1.
NICE, AUDIT AND HEART FAILURE CARE
The national heart failure audit
1
in England and Wales continues to grow and provides vital data for planning heart
failure services. The first formal report relates to over 6000 patients who were the
first 10 patients admitted with a primary diagnosis of heart failure each month to
one of 86 hospitals contributing data in 2008–09. Most had left ventricular systolic
dysfunction, but an echocardiogram result was available in only 75%. In-patient mortality
was 12% and in survivors, 80% were receiving an ACE inhibitor (or angiotensin receptor
blocker (ARB)), 50% a β blocker and 30% an aldosterone antagonist at discharge.
The audit for 21 000 patients hospitalised with heart failure in 2009–10 is also available.
2
In-hospital mortality had fallen slightly to 10.5%, but there was no dramatic change
in drug prescription rates. Some subsets of patients were particularly likely to be
actively treated (men aged 55–64, β blocker prescription rate >70%), and others much
less likely (women aged >85, β blocker prescription rate 40%). Aldosterone antagonists
were still prescribed for less than half the population.
Two striking features stand out from the data from both audits. First, prescription
rates vary greatly, with age—older patients and women being less likely to be treated—and
with admission ward—patients admitted to cardiology wards being much more likely to
receive active treatment. Second, pharmacological treatment was better for patients
admitted under cardiologists, and so was survival. Although a minority of patients
admitted with heart failure are managed by cardiologists, the survival benefit persists
after correction for age and sex (and other confounders).
The undertreatment of elderly patients with heart failure is a particular cause for
concern at a time when patients aged >80 represent an increasing proportion of admissions
for heart failure.
3
Treatment of older patients is hampered by their associated comorbidities and polypharmacy
and also by their systematic exclusion from clinical trials, depriving doctors of
the evidence base they need to guide management decisions.
4
Exclusion of the elderly by trial organisers shows no signs of going away: among 251
trials recruiting patients in December 2008, more than 25% had an upper age limit
for enrolment and more than 80% excluded patients with comorbid conditions.
4
The National Institute for Health and Clinical Excellence (NICE) has produced updated
guidelines for heart failure care.
5
6
While there has been a lot of comment on the importance of measuring natriuretic peptides
as an entry point to heart failure care, NICE has also firmly recommended that care
led by a specialist in heart failure should be the norm. This is true at assessment
and diagnosis (a patient suspected of having heart failure associated with a previous
myocardial infarct or with a very high natriuretic peptide level should receive “…specialist
assessment within 2 weeks”) and during admission to hospital (“when a patient is admitted
to hospital because of heart failure, seek advice on their management plan from a
specialist in heart failure”).
Such recommendations will impose new burdens. What is a ‘specialist’? NICE thinks
it is “…a doctor with subspecialty interest in heart failure (often a consultant cardiologist)
who leads a specialist multidisciplinary heart failure team of professionals …”, but
there are few such individuals available to take up the responsibility. However a
specialist is defined, there is no doubt that patients with heart failure fare better
when cared for by professionals with a particular interest in their condition. This
is reflected in recent US data that have shown lower mortality and readmissions for
patients with heart failure managed in high-volume compared with low-volume centres.
7
One of the problems for a specialist heart failure service is access to advanced treatments
such as heart transplantation. Transplantation in the UK is falling, partly owing
to a fall in the availability of donor organs,
8
but just as important is access to expert heart failure care.
9
We have managed to reconfigure health services to provide primary angioplasty for
patients with acute myocardial infarction (MI) (including for patients with non-ST
elevation MI on rather flimsy evidence
10
). We should do so for patients with heart failure, for whom reconfigured services
will have a more far-reaching benefit.
2.
TELEMONITORING
An exciting possible advance in patient care is the use of remote monitoring to guide
changes in treatment. Typically, automated devices in the home can measure weight,
pulse rate and heart rhythm and blood pressure and transmit the data to a centre.
Abnormal results then trigger patient contact with possible change in treatment. Initial
trials have suggested that there may be a benefit from such systems, particularly
when coupled with telephone contact.
11
A particular problem with telemonitoring is what to do with the data. With a large
number of patients potentially transmitting quantities of data daily, the resource
required to deal with the data might become impossibly large. Attempts to use automated
systems have proved disappointing: in a study of 1653 patients who had recently been
hospitalised for heart failure, which used telemonitoring with an interactive voice-response
system collecting daily information about symptoms and weight, Chaudhry et al found
no impact on re-admissions and mortality at 6 months.
12
In another recent study,
13
remote monitoring did not improve outcomes among 710 patients randomised to remote
monitoring using a system that transmitted ECG, blood pressure and weight and included
a home emergency call system.
It is important to remember that telemonitoring itself does not save lives or admissions,
but that actions taken in response to monitoring might do so. The reason recent trials
have been neutral may be that ‘usual care’ in these studies has progressed to the
point at which home monitoring can have little additional beneficial effect and it
may be that remote monitoring is only likely to be helpful in people at particularly
high risk. It may be, too, that the variables measured are simply too crude to be
helpful guides to changing treatment.
Another approach to remote monitoring is to use implantable devices to measure haemodynamic
changes invasively. The Chronicle device allows pulmonary artery pressure to be measured
continuously and an early trial (COMPASS) suggested that it might be helpful.
14
A more promising technique, perhaps, is the use of smaller devices implanted directly
into the pulmonary artery and communicating using acoustic wireless communication.
15
In the CHAMPION trial,
16
550 patients were randomised to have a CardioMEMS device or usual care. The device
was used to measure pulmonary artery pressure once a day: it has no internal power
source, but uses externally applied radiofrequency energy. Its use was associated
with a 30% reduction in the primary efficacy end point of hospitalisation for heart
failure at 6 months. It is not, of course, the devices that improve outcome, but the
changes in treatment that follow from device readings. In COMPASS
14
and CHAMPION,
16
for example, patients with the device were receiving higher doses of medication to
treat heart failure.
The final stage in the evolution of remote monitoring is likely to be to further empowerment
of the patient. The devices can be used to transmit data to the person most concerned
with the disease—the patient—who can then use the information to make daily changes
to his or her treatment. In HOMEOSTASIS, 40 patients with severe heart failure were
implanted with a device measuring left atrial pressure and made changes to treatment
based on the readings using a preprogrammed hand-held patient advisor module.
17
It is impossible to draw firm conclusions from such a small observational study, but
while diuretic treatment fell as a result of the intervention, β blocker and ACE inhibitor/ARB
treatment increased. At the same time, mean left atrial pressure fell and there did
seem to be a reduction in clinical events.
Invasive monitoring leads to an increase in prescription of medical treatment for
heart failure, which highlights another nagging question: although we have clinical
trial results to guide us towards ‘target’ doses of, for example, β blockers and ACE
inhibitors, how are we to know how much is enough? One possible guide is the use of
natriuretic peptides: perhaps treatment should continue to be increased until the
natriuretic peptide level is normal. Some small studies point in that direction, others
do not: but there is evidence of publication bias in a meta-analysis.
18
A recent single-centre trial in 364 patients with heart failure showed that treatment
guided by N-terminal pro-brain natriuretic peptide was associated with a 1-year mortality
identical to treatment guided by a clinical score.
19
The finding lends some weight to the argument against biomarker-guided treatment but
the question will only be resolved by a definitive large trial.
3.
EPIDEMIOLOGY
3.1.
Heart failure with a normal ejection fraction
Heart failure with a normal ejection fraction (HeFNEF) remains enigmatic. Epidemiology
suggests that it is common,
20
21
perhaps accounting for half of the cases of heart failure. However, researchers recruiting
patients to trials have often found it extremely difficult to identify suitable patients.
No clinical trial has as yet identified any successful treatment for HeFNEF and some
are sceptical of its existence as a single, well-defined entity.
22
23
Problems arise because, at least in part, breathlessness is very common in older people
and because some of the diastolic echocardiographic changes thought to indicate that
the heart is failing are simply consistent with ageing.
One possibility that has been under-researched is that HeFNEF is more obviously a
condition appreciated during exercise, and echocardiographic measurements during exercise
may highlight diastolic abnormalities.
24
An important observation from a study of echocardiography and exercise of over 400
patients with possible HeFNEF
25
was that very few—possibly as few as 3%—actually had heart failure. Holland and colleagues
25
emphasised the importance of measuring the ratio between E and E′ as an index of left
ventricular filling pressure, but others have concentrated on much more subtle abnormalities
of both systole and diastole in patients with HeFNEF that worsen with exertion.
26
Impaired left atrial function during exercise may also contribute.
27
While it remains a very active area of research, the cardinal problem with HeFNEF
and the main reason it has no (proven) treatment is the absence of a satisfactory
case definition. The incorporation of natriuretic peptides into the diagnostic pathway
for HeFNEF should help as a raised level makes it more certain that the heart is the
cause of any symptoms. However, natriuretic peptides may show that there has been
considerable overdiagnosis of HeFNEF in the past. Potentially relevant in this respect
is the recent analysis of mode of death data from I-Preserve: in patients with HeFNEF,
death from heart failure was surprisingly rare, the majority succumbing to other cardiovascular
events.
28
4.
TREATMENT
4.1.
Neurohormonal manipulation
ACE inhibitors, ARBs and β blockers, are of course, the mainstays of medical treatment
for patients with chronic heart failure. ACE inhibitors or ARBs should be given to
all patients with left ventricular systolic dysfunction, regardless of symptom class,
and there is general appreciation that the highest tolerated dose should be used,
side effects permitting. Evidence for this approach comes from trials such as ATLAS,
29
in which patients randomised to higher-dose lisinopril fared better than those receiving
a lower dose.
There has been little evidence that a high dose of ARBs is better until the HEAAL
study,
30
in which 3846 patients with heart failure and left ventricular ejection fraction <40%
and who were intolerant of ACE inhibitors were randomised to receive high-dose (150
mg) or low-dose (50 mg) daily losartan. After a median 4.7 years’ follow-up there
was a lower rate of deaths or hospitalisation for heart failure in the high-dose group
(HR=0.90, 95% CI 0.82 to 0.99; p=0.027). Thus it does thus seem that up-titrating
ARB doses confers clinical benefit.
With RALES
31
(spironolactone) and EPHESUS
32
(eplerenone), aldosterone blockade has also become important, with the proviso that
aldosterone blockade has not been shown to be beneficial in patients with mild heart
failure, at least until recently. In EMPHASIS-HF,
33
2737 patients with heart failure due to systolic dysfunction and New York Heart Association
(NYHA) class II symptoms were randomised to eplerenone (up to 50 mg daily) or placebo,
in addition to standard treatment. There was a 37% reduction in the risk of the primary
end point (cardiovascular death or hospitalisation for heart failure) in the eplerenone
group, at the cost of a small increase in the risk of hyperkalaemia. It seems likely
that guideline groups will now recommend the use of eplerenone in all those with heart
failure due to left ventricular systolic dysfunction.
A problem with the more widespread use of aldosterone antagonists is that the risk
of life-threatening hyperkalaemia may increase. Certainly after the RALES report,
there was a rapid uptake of spironolactone usage resulting in a marked increase in
morbidity and mortality from hyperkalaemia.
34
A possible approach to preventing hyperkalaemia is to use potassium-binding resins.
In PEARL-HF,
35
105 patients with heart failure and a history of hyperkalaemia which had interfered
with medical treatment, or who had chronic kidney disease, were recruited. The potassium
binder, RLY5016, was given in addition to spironolactone and led to a marked reduction
in the risk of hyperkalaemia compared with placebo (7.3% vs 24.5%, p=0.015); and a
higher proportion of patients reaching spironolactone 50 mg/day (91% vs 74%, p=0.019).
These are encouraging data, but lead to the obvious unanswered question: to what extent
is the benefit of aldosterone antagonism mediated by hyperkalaemia? If the answer
is ‘most’, or ‘all’, then potassium binding may not have much to offer.
4.2.
Ivabradine
The mechanism by which β blockers mediate their beneficial effects is not clear, but
has long been thought to be related to their ability to reduce heart rate.
36
37
Ivabradine reduces heart rate by reducing sinus node discharge rate while having no
other haemodynamic effect and might thus both test the heart rate hypothesis and provide
an alternative for patients intolerant of β blockers.
In SHIFT,
38
6558 patients with heart failure and a low ejection fraction and who were in sinus
rhythm with a heart rate of at least 70 beats/min were randomised to receive ivabradine
or placebo in addition to usual treatment (including β blocker, where tolerated).
Ivabradine was associated with an 18% reduction in the primary end point (cardiovascular
death or hospital admission for worsening heart failure), driven mainly by a reduction
in hospital admission.
The findings of SHIFT have been much discussed. It is important to point out that
the benefits of ivabradine were much more striking in those with a higher resting
heart rate,
38
39
and that although around 90% of patients were taking a β blocker at baseline, only
23% were taking a target dose, only 49% were receiving ≥50% of a target dose and 16%
were receiving a β blocker not shown to be beneficial.
The SHIFT findings do suggest that there is a role for ivabradine in patients with
chronic heart failure, but it is not a substitute for β blocker use. There is an enormous
body of evidence supporting the use of β blockers, which improve mortality as well
as hospitalisation. Ivabradine should be considered only in those patients who still
have a resting heart rate above 70 despite maximally tolerated doses of β blockers
(or perhaps used in patients truly intolerant of β blockers). Data from ‘real-world’
populations of patients with heart failure suggest that the proportion of patients
who might be eligible is low, perhaps around 5%.
40
4.3.
Iron
Is iron deficiency a target for treatment? Anaemia is very common in patients with
heart failure,
41
but iron deficiency without anaemia is also common. The best way to manage iron deficiency
is not clear: oral iron treatment is widely believed to be ineffective, yet intravenous
iron treatment is also thought to be difficult or dangerous. However, a new generation
of intravenous iron preparations is now available which allows both rapid and safe
administration of iron to patients.
Some preliminary studies suggested that intravenous iron repletion might lead to an
improvement in exercise capacity,
42
and the FAIR-HF study was designed to see if iron might be beneficial in a larger
group of patients.
43
Four hundred and fifty-nine patients were randomised 2:1 to receive iron or placebo
infusions (with only the patient blind to treatment). After 6 months, there was an
improvement in patient self-reported global assessment (50% ‘much or moderately improved’,
compared with 28% of patients in the placebo group) as well as in secondary end points,
including distance covered in a 6 min walk test (about 40 m increase compared with
no change in the placebo group). There were similar improvements regardless of starting
haemoglobin.
The results have to be treated with some caution: FAIR-HF was not a large trial, blinding
was difficult and the end points were to a varying degree subjective. Nevertheless,
iron treatment appeared safe and is now an option for patients who remain symptomatic
despite medical treatment. An absolutely essential question to answer, though, is
the extent to which patients with heart failure should be further investigated for
an underlying cause for any iron deficiency, a question not dealt with by FAIR-HF.
Another possible approach for correcting anaemia in heart failure is the use of erythropoiesis-stimulating
proteins. A meta-analysis of six randomised controlled trials found that treatment
was associated with a significantly lower risk of hospitalisation compared with placebo.
44
Mortality was unaffected. These outcomes are in contrast with studies in cancer and
kidney disease and prompted the authors to a call for a large phase III morbidity
and mortality trial of anaemia correction with erythropoiesisstimulating proteins
in patients with chronic heart failure.
4.4.
Metabolic manipulation
The energy-generating processes of the failing cardiac myocyte are abnormal. Some
investigators have focused on substrate use: fatty acid metabolism produces a lower
yield of ATP for each molecule of oxygen consumed than glucose metabolism (although
fatty acid oxidation yields more ATP per mole) and so it makes sense to try to switch
metabolism from fatty acids to glucose.
45
Various approaches have been tried: perhexiline, for example, blocks mitochondrial
free fatty acid uptake by inhibiting carnitine palmitoyltransferase. In a small study,
perhexiline led to improvements in exercise capacity and left ventricular function
and more rapid recovery of phosphocreatine after exercise.
46
Trimetazidine inhibits lipid β-oxidation and its use has been associated with both
an increase in left ventricular ejection fraction and reduction in resting energy
expenditure (known to be high in heart failure).
47
A meta-analysis of the available data for trimetazidine
48
even suggests that its use might improve mortality and it is surely time for a large-scale
trial of metabolic modulators.
4.5.
Cardiac resynchronisation therapy
Cardiac resynchronisation therapy (CRT: or biventricular pacing) is one of the most
exciting new developments for patients with chronic heart failure and left bundle
branch block (LBBB) introduced in recent years. Particularly important is its effect
on reducing mortality,
49
but around two-thirds of patients get marked symptomatic benefit from their devices.
50
That one-third do not has led to the concept of the ‘non-responder’ to CRT. How to
define ‘non-response’ varies from paper to paper, with some using symptomatic criteria
and others using measures of left ventricular function. What has proved difficult
to answer is whether ‘nonresponse’ is related to lack of mortality benefit.
A great deal of time and effort has been expended on trying to identify which patients
might benefit from CRT. The severity of symptoms does not seem to matter greatly:
those with modest symptoms appear to gain as much mortality benefit as those with
worse NYHA class of symptoms.
51
In MADIT-CRT,
52
1820 patients with NYHA class I or II symptoms and LBBB were randomised 2:1 to receive
CRT (or not) in addition to a defibrillator. There was a 34% reduction in the risk
of death or a heart failure event (defined as congestion treated either with intravenous
treatment (diuretics, nesiritide or inotrope) for more than 2 h, regardless of the
setting, or: with an increased heart failure regimen during formal hospital admission).
The reduction in risk was driven by a reduction in heart failure events. In RAFT,
53
which included 1438 patients with mild (NYHA class II) symptoms, CRT added to a defibrillator
led to a reduction in the rate of death and hospitalisation for heart failure.
Another possible selection criterion is the presence of dyssynchrony on some form
of cardiac imaging. Underlying this approach is the assumption that CRT works by improving
ventricular coordination, which in turn must in some way be measurable. However, of
the large, randomised trials showing a mortality benefit for CRT, none used measures
of dyssynchrony as an entry criterion other than a minority of patients in CARE-HF.
Vigorous efforts to prove the robustness of any of the very many potential measures
of dyssynchrony have failed thus far, with the PROSPECT study of nearly 500 patients
being the largest available set of data.
54
There was poor reproducibility of the measures, none of which related strongly to
the assessment of response.
The only selection criteria consistently shown to be related to outcome are electrocardiographic.
It is a commonplace observation that the mean QRS duration in the mortality trials
of CRT was around 150 ms and where it has been analysed, the broader the QRS, the
greater the benefit. Subgroup analysis of PROSPECT showed some symptomatic benefit
for CRT in patients with mechanical dyssynchrony and a narrow QRS complex
55
and similar findings have been reported in small single-centre trials.
56
There is no doubt, however, that the benefits of CRT are largely confined to patients
with left bundle branch block,
53
and it may even be that benefit is restricted to those with a QRS >150 ms.
57
Similarly, while small non-randomised studies have reported variable benefit of CRT
for patients in atrial fibrillation (AF), there is almost no evidence to support the
practice from randomised trials.
58
The few trials that included patients in AF showed no benefit with CRT.
53
Although the European Society of cardiology guideline updates suggest that CRT might
be considered in patients in AF,
59
the class of recommendation was only IIa, level B or C.
What should all this mean in practice? CRT should certainly be considered for all
patients with left ventricular systolic dysfunction and symptomatic heart failure
who are in sinus rhythm and have left bundle branch block. CRT might be tried for
those patients with intractable symptoms and AF (and left bundle branch block), but
only if the ventricular rate is well controlled to maximise pacing. Better still,
restoration of sinus rhythm in such patients may improve both quality of life and
LV function
60
while ensuring a more favourable response to CRT.
A more far-reaching question is whether patients with a standard bradycardia pacing
indication would benefit from biventricular pacing. A small study using echocardiographic
end points suggested that biventricular pacing was associated with less deterioration
in left ventricular function,
61
but whether widespread use of biventricular pacing is indicated will have to await
the outcome of larger outcome studies.
4.6.
Exercise training
The case for exercise training as a standard part of the management of patients with
chronic heart failure has been building over several years.
62
Training undoubtedly improves patients’ symptoms and several of the predictors of
an adverse prognosis.
63
Mounting a properly powered survival study has proved difficult, not least because
of the problems of blinding and the difficulty of cross-overs.
The HF-ACTION study managed to recruit 2331 patients randomised to usual care or an
intensive training regimen (36 supervised 30 min sessions three times a week, followed
by home exercise five times a week at moderate intensity for 40 min).
64
Although the primary end point of all-cause mortality and hospitalisation was no different
between the two groups at a median follow-up of 30 months, there was a signal that
training might be beneficial as after adjustment for baseline differences in predictors
of outcome, training was associated with an 11% reduction in the primary end point.
More importantly, perhaps, training was associated with a marked improvement in quality
of life, which appeared early during the intervention and continued throughout the
course of the study.
65
It is still unclear whether the type of training stimulus is important: most evidence
relates to aerobic training. A recent systematic review of trials of resistance training
found that the quality of the studies has been poor and effects were inconclusive
for quality-of-life outcomes.
66
Incorporating exercise training into standard heart failure management is difficult.
62
Compliance will always be a challenge—even in HF-ACTION, and after a year, patients’
compliance with exercise was only about 80%. Although home exercise is safe,
64
initial supervision may be helpful for both patients and their carers and the resource
implications are substantial. Whether a training programme is possible for many patients,
who may be elderly, frail and have multiple comorbidities, is debatable. Nevertheless,
patients can be reassured that exercise is safe and will improve their symptoms.
4.7
Revascularisation
The commonest cause of heart failure is underlying ischaemic heart disease. However,
there is no good evidence that treatments directed at ischaemia with, for example,
statins,
67
are beneficial, despite the intuitive feeling that treating ischaemia should be effective.
One of the more challenging questions has been whether revascularisation for patients
with heart failure and no angina might be beneficial. Observational studies suggest
that revascularisation might indeed improve prognosis, particularly in those with
demonstrable viability on functional testing,
68
but we now have two randomised trials that examine the problem directly.
In HEART,
69
patients with heart failure and viable but dysfunctional myocardium were randomised
to two strategies of care: conservative management or angiography with a view to revascularisation.
There was no difference in survival between the two groups at 59 months. Although
the trial recruited slowly and only 138 of the planned 800 patients were enrolled,
there was no signal suggesting benefit.
STICH
70
included 1212 patients with an ejection fraction ≤35% who were considered suitable
for coronary artery bypass grafting (CABG). The patients were randomised to CABG or
continued medical treatment. Over a median follow-up of 56 months, there was no difference
in all-cause mortality, the primary end point, between the treatment groups. The combined
end point of all-cause mortality and cardiovascular hospitalisation was reduced in
the CABG group, but the analysis excludes hospitalisation for the original operation,
which is scarcely a negligible event: the 60 hospitalisations prevented by CABG required
555 hospitalisations for the CABG procedure itself.
71
There were more deaths in the CABG group for more than 2 years after randomisation,
emphasising that this is not a benign intervention.
Together, HEART and STICH show that there is, at most, a marginal benefit for revascularisation
in patients with heart failure and underlying ischaemic heart disease. How the results
relate to clinical practice is not clear: in STICH, the average age of patients was
around 60, resting heart rate was >70 (suggesting, perhaps, inadequate β blockade)
and fewer than 10% had ‘chronic renal insufficiency’ (creatinine is not reported in
the paper). Despite the enormous effort expended to answer the question, it is still
not clear whether revascularisation is helpful for patients with heart failure.
Acute heart failure
After many years of clinical trials in patients with chronic heart failure, there
has been renewed interest in the problem of acute heart failure—in part, driven by
the availability of new drugs as potential treatments.
One of the most widely used new treatments for acute heart failure has been nesiritide,
licensed for use in the USA, largely as a results of trials showing some improvement
in haemodynamics.
72
It has always seemed a little strange from a European perspective that nesiritide
has been so widely used and the European Medicines Agency did not allow its use in
the EU. A 7000 patient trial comparing nesiritide with placebo in addition to standard
treatment has now been completed.
73
No statistically significant difference in symptoms scores was found between the two
groups, or in rehospitalisation or death at 30 days.
Another agent for possible use in patents with acute heart failure is rolofylline,
an adenosine antagonist. Rolofylline might help to prevent decline in renal function
with diuretic treatment by interrupting glomerulotubular feedback. However, in a 2000
patient study, rolofylline had no effect on the primary end point (a composite ‘treatment
success’ score), renal function or mortality.
74
75
Taken together, the trials of rolofylline and nesiritide highlight the importance
of using clinical trials appropriately to drive the evolution of treatment. Reliance
on relatively small trials with inappropriate end points led to the nesiritide debâcle,
whereas investigation of rolofylline followed an appropriate sequence with early small-scale
studies informing the design of a properly powered endpoint study.
The correct diuretic dosing regimen for patients admitted with fluid retention has
often been a controversial question and the DOSE trial
76
was designed to help guide this aspect of acute heart failure management. Three hundred
and eight patients with fluid retention due to heart failure were randomised to receive
furosemide either as a bolus every 12 h or by continuous infusion: both were given
as either low or high dose. There were two co-primary end points: patients’ global
symptom assessment over 72 h and change in creatinine level from baseline to 72 h.
No significant difference was found between bolus and infusion regimens, but a small
(and statistically non-significant) greater improvement in symptoms in the high-dose
versus low-dose groups was seen. The high-dose groups had a substantially greater
diuresis.
It can be difficult directly to compare practice in the USA with Europe. Typically,
patients with acute heart failure are in hospital for around 5 days in the USA, but
11 days in Europe and any acute weight loss during admission (presumably reflecting
fluid loss) is very much smaller, implying that patients are admitted in the USA with
very much less fluid overload than in Europe. Whether there are differences between
furosemide given by bolus or continuous infusion over a longer time scale cannot be
addressed by DOSE, but the message that high doses of furosemide (defined here as
2.5 times the patient’s usual oral dose) cause a greater diuresis is clear.