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European Journal of Heart Failure 2008 10(2):149-156; doi:10.1016/j.ejheart.2007.12.010
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© 2008 European Society of Cardiology

Heart failure with preserved ejection fraction: Clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial

John J.V. McMurraya,*, Peter E. Carsonb, Michel Komajdac, Robert McKelvied, Michael R. Zilee, Agata Ptaszynskaf, Christoph Staigerg, J. Mark Donovanf and Barry M. Massieh

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 Pitiê-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

* 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: j.mcmurray{at}bio.gla.ac.uk (J.J.V. McMurray).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
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.

Key Words: Heart failure • Diastolic heart failure • Clinical trial • Ejection fraction • Epidemiology

Received October 23, 2007; Revised December 5, 2007; Accepted December 19, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
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 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 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, morbidity-mortality 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
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
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 I-PRESERVE 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), non-cardiac causes of breathlessness and oedema (e.g. anaemia and lung disease), renal dysfunction, marked hypo- or hypertension and other diseases limiting life expectancy.


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  		Table 1 Design of major outcome trials in patients with heart failure and preserved left ventricular ejection fraction

 
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 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).

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
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Between June 2002 and April 2005, 4133 men and women were randomised in 25 countries. Tables 2 and 3 show the demographic characteristics, physiological measurements and baseline treatment of these patients.


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  		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)

 


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  		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)

 
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 >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.


Figure 01
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  		Fig. 1 Clinical evidence of heart failure at baseline.

 
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 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 (<13 g/dL in men and <12 g/dL in women) was 15%. Mean (SD) creatinine was 88 (28) {varepsilon}mol/L (1.00 [32] mg/dL) and median (inter-quartile 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 <60 ml/min/1.73 m2), according to the National Kidney Foundation criteria (Table 4). The median (inter-quartile range) NT proBNP concentration was 339 (133, 965) pg/ml.


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  		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)

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
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 I-PRESERVE 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 I-PRESERVE 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 >221 µmol/L (>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.

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 <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 <40% were enrolled in CHARM-Alternative or -Added whereas those with an ejection fraction of >40% 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 I-PRESERVE, 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.


   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.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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