European Heart Journal (2012) 33, 1750–1757 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehr254 Heart failure/cardiomyopathy

The survival of patients with heart failure with

preserved or reduced left ventricular ejection
fraction: an individual patient data meta-analysis
Meta-analysis Global Group in Chronic Heart Failure (MAGGIC)

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Received 18 March 2011; revised 30 May 2011; accepted 4 July 2011; online publish-ahead-of-print 6 August 2011

See page 1718 for the editorial comment on this article (doi:10.1093/eurheartj/ehr339)

Aims A substantial proportion of patients with heart failure have preserved left ventricular ejection fraction (HF-PEF). Previous
studies have reported mixed results whether survival is similar to those patients with heart failure and reduced EF (HF-REF).
.....................................................................................................................................................................................
Methods We compared survival in patients with HF-PEF with that in patients with HF-REF in a meta-analysis using individual
and results patient data. Preserved EF was defined as an EF ≥ 50%. The 31 studies included 41 972 patients: 10 347 with HF-PEF
and 31 625 with HF-REF. Compared with patients with HF-REF, those with HF-PEF were older (mean age 71 vs.
66 years), were more often women (50 vs. 28%), and have a history of hypertension (51 vs. 41%). Ischaemic aetiology
was less common (43 vs. 59%) in patients with HF-PEF. There were 121 [95% confidence interval (CI): 117, 126]
deaths per 1000 patient-years in those with HF-PEF and 141 (95% CI: 138, 144) deaths per 1000 patient-years in
those with HF-REF. Patients with HF-PEF had lower mortality than those with HF-REF (adjusted for age, gender,
aetiology, and history of hypertension, diabetes, and atrial fibrillation); hazard ratio 0.68 (95% CI: 0.64, 0.71). The
risk of death did not increase notably until EF fell below 40%.
.....................................................................................................................................................................................
Conclusion Patients with HF-PEF have a lower risk of death than patients with HF-REF, and this difference is seen regardless of
age, gender, and aetiology of HF. However, absolute mortality is still high in patients with HF-PEF highlighting the
need for a treatment to improve prognosis.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Heart failure † Prognosis † Meta-analysis

older and more often women, are less likely to have CAD, and
Introduction more likely to have underlying hypertension.1,2,5 In addition,
Heart failure is a leading cause of cardiovascular morbidity and patients with HF-PEF do not obtain similar clinical benefits from
mortality and arises as a consequence of many cardiovascular con- angiotensin-converting enzyme (ACE) inhibition or angiotensin
ditions, including coronary artery disease (CAD), valve disease, and receptor blockade compared with patients with HF-REF.6 – 8
hypertension. Heart failure has been traditionally viewed as a Several comparisons of survival between patients with HF-PEF
failure of contractile function and left ventricular (LV) ejection frac- and those with HF-REF have been reported but have given incon-
tion (EF) has been widely used to define systolic function, assess sistent results.1,2 Although a recent literature-based meta-analysis
prognosis, and select patients for therapeutic interventions. demonstrated that patients with HF-PEF may have lower mortality
However, it is recognized that heart failure can occur in the pres- than those with HF-REF,9 lack of patient-level data precluded
ence of normal or near-normal EF: so-called ‘heart failure with pre- careful adjustment for differences between these patient groups
served EF (HF-PEF)’ which accounts for a substantial proportion of in potentially important prognostic variables such as age, gender,
clinical cases of heart failure.1 – 4 co-morbidity, and aetiology of HF.
There are many differences between patients with heart failure Therefore, we undertook a meta-analysis using individual patient
with reduced EF (HF-REF) and patients with HF-PEF. The latter are data to examine mortality rates in patients with HF-PEF and HF-REF.

Corresponding author: Robert Neil Doughty, Department of Medicine, The University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
Tel: +64 9 923 9804, Fax: +64 9 367 7146, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]
Outcome for patients with HF and preserved LVEF 1751

Methods proportions for categorical variables. For all analyses, the outcome was
the rate of death from any cause at 3 years from hospital discharge or
A comprehensive search was undertaken for a literature-based baseline study visit. Three-year death rates and deaths per 1000
meta-analysis of observational studies and randomized controlled patient-years were calculated. Cox’s proportional hazard models
trials (RCTs) published to the end of 2006, and the details of this were used to estimate the hazard of HF-PEF compared with HF-REF,
have been reported.9 The same search process was repeated to the adjusted for age, gender, ischaemic aetiology, a history of hypertension,
end of 2008. In brief, we searched online databases including diabetes, and atrial fibrillation, and stratified by study. These variables
Embase, Medline, Medline In-progress, and PubMed using the key chosen for the model were selected for clinical relevance and where
words: prognosis, outcome, heart failure, left ventricle, and preserved. data were available for that variable in more than 90% of the patients
We also searched reference lists of articles obtained during the in the MAGGIC data set. Data on NYHA functional class and medi-
search and conference abstracts and made personal communication cations (ACE-inhibitor and/or angiotensin receptor antagonist and/or
with investigators and authors. Abstracts, unpublished studies, and b-blockers) were available on fewer patients in the MAGGIC data
articles published in languages other than English were not excluded. set. However, due to the importance of these variables in relation

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Eligible studies were those that included patients with heart failure to outcome, the Cox proportional hazards model was repeated with
and reported the outcome of interest (death from any cause) and incorporation of these variables in turn into the above model. In the
where EF criterion was not used for entry into the study. All the indi- whole group, within age groups and within gender, EF , 50% was
vidual studies were approved by Ethics Committees. The meta-analysis the referent; when comparing mortality across 10% bands of EF,
was approved by The University of Auckland Human Subjects Ethics EF ≥ 60% was the referent. The correlation between the scaled
Committee. Schoenfeld residuals and length of follow-up showed that there was
no violation of the proportional hazards assumption for all analyses.
Study selection and data extraction Mortality curves were created of adjusted models that were not stra-
We identified 56 potentially suitable studies: principal investigators for tified by study. Analyses were performed using R version 2.9.0.41
each of these studies were invited to participate in this meta-analysis.
An executive group was formed to oversee the data management and
analysis, and the steering group involved the principal investigator from
Results
each study. Investigators from 31 studies (3 pharmacotherapy RCTs, 4 Thirty one of the 56 identified studies contributed data on 54 416
management intervention RCTs, and 24 observational studies)10 – 40 patients (Figure 1). One thousand one hundred and seventy-nine
provided individual patient data on a pre-defined set of variables patients were excluded due to irresolvable dates or death during
including demographics (age, sex, and ethnicity), medical history an index hospital admission and 2246 excluded as heart failure
(history of myocardial infarction, coronary revascularization, diabetes, was secondary to severe valvular heart disease or hypertrophic
hypertension, stroke, lung disease, peripheral artery disease, and
cardiomyopathy. Ejection fraction data were not available for
smoking), medical treatment (ACE-inhibitor, angiotensin receptor
9019 patients, and thus the main analysis was based on 41 972
blocker, b-blocker, diuretic, and aldosterone antagonist), symptom
status [New York Heart Association (NYHA) functional class, dys- patients for whom EF data were available. Ejection fraction was
pnoea, paroxysmal nocturnal dyspnoea, and oedema], clinical variables assessed using echocardiography in 33 717 (80.4%), scintigraphy
(heart rate, blood pressure, and pulmonary rales), laboratory variables in 6899 (16.4%), and angiography in 1356 (3.2%). Quantitative EF
(serum sodium, creatinine, and EF), and outcome (deaths and data were available for 38 484 (92%) patients and the remainder
follow-up duration). Data from 30 of the individual studies were (3488, 8%) had semi-quantitative EF assessment: 10 347 (24.7%)
re-coded at the Central Coordinating Centre at the University of patients had HF-PEF and 31 625 (75.3%) had HF-REF. The baseline
Auckland into a uniform format. Data were checked and queries
resolved, and the summary data from each study compared against
the original published data prior to incorporation into a single data-
base. This data set was then sent to the London School of Hygiene
and Tropical Medicine finally where the CHARM trial data were incor-
porated to create the final data set (31 studies) within which these
analyses were undertaken.
Our primary hypothesis was that patients with HF-PEF would have a
lower mortality rate than patients with HF-REF, even after adjustment
for other prognostic variables.

Ejection fraction
In 18 studies, a preference for rounding EF to the nearest 5% was
observed. In these studies, EF at these rounded values was reallocated
within 2.5% either side of the rounded value by random selection from
a uniform distribution. For example, EF values of 20% were randomly
reallocated to values between 17.5 and 22.4%. Preserved EF was pre-
specified as EF ≥50%.

Statistical analysis
The baseline variables for the HF-PEF and HF-REF groups were com- Figure 1 Flow chart of studies for meta-analysis.
pared using Student’s t-test for continuous variables and the x 2 tests of
1752 R.N. Doughty

Table 1 Baseline characteristics of the groups

Whole group HF-PEF HF-REF Missing LVEF P-value (HF-PEF vs. HF-REF)
...............................................................................................................................................................................
n (31 studies) 50 991 10 347 31 625 9019 —
Age [years (SD)] 68 (12) 71 (12) 66 (12) 71 (13) ,0.001
Women (%) 35% 50% 28% 44% ,0.001
...............................................................................................................................................................................
Medical history
Hypertension 43% 51% 41% 40% ,0.001
Myocardial infarction 43% 27% 51% 31% ,0.001
Atrial fibrillation 21% 27% 18% 23% ,0.001
Diabetes 23% 23% 24% 21% 0.005

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Ischaemic aetiology 54% 43% 59% 49% ,0.001
...............................................................................................................................................................................
Medication
ACE-inhibitor or ARB 67% 44% 75% 64% ,0.001
b-Blocker 34% 33% 39% 23% ,0.001
Diuretic 82% 78% 83% 83% ,0.001
Spironolactone 21% 16% 24% 17% ,0.001
Digoxin 43% 32% 47% 44% ,0.001
...............................................................................................................................................................................
Clinical status
NYHA class (I/II/III/IV) (%) 11/47/34/8 14/48/29/9 10/46/37/7 19/48/25/8 All ,0.004
Heart rate (b.p.m.) 79 (18) 78 (21) 79 (18) 79 (17) 0.019
SBP (mmHg) 131 (23) 141 (25) 128 (22) 135 (24) ,0.001
DBP (mmHg) 77 (13) 79 (14) 76 (12) 80 (13) ,0.001
LVEF % (median, IQR) 36 (27, 48) 60 (55, 61) 31 (24, 39) — —

Values represent mean (standard deviation) unless stated. ARB, angiotensin receptor blocker; IQR, inter-quartile range; NYHA, New York Heart Association functional class;
LVEF, left ventricular ejection fraction.

characteristics are shown in Table 1. When compared with the

HF-REF patients, those with HF-PEF were older (mean age
71 years SD 12 vs. 66 years SD 12), were more often women (50
vs. 28%), more often had a history of hypertension (51 vs. 41%)
and atrial fibrillation (27 vs. 18%), and less often ischaemic aetiol-
ogy (43 vs. 59%). Patients with HF-REF were more commonly
receiving treatment with an ACE-inhibitor (75 vs. 44%),
b-blocker (39 vs. 33%), and spironolactone (24 vs. 16%) compared
with those with HF-PEF. For the 25 studies for which patient data
were not available, the weighted mean from published data
showed that these patients were slightly older (mean age
71 years), fewer were women (34%), and the proportion of
patients with missing EF was higher (33%) than the included
studies.
The median duration of follow-up for patients with a missing EF Figure 2 Mortality for patients with HF-PEF (heart failure with
was only 121 days [inter-quartile range (IQR) 85, 365] compared preserved left ventricular ejection fraction) and HF-REF (heart
with those with an available EF: HF-PEF group 1024 (IQR 246, failure with low left ventricular ejection fraction), adjusted for
1546) days and HF-REF group 933 (IQR 346, 1348) days. Due to age, gender, aetiology of heart failure, hypertension, diabetes,
the large difference in duration of follow-up, the group with atrial fibrillation.
missing EF was not considered further in this analysis. The primary
outcome of death from any cause occurred in 2422 (23.4%) patients
with HF-PEF and in 8332 (26.3%) in those with HF-REF. There were analysis, patients with HF-PEF were at lower risk of death than
121 [95% confidence interval (CI): 117, 126] deaths per 1000 those with HF-REF, hazard ratio (HR) 0.71 (95% CI: 0.67, 0.74). In
patient-years in those with HF-PEF and 141 (95% CI: 138, 144) the adjusted Cox proportional hazards model, patients with
deaths per 1000 patient-years in those with HF-REF. In univariate HF-PEF had lower mortality than those with HF-REF, adjusted HR
Outcome for patients with HF and preserved LVEF 1753

0.68 (95% CI: 0.64, 0.71; Figure 2 and Table 2). When the RCTs of hospitalized (n ¼ 20 213). Thus, irrespective of whether hospital-
pharmacotherapy (three trials, 20 878 patients) were excluded ized or not, patients with HF-PEF had a lower risk of death than
from the analysis, there were 146 (95% CI: 138, 154) deaths per patients with HF-REF. However, this difference appeared to be
1000 patient-years in those with HF-PEF and 159 (95% CI: 154, greater in ambulatory than in hospitalized patients.
165) deaths per 1000 patient-years in those with HF-REF, and the Data on cardiovascular death were available for 26 725 patients
risk of death remained lower in the patients with HF-PEF compared from 14 studies; in an adjusted Cox proportional hazards model,
with those with the HF-REF group: adjusted HR 0.76 (95% CI: 0.71, patients with HF-PEF had lower risk of cardiovascular death than
0.82). Correspondingly, in the randomized trials alone, there were those with HF-REF, adjusted HR 0.55 (95% CI: 0.49, 0.61;
101 (95% CI: 96, 107) deaths per 1000 patient-years in those with Table 2). When the adjusted Cox proportional hazards model
HF-PEF and 131 (95% CI: 127, 134) deaths per 1000 patient-years was repeated with inclusion of either NYHA functional class
in those with HF-REF and the risk of death remained lower in the (16 592 patients) or medications (11 908 patients), similar results
patients with HF-PEF compared with those with HF-REF, adjusted were seen for both death from any cause and cardiovascular
HR 0.61 [95% CI: 0.57, 0.65; interaction EF × study design (RCT

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death: NYHA included in model HR for death from any cause
or non-RCT), P ¼ 0.0007]. For studies that recruited patients who 0.68 (95% CI: 0.60, 0.77) and for cardiovascular death HR 0.62
were hospitalized at baseline (n ¼ 18 108), the adjusted HR for (95% CI: 0.52, 0.75); medications included in model HR for
death from any cause for patients with HF-PEF compared with death from any cause 0.66 (95% CI: 0.62, 0.69) and for cardiovas-
those with HF-REF was 0.70 (95% CI: 0.66, 0.74) and was 0.59 cular death HR 0.47 (95% CI: 0.33, 0.68).
(95% CI: 0.54, 0.66) for studies involving patients who were not Risk of death from any cause and cardiovascular death by EF cat-
egory is shown in Figure 3. The HR for death in patients with an EF
50 –59% and in those with an EF between 40 and 49% was not
increased compared with patients with an EF of 60% or above.
Table 2 Cox’s proportional adjusted hazards ratios However, the HR for death increased steadily below an EF of
for all-cause death and cardiovascular death 40%. The rate of death increased with age: 847 (12.8%) deaths
among 6624 patients aged ,55 years, 5617 (21.7%) deaths
Variable Death from any Cardiovascular
cause death among 25 882 patients aged 55–75 years, and 5510 (36.0%)
Hazard ratio Hazard ratio deaths among 15 280 patients aged .75 years. In all three age
(95% CI) (95% CI) groups, patients with HF-PEF had a lower risk of death than
...............................................................................
patients with HF-REF, with no differences in HR for men and
HF-PEF 0.68 (0.64, 0.71) 0.55 (0.49, 0.61)
women (Figure 4). There was no interaction between gender and
Male gender 1.23 (1.18, 1.28) 1.23 (1.14, 1.33)
age for death from any cause (P ¼ 0.604). However, the HR for
Age (years) 1.04 (1.04, 1.04) 1.03 (1.03, 1.04)
the difference in mortality between patients with HF-PEF and
Ischaemic 1.07 (1.02, 1.12) 1.11 (1.03, 1.19)
those with HF-REF appeared to differ according to age (age/EF
aetiology
group interaction, P , 0.0001). For example, for women aged
Hypertension 0.93 (0.89, 0.97) 0.94 (0.88, 1.00)
≥75 years, the adjusted HR comparing risk of death among
Diabetes 1.41 (1.35, 1.47) 1.51 (1.41, 1.62)
women with HF-PEF and those with HF-REF was 0.79 (95% CI:
Atrial fibrillation 1.10 (1.05, 1.16) 1.28 (1.16, 1.41)
0.72, 0.87) compared with 0.38 (95% CI: 0.22, 0.65) for women
aged ,55 years. Similarly, for men aged ≥75 years, the adjusted

Figure 3 Adjusted hazard ratios comparing death from any cause and cardiovascular death by groups of left ventricular ejection fraction (with
LVEF ≥ 60% as the reference group).
1754 R.N. Doughty

for patients with heart failure utilizing a cut-off of EF would have

EF measurements available for all patients, although this is rarely
the case. If missing EF measurements were to occur across all
patient groups, then this would not introduce bias. However, EF
measurement is undertaken less frequently in some patient
groups such as the elderly42 and patients with missing EF measure-
ment have worse outcome than those with EF measurements.43
Consequently, exclusion of patients due to missing EF measure-
ments can introduce systematic bias. While the current
meta-analysis was not able to obtain individual patient data from
all prior studies, the proportion of patients missing EF data was
only 18% from the studies providing data, while the studies not

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contributing data had EF missing in 42% of the patients, thus the
potential effects of missing EF data are likely to be lessened in
the current analyses.
Characterization of patients with HF-PEF has been hampered by
Figure 4 Adjusted hazard ratios comparing death from any lack of a consistent definition of this condition. Earlier recommen-
cause for patients with heart failure-preserved ejection fraction dations advocating the application of detailed assessment of LV dias-
and heart failure-reduced ejection fraction by age group. tolic function were complicated and effectively unworkable in clinical
practice.44 Furthermore, diastolic dysfunction is unlikely to be the
sole underlying cardiac abnormality in all such patients, and other
HR comparing risk of death among men with HF-PEF and those factors, such as atrial fibrillation, valve disease, and myocardial ischae-
with HF-REF was 0.74 (95% CI: 0.67, 0.81) compared with 0.50 mia, as well as non-cardiac conditions such as renal impairment,
(95% CI: 0.37, 0.69) for men aged ,55 years. This indicates that anaemia, obesity, and diabetes, are likely to contribute. A simple
the difference in the risk of death among patients with HF-PEF approach, as used in this current meta-analysis, is to define this symp-
and HF-REF was less among older patients than in younger tomatic group of patients by an EF cut-off. This is attractive in that EF
patients. is commonly utilized in clinical practice to guide application of
evidence-based therapies.45 However, this approach is effectively
one of ‘exclusion’ and likely results in a heterogeneous group of
patients with multiple underlying cardiac abnormalities contributing
Discussion to the heart failure despite preserved EF, including some with subtle
This large systematic review of over 40 000 patients evaluating the abnormalities of LV systolic function.46 – 48 In addition, there has been
survival of patients with HF-PEF or HF-REF has three principal find- concern that with this approach patients with non-cardiac causes of
ings. First, patients with HF-PEF had a 32% lower risk of death over breathlessness, exercise intolerance, and oedema may erroneously
3 years compared with those with HF-REF. Secondly, the pheno- be labelled as having heart failure.49
type of patients in this study with HF-PEF confirms early studies Furthermore, the optimal EF cut-off for the simple classification
demonstrating striking gender and age differences between the of heart failure (HF-PEF or HF-REF) remains uncertain. Our data
two syndromes. Compared with those with HF-REF, patients demonstrate that mortality risk does not increase substantially
with HF-PEF were typically 5 years older, half were women but until EF falls below 40%, consistent with prior arbitrary use of
were less likely to have ischaemic heart disease as the aetiology this cut-point in trials of pharmacological treatment. More recently,
of their heart failure. Thirdly, even after adjusting for these and recommendations have been made to incorporate LV size, and
other prognostic variables using individual patient data in this other echocardiographic and neurohormonal variables in this defi-
meta-analysis, the difference in mortality remained in both men nition,50 although these remain to be prospectively evaluated in
and women and was present irrespective of aetiology of heart large groups of patients with heart failure.
failure and age. Similar results were also observed whether the The current data are based on a large group of patients for
patients were hospitalized or not at baseline and whether involved whom one measurement of EF was available at the baseline assess-
in RCTs of pharmacotherapy or observational studies. These ment, which was used to define the group of patients with pre-
results, obtained by analysing more than 10 000 deaths among served or reduced EF. Prior studies suggest that EF
more than 40 000 patients, provide clear evidence that survival is measurements are similar whether obtained at the time of acute
different for these two distinct phenotypes of the heart failure heart failure decompensation or at a later time when compensated
syndrome. and symptoms improved.51 However, it remains uncertain whether
While a number of studies have reported on outcome for the group of patients with HF-PEF will develop progressive wor-
patients with HF-PEF compared with those with HF-REF, the indi- sening of EF in the longer-term as their disease progresses in
vidual results have been conflicting. Two large retrospective association with subsequent events, although there are some
community-based studies reported that mortality was similar for data to suggest that patients with HF-PEF may only develop pro-
patients with HF-PEF and HF-REF.1,2 Several sources of bias exist gressive LV remodelling if inter-current myocardial infarction
in studies reporting outcome, for example, ideally any such study occurs.52 As a result, for some patients, the clinical outcomes
Outcome for patients with HF and preserved LVEF 1755

may be influenced by progressive LV remodelling, and in others Funding

may be influenced by vascular or other effects. Much remains to The MAGGIC meta-analysis was supported by grants from the New
be learned as to why some patients with similar co-morbid con- Zealand National Heart Foundation, The University of Auckland and
ditions develop progressive remodelling, whereas others have The University of Glasgow. These sponsors had no role in the
worsened diastolic function. design, conduct, data management, and analysis; or in the manuscript
The extensive study of patients with HF-REF has developed an preparation or review; or in the authorization for submission.
understanding of the importance of mechanisms of death among
Conflict of interest: Dr Komajda is a member of the Executive
patients with heart failure. In particular, the relative contributions
Committee of the I-PRESERVE trial and is an ESC officer. Dr Rich
of sudden death or death due to progressive heart failure have
has received research funding from Astellas Pharma US (small grant)
become of particular importance in the era of device-based thera- and Sanofi-aventis (consultant, moderate).
pies.53 While it is now clear that patients with HF-PEF have lower
total mortality than those with HF-REF, understanding the mode of

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death among patients with HF-PEF is of importance. Recent phar-
macotherapy trials have reported that cardiovascular deaths
Appendix
account for 60% of all deaths in those with HF-PEF, with sudden MAGGIC Executive Group (responsible for the oversight and overall
death and death due to progressive heart failure appearing to be conduct of the meta-analysis): C. Berry, R.N. Doughty, C. Granger,
less common among patients with HF-PEF compared with those L. Køber, B. Massie, F. McAlister, J. McMurray, S. Pocock, K. Poppe,
with HF-REF.54 – 56 Community-based observational studies may K. Swedberg, J. Somaratne, and G.A. Whalley.
involve older patients with a wider range of co-morbidities than MAGGIC Steering Group: The Steering Group included investi-
patients in RCTs, and this may contribute to the lower proportion gators from the original studies that provided individual patient
of cardiovascular deaths (49%) reported in these studies.57,58 The data: A. Ahmed, B. Andersson, A. Bayes-Genis, C. Berry,
difference in mortality between patients with HF-PEF and HF-REF M. Cowie, R. Cubbon, R.N. Doughty, J. Ezekowitz,
in the current meta-analysis was less pronounced with more J. Gonzalez-Juanatey, M. Gorini, I. Gotsman, L. Grigorian-
advanced age which would be consistent with a greater influence Shamagian, M. Guazzi, M. Kearney, L. Køber, M. Komajda, A. di
of non-cardiovascular deaths among older patients. Further under- Lenarda, M. Lenzen, D. Lucci, S. Macı́n, B. Madsen, A. Maggioni,
standing of the mode of death in a wide range of patients with M. Martı́nez-Sellés, F. McAlister, F. Oliva, K. Poppe, M. Rich,
HF-PEF will further assist with the development of appropriate M. Richards, M. Senni, I. Squire, G. Taffet, L. Tarantini,
strategies to improve outcome for these patients. C. Tribouilloy, R. Troughton, H. Tsutsui, and G.A. Whalley.
Our meta-analysis has some limitations. While we combined the MAGGIC Coordinating Centre: R.N. Doughty, N. Earle, K. Perera,
data from a large number of studies and individual patients, their K. Poppe, and G.A. Whalley, The University of Auckland, New
value is still determined by the underlying limitations of the original Zealand.
individual studies. However, incorporating data from both random- MAGGIC Statistical Group: J. Dobson, S. Pocock, and K. Poppe.
ized trials and observational studies, resulting in a wide range of The MAGGIC Studies and Investigators: The following investigators
patients, with long follow-up and a large number of clinical kindly provided the individual patient data from their studies:
events, the results are likely to be an accurate reflection of patients AHFMS: R.N. Doughty, and G. Whalley; Andersson (two data sets):
commonly seen in clinical practice with the syndrome of heart B. Andersson, C. Hall; BATTLESCARRED and Richards:
failure. Data were only incorporated from studies that enrolled A.M. Richards, R. Troughton, and J. Lainchbury; Berry: C. Berry,
patients without an EF inclusion criterion at baseline; thus, K. Hogg, J. Norrie, K. Stevenson, M. Brett, and J. McMurray;
studies such as I-PRESERVE and PEP-CHF and the numerous indi- CHARM: M.A. Pfeffer, K. Swedberg, C.B. Granger, P. Held,
vidual studies of patients with HF-REF were not included in this J.J.V. McMurray, E.L. Michelson, B. Olofsson, J. Östergren, and
meta-analysis. Data on clinical, echocardiographic, and laboratory S. Yusuf for the CHARM Investigators and Committees; Diamond
variables were not universally available in all studies. The variables and ECHOS: L. Køber, and C. Torp-Pedersen; DIG Trial: DIG limited
incorporated into the Cox proportional hazards model were access data, Ali Ahmed; Euro HF Survey: M.J. Lenzen, W.J.M. Scholte
selected for clinical relevance and being available in the majority op Reimer, E. Boersma, P.J.M.J. Vantrimpont, F. Follath,
of patients. Other variables which may have prognostic importance K. Swedberg, J. Cleland, and M. Komajda; Gotsman: I. Gotsman,
were not selected due to the amount of missing data. A relatively D. Zwas, D. Planer, T. Azaz-Livshits, D. Admon, C. Lotan, and
low proportion of the patients with HF-REF were receiving A. Keren; Grigorian-Shamagian: L. Grigorian-Shamagian,
b-blockers and spironolactone, which may reflect the time that A. Varela-Roman, P. Mazón-Ramos, P. Rigeiro-Veloso,
the studies were conducted, and could influence the overall differ- M.A. Bandin-Dieguez, and J.R. Gonzalez-Juanatey; Guazzi:
ence in mortality seen in this analysis. M. Guazzi, J. Myers, and R. Arena; Heart Failure Clinic Edmonton:
In summary, in combining individual patient data from multiple F.A. McAlister, J. Ezekowitz, P.W. Armstrong, Bibiana Cujec, and
studies, we have demonstrated that patients with HF-PEF have Ian Paterson; Hillingdon: M.R. Cowie, D.A. Wood, A.J.S. Coats,
lower total mortality when compared with patients with HF-REF. S.G. Thompson, V. Suresh, P.A. Poole-Wilson, and G.C. Sutton;
In particular, risk of death appears to increase in patients with EF HOLA: M. Martı́nez-Sellés, J.A.G. Robles, L. Prieto, M.D. Muñoa,
below 40%. Further detailed study is required of outcome in E. Frades, O. Dı́az-Castro, and J. Almendral; Italian HF Registry
patients with HF-PEF to determine new therapeutic strategies to (IN-CHF): L. Tarantini, P. Faggiano, M. Senni, D. Lucci, D. Bertoli,
improve outcome for these patients. M. Porcu, C. Opasich, L. Tavazzi, and A.P. Maggioni; Kirk: V. Kirk,
1756 R.N. Doughty

M. Bay, J. Parner, K. Krogsgaard, T.M. Herzog, S. Boesgaard, 13. Berry C, Hogg K, Norrie J, Stevenson K, Brett M, McMurray J. Heart failure with
preserved left ventricular systolic function: a hospital cohort study. Heart 2005;91:
C. Hassager, O.W. Nielsen, J. Aldershvile, H. Nielsen, and
907 –913.
L. Kober; Macin: S.M. Macı́n, E.R. Perna, J.P. Cimbaro Canella, 14. Cowie MR, Wood DA, Coats AJS, Thompson SG, Suresh V, Poole-Wilson PA,
P. Alvarenga, R. Pantich, N. Rı́os, E.F. Farias, and J.R. Badaracco; Sutton GC. Survival of patients with a new diagnosis of heart failure: a population
Madsen: B.K. Madsen, J.F. Hansen, K.H. Stokholm, J. Brons, based study. Heart 2000;83:505 – 510.
15. Curtis J, Sokol S, Wang Y, Rathore S, Ko D, Jadbabaie F, Portnay E, Marshalko S,
D. Husum, and L.S. Mortensen; MUSIC: A. Bayes-Genis, Radford M, Krumholz H. The association of left ventricular ejection fraction, mor-
R. Vazquez, T. Puig, C. Fernandez-Palomeque, A. Bardajı́, tality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol
D. Pascual-Figal, J. Ordoñez-Llanos, M. Valdes, A. Gabarrus, 2003;42:736 –742.
16. Doughty RN, Wright SP, Pearl A, Walsh HJ, Muncaster S, Whalley GA, Gamble G,
R. Pavon, L. Pastor, J.R. Gonzalez-Juanatey, J. Almendral, M. Fiol,
Sharpe N. Randomised, controlled trial of integrated heart failure management:
V. Nieto, C. Macaya, J. Cinca, and A. Bayes de Luna; Newton: the Auckland Heart Failure Management Study. Euro Heart J 2002;23:139 – 141.
J.D. Newton, H.M. Blackledge, and I.B. Squire; NPC I: S.P. Wright, 17. Gotsman I, Zwas D, Planer D, Azaz-Livshits T, Admon D, Lotan C, Keren A. Clini-
G.A. Whalley, and R.N. Doughty; Rich (data set 1): R. Kerzner, cal outcome of patients with heart failure and preserved left ventricular function.
Am J Med 2008;121:997 –1001.

Downloaded from https://academic.oup.com/eurheartj/article/33/14/1750/525898 by guest on 02 January 2024

B.F. Gage, K.E. Freedland, and M.W. Rich; Rich (data set 2): 18. Grigorian Shamagian L, Roman AV, Ramos PM, Veloso PR, Bandin Dieguez MA,
B.C. Huynh, A. Rovner, K.E. Freedland, R.M. Carney, and Gonzalez-Juanatey JR. Angiotensin-converting enzyme inhibitors prescription is
M.W. Rich; Taffet: G.E. Taffet, T.A. Teasdale, A.J. Bleyer, N.J. Kutka, associated with longer survival among patients hospitalized for congestive heart
failure who have preserved systolic function: a long-term follow-up study.
and R.J. Luchi; Tribouilloy: C. Tribouilloy, D. Rusinaru, H. Mahjoub,
J Cardiac Fail 2006;12:128 –133.
V. Soulière, F. Lévy, and M. Peltier; Tsutsui: H. Tsutsui, 19. Guazzi M, Myers J, Arena R. Cardiopulmonary exercise testing in the clinical and
M. Tsuchihashi, and A. Takeshita; UK Heart Study: P.A. MacCarthy, prognostic assessment of diastolic heart failure. J Am Coll Cardiol 2005;46:
M.T. Kearney, R. Cubbon, J. Nolan, A.J. Lee, R.J. Prescott, 1883 –1890.
20. Gustafsson F, Torp-Pedersen C, Brendorp B, Seibaek M, Burchardt H, Kober L,
A.M. Shah, W.P. Brooksby, and K.A.A. Fox; Varela-Roman: for the Diamond Study Group. Long-term survival in patients hospitalized with
A. Varela-Roman, J.R. Gonzalez-Juanatey, P. Basante, R. Trillo, congestive heart failure: relation to preserved and reduced left ventricular systolic
J. Garcia-Seara, J.L. Martinez-Sande, and F. Gude. function. Euro Heart J 2003;24:863 –870.
21. Kerzner R, Gage BF, Freedland KE, Rich MW. Predictors of mortality in younger
and older patients with heart failure and preserved or reduced left ventricular
References ejection fraction. Am Heart J 2003;146:286 –290.
1. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in 22. Kirk V, Bay M, Parner J, Krogsgaard K, Herzog TM, Boesgaard S, Hassager C,
prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Nielsen OW, Aldershvile J, Nielsen H. N-terminal proBNP and mortality in hos-
Med 2006;355:251 –259. pitalised patients with heart failure and preserved vs. reduced systolic function:
2. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome data from the prospective Copenhagen Hospital Heart Failure Study (CHHF).
of heart failure with preserved ejection fraction in a population-based study.
Eur J Heart Fail 2004;6:335 –341.
N Engl J Med 2006;355:260 –269.
23. Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A,
3. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical pres-
Yandle TG, Hamid AK, Nicholls MG, Richards AM. N-terminal pro-B-type
entation, management, and in-hospital outcomes of patients admitted with acute
natriuretic peptide-guided treatment for chronic heart failure: results from the
decompensated heart failure with preserved systolic function: a report from the
BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac
Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am
Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53–60.
Coll Cardiol 2006;47:76–84.
24. Lenzen MJ, Scholte op Reimer WJM, Boersma E, Vantrimpont PJMJ, Follath F,
4. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M,
Greenberg BH, O’Connor CM, Sun JL, Yancy CW, Young JB. Characteristics, Swedberg K, Cleland J, Komajda M. Differences between patients with a pre-
treatments, and outcomes of patients with preserved systolic function hospital- served and a depressed left ventricular function: a report from the EuroHeart
ized for heart failure: a report from the OPTIMIZE-HF registry. J Am Coll Failure Survey. Eur Heart J 2004;25:1214 –1220.
Cardiol 2007;50:768 –777. 25. MacCarthy PA, Kearney MT, Nolan J, Lee AJ, Prescott RJ, Shah AM, Brooksby WP,
5. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular Fox KAA. Prognosis in heart failure with preserved left ventricular systolic func-
systolic function: epidemiology, clinical characteristics, and prognosis. J Am Coll tion: prospective cohort study. BMJ 2003;327:78 –79.
Cardiol 2004;43:317 –327. 26. Macı́n SM, Perna ER, Cimbaro Canella JP, Alvarenga P, Pantich R, Rios N, Farias EF,
6. Cleland JGF, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, on behalf Badaracco JR. Differences in clinical profile and outcome in patients with decom-
of PEP-CHF Investigators. The perindopril in elderly people with chronic heart pensated heart failure and systolic dysfunction or preserved systolic function. Rev
failure (PEP-CHF) study. Eur Heart J 2006;27:2338 –2345. Esp Cardiol 2004;57:45 –52.
7. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, 27. Madsen BK, Hansen JF, Stokholm KH, Brøns J, Husum D, Mortensen LS. Descrip-
Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A, the IPI. Irbesartan tion and survival of 190 consecutive patients with a diagnosis of chronic conges-
in patients with heart failure and preserved ejection fraction. N Engl J Med tive heart failure based on clinical signs and symptoms. Eur Heart J 1994;15:
2008;359:2456 – 2467. 303 –310.
8. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, 28. Martinez-Selles M, Robles JAG, Prieto L, Munoa MD, Frades E, Diaz-Castro O,
Olofsson B, Ostergren J. Effects of candesartan in patients with chronic heart Almendral J. Systolic dysfunction is a predictor of long term mortality in men
failure and preserved left-ventricular ejection fraction: the CHARM-Preserved but not in women with heart failure. Eur Heart J 2003;24:2046 –2053.
Trial. Lancet 2003;362:777 –781. 29. McAlister FA, Teo KK, Taher M, Montague TJ, Humen D, Cheung L, Kiaii M,
9. Somaratne JB, Berry C, Mcmurray JJV, Poppe K, Doughty RN, Whalley GA. The Yim R, Armstrong PW. Insights into the contemporary epidemiology and outpa-
prognostic significance of heart failure with preserved left ventricular ejection tient management of congestive heart failure. Am Heart J 1999;138:87 –94.
fraction: a literature-based meta-analysis. Euro J Heart Fail 2009;11:855 –862. 30. Newton JD, Blackledge HM, Squire IB. Ethnicity and variation in prognosis for
10. Andersson B, Hall C. N-terminal proatrial natriuretic peptide and prognosis in
patients newly hospitalised for heart failure: a matched historical cohort study.
patients with heart failure and preserved systolic function. J Cardiac Fail 2000;6:
Heart 2005;91:1545 –1550.
208 –213.
31. Pfeffer M, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson El,
11. Andersson B, Kjörk E, Brunlöf G. Temporal improvement in heart failure survival
Olofsson B, Ostergren J, Yusuf S, for the CHARM Investigators and Committees.
related to the use of a nurse-directed clinic and recommended pharmacological
Effects of candesartan on mortality and mobidity in patients with chronic heart
treatment. Int J Cardiol 2005;104:257–263.
failure: the CHARM-Overall Programme. Lancet 2003;362:759 – 766.
12. Bayes-Genis A, Vazquez R, Puig T, Fernandez-Palomeque C, Fabregat J, Bardajı́ A,
32. Pilbrow AP, Palmer BR, Frampton CM, Yandle TG, Troughton RW, Campbell E,
Pascual-Figal D, Ordoñez-Llanos J, Valdes M, Gabbarrús A, Pavon R, Pastor L,
Juanatey JRG, Almendral J, Fiol M, Nieto V, Macaya C, Cinca J, de Luna AB. Skelton L, Lainchbury JG, Richards AM, Cameron VA. Angiotensinogen M235T
Left atrial enlargement and NT-proBNP as predictors of sudden cardiac death and T174M gene polymorphisms in combination doubles the risk of mortality
in patients with heart failure. Eur J Heart Fail 2007;9:802 – 807. in heart failure. Hypertension 2007;49:322–327.
Outcome for patients with HF and preserved LVEF 1757

33. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A 47. Zile MR. Heart failure with preserved ejection fraction: is this diastolic heart
multidisciplinary intervention to prevent the readmission of elderly patients failure? J Am Coll Cardiol 2003;41:1519 –1522.
with congestive heart failure. N Engl J Med 1995;333:1190 –1195. 48. Petrie MC, Caruana L, Berry C, McMurray JJV. ‘Diastolic heart failure’ or heart
34. Taffet GE, Teasdale TA, Bleyer AJ, Kutka NJ, Luchi RJ. Survival of elderly men with failure caused by subtle left ventricular systolic dysfunction? Heart 2002;87:29– 33.
congestive heart failure. Age Ageing 1992;21:49– 55. 49. Caruana L, Petrie MC, Davie AP, McMurray JJV. Do patients with suspected heart
35. Tarantini L, Faggiano P, Senni M, Lucci D, Bertoli D, Porcu M, Opasich C, failure and preserved left ventricular function suffer from ‘diastolic heart failure’ of
Tavazzi L, Maggioni AP. Clinical features and prognosis associated with a pre- from misdiagnosis? A prospective descriptive study. BMJ 2000;321:215 –219.
served left ventricular systolic function in a large cohort of congestive heart 50. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE,
failure outpatients managed by cardiologists. Data from the Italian Network on Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely A, Edes I,
Congestive Heart Failure. Ital Heart J 2002;3:656 – 664. Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG,
36. Torp-Pedersen C, Kober L, Carlsen JE, Akkan D, Bruun NE, Dacoronias D, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement
Dickstein K, Haghfelt T, Ohlin H, McMurray JJV. A randomised trial of a pre- on the diagnosis of heart failure with normal left ventricular ejection fraction
synaptic stimulator of DA2-dopaminergic and a2-adrenergic receptors on mor-
by the Heart Failure and Echocardiography Associations of the European
bidity and mortality in patients with heart failure. Eur J Heart Fail 2008;10:89 –95.
Society of Cardiology. Eur Heart J 2007;28:2539 –2550.
37. Tribouilloy C, Rusinaru D, Mahjoub H, Souliere V, Levy F, Peltier M, Slama M,
51. Gandhi SK, Powers JC, Nomeir A-M, Fowle K, Kitzman DW, Rankin KM,
Massy Z. Prognosis of heart failure with preserved ejection fraction: a 5 year pro-
Little WC. The pathogenesis of acute pulmonary edema associated with hyper-

Downloaded from https://academic.oup.com/eurheartj/article/33/14/1750/525898 by guest on 02 January 2024

spective population-based study. Eur Heart J 2008;29:339 – 347.
tension. N Engl J Med 2001;344:17–22.
38. Tsutsui H, Tsuchihashi M, Takeshita A. Mortality and readmission of hospitalized
52. Desai RV, Ahmed MI, Mujib M, Aban IB, Zile MR, Ahmed A. Natural history of
patients with congestive heart failure and preserved versus depressed systolic
function. Am J Cardiol 2001;88:530 –533. concentric left ventricular geometry in community-dwelling older adults
39. Varela-Roman A, Grigorian L, Barge E, Bassante P, de la Pena MG, without heart failure during seven years of follow-up. Am J Cardiol 2011;107:
Gonzalez-Juanatey JR. Heart failure in patients with preserved and deteriorated 321 –324.
left ventricular ejection fraction. Heart 2005;91:489 –494. 53. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M,
40. Wright SP, Doughty RN, Pearl A, Gamble GD, Whalley GA, Walsh HJ, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N,
Gordon G, Bagg W, Oxenham H, Yandle T, Richards AM, Sharpe N. Plasma Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH, the Sudden
amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagno- Cardiac Death in Heart Failure Trial Investigators. Amiodarone or an implantable
sis in primary care: a randomized, controlled trial. J Am Coll Cardiol 2003;42: cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:
1793– 1800. 225 –237.
41. R Development Core Team. R: A Language and Environment for Statistical Comput- 54. Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB, Lopez-Sendon J,
ing. Vienna, Austria: R Foundation for Statistical Computing, 2009. Teerlink JR, White M, McMurray JJ, Komajda M, McKelvie R, Ptaszynska A,
42. Lindenfeld J, Fiske KS, Stevens BR, Debuhr J, Havranek EP, Abrams FR. Age, but Hetzel SJ, Massie BM, Carson PE, for the IPI. Mode of death in patients with
not sex, influences the measurement of ejection fraction in elderly patients hos- heart failure and a preserved ejection fraction: results from the Irbesartan in
pitalized for heart failure. J Cardiac Fail 2003;9:100 –106. Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial. Circulation
43. McDermott MM, Feinglass J, Lee PI, Mehta S, Schmitt B, Lefevre F, 2010;121:1393 – 1405.
Gheorghiade M. Systolic function, readmission rates, and survival among consecu- 55. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray JJV, Swedberg K,
tively hospitalized patients with congestive heart failure. Am Heart J 1997;134: Yusuf S, Granger CB, Michelson EL, Pocock S, Pfeffer MA. Effect of candesartan
728 –736. on cause-specific mortality in heart failure patients: the Candesartan in Heart
44. European Study Group on Diastolic Heart Failure. How to diagnose diastolic failure Assessment of Reduction in Mortality and morbidity (CHARM) Program.
heart failure. Eur Heart J 1998;19:990 –1003. Circulation 2004;110:2180 –2183.
45. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJV, Ponikowski P, 56. Solomon SD, Anavekar N, Skali H, McMurray JJV, Swedberg K, Yusuf S,
Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Granger CB, Michelson EL, Wang D, Pocock S, Pfeffer MA, for the Candesartan
Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K. ESC guidelines for in Heart Failure Reduction in Mortality Investigators. Influence of ejection fraction
the diagnosis and treatment of acute and chronic heart failure 2008: the Task
on cardiovascular outcomes in a broad spectrum of heart failure patients.
Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure
Circulation 2005;112:3738 –3744.
2008 of the European Society of Cardiology. Developed in collaboration with
57. Henkel D, Redfield MM, Weston S, Gerber Y, Roger V. Death in heart failure: a
the Heart Failure Association of the ESC (HFA) and endorsed by the European
community perspective. Circ: Heart Fail 2008;1:91 –97.
Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29:2388 – 2442.
58. Grigorian-Shamagian L, Raviña FO, Assi EA, Perez RV, Teijeira-Fernandez E,
46. Kono M, Kisanuki A, Takasaki K, Nakashiki K, Yuasa T, Kuwahara E, Mizukami N,
Roman AV, Sayagues LM, Gonzalez-Juanatey JR. Why and when do patients
Uemura T, Kubota K, Ueya N, Miyata M, Tei C. Left ventricular systolic function is
with heart failure and normal left ventricular ejection fraction die? Analysis of
abnormal in diastolic heart failure: re-assessment of systolic function using cardiac
time interval analysis. J Cardiol 2009;53:437 –446. .600 deaths in a community long-term study. Am Heart J 2008;156:1184 –1190.