patients.
Secular Trends in the Prevalence of Heart Failure with Preserved Ejection Fraction
The prevalence of preserved ejection fraction among patientswith a discharge diagnosis of heart failure increased over time(Figure 1A). The average prevalence increased from 38 percentto 47 percent to 54 percent in the three consecutive five-yearperiods included in the study. The increase in the prevalenceof preserved ejection fraction was due to an increase in thenumber of patients admitted with preserved ejection fraction,with no significant change in the number of patients admittedwith reduced ejection fraction (Figure 1B). After adjustmentfor age, there was no substantive change in these secular trends.The increase in the prevalence of preserved ejection fractionover time was also observed when it was defined as an ejectionfraction greater than 60 percent.
Figure 1. Secular Trends in the Prevalence of Heart Failure with Preserved Ejection Fraction.
Panel A shows the increase during the study in the percentage of patients with heart failure who had preserved ejection fraction. Panel B shows that the number of admissions for heart failure with preserved ejection fraction increased during the study period, whereas the number of admissions for heart failure with reduced ejection fraction did not change. The solid lines represent the regression lines for the relation between the year of admission and the percentage of patients with heart failure who had preserved ejection fraction (Panel A) and the number of admissions for heart failure with preserved or reduced ejection fraction (Panel B). The dashed lines indicate 95 percent confidence intervals.
The proportion of patients with preserved ejection fractionwas higher among community patients (599 of 1093, 55 percent)than among referral patients (1568 of 3503, 45 percent; P<0.001).The prevalence of heart failure with preserved ejection fractionincreased over time in both community patients (r=0.62, P=0.01)and referral patients (r=0.66, P=0.006).
Secular Trends in the Prevalence of Cardiovascular Diseases among Patients with Heart Failure
The proportion of patients with hypertension increased overtime (r=0.98, P<0.001) from 48 percent to 53 percent to 63percent in the three consecutive five-year periods includedin the study. During these periods, the proportion of patientswith atrial fibrillation increased from 29 percent to 33 percentto 41 percent (r=0.90, P<0.001) and the proportion with diabetesmellitus increased from 32 percent to 33 percent to 36 percent(r=0.65, P=0.008), whereas the prevalence of coronary arterydisease was stable at 59 percent, 58 percent, and 59 percent(r=0.10, P=0.73).
Mortality
Survival data were available for 4594 of the 4596 patients,with a mean (±SD) follow-up of 10.0±4.2 years.A total of 3691 deaths occurred during follow-up, 120 of themduring the index hospitalization.
The survival rate was higher among patients with preserved ejectionfraction than among those with reduced ejection fraction, althoughthe difference was small (Figure 2). The respective mortalityrates were 29 percent and 32 percent at one year and 65 percentand 68 percent at five years. The unadjusted hazard ratio fordeath in the group with preserved ejection fraction as comparedwith the group with reduced ejection fraction was 0.96 (95 percentconfidence interval, 0.93 to 1.00; P=0.03). After adjustmentfor differences in baseline characteristics and the year ofadmission, the likelihood of survival was still slightly higheramong patients with preserved ejection fraction than among thosewith reduced ejection fraction (hazard ratio for death, 0.96;95 percent confidence interval, 0.92 to 1.00) (Table 2). Amongpatients with reduced ejection fraction, the likelihood of survivalincreased during the study period (Figure 3A), with an unadjustedhazard ratio for death of 0.98 per year (95 percent confidenceinterval, 0.97 to 1.00; P=0.005). The survival rate among patientswith preserved ejection fraction did not change significantlyover time (Figure 3B). After adjustment for differences in baselinecharacteristics, the survival rate increased over time amongthose with reduced ejection fraction but not among those withpreserved ejection fraction (Table 2). Secular trends in survivalwere similar when preserved ejection fraction was defined asan ejection fraction greater than 60 percent and reduced ejectionfraction was defined as an ejection fraction less than 40 percent.
Figure 3. Secular Trends in Survival among Patients with Heart Failure and Preserved or Reduced Ejection Fraction.
Kaplan–Meier survival curves for three five-year periods according to the year of admission show that survival improved over time in patients with reduced ejection fraction (Panel A) but not in patients with preserved ejection fraction (Panel B).
In Kaplan–Meier survival analysis, the difference in survivalbetween patients with reduced ejection fraction and those withpreserved ejection fraction appeared less dramatic in the groupof patients who were 65 years of age or older (hazard ratio,0.97; P=0.06) than in the group of patients who were youngerthan 65 (hazard ratio, 0.87; P=0.003). In Cox proportional-hazardsanalysis, the interaction between the effects of age group andtype of heart failure on survival was significant (P=0.03).
Discussion
We found that the prevalence of heart failure with preservedejection fraction among patients with a discharge diagnosisof heart failure increased significantly from 1987 to 2001.The prevalence of hypertension, atrial fibrillation, and diabetesincreased during the study period, while the prevalence of coronarydisease remained stable. Patients with preserved ejection fractionfared slightly better than patients with reduced ejection fraction.However, although survival improved during the study periodamong patients with reduced ejection fraction, it did not improveamong patients with preserved ejection fraction.
Heart failure has been classified as "diastolic" (preservedejection fraction) or "systolic" (reduced ejection fraction),but this nomenclature has become the subject of controversy.10,11Because the recently revised American College of Cardiology–AmericanHeart Association guidelines for the diagnosis and managementof heart failure12 use the term "heart failure with preservedejection fraction" rather than "diastolic heart failure," thisterminology has been adopted here.
The increase in the prevalence of heart failure with preservedejection fraction over time noted in our analysis has also beensuggested by previous studies. A review of 31 studies of patientswith heart failure conducted from 1970 through 1995 noted thatmost studies (90 percent) involved patients who had been referredfor treatment and that the prevalence of preserved ejectionfraction among patients with heart failure ranged from 13 to74 percent, with a median value of 40 percent.9 Subsequently,12 community-based studies published from 1998 through 2003found that the prevalence of preserved ejection fraction amongpatients with heart failure ranged from 40 to 71 percent, witha mean of 54 percent.7,8 The difference between the averageprevalence rates reported in the early referral-based studiesand those reported in the later community-based studies doessuggest that the prevalence of preserved ejection fraction amongpatients with heart failure has either increased over time ordiffers between referral and community settings. Our findings,obtained with the use of consistent methods of patient identificationat a single center serving both referral and community patientsover a 15-year period, suggest that both factors are important.
A true increase in the age-specific prevalence of heart failurewith preserved ejection fraction could be related to changesin associated cardiovascular disease in the population. In ouranalysis, the prevalence of atrial fibrillation increased overtime; this dysrhythmia is a common precipitant of acute decompensationin patients with heart failure with preserved ejection fraction.13,14The prevalence rates of hypertension and diabetes mellitus,both of which are commonly associated with heart failure withpreserved ejection fraction, also increased significantly overtime among patients with heart failure.
The observed increase in heart failure with preserved ejectionfraction could also be a consequence of changing physician behaviorover time. The concept of "diastolic dysfunction" evolved markedlyduring the study period, and it is likely that the propensityto diagnose heart failure with preserved ejection fraction hasevolved as well. The likelihood that this diagnosis will bemade also depends to some extent on the rigor with which otherdiagnoses are considered.15,16 Some patients admitted duringthe early period of this study with symptoms of heart failurewho were found to have preserved ejection fraction might havebeen assigned a different diagnosis at discharge and would thereforenot be included in our data set. The prevalence of preservedejection fraction among hospitalized patients with heart failurefrom Olmsted County in 1991 (45 percent) was similar to thatfound in a study conducted in Olmsted County in the same yearthat included both inpatients and outpatients (43 percent)17;however, similar reservations regarding diagnosis may applyto the outpatients in that report.
The survival rates of patients with heart failure with reducedejection fraction and of those with preserved ejection fractionhave been extensively studied and compared, with disparate conclusions.Previous reviews noted the variation in findings of studiesperformed before 2001.7,8,9,18 More recent studies also reportvariable findings.19,20,21,22,23,24,25,26,27,28,29,30,31,32Six studies reported findings similar to ours, with time-specifichazard ratios within approximately 10 percent of those in ourstudy.19,20,22,23,24,32 These studies had a design similar toours — that is, they were single-center or single-regionstudies confined to patients hospitalized for heart failure,measurements of ejection fraction were available for most ofthe patients, and all consecutive patients for whom measurementsof ejection fraction were available were included in the study.Eight recent studies reported greater differences in survivalbetween patients with reduced ejection fraction and those withpreserved ejection fraction than we found in our study.21,25,26,27,28,29,30,31Most of these studies enrolled outpatients,21,29,30,31 enrolledhospitalized patients who were not admitted specifically forheart failure,28 did not include all consecutive patients admittedfor heart failure,27 or included a much smaller percentage ofconsecutive patients with heart failure than we did, becauseof the lack of echocardiographic data.21,26
The methodologic differences described above may have resultedin cohorts of patients with preserved ejection fraction whohad much milder heart failure than did patients with reducedejection fraction. In contrast, we enrolled patients with reasonablyuniform symptom status (i.e., their symptoms were sufficientlysevere that they were hospitalized for heart failure). The diagnosisof heart failure in patients with preserved ejection fractionand milder symptoms not requiring hospital admission raisesconcern about the possible misdiagnosis of heart failure andabout comparisons between cohorts of patients with heart failureof different severity. On the other hand, our requirement thatpatients be hospitalized emphasized the prognosis of patientswho had reached a somewhat advanced stage in their illness anddid not permit us to incorporate the natural history of heartfailure with preserved ejection fraction from the time of firstdiagnosis until the need for hospitalization.
Community-based studies suggest that overall survival amongpatients with heart failure is improving.1,2 We found a trendtoward improved overall survival that did not achieve statisticalsignificance. However, among patients with reduced ejectionfraction, survival improved significantly over time, whereasthere was no trend toward improvement among patients with preservedejection fraction. These observations suggest that improvementover time in the survival of broader populations of patientswith heart failure may be due primarily to improvement amongthose with reduced ejection fraction. Although several interventionsknown to improve survival among patients with reduced ejectionfraction were introduced into clinical practice during the studyperiod, no agents have been proven to improve survival amongpatients with preserved ejection fraction. Thus, it is not unexpectedthat survival among patients with preserved ejection fractiondid not change significantly over the study period.
This study is subject to the limitations inherent in retrospectivestudies. Restriction to patients with DRG code 127 providesa potential for bias based on coding practices. The absenceof ejection-fraction data from some patients could have affectedthe absolute prevalence of heart failure with preserved ejectionfraction as well as secular trends (although the proportionof patients who underwent echocardiography was stable duringthe study period). Restriction of the study to hospitalizedpatients might have introduced bias, since the results fromthis population may not reflect larger trends in disease prevalencein the community. We were not able to take into account anypossible evolution of the diagnostic behavior of physicians.Our data may not reflect secular trends among patients withdifferent racial or ethnic, regional, or socioeconomic backgrounds.
The increase in the prevalence of heart failure with preservedejection fraction over time and the stability in the rates ofdeath from this condition underscore the importance of studiesto determine the pathophysiology of this form of heart failureand develop therapeutic stategies against it. Indeed, shouldthese trends be confirmed and should they continue, heart failurewith preserved ejection fraction may become the most commonform of heart failure. Because no proven therapy for heart failurewith preserved ejection fraction currently exists, there isa need for coordinated efforts to address this growing problem.
Supported by grants from the Miami Heart Research Instituteand the National Institutes of Health (T32-HL07111-27, HL64112,AR30582, and HL72435).
Dr. Redfield reports having received grant support from Biosite,Scios, Medtronic, Guidant, Alteon, and St. Jude Medical. Noother potential conflict of interest relevant to this articlewas reported.
Source Information
From the Cardiorenal Research Laboratory (T.E.O., M.M.R.), the Division of Biostatistics (D.O.H., R.M.H.), and the Section of Health Science Research (S.J.J., V.L.R.), Mayo Clinic College of Medicine, Rochester, Minn.
Address reprint requests to Dr. Redfield at Cardiovascular Research, Guggenheim 9, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or at redfield.margaret{at}mayo.edu.
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Heart Failure with Preserved Ejection Fraction
Fiack C. A., Farber H. W., Arias M. A., Alonso-Fernández A., García-Río F., Kessler K. M., Ahmed A., Fleg J. L., Gheorghiade M., Owan T. E., Redfield M. M., Liu P. P., Lee D. S., Tu J. V., Ph.D. M.D.
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