Independence of restrictive filling pattern and LV ejection fraction with
mortality in heart failure: An individual patient meta-analysis
Meta-analysis Research Group in Echocardiography (MeRGE) Heart Failure Collaborators⁎
Received 15 April 2008; accepted 10 June 2008
Background: The Doppler echocardiographic restrictive mitral filling pattern (RFP) is an important prognostic indicator in patients with heart
failure (HF), but the interaction between RFP, left ventricular ejection fraction (LVEF) and filling pattern remains uncertain.
Aims: To determine whether the RFP is predictive of mortality independently of LVEF in patients with HF.
Methods: Online databases were searched to identify studies assessing the relationship between prognosis and LV filling pattern in patients
with HF. Individual patient data from 18 studies (3540 patients) were extracted and collated at the MeRGE Coordinating Centre (The
University of Auckland).
Results: Overall, RFP was associated with higher all-cause mortality than the non-restrictive filling pattern: hazard ratio 2.42 (95% CI 2.06,
2.83). In multivariable analysis the RFP, LVEF, NYHA class and age were independent predictors of mortality. The prevalence of the RFP
was inversely related to LVEF but remained a predictor of mortality even in those patients with preserved LVEF.
Conclusions: The restrictive mitral filling pattern is a powerful predictor of mortality, independent of LVEF and age, in patients with HF.
Doppler-derived LV filling patterns are an accessible marker from echocardiography that can readily be incorporated in risk stratification of
all patients with HF.
© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Restrictive filling pattern; Doppler echocardiography; Heart failure; Prognosis; LV ejection fraction
Congestive heart failure is a major clinical condition with
increasing prevalence, annual mortality rates often exceed-
ing 20% even after institution of contemporary treatment,
and more than one million hospitalisations each year .
The total cost of heart failure in the United States in 2006
was estimated at US$29.6 billion . However, the clinical
course of individual patients with heart failure is highly
variable and better understanding of the clinical, laboratory
and echocardiographic factors that are associated with poor
clinical outcome is important.
Pulsed wave Doppler echocardiography of left ventricular
(LV) filling is now widely accepted as a reliable clinical tool
in the non-invasive evaluation of diastolic function . With
severe diastolic impairment a restrictive filling pattern (RFP)
may develop, characterized by left ventricular inflow
predominantly occurring in early diastole with a large mitral
E wave, rapid deceleration and reduced atrial contribution to
filling (mitral A wave). This is associated with elevated left
atrial pressures [3–9], increased LV stiffness , higher
neurohormone levels [11,12], and higher NYHA class .
In a recent literature-based meta-analysis, involving 3024
patients with heart failure from 26 prospective studies the
unadjusted odds ratio of a RFP for all-cause mortality was
4.36 (CI: 3.60, 5.29) .
Many patients with RFP also have concomitant severe LV
systolic impairment and although in some studies RFP
remained a prognostic predictor in multivariable analyses,
none of the individual studies possessed sufficient power to
European Journal of Heart Failure 10 (2008) 786–792
⁎R.N. Doughty, Department of Medicine, The University of Auckland,
Private Bag 92019, Auckland, New Zealand. Tel.: +64 9 373 7599x89804;
fax: +64 9 3677146.
E-mail address: firstname.lastname@example.org.
1388-9842/$ - see front matter © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
adequately assess the interaction between RFP and systolic
function. Thus, it remains uncertain whether RFP merely
reflects poor systolic function or predicts outcome indepen-
dently of LV systolic function. The aim of this individual
patient meta-analysis was to determine whether the RFP was
predictive of mortality independently of LVejection fraction
2.1. Study selection and data collection
This study was designed as an individual patient meta-
analysis of observational data and as such followed the
MOOSE convention for study selection, collation of data and
studies, data management and analysis has been described in
detail elsewhere . In brief, to be eligible, studies needed to
be prospective, enrol patients with a confirmed diagnosis of
heart failure, and include Doppler echocardiographic diastolic
measurements, a measure of systolic function and mortality
outcome. Thirty two such studies were identified, 14 studies
18 studies (16 published, 2 unpublished) involving 3540
patients(79% ofpotentially eligiblepatients) wereincluded in
this analysis [9,17–32]. All studies met appropriate clinical
definitions of heart failure at the time the studies were
conducted. Individual study databases were collated (MeRGE
Coordinating Centre, The University of Auckland), variables
identified, measurements verified and comparison with
Characteristics of patients
Whole group LVEF b30%LVEF 30–44%LVEF ≥45%
Non-RFP RFPNon-RFPRFPNon-RFPRFP Non-RFPRFP
Men, n (%)
Ischaemic aetiology, n (%)
RFP = restrictive filling pattern; yrs = years; NYHA = New York Heart Association function class; LVEF = left ventricular ejection fraction; DT = mitral
deceleration time; E/A ratio = ratio of mitral E and A wave velocities.
aDeaths = all-cause in 364/2021, CV in 256/1098.
Fig. 1. Kaplan–Meier survival curves for patients with heart failure with
restrictive filling pattern versus non-restrictive filling pattern.
Multivariable predictors of all-cause mortality among all patients
All patients (n=3020)
Restrictive filling pattern
Ejection fraction per 10%
Age per 10 years
Ischaemic aetiology (n=1590)
Restrictive filling pattern
Ejection fraction per 10%
Age per 10 years
Non-ischaemic aetiology (n=1228)
Restrictive filling pattern
Ejection fraction per 10%
Age per 10 years
787MeRGE Heart Failure Collaborators / European Journal of Heart Failure 10 (2008) 786–792
individual reports made. Diagnostic criteria for heart failure
were clearly stated in all studies. Studies that enrolled patients
on the basis of LV dysfunction only without a diagnosis of
heart failure were excluded. Patients with permanent atrial
fibrillation were excluded from the analysis. The host Ethics
Committee approved each original study.
All-cause mortality at four years was the primary end-
point of the study. Eleven studies reported all-cause mortality
and 7 studies reported cardiovascular mortality (for the
purposes of these analyses these deaths were treated as all-
patients according to standard protocols for each study. The
restrictive mitral filling pattern classification was either that
provided from each individual study (based on E:A ratio and
deceleration time) or when it was not provided (6 studies) the
cut-off of deceleration time b140 ms was used. Patients were
mic or non-ischaemic) was determined from the classification
of aetiology from each individual study. LVEF was assessed
in 17 studies using quantitative echocardiography (14 studies
using volumetric methods [9,17–24,26,27,29–31], 3 studies
M-mode [25,32]) and in 1 study using ventriculography .
Fig. 2. Kaplan–Meier survival curves for patients with heart failure with
restrictive filling pattern versus non-restrictive filling pattern by group of LV
Fig. 3. Kaplan–Meier survival curves for patients with heart failure with
restrictive filling pattern versus non-restrictive filling pattern by aetiology of
788 MeRGE Heart Failure Collaborators / European Journal of Heart Failure 10 (2008) 786–792
Multivariable analysis to investigate independent pre-
dictors of all-cause mortality was performed using the Cox
proportional hazards model. Information on LVEF, age,
gender,NYHA class and the presence of a RFP was provided
by all studies in this analysis and so formed the group of
predictors. In order for relevant hazard ratios to be calcu-
lated, age was categorised into 10-year bands (b50, 50–60,
60–70 and ≥70 years), LVEF categorised into 10% bands
(b20, 20–30, 30–40, 40–50 and ≥50%) and NYHA class
was categorised into two bands (NYHA I/II and NYHA III/
IV). The assumption of proportionality of hazards for RFP
was assessed using Schoenfeld residuals and considered
acceptable (plot available on request). Heterogeneity across
the studies was examined using the same multivariable
model within each study. Univariate hazard ratios were used
to investigate the association between RFP and all-cause
mortality. The influence of the RFP on survival was analyzed
with the Kaplan–Meier method and assessed with the log-
rank test. The group was then divided into (a) three pre-
specified groups on the basis of LVEF (LVEF b30%, 30–
44%, ≥45%)  and (b) two pre-specified groups based on
the aetiology of heart failure and the same dichotomous
comparison was made within each group. Procedures of SAS
v 9.1 (SAS Institute, Cary, NC) were employed. A p value
b0.05 was considered significant.
Data were available for 3540 patients from 18 studies,
421 patients were excluded from this analysis due to the
presence of atrial fibrillation (172), or missing data for RFP
classification (177) or missing follow up (27). The mean age
of the group was 62 years (SD 13 years), 78% were men and
mean LVEF was 29% (SD 10.8%) (Table 1). At baseline a
RFP was found in 1174 (38%) of the patients and a non-RFP
in the remaining 1945 (62%). The median duration of follow
up was 1.7 years.
There were 620 deaths over 5818 person-years of follow
up. Among patients with a non-RFP, 266 (13.7%) died
compared with 354 (30.2%) patients with a RFP (hazard
ratio 2.42; 95% CI 2.06, 2.83; pb0.0001) (Fig. 1). In
multivariable analysis RFP, LVEF, NYHA and age were
independent predictors of mortality (Table 2). Examination
of the multivariable hazard ratio of RFP for each study
revealed no heterogeneity across the studies (Chi2=14.5,
The prevalence of the RFP was inversely related to LVEF
occurring in 50% of patients with LVEF b30%, in 26% of
those with LVEF 30–44% and in 14% of those with LVEF
≥45% (Table 1). Similarly mortality was inversely related to
LVEF occurring in 26% (431/1642) of those with LVEF
b30%, in 14% (169/1231) of those with LVEF 30–44% and
in 8% (20/246) of those with preserved LVEF (≥45%). The
RFP was associated with higher mortality compared with the
non-RFP group in each triad of LVEF (Fig. 2): LVEF group
b30% hazard ratio 2.04 (95% CI 1.68, 2.48), LVEF 30–44%
hazard ratio 2.45 (95% CI 1.81, 3.32), LVEF ≥45% hazard
ratio 3.35 (95% CI 1.33, 8.45).
The aetiology of heart failure was clearly defined in 2869
patients: 1616 (56.3%) patients were classified as ischaemic
heart disease and 1253 (43.7%) as non-ischaemic heart
disease (Table 3). The prevalence of RFP was similar in
patients with ischaemic and non-ischaemic heart disease
(37.9% and 37.6% respectively). Mortality was similar in
patients with ischaemic and non-ischaemic heart disease
(335 deaths, 20.7% versus 240 deaths, 19.2%) and this
similarity was irrespective of RFP (p=0.30). However, a
RFP was associated with higher mortality in both groups:
32% versus 14% in patients with ischaemic heart disease,
hazard ratio 2.41 (95% CI 1.94, 3.00); and 29% versus 13%
in those with non-ischaemic heart disease, hazard ratio 2.57
(95% CI 1.99, 3.32) (Fig. 3).
Characteristics of patients with ischaemic and non-ischaemic heart disease
Whole groupIschaemic heart diseaseNon-ischaemic heart disease
Men, n (%)
Abbreviations as per Table 1.
aDeaths = all-cause in 363/2015, CV in 212/854.
789MeRGE Heart Failure Collaborators / European Journal of Heart Failure 10 (2008) 786–792
Multivariable analyses in both aetiology sub-groups
revealed similar results as the main study, with RFP, LVEF,
NYHA and age independent predictors in both ischaemic
and non-ischaemic HF patients (Table 2).
In this individual patient meta-analysis, involving over
3000 patients with heart failure and 620 events, the RFP is
associated with a 2-fold increase in the risk of death.
Importantly, this is the first time that the relationship of the
RFP and survival has been demonstrated to be independent
of LVEF and age and applies for patients with heart failure of
ischaemic and non-ischaemic aetiology.
The RFP is associated with high left atrial pressure [3–9],
neurohormonal activation [11,12], and higher NYHA class
. However, the unique contribution of this large study is
that the relationship between restrictive filling and outcome
is independent of LVEF. While previous studies have
demonstrated that the RFP is a poor prognostic sign in
patients with depressed LVEF it has been uncertain whether
the RFP was merely a reflection of more severe LV systolic
dysfunction. In the current study, while the prevalence of the
RFP was higher among those patients with lower LVEF, the
data confirm that this filling pattern is associated with worse
outcome independently of LVEF.
Heart failure is the end stage of many common conditions
including hypertension and coronary artery disease. Despite
aggressive pharmacological intervention, cardiac resynchro-
nisation therapy and antiarrhythmic device implantation in
appropriate patients mortality for patients with heart failure
remains high [34,35]. Multiple demographic, clinical,
laboratory and echocardiographic variables have been
associated with outcome in these patients. Assessment of
prognosis is now incorporated into contemporary heart
failure management guidelines , although it is recog-
nized that this is often complex and that the optimal methods
of estimating prognosis are uncertain. Echocardiography is
widely available and commonly utilised in the evaluation of
patients with heart failure. However the focus is often
directed towards indices of LV systolic function and LV
diastolic function is often not reported . Newer tissue
Doppler echocardiographic techniques combined with
transmitral velocities may provide independent prediction
of clinical outcomes over transmitral Doppler alone in
patients with LVEF b35% . However, the RFP is readily
identified from echocardiography, is associated with 2-fold
higher mortality across a broad range of patients with heart
failure and is thus an accessible and clinically useful marker
of prognosis. Consequently, this simple prognostic marker
can readily be made available to clinicians managing patients
with heart failure without the requirement for additional
Approximately 30–50% of patients with heart failure
present with preserved LVEF [38,39]. Patients with heart
failure with preserved LVEF are more likely to be older, to be
female and to have a history of hypertension and atrial
fibrillation compared with patients with impaired LVEF
[38,39]. In addition, the prevalence of heart failure with
preserved LVEF appears to have increased over recent
decades . As such, heart failure with preserved LVEF is
an important clinical condition and yet there has been little
evidence to guide treatment among such patients. Recent
clinical trials involving patients with heart failure with
preserved LVEF have not demonstrated improved survival
with ACE inhibitor therapy [40,41]. In the current study, 246
patients had LVEF≥45%, and when compared with the
patients with LVEFb45% were older, more were women and
fewer were classified as having heart failure of ischae-
mic aetiology. Thus, while a small sample, these patients
have characteristics similar to those previously described
in other studies [38,39] and although mortality in this group
of patients with preserved LVEF was relatively low (8%)
the mortality in patients with RFP was high (21% versus
Ideally, markers of outcome should not only allow
assessment of prognosis but also trigger changes in
management to improve outcome. Currently, there are no
randomised, controlled trials of therapeutic interventions
directed specifically at patients with the RFP. Data from non-
randomised studies have reported improved outcome for
patients with RFP who were treated with conventional
pharmacotherapy (including ACE inhibitors, beta-blockers
and diuretics) [29,42]. These data suggest that further studies
should be undertaken with therapies targeted at patients with
RFP, and the group of patients with heart failure with
preserved LVEF may be an ideal group for such studies.
Each of the studies from which the individual patient data
were combined had slightly different inclusion criteria, for
example, some recruited patients during a hospitalisation
with an exacerbation of heart failure while others included
patients attending an outpatient visit. As a result the
echocardiograms from which the filling pattern classification
was derived were not performed at a standardised stage of
disease or after a certain period of treatment. While this is an
inherent limitation of these data this does support the value
of the RFP across a range of patients with heart failure and at
different stages of the disease process.
The number of patients with preserved LVEF (N45%) was
to the patients with impaired LVEF (b45%). Thus, while the
hazard ratio for RFP predicting death was statistically
significant, the confidence intervals were wide and thus the
magnitude of the risk associated with the RFP remains
uncertain. In addition, detailed clinical characteristics of this
group of patients with LVEF N45% were not available from
these data. Patients with atrial fibrillation were excluded from
this meta-analysis and thus the prognostic importance of
restrictive filling in patients with atrial fibrillation is uncertain.
790MeRGE Heart Failure Collaborators / European Journal of Heart Failure 10 (2008) 786–792
The presentresult maybe subjected topublicationbias; studies
published data). However, despite these factors, the different
inclusion criteria and major temporal changes in the manage-
ment of heart failure, the risk associated with a RFP was
heterogeneity in the importance of a RFP across the 18 studies
included in the meta-analysis.
In summary, in patients with heart failure the Doppler
echocardiographic RFP is associated with a 2-fold increase
in the risk of death and is independent of LVEF, NYHA class
and age. The RFP is an accessible marker from routine
echocardiography that provides additional information to
LVEF alone and thus should be incorporated into the risk
stratification of all patients with heart failure, irrespective of
the degree of LV systolic dysfunction.
MeRGE coordinating centre: Cardiovascular Research Laboratory,
The University of Auckland, New Zealand: RN Doughty (co-
principal investigator), GD Gamble (statistician), KK Poppe
(statistician), JB Somaratne, GAWhalley (co-principal investigator).
Writing committee: RN Doughty (co-chair), AL Klein (co-chair),
KK Poppe, GD Gamble, FL Dini, JE Møller, M Quintana, CM Yu
and GA Whalley.
MeRGE steering committee members: FL Dini (Santa Chiara
Hospital, Pisa, Italy), RN Doughty (Co-chair, The University of
Auckland, New Zealand), GD Gamble (The University of Auck-
land, New Zealand), AL Klein (The Cleveland Clinic Foundation,
Ohio, USA), JE Møller (Copehagen University Hospital Rigshos-
pitalet, Denmark), M Quintana (Huddinge University Hospital,
Karolinska Institute, Sweden), GA Whalley (Co-chair, The
University of Auckland, New Zealand) and CM Yu (Prince of
Wales Hospital, The Chinese University of Hong Kong, China).
MeRGE Heart Failure Collaborators:
MeRGE steering committee plus C Bruch (Germany), M Feola
(Italy), S Ghio (Italy), P Giannuzzi (Italy), A Hansen (Germany),
J Ortiz (Brazil), B Pinamonti (Italy), DL Prior (Australia), A Rossi
(Italy), J-Y Tabet (France), PLTemporelli (Italy) and T Yamamoto
Australia: St Vincent's Hospital, Melbourne: DL Prior*; Brazil:
OMNI-CCNI Medicina Diagnóstica, São Paulo: J Ortiz*, CG
Monaco, CES Silva, LDC Ferreira, MA Gil, NC Nanda, CAF
Monaco; China: The Prince of Wales Hospital, The Chinese
University of Hong Kong, Hong Kong: JE Sanderson, CM Yu*;
France: Hôpital Beaujon, Clichy: A Cohen-Solal, M Dahan, PV
Ennezat, C Geyer, C Guiti, D Logeart, J-Y Tabet*; Germany:
University Hospital of Münster, Münster: G Breithardt, C Bruch*,
L Eckardt, M Gotzmann, M Grude, M Rothenburger, HH Scheld,
J Stypmann, F Wenzelburger, T Wichter; University of Heidelberg,
Heidelberg: M Haass, A Hansen*, C Krueger, W Kuebler, H
Kuecherer, K Unnebrink, R Zimmermann, C Zugck; Italy:
Salvatore Maugeri Foundation, Veruno: E Bosimini, U Corrà, M
Galli, P Giannuzzi*, A Giordano, A Imparato, F Scapellato, P
Silva, PL Temporelli*; Istituto di Ricovero e Cura a Carattere
Scientifico Policlinico S Matteo, Pavia: N Ajmone-Marsan, C
Campana, A Gavazzi, S Ghio*, C Klersy, ML Laudisa, F Recusani,
R Sebastiani, L Tavazzi; Villamarina Hospital, Piombino, Campo
di Marte Hospital, Lucca: U Baldini, A Boni, L Barsotti, L
Cortigiani, FL Dini*, G Micheli R Nuti; Division of Cardiology,
University of Verona, Verona: A Rossi*, M Cicoira, S Bonapace;
University of Trieste, Trieste: F Camerini, A Di Lenarda, D
Gregori, B Pinamonti*, G Sinagra, M Zecchin; Ospedale S. Croce-
Carle, Cuneo & Ospedale Santo Spirito, Rome & San Dona' di
Piave: N Aspromonte, M Feola*, P Giovinazzo, L Milani, RValle;
Japan: University of Tokushima, National Higashi Tokushima
Hospital, Tokushima: T Ishimoto, S Ito, T Oki, T Tabata, H
Tanaka, T Wakatsuki, H Yamada, T Yamamoto*; New Zealand:
The University of Auckland, Auckland: RN Doughty*, GD
Gamble, HJ Walsh, N Sharpe, GA Whalley*, SP Wright; USA:
The Cleveland Clinic Foundation, Ohio: A Fogarty, CM Frampton,
AL Klein*, MS Lauer, M Martin, AJ Morehead, PJ Nash, JJ
Pereira, DL Prior, RC Starling, W Tang, JD Thomas, R Troughton,
JB Young; Multi-centre clinical trials: Australia–New Zealand
Heart Failure Research Collaborative Group: RN Doughty*, GD
Gamble, S MacMahon, DN Sharpe, GA Whalley*.
*Indicates principal collaborator.
This research was funded by grants from The University of
Auckland Vice-Chancellor’s Development Fund and from the
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