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European Journal of Heart Failure 10 (2008) 149 – 156
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Heart failure with preserved ejection fraction: Clinical characteristics of
4133 patients enrolled in the I-PRESERVE trial
John J.V. McMurray a,⁎, Peter E. Carson b , Michel Komajda c , Robert McKelvie d ,
Michael R. Zile e , Agata Ptaszynska f , Christoph Staiger g , J. Mark Donovan f , Barry M. Massie h
a
Department of Cardiology, Western Infirmary, Glasgow, and Faculty of Medicine, University of Glasgow, Scotland, UK
b
Washington Veterans Affairs Medical Center and Georgetown University, Washington DC, USA
c
University Pierre et Marie Curie, Paris 6; Hôpital Pitié-Salpêtrière, Paris, France
d
McMaster University, Hamilton ON, Canada
e
Medical University of South Carolina and Veterans' Affairs Medical Center, Charleston SC, USA
f
Pharmaceutical Research Institute, Bristol Myers Squibb, Princeton NJ, USA
g
Sanofi-Aventis, Bridgewater, New Jersey, USA
h
University of California and San Francisco Veterans Affairs Medical Center, San Francisco CA, USA
Received 23 October 2007; received in revised form 5 December 2007; accepted 19 December 2007
Abstract
Background: We describe the baseline characteristics of subjects randomised in the largest placebo-controlled, morbidity-mortality trial
to date in patients with heart failure and preserved ejection fraction — the irbesartan in heart failure with preserved systolic function
trial (I-PRESERVE).
Methods and results: 4133 patients with a mean age of 72 years (a third were 75 years or older) were randomised and 60% were women. The
mean (SD) LVEF was 59 (9)% and almost 80% of patients were in NYHA Class III or IV. Approximately 80% of patients were also
overweight or obese. Heart failure was reported by investigators to have a hypertensive aetiology in 64% of patients. Prior myocardial
infarction was relatively uncommon (24%), as was coronary revascularisation (13%). Atrial fibrillation and diabetes each occurred in
between a quarter and a third of patients. The following treatments were used at baseline: diuretic 83%, beta-blocker 59%, calcium channel
blocker 40%, ACE inhibitor 25%, spironolactone 15% and digoxin 14%.
Conclusions: Patients in I-PRESERVE are broadly representative of those seen in epidemiological studies and, because of this, the results of
this trial should be generally applicable to “real world” patients with heart failure and preserved ejection fraction.
© 2008 European Society of Cardilogy. Published by Elsevier B.V. All rights reserved.
Keywords: Heart failure; Diastolic heart failure; Clinical trial; Ejection fraction; Epidemiology
1. Introduction
To date, the drug and device treatments shown to reduce
morbidity and mortality in heart failure have been tested and
approved in patients with a left ventricular ejection fraction
⁎ Corresponding author. BHF Cardiovascular Research Centre, University
of Glasgow, 126 University Place, Glasgow G12 8TA, Scotland, UK. Tel.:
+44 141 330 3479; fax: +44 141 330 6955.
E-mail address: [email protected] (J.J.V. McMurray).
of 35% or less [1–6]. Half or more of patients with heart
failure, however, have a higher ejection fraction, with many
having an ejection fraction of 45% or greater [7,8]. These
patients with a “preserved” ejection fraction have a distinct
demographic profile, aetiological background, and pathophysiology [7,9]. Compared to patients with a low ejection
fraction, those with preserved ejection fraction are older,
more often women and are more likely to have a hypertensive aetiology [11–18]. Diastolic rather than systolic left
1388-9842/$ - see front matter © 2008 European Society of Cardilogy. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2007.12.010
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J.J.V. McMurray et al. / European Journal of Heart Failure 10 (2008) 149–156
Table 1
Design of major outcome trials in patients with heart failure and preserved left ventricular ejection fraction
I-PRESERVE [25]
DIG-PEF [26]
CHARM-Preserved [27]
PEP-CHF [28]
≥60 years
LVEF ≥ 45%
≥21 years
LVEF N 45%
≥18 years
LVEF N 40%
NYHA class II–IV and CHF
hospitalisation ≤ 6 months or
NYHA class III/IV and abnormal CXR
(pulmonary congestion), ECG (LVH,
LBBB) or echocardiogram (LVH,
enlarged LA)
Current or past clinical symptoms (limitation of
activity, fatigue, dyspnoea or orthopnoea), signs
(oedema, elevated JVP, rales, S3 gallop) or
radiological pulmonary congestion
NYHA class
II–IV ≥ 4 weeks
(NYHA III/IV in
prior 6 months
if taking ACE-I)
≥70 years
No major LV systolic dysfunction
(e.g. LVEF b 40%)
Diuretic ≥ 1 week
Sinus rhythm
Prior cardiac
hospitalisation
3 of 9 clinical criteria (e.g. exertional
or paroxysmal nocturnal dyspnoea,
oedema, raised JVP etc) and
2 of 4 echo criteria (preserved wall
motion, LA enlargement, LVH or
Doppler evidence of DD)
Cardiac hospitalisation in prior
3 months
ACE-I = angiotensin converting enzyme inhibitor, JVP = jugular venous pressure, LA = left atrium, ECG = electrocardiogram, DD = diastolic dysfunction,
LVEF = left ventricular ejection fraction, NYHA = New York Heart Association, CXR = chest X-ray, LVH = left ventricular hypertrophy, LBBB = left bundle
branch block.
ventricular dysfunction appears to be the major underlying
pathophysiological abnormality [7,10,19,20].
Despite having a similar symptom burden and reduction in
quality of life to patients with a low ejection fraction, those
with preserved ejection fraction have a different natural history
[7,13,21,22]. While the risk of death in patients with preserved
ejection fraction is high compared to age and sex-matched
controls, most studies show that it is less than in patients with
low ejection fraction (with one notable exception [22]). The
same is true for the risk of hospitalisation with worsening heart
failure, although the difference between the two types of heart
failure maybe less marked than for death [7,13].
Despite knowing much about the epidemiology, natural
history and disease burden related to heart failure with
preserved ejection fraction, we do not know how to treat this
syndrome in order to improve outcome [23,24]. The present
report describes the baseline characteristics of patients
randomised in the largest placebo-controlled, morbiditymortality trial to date — the irbesartan in heart failure with
preserved systolic function trial (I-PRESERVE) [25]. The
baseline characteristics in I-PRESERVE are also compared
to those from patients enrolled in other community and
hospitalisation cohorts, which enrolled patients with preserved ejection fraction heart failure. A comparison to
patients with low ejection fraction heart failure who were
enrolled in parallel in some of the trials randomising patients
with preserved ejection fraction was also performed.
2. Methods
The design of the I-PRESERVE trial has been described
previously in detail and is summarised below [25]. The aim of
the current report is to describe the baseline characteristics of
the patients in I-PRESERVE and to compare and contrast IPRESERVE patients to those with heart failure and preserved
ejection fraction in epidemiological studies and to patients
with heart failure and preserved and low ejection fraction
other trials.
2.1. Objectives of I-PRESERVE
The primary objective of I-PRESERVE is to study the
effect of irbesartan, compared to placebo, on morbidity and
mortality in patients with heart failure and preserved ejection
fraction.
2.2. Study patients
The specific inclusion criteria for I-PRESERVE are listed
in Table 1 (and compared to other trials in patients with heart
failure and preserved ejection fraction) [25–28]. The
inclusion criteria were designed to enrol patients similar to
those identified in epidemiological and community based
studies. The main exclusion criteria [25] were designed to
prevent recruitment of patients with other cardiac problems
(e.g. haemodynamically significant valve disease, infiltrative
myocardial diseases and constrictive pericarditis), noncardiac causes of breathlessness and oedema (e.g. anaemia
and lung disease), renal dysfunction, marked hypo- or
hypertension and other diseases limiting life expectancy.
2.3. Study design
I-PRESERVE is a placebo-controlled, double-blind,
multicentre, international, parallel-group study. Subjects
were randomised to placebo or irbesartan in a 1:1 ratio,
stratified by site and by use of an ACE-inhibitor at baseline.
ACE inhibitor use was limited to patients with a specific
indication other than hypertension (such as diabetes mellitus
with complications and significant coronary or peripheral
arterial disease). In addition, only a maximum of one third of
patients at each site were permitted to be treated with an ACE
J.J.V. McMurray et al. / European Journal of Heart Failure 10 (2008) 149–156
inhibitor at the time of randomisation. The trial is monitored
by an independent data safety monitoring committee and all
potential endpoints are adjudicated by an independent
endpoint committee.
2.4. Study endpoints
The primary endpoint is defined as time from randomisation to the first occurrence of the composite outcome of death
(any cause) or cardiovascular hospitalisation. A cardiovascular hospitalisation is defined as one with the primary
diagnosis of: worsening heart failure (HF), unstable angina,
myocardial infarction (MI), ventricular arrhythmia, atrial
arrhythmia or stroke. Myocardial infarction or stroke
occurring during any hospitalisation, are also included in
the primary endpoint.
Secondary endpoints include the effect of irbesartan,
compared to placebo, on: cardiovascular death, all cause
mortality, a combined vascular endpoint (cardiovascular death,
non-fatal MI or non-fatal stroke) and a combined HF endpoint
(HF mortality or hospitalisation), quality of life, change in
NYHA functional class, change in patient global assessment of
symptoms and N-terminal pro B-type natriuretic peptide (NT
proBNP) level in blood (Roche Elecsys assay).
151
2.5. Sample size and statistical plan
The trial was designed to provide 90% power to detect a
14.5% reduction in the primary event rate with a two-sided
type I error rate of 0.05, which required a total of 1440
patients to experience a primary event. An annual primary
event rate of 18% was estimated for the placebo group. With
that projected event rate, a sample size of at least 3600
subjects and two years of uniform recruitment, it was
projected that a minimum follow-up of two years (i.e. total
trial duration of four years) would be required to attain 1440
primary events. By the second year of the study, it became
apparent that the total event rate was lower than projected.
As a result, in April 2004 the I-PRESERVE Executive
Committee recommended that the sample size should be
increased to 4100 patients in order to reach the requisite 1440
events within the initially projected timeline. Because the
event rate has continued to be lower than anticipated, the
final duration of the study is expected to be six years.
3. Results
Between June 2002 and April 2005, 4133 men and
women were randomised in 25 countries. Tables 2 and 3
Table 2
Baseline characteristics of patients in community (white columns) and hospital based (light grey columns) studies of heart failure with preserved ejection,
compared to I-PRESERVE (dark grey column)
CHD = coronary heart disease, MI = myocardial infarction, AF = atrial fibrillation, COPD = chronic obstructive pulmonary disease, LVH = left ventricular
hypertrophy, BMI = body mass index, SBP = systolic blood pressure, DBP = diastolic blood pressure.
a
Patients aged 65 years or older (subset with measurement of LVEF).
Admissions (not patients).
c
Ischaemic aetiology.
d
Atrial arrhythmia.
e
On first ECG.
2
f
ml/min/1.73 m in I-PRESERVE and ml/min in Olmsted County.
b
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J.J.V. McMurray et al. / European Journal of Heart Failure 10 (2008) 149–156
Table 3
Baseline characteristics of patients in trials of heart failure and preserved ejection fraction (white columns), low ejection fraction (light grey columns),
compared to I-PRESERVE (dark grey column)
HR = heart rate, SBP = systolic blood pressure, DBP = diastolic blood pressure, pp = pulse pressure, BBB = bundle branch block.
⁎ k+ sparing diuretic.
⁎⁎ Pre-trial use.
CCB = calcium channel blocker, LVEF = left ventricular ejection fraction.
BMI categories: underweight b18.5, normal 18.5–24.9, overweight 25.0–29.9 and obese N30 kg/m2.
a
Patients had to be N70 years.
b
Normal or underweight.
c
Left bundle branch block in I-PRESERVE.
d
Stroke or TIA in I-PRESERVE.
J.J.V. McMurray et al. / European Journal of Heart Failure 10 (2008) 149–156
153
Fig. 1. Clinical evidence of heart failure at baseline.
show the demographic characteristics, physiological measurements and baseline treatment of these patients.
3.1. Demographics, aetiology, history and ECG findings
The patients randomised were elderly, with a mean age of
72 years (a third were 75 years or older) and 60% were
women.
The mean (SD) LVEF was 59 (9)% and almost 80% of
patients were in NYHA Class III or IV. Approximately 80%
of patients were also overweight or obese.
The median (inter quartile range) duration of heart failure
before randomisation was 13 (3, 43) months. Heart failure
was reported by investigators to have a hypertensive
aetiology in 64% of patients. Mean systolic/diastolic arterial
pressure at randomisation was 136/79 mm Hg, 49% of
patients had a systolic blood pressure ≥ 140 mm Hg and
15.6% had a diastolic pressure ≥ 90 mm Hg (51% had either
a systolic ≥ 140 or diastolic pressure ≥ 90 mm Hg).
Consistent with the high prevalence of hypertension,
investigators reported that almost a third of patients had ECG
evidence of left ventricular hypertrophy.
Prior myocardial infarction was relatively uncommon
(24%), as was coronary revascularisation (13%). Atrial
fibrillation and diabetes each occurred in between a quarter
and a third of patients.
A high proportion (41%) of patients were obese (body
mass index N 30 kg/m2) or overweight (42%; body mass
index 25.0–29.9 kg/m2).
3.2. Clinical evidence of heart failure
Clinical evidence of heart failure at baseline is shown in
Fig. 1. The most frequent signs were peripheral oedema and
rales. Forty four per cent of patients had been hospitalised for
heart failure in the six months before randomisation.
3.3. Treatment
The majority of patients were treated with a diuretic (and
in most this was a loop diuretic). Spironolactone was used in
15% of patients and digoxin was used in a similar proportion.
ACE inhibitor use was low at 25%. Conversely, beta-blocker
use was common with 59% of patients treated with an agent
Table 4
Haematological and biochemical findings in trials of heart failure and preserved ejection fraction (white columns), low ejection fraction (light grey columns),
compared to I-PRESERVE (dark grey column)
WHO criteria haemoglobin b13 in men and b12 g/dL in women; patients with a haemoglobin b11 g/dL excluded in I-PRESERVE; no haemoglobin exclusion
in CHARM; haemoglobin not measured in DIG-PEF.
b
CKD = chronic kidney disease (eGFR b 60 ml/min/1/73 m2); Creatinine exclusion: I-PRESERVEN221 µmol/L (N2.5 mg/dL), CHARM-Preserved N 265 μmol/L
(N3 mg/dL) and DIG-PEF N 265 µmol/L (N3 mg/dL).
c
Median.
a
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J.J.V. McMurray et al. / European Journal of Heart Failure 10 (2008) 149–156
in this class. Calcium channel blocker use was also common
(40%). Aspirin treatment was used in 55% and lipid lowering
therapy in 31% of patients. Few patients had a pacemaker or
ICD in situ at randomisation.
3.4. Biochemistry and haematology
The mean (SD) baseline haemoglobin concentration was
14.0 (1.5) g/dL. The proportion of patients with anaemia, as
defined by the World Health Organisation (b 13 g/dL in men
and b 12 g/dL in women) was 15%. Mean (SD) creatinine
was 88 (28) µmol/L (1.00 [32] mg/dL) and median (interquartile range i.e. between 25% and 75% percentiles)
estimated glomerular filtration rate (eGFR) was 72 (57, 87)
ml/min/1.73 m2 (Table 4). Thirty one per cent of patients had
chronic kidney disease (eGFR b60 ml/min/1.73 m 2 ),
according to the National Kidney Foundation criteria
(Table 4). The median (inter-quartile range) NT proBNP
concentration was 339 (133, 965) pg/ml.
4. Discussion
The patients randomised in I-PRESERVE are generally
representative of patients with heart failure and preserved
ejection fraction described in community and hospitalisation
cohort studies, as illustrated in Table 2 [11–18]. In other
words, they are elderly and predominantly female. Indeed,
the average age (72 years) and proportion of women (60%)
of patients in I-PRESERVE closely match those of patients
in the epidemiological studies. These characteristics also
clearly differentiate I-PRESERVE patients from those with
heart failure and low ejection fraction, which have been
enrolled in most clinical trials to date [1–6,27,28]. The latter
patients typically had an average age of 65 years and have
been mainly male (usually more than 60% male compared to
only 40% in I-PRESERVE). These differences are illustrated
in Table 3, which shows the baseline characteristics of
patients in I-PRESERVE compared to those in the CHARM
and DIG low ejection fraction trials [6,26–30].
A high proportion of I-PRESERVE patients were also
reported to have had a hypertensive aetiology, in keeping
with the epidemiological findings (Table 2) and contrasting
to patients with low ejection fraction heart failure (Table 3)
[6,11–18,26–30]. The greater prevalence of hypertensive
aetiology in patients with preserved, ejection fraction heart
failure was supported by a higher prevalence of history of
hypertension and electrocardiographic left ventricular hypertrophy, than in low-ejection fraction patients. Systolic,
diastolic and pulse pressure were also higher in patients
with preserved ejection fraction in general and I-PRESERVE
in particular. In I-PRESERVE, 88% of patients were reported
to have a prior history of hypertension and a similarly high
prevalence was reported in the Olmsted County study [12].
The converse was true for ischaemic aetiology and the lower
rate of ischaemic aetiology was supported by a low
prevalence of prior myocardial infarction and coronary
revascularisation in patients in I-PRESERVE, consistent
with both prior epidemiological studies and clinical trials in
patients with preserved ejection fraction patients [7]. The
prevalence of prior myocardial infarction of 24% in IPRESERVE was identical to that reported in the Framingham Heart Study [11] and consistent with the other
epidemiological studies shown in Table 2. The low rate of
ischaemic aetiology in I-PRESERVE may, however also
reflect the inclusion criterion permitting a maximum of one
third of patients with a clinical indication for an ACE
inhibitor.
There were other interesting differences between the
patients in I-PRESERVE (and in other studies of patients
with preserved ejection fraction) and those with low ejection
fraction heart failure. Mean body mass index (BMI) in IPRESERVE was 29.6 kg/m2, identical to that in the Olmsted
County study [12] and 41% of patients in I-PRESERVE were
obese (a further 42% were overweight). A higher BMI has
also been reported in patients with preserved, compared to
low, ejection fraction, enrolled in prior trials (Table 3).
Higher BMI is associated with a better prognosis in patients
with low ejection fraction heart failure (the so-called
“obesity paradox”) [31] and the finding of a high proportion
of obese and overweight individuals amongst patients with
preserved ejection fraction is consistent with their better
outcome, compared to patients with low ejection fraction
heart failure, reported in most studies.
The one finding in our patients in I-PRESERVE that does
not closely mirror the epidemiological observations is
baseline creatinine and renal function (Tables 2 and 4).
This presumably reflects the exclusion criterion of a
creatinine concentration N 221 μmol/L (N 2.5 mg/dL). This
criterion probably also accounts for the slightly higher eGFR
in I-PRESERVE, compared to the other trials (which had a
higher creatinine exclusion concentration; see Table 4).
Compared to prior reports in low ejection fraction heart
failure, fewer patients had a third heart sound, as might be
expected — whereas the prevalences of other clinical
findings were similar [19]. Use of calcium channel blockers
was much higher in patients with preserved ejection fraction
as expected.
There were some similarities as well as differences
between preserved and low ejection fraction patients. The
prevalence of diabetes and atrial fibrillation was similar, with
each affecting between a quarter and a third of patients. The
prevalences of both of these co-morbidities in the patients in
I-PRESERVE was not only consistent with those reported in
prior trials but also with the prevalences reported in the
community and hospitalisation cohort studies of patients
with preserved ejection fraction heart failure summarized in
Table 2. Diuretic treatment was used in the majority of both
types of patients.
The similar rate of use of a beta-blocker, aspirin and lipid
lowering therapy in both the low ejection fraction and
preserved ejection fraction trials is of interest, given the
difference in prevalence of coronary heart disease.
J.J.V. McMurray et al. / European Journal of Heart Failure 10 (2008) 149–156
It is also of interest to compare our patients with the other
three large trials in patients with heart failure and preserved
ejection fraction [26–28]. Patients in I-PRESERVE and
PEP-CHF [26] were quite similar whereas those in DIG-PEF
[24] and CHARM-Preserved [25] were somewhat different
in their baseline characteristics, notably in the proportion of
women, average age and aetiology. In all these respects,
patients in DIG-PEF and CHARM-Preserved were more
similar to low ejection fraction patients and the lower mean
ejection fraction in those two trials (55% in DIG-PEF and
54% in CHARM-Preserved) than either I-PRESERVE (59%)
or PEP-CHF (64%) is consistent with this interpretation.
These differences probably reflect the different design of
DIG-PEF and CHARM-Preserved compared with PEP-CHF
and I-PRESERVE. While I-PRESERVE and PEP-CHF were
“stand-alone” trials which sought to recruit patients with
preserved ejection fraction, DIG-PEF and CHARM-Preserved were part of a programme of two and three trials,
respectively, seeking to enroll patients across the full
spectrum of ejection fraction [6,30]. In DIG, patients with
an ejection fraction b 45% were enrolled in the main trial and
those above 45% in the ancillary preserved ejection fraction
trial [28]. Similarly, in the CHARM Programme, patients
with an ejection fraction of b 40% were enrolled in CHARMAlternative or -Added whereas those with an ejection
fraction of N40% were enrolled in CHARM-Preserved [6].
PEP-CHF and I-PRESERVE also differed from DIG-PEF
and CHARM-Preserved by requiring additional echocardiographic, electrocardiographic or radiological support for
cardiac disease [25–28]. Neither of the prior studies, nor IPRESERVE, required invasive haemodynamic measurements, measurement of natriuretic peptides or Doppler
measurement of diastolic function for diagnosis of heart
failure with preserved ejection fraction, as recently advocated [32].
The cited epidemiological studies did not report NT
proBNP concentrations in patients with heart failure and
preserved ejection fraction and natriuretic peptides were not
measured in the DIG trial. Plasma concentration of NT
proBNP was similar in I-PRESERVE (median 339 pg/mL) and
PEP-CHF (median 409 pg/mL) [33]. Few population based
studies which included a substantial number of elderly subjects
have been performed with the assay that we used [34,35]. The
two studies that we identified suggest that our subjects have
NT proBNP concentrations higher than healthy age and sex
matched controls and consistent with those found in subjects
with left ventricular diastolic dysfunction (but lower than in
individuals with systolic dysfunction) [34,35].
In summary, the I-PRESERVE investigators enrolled
patients with heart failure and preserved ejection fraction
which are generally representative of those seen in epidemiological studies although, as in any clinical trial, some degree of
selection was inevitable. The results of I-PRESERVE should,
however, be reasonably applicable to “real world” patients
with heart failure and preserved ejection fraction, excepting
those who fulfil the trial exclusion criteria.
155
Acknowledgements
We wish to thank Dr A. Ahmed, University of Alabama,
Birmingham, AL, USA for unpublished information on the
Digitalis Investigators Group trial and Dr JGF Cleland,
University of Hull, Kingston-upon-Hull, England for
information on the Perindopril in Elderly People with
Chronic Heart Failure trial presented in Tables 2, 3 and 4.
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