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European Journal of Heart Failure 2007 9(1):83-91; doi:10.1016/j.ejheart.2006.10.012
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© 2007 European Society of Cardiology

Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM

Eldrin F. Lewisa,*, Gervasio A. Lamasb, Eileen O'Mearac, Christopher B. Grangerd, Mark E. Dunlape, Robert S. McKelvief, Jeffrey L. Probstfieldg, James B. Youngh, Eric L. Michelsoni, Katarina Hallingj, Jonas Carlssonj, Bertil Olofssonj, John J.V. McMurrayk, Salim Yusufl, Karl Swedbergm, Marc A. Pfeffera and for the CHARM Investigators

a Cardiovascular Division, Department of Medicine, Brigham and Women' Hospital 75 Francis Street, Boston, MA 02115, USA
b Mt. Sinai Medical Center Miami Beach, FL, USA
c Montreal Heart Institute Canada
d Duke University Medical Center Durham, NC, USA
e Case Western Reserve University and MetroHealth Medical Center Cleveland, OH, USA
f Hamilton General Hospital Hamilton, Ontario, Canada
g University of Washington Seattle, WA, USA
h Cleveland Clinic Foundation Cleveland, OH, USA
i AstraZeneca LP Wilmington, DE, USA
j AstraZeneca R&D Molndal, Sweden
k Western Infirmary Scotland, UK
l McMaster Clinic Hamilton, Ontario, Canada
m Sahlgrenska University Hospital/Ostra Goteborg, Sweden

* Corresponding author. Tel.: +1 617 525 7057; fax: +1 617 582 6027. eflewis{at}partners.org


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Limited comparative studies assessing the health-related quality of life (HRQL) in heart failure (HF) patients with preserved vs. low ejection fraction (LVEF) have been disparate.

Aims: The aims of this study were a) to characterize HRQL in a large population of HF patients with preserved and low LVEF and b) to determine the factors associated with worse HRQL.

Methods: Patients with symptomatic HF (NYHA Class II—IV) enrolled in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) HRQL study completed the Minnesota Living with Heart Failure questionnaire at randomization. Patients were stratified into 2 HF cohorts: preserved LVEF (>40%) and low LVEF (≤40%).

Results: In 2709 of the eligible 2744 (98.6%) patients, the summary scores ranged from 0 to 105 (mean 40.9). There were no differences in overall responses of HF patients with preserved vs. low LVEF (41.1 vs. 40.8). Independent factors associated with worse HRQL in both populations included female gender, younger age, higher body mass index, lower systolic blood pressure, greater symptom burden, and worse functional status.

Conclusions: In symptomatic HF patients, HRQL is equally impaired in both preserved and low LVEF populations. Targeting improvement in symptoms and HRQL is an important treatment objective in all HF patients.

Key Words: Heart failure • Quality of life • Preserved ejection fraction • Predictors • Clinical trials

Received July 27, 2006; Revised August 18, 2006; Accepted October 12, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Heart failure is a clinical syndrome resulting from structural or functional damage that impairs the heart's ability to fill or eject blood resulting in dyspnea, fatigue, fluid retention and limited exercise capacity [1]. The constellation of signs and symptoms recognized as the clinical syndrome of heart failure occur irrespective of left ventricular ejection fraction (LVEF). Approximately a third to a half of all patients with symptomatic heart failure have preserved ejection fraction [2-4]. Recent evidence demonstrates a lower mortality rate [3,5-8] and lower hospitalization rate [9-11] among patients with heart failure and preserved ejection fraction (Heart Failure-Preserved EF) as compared with patients with heart failure and low ejection fraction (Heart Failure-Low EF). Despite these differences in outcomes, both populations appear to have similar symptoms and signs of heart failure, suggesting that the impact of the disease on their sense of well-being may be similar although unrelated to their comparative risk of death [12,13]. However, there is limited and conflicting data comparing health-related quality of life (HRQL) in heart failure patients with low and preserved EF.

Improving HRQL is an important goal in heart failure treatment [14]. However, most of the HRQL research has focused in patients with low ejection fraction. There is much less information on the comparative perceptions of HRQL in these two populations of heart failure patients. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program was an assessment of Candesartan in heart failure patients with LVEF higher than 40% (CHARM-Preserved) and in two populations with heart failure and LVEF less than or equal to 40% (CHARM-Added and CHARM-Alternative). These trials provided a unique opportunity to study the HRQL of heart failure patients in these 2 distinct populations. Moreover, an understanding of clinical characteristics associated with worse baseline HRQL and possible differences in the 2 populations may be helpful in clinical management and future trial design.

The objectives of this study were to characterize HRQL in Heart Failure-Preserved EF and Heart Failure-Low EF patients to test the hypothesis that HRQL perceptions between the two groups are similar. Secondly, we investigated the clinical determinants of HRQL in the two populations, with special attention to the interaction with left ventricular ejection fraction.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study population
The design, baseline findings and primary results of the CHARM Program have been reported in detail [15-19]. Briefly, the CHARM Program consisted of three independent, concurrent trials in which 7599 patients with New York Heart Association Class II-IV heart failure ≥4 weeks duration were randomized to placebo or Candesartan (target dose 32 mg once daily). Patients were enrolled into the component trials based upon left ventricular ejection fraction and treatment with ACE-inhibitors at baseline. "CHARM-Alternative" patients had a left ventricular ejection fraction ≤40% and were not receiving an ACE-inhibitor due to intolerance. "CHARM-Added" patients had a left ventricular ejection fraction ≤40% and were taking an ACE-inhibitor. Patients with New York Heart Association Class II required an admission to hospital with a cardiovascular problem in the previous 6 months which had the effect of increasing the proportion of New York Heart Association Class III/IV patients in CHARM-Added. "CHARM-Preserved" patients had a left ventricular ejection fraction >40% with or without concomitant ACE-inhibitors. Median follow-up was 38 months overall. Patient characteristics of the 3 trials have been described previously [16-19].

2.2. Health status and functional status assessment
Patients enrolled at the 243 sites in the United States and Canada were asked prospectively to participate in the CHARM HRQL study and signed a second written consent form. The investigation conforms to the principles outlined in the Declaration of Helsinki. Enrolled patients completed the Minnesota Living with Heart Failure (MLHF) questionnaire at baseline, a 21-item disease-specific instrument with scores for each item ranging from 0 to 5 and a summary score ranging from 0 to 105 with a higher score representing worse HRQL. There are two specific HRQL domains: physical limitations (questions 2-7, 12-13; maximum score=40) and emotional limitations (questions 17-21; maximum score=25) [20]. Validity, reliability, and reproducibility of the MLHF questionnaire have been established [20,21] and it has been translated and validated in multiple languages [22]. A standardized procedure for administration of the instrument was followed. The MLHF questionnaire was completed by each subject alone in a quiet environment prior to any other assessments.

Patients were stratified into 2 groups based upon LVEF: "Heart Failure-Low EF" (LVEF≤40%) and "Heart Failure-Preserved EF" (LVEF>40%). The Heart Failure-Low EF cohort comprised patients in CHARM-Alternative and CHARM-Added combined, and the Heart Failure-Preserved EF cohort included patients in CHARM-Preserved. Clinical characteristics thought to possibly influence HRQL perceptions, including demographics, co-morbidities, vital signs, medicines, and recent hospital admissions, were collected at baseline and were used to identify independent determinants of overall HRQL.

2.3. Statistical analysis
The principal aim of the analysis was to assess the determinants of HRQL in symptomatic patients with heart failure across the spectrum of left ventricular ejection fraction. All statistics were completed using SAS, version 8.2. Baseline characteristics of Heart Failure-Low EF and Heart Failure-Preserved EF patients were compared. Although the majority of the questions were answered, missing items were imputed using the mean scores of the non-missing items if >50% of the MLHF questionnaire was completed. A sensitivity analysis was performed to ensure that the results with and without imputed data were similar [23,24]. A multivariable analysis was performed to assess independent determinants of baseline HRQL in the CHARM HRQL population. MLHF summary scores were assumed to follow a linear model, and Analysis of Covariance (ANCOVA) was performed utilizing MLHF summary score as the dependent variable and clinically important factors as the explanatory variables which were entered simultaneously. LVEF was treated as a continuous variable in the multivariable model. Given the small proportion of patients with New York Heart Association Class IV functional status, New York Heart Association Class III and IV were grouped together for the multivariable model only. A Bonferroni correction was utilized to adjust for multiple comparisons with a significance level of p<0.001.

Descriptive statistics were performed for each of the explanatory variables. Given the lack of clear boundaries for categorizing patients based upon HRQL into less and more impairment, patients were divided into quartiles based upon the overall MLHF score depicting overall HRQL to assess the differences in characteristics in groups of patients with worsening HRQL scores. An interaction term was developed to assess the significance of the factors on quality of life in the two HF populations.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Patient characteristics
Of the 7599 patients randomized in the CHARM Program, 2744 (36.1%) were enrolled in the United States and Canada and were eligible for the CHARM HRQL study. Of these, 2709 (98.7%) completed the baseline MLHF questionnaire. Over 40% of patients had Heart Failure-Preserved EF, 33% of patients were female, and 15% of patients were non-White (Table 1). As expected, there were several differences in the characteristics of Heart Failure-Preserved EF and Heart Failure-Low EF patients. A higher proportion of the Heart Failure-Preserved EF patients were women compared to the Heart Failure-Low EF patients. Heart Failure-Preserved EF patients also had a higher systolic blood pressure and antecedent hypertension, a higher prevalence of diabetes mellitus, and were less likely to have concomitant coronary artery disease or prior coronary revascularization. Approximately 47% of Heart Failure-Preserved EF patients had New York Heart Association Class II functional status compared with 29% of Heart Failure-Low EF patients. Approximately two-thirds of both Heart Failure-Preserved EF and Heart Failure-Low EF patients had an admission to hospital with heart failure in the previous 6 months.


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  		Table 1 Baseline characteristics of patients enrolled in CHARM quality of life study stratified by ejection fraction category

 
3.2. Quality of life responses in heart failure patients with preserved and low ejection fraction
Of the 2709 enrolled patients, most patients (n=2304, 85.0%) completed all 21-items and 2655 (98%) completed >75% of items of the MLHF questionnaire. Sensitivity analysis demonstrated no impact of including the imputed data in the overall results and thus both imputed and non-imputed scores were included in the final analysis. The distribution of the MLHF scores reflects the wide range of HRQL among chronic heart failure patients with scores ranging from 0 to 105 (Fig. 1). Heart Failure-Low EF and Heart Failure-Preserved EF patients had a similar distribution of MLHF scores.


Figure 01
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  		Fig. 1 Distribution of the Minnesota Living with Heart Failure questionnaire responses in patients with heart failure-preserved ejection fraction and heart failure-low ejection fraction. Scores range from 0 to 105 with a low score reflecting a better health-related quality of life. Abbreviations: MLHF—Minnesota Living with Heart Failure questionnaire, HF—Heart failure, EF—Ejection fraction.

 
Overall, there was no difference in the unadjusted mean summary MLHF score of Heart Failure-Preserved EF and Heart Failure-Low EF patients (41.1 vs. 40.8, p=0.67). In both groups, the MLHF scores were higher (i.e., worse HRQL) than the benchmark HRQL using this instrument in asymptomatic patients with low ejection fraction in which the MLHF score was 10 [20]. Moreover, the emotional scores were also similar between the two groups (8.4 vs. 8.5, p=0.72) with a slightly worse physical score in the HF-Preserved EF patients (19.4 vs. 18.5, p=0.04).

3.2.1. Association of HRQL with clinical factors
Table 2 details the univariate MLHF summary scores in the two populations stratified by various patient characteristics. As expected, there was a significant linear association between worsening New York Heart Association functional class and more impaired HRQL scores in both Heart Failure-Low EF and Heart Failure-Preserved EF patients. There were similar linear trends with worse HRQL in increasingly younger patients, higher heart rate, and lower systolic blood pressure. Women had worse HRQL scores than men. Table 3 stratifies patients based upon their MLHF summary scores into quartiles, with the higher quartiles representing worse HRQL. This demonstrates consistent association between worse HRQL and younger age, female gender, and higher symptom burden.


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  		Table 2 Median Minnesota Living with Heart Failure (MLHF) responses stratified by patient characteristics

 


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  		Table 3 Characteristics of patients with heart failure and low vs. preserved ejection fractions

 
3.2.2. Independent determinants of health-related quality of life
There were 9 independent clinical determinants of worse HRQL after adjusting for 20 additional clinical factors (Table 4). The main continuous determinants of worse HRQL (higher MLHF summary score) included younger age, higher BMI, and lower systolic blood pressure. Categorical variables predictive of worse HRQL included female gender, worse New York Heart Association, angina, paroxysmal nocturnal dyspnea, rest dyspnea, and lack of ACE-inhibition. These characteristics predicted HRQL similarly in both Heart Failure-Preserved EF and Heart Failure-Low EF patients with all tests for interaction with p>0.05 (Table 4). Even after adjusting for 28 other clinical factors, left ventricular ejection fraction was not a determinant of HRQL with no differences in the adjusted MLHF score between Heart Failure-Preserved EF and Heart Failure-Low EF patients (regression parameter 0.06, p=0.619). Finally, a second multivariable model was developed without rest dyspnea, paroxysmal nocturnal dyspnea, or New York Heart Association as these factors may be measured in part by the MLHF tool. In the absence of these 3 factors, all other factors remained independent determinants of HRQL except the lack of ACE-inhibitors use at baseline in (MLHF score 44.2 vs. 42.1, p=0.03).


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  		Table 4 Independent determinants of quality of life in heart failure patients with preserved and low ejection fraction *

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The CHARM Program enrolled a cohort of patients with symptomatic, chronic heart failure that included the largest number of patients with Heart Failure-Preserved EF yet reported in a randomized clinical trial. Over one-third of CHARM patients participated in the HRQL study, representing nearly 99% of patients randomized in North America. This provided a unique opportunity to characterize HRQL in patients with chronic heart failure with both preserved and low ejection fraction. This study demonstrates that patients with Heart Failure-Preserved EF have a similarly impaired HRQL compared to patients with Heart Failure-Low EF. We identified 9 characteristics that were independently associated with impaired HRQL in heart failure patients across the left ventricular ejection fraction spectrum. These factors included demographic features (younger age and women), symptom burden (dyspnea, paroxysmal nocturnal dyspnea, angina), functional limitation (advanced New York Heart Association class), physical findings (higher BMI and lower systolic blood pressure), and lack of baseline use of ACE-inhibitors. Comparable determinants of HRQL in both populations support the similarity in HRQL between the two populations and the importance of these clinical factors.

Among patients living with chronic heart failure, nearly half have a normal or "near normal" left ventricular ejection fraction. These patients with Heart Failure-Preserved EF have a lower mortality rate than patients with Heart Failure-Low EF patients [9,25]. However, previous data comparing differences in HRQL between patients with Heart Failure-Preserved EF and Heart Failure-Low EF are limited and conflicting. There are several small studies that compared quality of life in the two populations and demonstrated no significant differences in HRQL scores using the Ladder of Life scale (n=23) [26] and SF-36 (n=26) [27]. Other studies demonstrated differences in HRQL. Kitzman et al. demonstrated more impaired HRQL in 60 patients with Heart Failure-Low EF as compared with 59 Heart Failure-Preserved EF patients (MLHF score 43.8±3.9 vs. 24.8±4.4, p=0.002) [28]. However, patients with preserved EF had a better functional capacity. In the EuroHeart Failure Survey, patients were asked a single question "how would you rate your quality of life", using a 7-point rating scale (0—poor to 7—excellent). A greater percentage of Heart Failure-Low EF patients rated their HRQL as quite poor-very poor than Heart Failure-Preserved EF (29% vs. 23%, p=0.04). In a smaller cohort of patients recently admitted to hospital with heart failure, there was better HRQL (as measured by the ladder of life score in which 10 represented perfect HRQL) in patients with left ventricular ejection fraction 40-49% compared with patients with left ventricular ejection fraction <40% and patients with left ventricular ejection fraction ≥50% [7]. Our study characterized HRQL in a much larger population of symptomatic heart failure patients with a large representation of Heart Failure-Preserved EF patients and demonstrates that HRQL is not associated with left ventricular ejection fraction and is equally impaired in both populations. Moreover, we used a disease-specific instrument compared with the relatively generic instruments in the other studies.

Although heart failure is a heterogeneous syndrome with many etiologies and a wide range of ejection fractions, HRQL is diminished in the majority of patients as compared to patients without heart failure. However, there is considerable variability in HRQL despite similar disease severity, which makes interpretation of HRQL data difficult. Mean HRQL expressed by CHARM patients was similar to the HRQL of patients enrolled in other randomized clinical trials in heart failure. Elderly patients with heart failure enrolled in ELITE had a mean MLHF summary score of 25.3 [29]. Other trials had similar mean HRQL responses, including the DIG trial (mean MLHF score of 33.7) [30], V-HeFT II (mean MLHF 31+/–24), and Val-HeFT (mean MLHF 32+/–23). However, the degree of HRQL impairment in patients in CHARM was not as severe as patients undergoing cardiac resynchronization therapy (mean MLHF score 59) or LVAD implantation (mean MLHF score 75) [31,32].

In general, older patients reported a better HRQL than younger patients irrespective of baseline left ventricular ejection fraction. Prior studies have also reported a better HRQL among older patients than younger patients with Heart Failure-Low EF, despite having a worse functional status and worse performance on a 6-min walk test [33]. This suggests that functional status, though a contributor to HRQL, cannot be used as a surrogate for self-assessed HRQL and emphasizes that HRQL may be as much a reflection of health expectations as physical limitation. Social scientists have suggested that the acceptance of certain conditions changes as a person progresses through different life stages. This is supported by a recent study that demonstrated a progressive decrease in the gap between the HRQL of HF patients and those of healthy, age-matched population as patients get older [34]. Thus, HRQL perception may be better among older patients with chronic illnesses although, in general, HRQL declines with age. Depression has been demonstrated to be worse in younger symptomatic patients also and may contribute to the worse HRQL [35,36]. Thus, this likely represents a significant impairment of HRQL, especially in the young.

After adjusting for older age among women with heart failure, women still reported a worse HRQL than men as a group. The literature has suggested more perceived impairment among women due to less social support or more depression [35,37]. The reported association between gender and HRQL has varied in the literature. Some studies demonstrated more impairment in HRQL among women, but others have suggested no differences [38-42]. However, HRQL has also been demonstrated to be more impaired in women in other chronic diseases [43-46], which is further supported by these findings.

It is not surprising that symptom burden appears to negatively impact HRQL. Patients may not be able to distinguish limitations due to dyspnea versus angina. Angina has been demonstrated to be associated with worse HRQL in SOLVD, and improving this symptom may improve overall HRQL in heart failure patients [40]. The cumulative symptom burden may have as much of an impact on HRQL as the severity of one particular symptom. However, one conceptual model supports the delicate interaction between pathophysiological changes leading to increased symptom burden which causes worse functional limitations and distress. These factors cumulatively impair HRQL [46]. It is difficult to distinguish patient's perception of symptom burden from HRQL and has resulted in considerable debate. The MLHF tool likely captures the concept of HRQL better than many instruments [47]. Recently, individual patient's self-assessment of dyspnea and fatigue was reported to have independent prognostic implications for survival and morbidity over five years in the COMET trial [48]. Nevertheless, removal of symptom burden from heart failure did not affect the significance of most of the determinants of heart failure with an exception of ACE-inhibitor use.

There are several limitations to this study. This is a population healthy enough to be enrolled in a randomized clinical trial, which may limit the prevalence of co-morbidities and may not be the same as a population-based cohort. In addition, we cannot characterize the HRQL in patients who were asymptomatic (New York Heart Association Class I patients) as they were excluded from CHARM. Patients enrolled in the HRQL study were restricted to Canada and United States and may not reflect the HRQL perceptions of patients outside of these countries. Also, one segment of the CHARM population was entered into the study based upon their "ACE intolerance", and another large segment was entered in the Heart Failure-Preserved EF population not taking an ACE-inhibitor, and these populations may have characteristics that influenced the association between lack of ACE inhibition and worse HRQL. Left ventricular ejection fraction was measured at the clinical sites and not confirmed at a core lab and there may be some variability in the actual value. We did not measure depression or social support, which may affect HRQL. The imputation method used a mean HRQL score and assumes that the decision not to answer an item is independent from their overall HRQL and is random. Finally, HRQL was only measured with one instrument and the determinants of HRQL should be validated using a different tool. Moreover, there is no "gold standard" for absolute assessment of the various forms of validity and it is assumed that the MLHF measures HRQL. Despite these limitations, this study represents the largest sample size to date that included both Heart Failure-Preserved EF and Heart Failure-Low EF patients, which allows the characterization of determinants of HRQL in symptomatic heart failure patients across the spectrum of left ventricular ejection fraction.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Ambulatory, symptomatic chronic heart failure patients with preserved ejection fraction have similar HRQL compared to those patients with low ejection fraction. The degree of HRQL impairment and clinical determinants of HRQL are independent of left ventricular ejection fraction. The dissociation between HRQL and ejection fraction illustrates the complexity of symptom development in chronic heart failure and it indicates the need to move beyond traditional pathophysiological models for understanding symptoms [49]. Nevertheless, few studies have been completed evaluating strategies to improve HRQL in the ever increasing numbers of individuals living with heart failure. Identifying these clinical factors associated with worse HRQL creates a framework for future studies to test strategies to improve HRQL in heart failure populations irrespective of ejection fraction as increased emphasis is placed on improving quality as well as quantity of life.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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