1. health and fitness
2. disease

European Heart Journal Supplements (2004) 6 (Supplement H), H61–H66
Treatment of heart failure with preserved
systolic function: a review of the evidence
Karen Hogg, John J.V. McMurray*
Department of Cardiology, Western Infirmary, Glasgow, UK
The importance of heart failure with preserved systolic function (HF-PSF) has been
increasingly recognised during the last decade. However, until recently there were no
large, randomised, controlled clinical outcome trials in patients with this condition.
Indeed, the best evidence of symptom improvement came from two very small studies
with the rate-limiting calcium-channel blocker verapamil, in a total of fewer than
50 patients. The largest outcome trial was an ancillary study (with about 900 patients)
of the Digitalis Investigators Group (DIG) trial, in which digoxin was reported to have
a proportionately similar effect on morbidity to that seen in patients with reduced
systolic function.
Recently, the CHARM-Preserved study randomised over 3000 patients to placebo
or candesartan. There was a trend to a reduction in cardiovascular death or
hospitalisation for heart failure with candesartan (333 vs. 366 patients, unadjusted
p = 0.118; co-variate adjusted p = 0.051), and clear reductions in the proportion
of patients admitted (by 15% from 270 to 230 patients, p = 0.017) and the total
number of hospital admissions for worsening heart failure (by 29% from 566 to 402
admissions, p = 0.014). Overall the results of the CHARM Programme showed that
candesartan exerted a favourable effect across a broad spectrum of patients with
heart failure, irrespective of left-ventricular function, co-morbidity, symptomatic
class or concomitant treatment.
© 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.
Introduction
Heart failure (HF) is now fully recognised as a major
public health problem 1,2 . It has been estimated that
there are nearly 23 million people with heart failure
worldwide 1 . The escalating public health problem of
HF in industrialised countries is due to the ageing
population. In the UK the overall prevalence of HF has
been estimated to be 3–20 cases per 1000 population,
rising to >100 cases per 1000 population in those
aged 65 years and older 3 . HF is a huge burden to
patients in terms of mortality and morbidity, but is
also a considerable financial cost to the National Health
* Correspondence: Professor JJV McMurray. Department of Cardiology,
Western Infirmary, Glasgow G11 6NT, UK.
Tel.: +44-141-211-1838; fax: +44-141-211-2252.
E-mail address: [email protected] (J.J.V. McMurray).
0169-5002/$ – see front matter
Service (NHS), accounting for approximately 2% of the
entire NHS budget in the UK 3 , and 15–40 billion dollars
in the USA 4,5 . Great advances have been made in terms
of the epidemiology and treatment of this kind of
heart failure.
Over the past decade heart failure with preserved
systolic function (HF-PSF) has become a clinical entity
in its own right. Cohort studies of hospitalised patients
suggest that a third to a half of patients thought to
have clinical heart failure have preserved left-ventricular
systolic function 6–13 . Various studies have now reported
that patients with this type of heart failure have
a mortality rate which is lower than heart failure
with reduced systolic function (HF-RSF) but is still
high overall 14–17 . In addition, hospital admission (and
re-admission) is common and length of stay in hospital
is comparable to that with HF-RSF 9,18,19 . What is still
not clear, however, is how best to treat this group of
© 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
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KEYWORDS
Candesartan;
Clinical trials;
Heart failure;
Left-ventricular systolic
function
H62
patients. One problem is that, until recently, there have
been few large randomised, controlled trials in patients
with HF-PSF 20 . However, with the CHARM results now
available, and other trials in progress, the situation is
improving.
Studies with symptoms/functional capacity
as endpoints
Heart-rate-limiting calcium-channel blockers
(2.16±0.48 EDV/s). There was a suggestion of a carryover effect on the PFR in those patients receiving
verapamil before placebo treatment.
The average systolic blood pressure did not differ
significantly between the two groups. However, verapamil did lower diastolic blood pressure (baseline
84±6 mmHg, 79±6 mmHg during verapamil treatment,
P < 0.05; placebo 82±8 mmHg at the end of the placebo
period). Verapamil also reduced mean heart rate
(baseline 79±11 bpm, verapamil 71±11 bpm, P < 0.05;
placebo 78±9 bpm). Verapamil did not reduce peak
heart rate or systolic blood pressure during exercise.
Treatment with verapamil improved the patients’
symptoms as indicated by a reduction in the CHF scores
from a baseline of 6.7±1.7 to 3.8±1.6 following
treatment with verapamil. With placebo treatment, the
CHF score increased (worsened) to 6.1±1.9 (P < 0.01).
Verapamil improved exercise tolerance in the 12 patients who were able to exercise. Baseline time
was 10.7±3.4 min and this increased to 13.9±4.3 min
(P < 0.05) with verapamil. The between-treatment-group
comparison was also significant (P < 0.01).
Very similar improvements in symptoms and exercise tolerance were also reported by Hung et al. 23 in
an almost identical study. In that study treatment with
verapamil improved the CHF score from 5.5 to 3.5 and
increased exercise tolerance from 7.4 min to 8.3 min on
treadmill testing 23 .
Angiotensin-converting-enzyme (ACE) inhibitors
Angiotensin II is thought to play a causal role in
left-ventricular hypertrophy (LVH), and reduces leftventricular (LV) relaxation and increases LV stiffness.
ACE inhibitors are known to reduce LVH and to improve
diastolic filling. In patients with prior myocardial
infarction, an ACE inhibitor is of benefit in reducing
the risk of future vascular events. Philbin et al. 24
compared outcome data from patients with ‘diastolic
heart failure’ receiving and not receiving ACE inhibitors,
and suggested that treatment may reduce heart-failure
hospitalisation. As the study was non-randomised, firm
conclusions cannot be drawn. Aronow et al. 25 compared
treatment with enalapril to no treatment with enalapril
in 21 elderly patients (mean age 80 yrs) with NYHA
class-III HF associated with prior Q-wave myocardial
infarction but with preserved LV systolic function
(EF > 0.50). All patients in this study were in sinus
rhythm and were treated with frusemide but no other
cardiac medication. The target dose of enalapril was
10 mg twice daily (by week 5 of titration). A chest
X-ray, echocardiogram and modified Bruce treadmill
exercise test were performed at baseline and repeated
following 3 months of treatment.
Cardiothoracic ratio, ejection fraction, NYHA class
and exercise time all improved in the enalapril group
but not in the control (no enalapril) group. Leftventricular mass fell after enalapril treatment (from
313±43 g to 280±46 g, P < 0.001) but not in the control
group (306±51 g to 309±55 g). Peak mitral Doppler
E/A ratio increased with enalapril from 0.6±0.1 to
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Conceptually, the pharmacology of this class of drugs
which slow heart rate and reduce myocardial contractility is attractive in a therapeutic sense in patients
with HF-PSF who in many (if not most) cases will have
diastolic dysfunction 21 . There have been two small,
controlled, randomised, cross-over, blinded comparisons
of placebo and verapamil 22,23 . Setaro et al. 22 studied
22 patients with clinical heart failure but preserved
systolic function for >3 months (ejection fraction >0.45)
but an abnormal peak filling time (PFR) >2.5 end-diastolic
volume (EDV)/s 22 . Exclusion criteria included obstructive
airways disease, valve disease, hypertrophic obstructive
cardiomyopathy and symptomatic or occult myocardial
ischaemia. The authors did not mention whether atrial
fibrillation (AF) was an exclusion criterion.
Baseline assessments were made of symptoms, exercise tolerance and left-ventricular systolic and diastolic
function using a Chronic Heart Failure (CHF) score, a
treadmill exercise test (modified Naughton protocol)
and cardiac radionuclide studies, respectively. Baseline
blood pressure and heart rate were also recorded.
The diuretic dose was kept constant, but digoxin was
withdrawn 7 days before randomised treatment was
started. Withdrawal of digoxin can be associated with
a clinical deterioration. However, the authors did not
mention the proportion of patients receiving digoxin at
baseline and how many of these were randomised to
verapamil or placebo.
The initial verapamil dose was 80 mg three times daily
for 1 week and if tolerated this was increased to 120 mg
three times daily. If the initial dose was not tolerated
then it could be reduced to 80 mg twice daily. The
mean daily dose of verapamil taken was 256 mg (range
160–360 mg).
Following 2 weeks of randomised treatment, the
patients were re-evaluated by a blinded investigator; this
assessment included clinical examination, CHF scoring,
exercise testing and radionuclide scanning.
Following a 4-day wash-out period, patients were
crossed over to the second treatment period with
a similar re-evaluation. Twenty of the 22 patients
completed the study: one did not comply and the other
developed a supraventricular tachycardia requiring openlabel verapamil treatment.
Verapamil had no effect on ejection fraction (baseline 60±9%, placebo 60±10%, verapamil 62±8%, respectively). PFR increased from baseline with verapamil
(1.85±0.45 EDV/s vs. 2.29±0.54 EDV/s, P < 0.05) but
did not change significantly with placebo treatment
K. Hogg, J.J.V. McMurray
Treatment of heart failure with preserved systolic function: a review of the evidence
0.7±0.1 (P < 0.001), but not in the control group (0.6±0.2
to 0.6±0.2). Resting systolic and diastolic blood pressure
fell during enalapril treatment, but not in the control
group. These findings, whilst encouraging, do not support
routine use of ACE inhibitors in patients with HF-PSF. A
very small number of patients were studied, within-group
rather than between-group differences were described,
and the study had an open design 25 .
Angiotensin-receptor blockers (ARBs)
Studies examining the effect of treatment
on morbidity/mortality
Two-dimensional echocardiography was carried out at
baseline, before randomisation, and again after one
year of treatment. LVEF and left-ventricular mass were
measured by a blinded echocardiographer.
Mortality and the composite endpoint of death or
non-fatal myocardial infarction (MI) were also assessed
by intention to treat. Propranolol was discontinued by
11 of 79 patients (14%) because of adverse effects
(worsening HF in 7 and hypotension in 14).
Following a year of treatment, there was a significant
increase in LVEF and a greater reduction in leftventricular mass in the propranolol group. Treatment
with propranolol was associated with a lower mortality
(44/79 [56%] of the propranolol patients died compared
to 60/79 [76%] in the no-propranolol group, P = 0.007)
and a lower risk of death or non-fatal MI (47 [59%] vs.
65 [82%], respectively, P = 0.002).
Although these results are favourable they are
interpreted on the background of the lack of a placebo
control group and a highly selected group of patients.
Also, the beneficial action of b-blockers in post-MI
patients is well recognised already, and so the results
of this study may have been anticipated. Similarly, the
composite death or MI endpoint, while important, is
perhaps not the most relevant one in the more general
population of patients with HF-PSF.
The role of b-blockers in HF-PSF will, hopefully, be
clarified by the results of the Study of Effects of Nebivolol
Intervention on Outcomes and Re-hospitalisation in
Seniors with heart failure (SENIORS) 34 . SENIORS is
a large double-blind, prospective, randomised controlled morbidity/mortality trial, comparing placebo to
nebivolol in approximately 2000 patients with HF aged
70 years 34 . The inclusion criteria require either a
documented LVEF 0.35 or a hospital admission with HF
within 12 months. It is expected that about a third
of the patients in SENIORS will have HF-PSF. The
primary endpoint in this trial is death or cardiovascular
hospitalisation.
b-blockers
As with verapamil, b-blockers might be expected to be
beneficial in HF-PSF; since they reduce the heart rate
their negative inotropic properties should also improve
diastolic function. Aronow et al. 33 studied the effect
of propranolol in an open study on 158 elderly patients
(62 yr) with heart failure and preserved left-ventricular
systolic function (LVEF 0.40). In contrast to the study
of Setaro et al. 22 with verapamil, there were several
important differences in enrolment criteria: patients
with coronary heart disease were not excluded and, in
fact, all had a prior Q-wave infarction. All patients in
this study were receiving baseline diuretic and b-blocker
therapy. A third of patients were in atrial fibrillation and
the study had an open design. In total, 79 patients were
randomised to receive propranolol and 79 did not receive
propranolol. The follow-up period was 32 months. The
initial dose of propranolol was 10 mg per day. The dose
was increased by 10-mg increments at 10-day intervals
until the target dose of 30 mg three times daily was
reached.
ACE inhibitors
ACE inhibitors should be of value in HF-PSF as these
patients often have hypertension, LVH, diabetes and
coronary artery disease. Studies such as HOPE and
EUROPA with ACE inhibition, and LIFE, SCOPE, RENAAL,
IDNT, Val-Heft, CHARM and VALIANT with angiotensinreceptor blockers suggest that interruption of the
renin–aldosterone–angiotensin system (RAAS) will be of
benefit.
The Perindopril for Elderly People with Chronic
Heart Failure (PEP-CHF) study has recruited around
1000 patients aged >70 yrs with HF and no major leftventricular systolic dysfunction (LVEF < 0.40 or wallmotion index <1.4). Patients were also required to have
echocardiographic evidence of left atrial enlargement,
left-ventricular hypertrophy or diastolic dysfunction (by
Doppler criteria). The primary outcome in this ongoing
comparison of placebo and perindopril is death or heartfailure hospitalisation 35 .
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ARBs are also known to reduce left-ventricular hypertrophy and improve diastolic filling 26 . Elevated
systolic blood pressure impairs diastolic function 27 .
Systolic arterial blood pressures normally increase during
exercise, but in the elderly and hypertensive subjects
this physiological response is exaggerated 27–30 ; and it
is thought that this may be partially mediated by
angiotensin II, the circulating levels of which increase
during exercise 31 . In one small, randomised, placebocontrolled, double-blind, cross-over study, losartan
improved exercise time, exercise systolic blood pressure,
and quality of life (QOL) as measured by the Minnesota
Living with Heart Failure Questionnaire in patients undergoing investigation of breathlessness. These patients had
preserved left ventricular systolic function and Doppler
evidence of diastolic dysfunction and a hypertensive
response to exercise. However, these patients did not
have heart failure 30 . The same investigators reported a
second study with similar patients and study design. The
patients were randomised to receive either verapamil or
candesartan. Candesartan treatment was associated with
a significant improvement in exercise tolerance and QOL,
compared with baseline, but in this study there was only
a trend towards improvement with verapamil 32 .
H63
H64
K. Hogg, J.J.V. McMurray
Fig. 1. Kaplan–Meier plot showing the incidence of the primary outcome measure (cardiovascular death or hospitalization) in the
CHARM-Preserved study. Reproduced from Yusuf et al. 40 with permission from Elsevier.
Angiotensin-receptor blockers (ARBs)
Until recently (i.e. until CHARM), the largest trial
with any anti-failure medication in patients with
‘diastolic heart failure’ was with digoxin 36,37 . Classically,
digitalis glycosides are thought of as agents which
increase cytosolic calcium concentrations which, if not
rapidly reversed, should impair myocardial relaxation.
It is possible, however, that the sympatho-inhibitory,
pro-parasympathetic and renin–angiotensin–aldosteronesuppressing actions of digoxin are beneficial in HF 38 .
The Digitalis Investigation Group (DIG) study had an
ancillary trial in patients with HF and a preserved LVEF.
As part of the overall DIG programme, 988 patients
with a clinical diagnosis of HF and a LVEF > 0.45 were
randomised to receive placebo (n = 496) or digoxin
(n = 492). By comparison, 3403 patients with HF and a
LVEF 0.45 were randomised to placebo and 3397 to
digoxin in the main trial. There were 116 deaths (23.4%)
in the placebo group and 115 deaths (23.4%) in the
digoxin group in the ancillary trial. For the combined
endpoint of death or hospitalisation, the results in the
ancillary trial (risk ratio with digoxin 0.82, 95% CI:
0.63–1.07) were consistent with the findings in the
main trial (risk ratio 0.85, 95% CI: 0.79–0.91; P < 0.001).
Unfortunately no further information on outcome in the
preserved-LVEF ancillary trial is available.
The findings of the DIG trial are supported, to
some extent, by those of a trial primarily designed to
evaluate xamoterol 39 . This study compared the effects
of placebo, xamoterol and digoxin on symptoms, signs
and exercise capacity in patients with a spectrum of HF.
LVEF was not reported but 80–90% of patients were
in NYHA Class I or II, about half had angina, only
a quarter were taking diuretics, and just over a
third had radiological cardiomegaly (a cardiothoracic
ratio of 0.52). Thus, it was highly likely that many
of these patients had ‘diastolic heart failure’. Digoxin
significantly improved breathlessness, tiredness, chest
pain, oedema and basal crepitations 39 . Digoxin also
reduced weight and cardiothoracic ratio more than
placebo.
It is with this group of drugs that the unsatisfactory
state of affairs regarding adequate clinical trials in
patients with HF-PSF has begun to improve. The
Candesartan in Heart Failure: Assessment of reduction in
mortality and morbidity (CHARM) programme consisted
of three component trials. One, CHARM-Preserved,
randomised 3023 patients with HF and a LVEF > 0.40
to placebo or candesartan (target dose 32 mg daily) 40 .
The primary outcome of this study was the composite
of cardiovascular death or heart-failure hospitalisation.
There was only a non-significant trend towards a
reduction in the primary endpoint with candesartan in
this particular component trial (Fig. 1); a similar trend
was observed for the pre-specified secondary endpoints
(Fig. 2). Overall, however, there was no heterogeneity in
the treatment effect of candesartan across all the CHARM
trials or by ejection fraction (Figs. 3, 4). In other words,
the CHARM Programme suggests that candesartan exerts
a favourable effect across a broad spectrum of patients
with HF, irrespective of LVEF or background therapy 41 .
This is supported by the significant reduction in both
the proportion of patients hospitalised with worsening
heart failure (15% reduction, P = 0.017) and the total
number of heart-failure hospitalisations (29% reduction,
P = 0.014) in CHARM-Preserved (Fig. 5). Similarly, in
CHARM-Overall, candesartan improved NYHA functional
class, with no evidence of heterogeneity across the
component trials.
I-PRESERVE is another major morbidity/mortality trial
comparing placebo to treatment with irbesartan in
patients with HF-PSF. Patients must be 60 years or
older and have a LVEF 0.45. In addition, patients
in NYHA class II–IV CHF must have had a hospital
admission for heart failure within the previous 6 months
or, if NYHA class III or IV, have an abnormal chest
radiograph (pulmonary oedema) or ECG (left-ventricular
hypertrophy [LVH] or left bundle-branch block) or
echocardiogram (LVH or enlarged left atrium). This trial
is still in the recruitment phase.
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Digoxin
Treatment of heart failure with preserved systolic function: a review of the evidence
(a) Primary and secondary outcomes
H65
(b) Investigator-reported outcomes
Fig. 2. Effects of candesartan on (a) primary and secondary outcomes, and (b) investigator-reported outcomes in CHARMPreserved 40 .
Aldosterone blockers
Conclusions
Fig. 3. Overall mortality and morbidity in the CHARM Programme 41 .
Fig. 4. Cardiovascular deaths or hospitalizations in the CHARM
Programme. Reproduced from Pfeffer et al. 41 with permission from
Elsevier.
Fig. 5. Investigator-reported hospitalizations for CHF in CHARMPreserved 40 .
In summary, the development of treatments for HF-PSF
has been neglected until recently. CHARM-Preserved is
the only completed large randomised outcome trial,
though the results of a number of ongoing trials are
eagerly awaited. What can we conclude from the
limited evidence currently available? There seems to be
reasonable evidence that verapamil improves symptoms
and exercise time in patients with HF-PSF. The safety and
efficacy of this drug has been generally established in
patients with hypertension and coronary heart disease 42 .
Similarly, ARBs have established benefits in hypertension,
myocardial infarction, HF-RSF and diabetic nephropathy.
In CHARM, candesartan also substantially reduced the risk
of heart-failure hospitalisation in patients with HF-PSF. In
addition, candesartan improved NYHA class in the overall
CHARM Programme without evidence of heterogeneity
across the component trials or by LVEF.
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