Heart Fail Rev (2012) 17:133149

DOI 10.1007/s10741-012-9306-2

Renal dysfunction in acute and chronic heart failure: prevalence,

incidence and prognosis
John G. F. Cleland Valentina Carubelli
Teresa Castiello Ashraf Yassin Pierpaolo Pellicori
Renjith Antony

Published online: 17 March 2012

Springer Science+Business Media, LLC 2012

Abstract Most patients with heart failure have mild or

moderate renal dysfunction. This reflects the combined
impact of chronic renal parenchymal disease, renal artery
disease, renal congestion and hypoperfusion, neuroendocrine
and cytokine activation and the effects of treatments for heart
failure. Remarkably, with good treatment, the average annual
rate of decline in renal function is similar in patients with
chronic heart failure and healthy people of a similar age. Urea
appears to be a stronger marker of an adverse prognosis than
creatinine-based measures of renal function. Recent evidence
suggests that minor, transient increases in creatinine in the
setting of acute heart failure are not prognostically important
but persistent deterioration does indicate a higher mortality.
The poor prognosis of patients with worsening renal function
ensures that few require renal dialysis but this may change as
methods to prevent sudden death improve and new ways are
found to control fluid congestion. Reversing renal dysfunction
and stopping its progression remain important targets for
treatment of heart failure.
Keywords Renal dysfunction
Heart failure
Prognosis

Prevalence
Incidence

Introduction
Over the last decade, research has shown that renal dysfunction is a major determinant of outcome in patients with

J. G. F. Cleland (&)
V. Carubelli
T. Castiello
A. Yassin

P. Pellicori
R. Antony
Department of Cardiology, Hull York Medical School,
University of Hull, Castle Hill Hospital, Kingston upon Hull
HU16 5JQ, UK
e-mail: j.g.cleland@hull.ac.uk

heart failure. This has given rise to the concept of a cardiorenal syndrome [1, 2] with a vicious cycle of deterioration, but whether the heart is the chicken or the egg
in this concept is unclear. It is likely that the aetiology of
renal dysfunction in patients with heart failure is much
more complex (Fig. 1) and represents a matrix of interactions and the sum total of independent but interacting
processes with effects on both the kidney and the heart.
This article provides an updated review of the prevalence
and prognostic significance of renal dysfunction in acute
and chronic heart failure. In addition, this review will
consider the aetiology of renal dysfunction and its natural
history in patients with heart failure; when does it occur, is
it reversible and how fast does it progress?

Which renal marker?

For more than 100 years, clinicians have used measurements
of creatinine as an index of renal function. Most of the epidemiology of renal dysfunction focuses either on serum creatinine itself or on calculated creatinine clearance using either
the CockroftGault or one of the modification of diet in renal
disease (MDRD) equations to estimate glomerular filtration
rate (eGFR) [3]. These various measures of renal function are
highly correlated. In multivariable prognostic models, serum
creatinine performs about as well as the derived measures
since these models usually already contain all of the variables
in the equation used to calculate renal function, such as age,
sex and body mass. However, in some groups of patients, for
instance, those with muscle wasting or cachexia, creatininebased measurements may underestimate the severity of renal
dysfunction [3].
There is growing evidence that other blood markers of
renal dysfunction including cystatin-C [4, 5] and serum

123

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Heart Fail Rev (2012) 17:133149

Fig. 1 Schematic diagram

showing factors likely to be
important in the genesis of renal
dysfunction in patients with
heart failure. Note that much of
the renal dysfunction may predate the development of heart
failure. Mechanisms linking
heart failure to renal
dysfunction are shown in an
approximate sequence of events.
Renal vein obstruction and renal
parenchymal oedema are
probably late-stage phenomena.
Important consequences of renal
dysfunction are salt and water
retention, anaemia and further
neuroendocrine and cytokine
activation

urea [68] are superior to creatinine when it comes to

predicting prognosis in patients with heart failure. Up to
50% of filtered urea is reabsorbed in the renal tubules;
therefore, it is as much a marker of renal tubular reabsorption as of GFR [9, 10]. Serum urea concentrations may
be a better measure of intravascular dehydration and
diuretic resistance than creatinine. Serum urea also rises
during the periods of increased protein catabolism due to
either worsening heart failure or concomitant problems
such as infection and reduced dietary protein [11]. Urea
may be a better marker of prognosis than creatinine precisely because it reflects a constellation of renal dysfunction, diuretic resistance and cachexia rather than just the
GFR. This may be its strength rather than its weakness as a
prognostic marker. On the other hand, this does not explain
why cystatin-C, thought to be a more specific measure of
GFR, is a better marker of prognosis than creatinine. Elevated plasma concentrations of cystatin-C indicate a worse
prognosis even when serum creatinine is normal [4, 12]. As
this group of patients has a very high mortality (40% at
1 year), it may reflect deceptively low serum creatinine in
patients with cardiac cachexia and a low skeletal muscle
mass, a situation where creatinine is known to underestimate GFR. Urea and cystatin-C have not been compared,
head-to-head, in a multivariable prognostic model. However, the prevalence of renal dysfunction classified by
either cystatin-C or urea is poorly described. The bulk of

123

the literature is based on measures of renal function derived

from creatinine-based measures of renal dysfunction.

Aetiology of renal dysfunction in heart failure

Many cardiologists view renal dysfunction as a barometer
of cardiac function. This is true, in part, but a gross oversimplification [13]. Reduced cardiac output leads to renal
vasoconstriction and an excessive fall in renal blood flow.
This is partially compensated for by efferent arteriolar
vasoconstriction, largely mediated by angiotensin II, which
leads to an increase in filtration fraction (the ratio of GFR
to renal blood flow), which is the hallmark of the renal
response to heart failure. A fall in GFR is a relatively late
response, occurring only with a substantial fall in cardiac
output. Renal blood flow is dependent on the arterial perfusion pressure, renal vascular resistance and the renal
venous pressure [14, 15]. In heart failure, arterial pressure
tends to fall, renal vasoconstriction occurs, and central and
renal venous pressures rise, resulting in a marked fall in
renal blood flow. Reductions in venous compliance will
cause a further rise in renal venous pressure [1618].
Oedema can affect any organ, and presumably, the kidney
is no exception. Renal parenchymal oedema will lead to a
rise in pressure within the renal parenchyma due to
restraint by the renal capsule, and oedema of abdominal

Heart Fail Rev (2012) 17:133149

organs and ascites may lead to a rise in intra-abdominal and

renal venous pressure [1922]. This would be expected to
lead to a substantial decline in renal function and to
diuretic resistance. The relative importance of each of these
determinants of renal blood flow will vary from one patient
to the next.
Heart failure is also characterised by neuroendocrine
activation that may either help sustain renal function or
make it worse [23, 24]. Reninangiotensin system activation causes renal vasoconstriction but, because this is
predominantly in the efferent arteriole, it helps maintain
GFR. Activation of the sympathetic nervous system causes
afferent arteriolar constriction and, at least in theory,
should cause a rise in renal vascular resistance and a fall in
renal blood flow and GFR. Endothelin is also a powerful
vasoconstrictor, although less specific for the renal circulation [25, 26]. Increases in adenosine may also contribute
to renal dysfunction and sodium retention [27, 28].
Inflammatory cytokines and galectin-3 might also be
responsible for renal glomerular damage [29]. However,
protective systems are also activated. Natriuretic peptides
may cause renal afferent vasodilatation, helping sustain
GFR [30], although systemic administration of at least
some natriuretic peptide analogues does not improve renal
function [31]. Increases in vasodilator prostaglandins also
probably play a key role in protecting the kidney in heart
failure [3234].
However, this is a very heart failure-centric view of
renal dysfunction that may be of little relevance to most
patients during the greater part of the course of their disease. Most patients with heart failure have had decades of
cardiovascular disease preceding the onset of heart failure.
Most of the renal dysfunction observed at the onset of heart
failure is probably long-standing and reflects the effects of
hypertension, diabetes mellitus and renal atherosclerosis on
the kidney. In other words, renal dysfunction precedes, and
may often beget, heart failure rather than the other way
around [35, 36]. Most patients with heart failure have a past
medical history of hypertension. Many patients have longstanding diabetes mellitus. The prevalence of atherosclerotic renal disease in this population is high [37, 38], which
may not only cause renal artery stenosis but also lead to
damage to the kidney by local activation of inflammatory
cytokines.
A further substantial cause of renal dysfunction in heart
failure is doctors, or at least the medications they prescribe
[13, 39]. Although renal dysfunction is a strong predictor
of a poor outcome, many treatments for heart failure make
renal function worse, but nonetheless improve prognosis
[4042]. Initiation of ACE inhibitors, angiotensin receptor
blockers, beta-blockers and aldosterone antagonists all
cause a sudden, usually modest, reduction in GFR but may
then slow the rate of subsequent deterioration after this

135

initial decline. There is an association between the use and

dose of diuretics used and the severity of renal dysfunction
[43] although this was not confirmed in a short-term study
comparing lower and higher doses of intravenous loop
diuretics given for 4872 h [46]. Exactly how diuretics
cause renal dysfunction is not clear. It cannot simply be
due to reninangiotensin or sympathetic nervous system
activation, or the problem would disappear with the use of
ACE inhibitors and beta-blockers, but these therapies
usually exacerbate renal dysfunction in patients treated
with diuretics. The problem may be due to the disruption of
the medullary concentration gradient and tubulo-glomerular feedback, mediated, in part, by adenosine [44]. The
excessive rise in urea compared to creatinine implies
increased tubular reabsorption. However, the relationship
between diuretic dose and renal dysfunction may be yet
another of those chicken and egg vicious cycles of heart
failure. Declining renal dysfunction may require larger
diuretic doses to control fluid retention. It gets even more
complex! Effective diuresis in patients with severe congestion can lead to a paradoxical improvement in renal
function, possibly due to a reduction in renal venous
pressure [1922]. Use of higher doses of diuretics in acute
heart failure is associated with a greater rise in serum
creatinine, but this does not translate into a worse prognosis
[45, 46]. Switching from diuretics to ultrafiltration [47] or
arginine vasopressin antagonists [48] does not reduce the
rate of renal dysfunction and may exacerbate it, implying
that renal dysfunction is a generalised problem with
dehydrating therapies. The importance of activation of
renal vasodilator prostaglandins is demonstrated by the
adverse effects of nonsteroidal inflammatory drugs on renal
function in patients with heart failure [39]. Manipulation of
natriuretic peptides can worsen or improve renal function
depending on the circumstances [31, 49].
If cardiac function was such an important determinant of
renal function, then powerful interventions to improve
heart function should lead to improved renal function.
There is no evidence that any pharmacological intervention
to improve cardiac function improves renal function substantially, as noted above. Cardiac resynchronisation therapy (CRT) can cause dramatic improvements in cardiac
function. There is anecdotal evidence that this may lead to
an improvement in renal function, but this may be related
to the withdrawal of diuretics rather than due directly to
improved cardiac function. In the cardiac resynchronisation
in heart failure study (CARE-HF), a large randomised
controlled trial, CRT did not improve renal function
compared to pre-treatment values but did prevent the
longer-term deterioration observed in the control group
[50]. Heart transplantation causes a sudden large change in
cardiac function, and yet renal function often declines,
which can only be partially attributed to the use of

123

136

cyclosporin [51]. Implantation of a left ventricular assist

device can lead to improvement in renal function in
patients with severe heart failure, but this may apply only
to patients with a relatively short history of renal dysfunction and where intrinsic renal disease has been excluded [52]. In summary, there is remarkably little evidence
that improving cardiac function will improve renal function
for many patients, and this may reflect the fact that cardiac
haemodynamics are the junior partner in causing renal
dysfunction in heart failure.

Prevalence, incidence and prognosis of renal

dysfunction in acute heart failure
Epidemiological studies report that 1730% of patients
with acute heart failure have renal dysfunction according to
the local investigator at the time of enrolment, but studies
rarely provide a definition of renal dysfunction [5355]
(Table 1). There is evidence of substantial under-reporting
[56]. Rates seem somewhat lower in Europe than in North
America, which may reflect the inclusion of younger
patients from Eastern Europe. The EuroHeart Failure
Surveys suggest that only about 10% of patients will have a
serum creatinine [200 lmol/L, and another, single-centre
epidemiological study reported 17% [57, 58]. Age-related
decline in renal function with the super-added effects of
intrinsic renal disease, impaired cardiac function and drug
therapies accounts for the high prevalence of renal dysfunction in acute heart failure. Generalised atherosclerotic
disease is common in patients with heart failure including
the renal arteries. Many patients have a prior history of
hypertension, and studies report that mean systolic blood
pressure hovers around 140 mmHg on admission, indicating that many patients had high blood pressure at admission. Diabetes is reported in 3045% of patients. The
prevalence of hypertension and diabetes as well as renal
dysfunction is higher in North America than in Europe,
perhaps reflecting the older age of the patients and higher
rates of obesity in North America.
If renal dysfunction is defined as a serum creatinine
[130 lmol/L (*1.5 mg/dL), then almost half of the
patients with acute heart failure are affected in most epidemiological studies [56, 57]. A similar proportion of
patients have renal dysfunction if defined as a serum urea
[10 mmol/L, equivalent to a blood urea nitrogen (BUN)
of 28 mg/dL. If renal dysfunction is defined in chronic
kidney disease (CKD) stages, then fewer than 10% of
patients with acute heart failure will have normal renal
function, with about 25, 45, 15 and 5% classified in stages
IIV, respectively[56, 57, 59].
Worsening heart failure is often associated with worsening renal function, and presumably, one will often

123

Heart Fail Rev (2012) 17:133149

exacerbate the other. Various definitions of worsening

renal function can be used. Using a definition of a rise in
serum creatinine to[200 lmol/L, one study suggested that
19% of patients would be affected [58]. Using a definition
of an increase by [0.3 mg/dL (26.5 lmol/L), a large study
(n = 20,063) of US Medicare patients aged [65 years
reported an incidence of 17.8% [60]. Another smaller US
study suggested an incidence of 45% using the same definition and 25% if the threshold was raised to 0.5 mg/dL
(44.2 lmol/L) [61]. Major determinants of the risk of WRF
are pre-existing renal dysfunction, the severity of heart
failure, diuretics and other treatments for heart failure,
anaemia and either a very high blood pressure or a low one
[43, 62, 63].
Some observational studies suggested that transient
increases in serum creatinine, even of modest degree, were
associated with an adverse prognosis [61]. There appeared
to be a doseresponse relationship with a hazard ratio of
1.67 for a rise in serum creatinine of [0.3 mg/dL and 2.90
for elevations [0.5 mg/dL. However, if true, the relationship is not strong [60]. Renal function measured at [54], or
even prior to [64], admission is a much stronger predictor
of prognosis, perhaps because this is the best measure of
the underlying severity of chronic renal dysfunction. Only
if increases in creatinine are persistent or large are they
associated with an adverse outcome. Accordingly, minor
changes in creatinine should be considered neither a target
for therapy in clinical trials of heart failure nor a reason to
change guideline-indicated treatment. However, large
reductions in GFR associated with worsening heart failure
greatly complicate management and portend an unfavourable outcome unless the cause can be reversed. The definition and incidence of severe reductions in GFR in the
setting of acute heart failure are not well described.
Renal function at the time of admission is a strong
predictor of outcome (Fig. 2) [54]. There is growing evidence that urea is a stronger predictor of outcome than
creatinine in patients with acute heart failure [7]. In the
acute decompensated heart failure national registry
(ADHERE), observations on 33,046 hospitalisations
revealed that a serum urea of 15 mmol/L (43 mg/dL) was
the strongest predictor of prognosis, with systolic blood
pressure \115 mmHg and serum creatinine above
approximately 250 lmol/L (2.75 mg/dL) adding further
predictive information [53]. In ADHERE, 22% of patients
had a urea [15 mmol/L. Inpatient mortality was 9.0% in
this group, accounting for about half of all deaths. Mortality in patients with urea \15 mmol/L was 2.7%. About
half of patients will develop a substantial rise in serum urea
during admission, and about 20% will develop an increase
in serum urea to [20 mmol/L (56 mg/dL). In contrast to
changes in creatinine, transient increases in urea may be
associated with an adverse outcome [64].

65,275

48.612

524

4,953

182

4,031

11,327

3,580

ADHERE [53, 56]

OPTIMIZE-HF [54, 79]

URGENT [80]

ALARM-HF [81]

MEASURE-HF [82]

EFFECT [55]

EHFS-I [57]

EHFS-II [58, 83]

53.6
32.8

70

27

47

38.7

68

34

51
71

37 (MI)

50

33
76

61

45

38
69

31

37

68 yrs

43

70
43

46
42

44

52

73
52

58

CAD (%)
Diabetes (%)

73

Age (years)
Women (%)

38%

135

EF\40% in 51%
of men and in
28% of women

NR

51

148

68

130

36

130

50

140

143
49

54

144

Sys BP (mmHg)
LVSD (%)

Mean SCr: 88 lmol/L

SCr [177 lmol/L: 17%

SCr [150 lmol/L 16%

SCr [200 lmol/L 7%

Prevalent: 17%

Mean SCr: 130 lmol/L

Mean Urea: 10 mmol/L

Prevalent: NR

Mean SCr: 133 lmol/L

Mean Urea: NR

Prevalent: 44%

Mean SCr: NR

Mean Urea: NR

Prevalent: 21%

Also, age, frailty, vascular

disease, diabetes, S. Sod

Sys BP \110 mmHg

12-week follow-up

Age, Hb, SCr, S. Sod,

LVEF, AF

In-hosp mortality 6.7%

Death 13.5%
Readmission 24.2%

Similar variables
predicted mortality at
1 year

5% inpatient mortality
and 6% at 60 days
Mortality at 30 days: age,
SBP, RR, sodium, BUN,
COPD, cancer, dementia

NR

12% inpatient mortality

NR

Mean Urea: 8 mmol/L

NR

Mortality not reported

Urea not reported

Mean SCr: 159 lmol/L

Prevalent: 26%

See Fig. 2. Same

variables plus weight
and comorbidities
predicted 60-day
mortality

SCr, sys BP, age, HR and S.

Sod predicted IP mortality

Prevalent: 20%
Mean Urea: NR

Sys BP \115
Also, SCr, age and HR in
other analyses

Inpatient mortality of
2.7% v 9.0% below
and above urea
threshold

Urea C15.4 mmol/L

Mean SCr: 159 lmol/L

Comment

Strongest prognostic
markers #

Mean Urea: 11.4 mmol/L

Prevalent: 30%

Renal dysfunction

NR not reported, AF atrial fibrillation, LVSD left ventricular systolic dysfunction. Urea mean or median serum urea. To convert urea to BUN multiply by 2.8. SCr mean or median serum
creatinine in lmol/L (divide by 88.4 to convert to mg/dL). Sys BP systolic blood pressure. S. Sod serum sodium concentration, HR heart rate, RR respiratory rate. Hb haemoglobin, LVEF left
ventricular ejection fraction. For acronyms please refer to relevant reference

# therapies are excluded as these may be confounded by indication (for example, sicker patients may not receive a beta-blocker so it is unclear whether worse outcome in patients not given a
beta-blocker is due to an intrinsically worse prognosis or poorer management or both). Prevalent and incident renal dysfunction are the rates reported by investigators unless otherwise specified

Study
Year

Table 1 Prevalence of renal dysfunction in epidemiological studies of acute heart failure

Heart Fail Rev (2012) 17:133149

137

123

138

Fig. 2 Data from the OPTIMIZE-HF study. In-hospital mortality

according to systolic blood pressure (SBP) and serum creatinine (SCr)
concentration. Patients with a systolic blood pressure [100 mmHg
and serum creatinine \2.0 mg/dL (*177 lmol/L) have an inpatient
mortality of only 2.6% [54]

Renal dysfunction is common in trials of acute heart

failure (Table 2), but treatments for acute heart failure that
cause transient renal dysfunction have not generally led to
worse outcomes [27, 65]. Use of higher doses of diuretics is
often blamed for worsening renal function, and some
observational studies do suggest a link, although others do
not [66]. A randomised controlled trial comparing higher
and lower doses of furosemide confirms that using higher
doses initially causes a greater rise in creatinine but the
difference is short-lived and disappears by day 7 [46].
Regardless of diuretic dose, about 25% of patients developed worsening renal function in the study by day 7.
However, higher doses of diuretic were associated with a
somewhat better outcome despite their adverse effect on
renal function. Ultrafiltration is an alternative method to
remove fluid from a congested patient that avoids the
potential renal toxicity of diuretics. However, ultrafiltration
leads to a similar increase in creatinine, and the incidence
of worsening renal function ([0.3 mg/dL increase) was
again about 20% and similar in those assigned to diuretic or
ultrafiltration [47]. Readmission rates appeared lower with
ultrafiltration. The efficacy of vasopressin antagonism in
heart failure (EVEREST) study showed that tolvaptan, an
arginine vasopressin antagonist, could increase fluid loss,
reduce weight and lower conventional diuretic dose
requirements compared to placebo. This was associated
with a small acute and persistent rise in creatinine despite
the use of lower doses of loop diuretics in patients assigned
to tolvaptan. Interestingly, plasma concentrations of urea
fell and remained lower, perhaps reflecting reduced tubular
reabsorption [65]. The reported incidence of renal failure
was about 6% in each group. There was no difference in
prognosis between groups. More recently, the PROTECT
study, comparing placebo and rolofylline, an adenosine A1
receptor antagonist, reported a 14% incidence of worsening

123

Heart Fail Rev (2012) 17:133149

renal function, defined as a rise in serum creatinine of

0.3 mg/dL or more at day 7 that persisted until at least day
14 [27]. The incidence of worsening renal function was
somewhat greater in patients who received rolofylline, but
there was no difference in morbidity and mortality between
groups.
In summary, renal dysfunction is common in patients
with acute heart failure and is likely to be a major determinant of the response to diuretics and the deployment of
life-saving therapies such as ACE inhibitors and aldosterone receptor antagonists. However, it is the underlying
chronic severity of renal dysfunction, rather than transient
changes, which is the major determinant of prognosis,
although severe reductions in renal function that might lead
to the need for renal dialysis must surely be associated with
an adverse prognosis.

Prevalence, incidence and prognosis of renal

dysfunction in chronic heart failure
In large, epidemiologically representative patient populations
with chronic heart failure, fewer than 10% will have normal
renal function, about 60% of patients will have an estimated
GFR\60 mL/min/1.73 m2, and most of these will be in CKD
stage 3A (4559 mL/min/1.73 m2) or 3B (3045 mL/min/
1.73 m2) (Table 3). About 10% of patients will be in class 4
(1529 mL/min/1.73 m2) [1, 67]. Currently, it is rare to find
more severe renal dysfunction in outpatients with chronic
heart failure for reasons explained further below. This may
change. Major determinants of renal dysfunction are age, a
prior history of hypertension, evidence of atherosclerotic
coronary or peripheral artery disease, the severity of heart
failure, the intensity of diuretic therapy and lower diastolic
blood pressure [67]. A combined approach to management
including withdrawing aspirin [33], reducing the doses of
diuretics and ACE inhibitors and switching to carvedilol as the
preferred beta-blocker may cause a modest improvement in
chronic renal function [39]. Although in cross-sectional
studies renal dysfunction is poorly related to systolic blood
pressure, hypotension may be an important reason for a
decline in renal function in an individual patient. Clinical trials
of heart failure have, over the years, shown a similar high
prevalence of renal dysfunction despite excluding many
patients with more severe renal dysfunction [6870]
(Tables 4, 5, and 6).
Although many epidemiological studies and trials have
reported on the prevalence of renal dysfunction in patients
with chronic heart failure, remarkably few have reported on
its incidence and persistence in the outpatient setting. De
Silva et al. [67] reported that of 1,216 patients with chronic
heart failure, renal function would deteriorate within
6 months by one CKD class in 18% of patients but by two

949

433

4,133

1,448

1,327

2,033

1,069

OPTIME-HF [84]

ESCAPE [85]

EVEREST [65]

VERITAS [86]

SURVIVE [87]

PROTECT [27]

3CPO [88]

63
31

56.9

46

78

70

33

33

28

70

76

48

67

68

70

39

26

40.5

66

35

66

50

56

44

34

26

51

CAD (%)
Diabetes (%)

66

Age (years)
Women (%)

NR

16

32.4

124

24

116

27

131

28

120

20

106

24

120

Sys BP (mmHg)
LVSD (%)

NR

Incident 14.4%
NR

30-days: 16%

7-days: 10%

Death

Death/readm (CV or renal)

at 60-days: 28.6%
Mean CC 51 mL/min

180-days: 17.6%

7-days: 1.8%

180-days: 27%

Mean SCr 124 lmol/L

Urea

Death
5-days: 5%
31-days: 13%

Mean Urea 10 mmol/L

Prevalent: NR

SCr [220 lmol/L in 7%

NT-proBNP (BNP) and SCr

30-days: 4.4/32.5%

Incident: NR

7-days: 1.3/26%

Death/death or WHF

Death or CV readm 41%

All-cause mortality 26%

Mean FU 9.9 months

Baseline ? discharge renal

impairment but not WRF,
predicted death/readm

Mean SCr 115 lmol/L

NR

Rales, peripheral oedema,

S. Sod, GFR, BNP,
KCCQ

BNP, urea, resuscitation or

ventilation during hosp, S.
Sod, age, loop diuretics
dose, 6 MWD

6-month mortality 18.7%

and readm 64%

60-day mortality 9.6% and

death or readm 35.1%

Of death at 60 days: age,

SBP, NYHA, Urea, S.
Sod
Of death/readm at 60 days:
BUN, SBP, Hb, h/o PCI

Comment

Strongest prognostic
markers #

Mean Urea 10 mmol/L

Baseline CKD 37%

Incident: 2%

Mean SCr 124 lmol/L

Mean Urea 11 mmol/L

Prevalent: 27%

WRF 30%

Persistent RD 45%

Mean SCr 133 lmol/L

Mean Urea 13 mmol/L

: BUN [25%: 39%

; GFR [25%: 12%

Incidence

Mean eGFR 51 mL/min

Mean SCr 128 lmol/L

Mean Urea 9 mmol/L

Renal dysfunction

# therapies, except diuretic dose, are excluded as these may be confounded by indication. Prevalent renal dysfunction are the rates reported by investigators. NR not reported, Urea serum
urea - to convert to BUN multiply by 2.8, SCr serum creatinine in lmol/L (divide by 88.4 to convert to mg/dL), Sys BP systolic blood pressure, S. Sod serum sodium concentration, HR heart
rate, RR respiratory rate, Hb haemoglobin, BNP brain natriuretic peptide, NT-proBNP amino-terminal pro-BNP, 6MWD 6-min walk distance, KCCQ Kansas City cardiomyopathy questionnaire,
Readm readmission, LVSD left ventricular systolic dysfunction, eGFR estimated glomerular filtration rate, CV cardiovascular, CC creatinine clearance, FU follow-up, LVEF left ventricular
ejection fraction, WHF worsening renal failure, NYHA New York heart association class, CKD chronic kidney disease. For acronyms please refer to relevant reference

Study
Year

Table 2 Prevalence and/or incidence of renal dysfunction in randomised controlled trials of acute heart failure

Heart Fail Rev (2012) 17:133149

139

123

123

Values for urea and creatinine are median or mean

22

WRF worsening renal function, WRF worsening renal failure, CAD coronary artery disease, eGFR estimated glomerular filtration rate, LVEF left ventricular ejection fraction, SCr serum
creatinine, Sys BP systolic blood pressure, COPD chronic obstructive pulmonary disease, FU follow-up

Incident WRF: 13% at 6 m

57% eGFR \60 mL/min

32% SCr [130 lmol/L

Baseline serum urea

stronger predictor than
SCr. Most of prognostic
information from baseline
renal function
LVEF, COPD, urea
Mean Urea: 9 mmol/L

Mean SCr: 123 lmol/L

21
31

135 mmHg
65
71
1,216
Hull LifeLab [67]

1.4 years

Sys BP (mmHg)
LVEF (%)
CAD (%)
Diabetes (%)
Age (years)
Women (%)
N
FU
Mortality (%)
Study
Year

Table 3 Epidemiological studies of incident renal dysfunction in chronic heart failure

Renal dysfunction

Comment

Heart Fail Rev (2012) 17:133149

Strongest prognostic
markers #

140

classes in only 1%. However, renal function also improved

in some patients: by one class in 11% and by two classes in
0.6%. Both baseline serum creatinine and change in serum
creatinine at 6 months were independent predictors of longterm prognosis (Fig. 3). In the studies of left ventricular
dysfunction (SOLVD) treatment and prevention trials, 16%
of patients assigned to enalapril and 12% assigned to placebo had a rise in serum creatinine by [44 lmol/L over
2 years (p = 0.003 for the difference between enalapril and
placebo) [71]. Patients followed for four or more years had a
25% chance of worsening renal function as defined above.
Older patients and those treated with diuretics were at
increased risk of declining renal function, especially if
treated with an ACE inhibitor. Patients with diabetes were
also at increased risk of developing renal dysfunction, but
the risk was reduced by enalapril. As less than half of
patients in SOLVD received diuretics, one can assume a
substantially higher rate of worsening renal function in
patients with left ventricular dysfunction treated with
diuretics. In the carvedilol or metoprolol European trial
(COMET) study, a similar pattern was observed to the above
study of de Silva with about 8% of patients having a fall in
serum creatinine of [20 lmol/L by 1 year and 15% an
increase by more than this amount [72]. Introduction of
either metoprolol or carvedilol was associated with an acute
decline in eGFR of about 2 mL/min and then only an
average of about 1 mL/min/year thereafter, a rate very
similar to that observed in healthy older people. This may
reflect the combined effects of ACE inhibitors and betablockers on long-term renal function. Few patients with
heart failure have grossly elevated blood pressure once they
have received effective therapy, which might account for the
rather similar average rate of decline in eGFR in patients
with heart failure and the normal population. Over 5 years of
follow-up, eGFR fell below 30 mL/min in only 8.8% of
patients assigned to carvedilol and 11.3% of those assigned
to metoprolol (p = 0.020).
All substantial trials have shown that measures of renal
function are powerful markers of prognosis in heart failure.
The big remaining issues are which measure is most strongly
related to prognosis and, since risk changes over time, how
often it needs to be measured. Creatinine-based measures
have been used traditionally, but urea and cystatin-C [5, 73,
74] may be stronger markers. Evidence on both will accumulate rapidly in the next few years, and it is likely that
creatinine-based measures of renal function will be displaced, perhaps by urea since it is so widely available and
inexpensive. Use of time-dependent prognostic models
using serial measures will make the link between renal
markers and prognosis even stronger [67, 75]. Renal function
is an important determinant of plasma natriuretic peptide
concentrations [76]. Indeed, it is likely that one of the reasons
why this family of peptides provides such powerful

CHARM-added [98]

Val-HeFT [97]

A-HeFT [96]

ATLAS [69, 95]

SOLVD-T [93, 94]

SOLVD-P [40, 93]

CONSENSUS [91, 92]

V-HeFT-II [90]

20

23 years

20

2.5 years

23

30

15

11.5

3.1 years

20

30

21

31%

62

64

3.4 years

26

2,548

20%

63

5,010

1.9 years

57

40

40

0.9 years

8%

23

56

65
19

1,050

38%

3,164
3.8 years

64
21

26

19.7

38%

71

61

2,569

3.5 years

15%

83

59

4,228

35%

73

71

253

0.5 years

35%

53

60

804

30%

44

58

642

V-HeFT-I [89]

CAD (%)
Diabetes (%)

Age (years)
Women (%)

N
FU
Mortality

Study
Year

28

125

27

124

24

126

126
23

25

125

28

126

121

EF 29

126

30

119

Sys BP
(mmHg)
LVEF (%)

GFR, LVEF, BMI, Hb, DM,

bilirubin, QRS, ECG LVH,
RDW, HbA1c, BNP

eGFR \60 mL/min 33%

Incident: 7%

BNP, NYHA, SCr, age, LVEDD,

Hb, EF, CRP, BMI, low sys BP,
DM, 3rd heart sound, bilirubin,
sex, proteinuria

Age, sex, IHD, HR, SCr

Age, LVEF, DM, AF, sex

Fall in blood pressure and, to a

lesser extent, dose of furosemide
predicted WRF

LVEF, VO2, and CTR. Ventricular

arrhythmias in V-HeFT-II

Strongest prognostic markers or

other comments

Mean eGFR 57 mL/min

17% reported to have renal

insufficiency (defined by
history alone)

WRF as an AE: 8.4%

Urea: NR
Mean Scr: 121 lmol/L

# placebo 7.7% (p \ 0.01)

# enalapril 10.7%

Incident [177 lmol/L

eGFR \60 mL/min: 36%

Mean SCr 106 lmol/L

eGFR \60 mL/min: 20%

Mean SCr 106 lmol/L

SCr doubled in 3% assigned

to placebo and 11%
assigned to enalapril at
6 months

Mean SCr: 128 lmol/L

Not reported

Not reported

Renal dysfunction

Table 4 Renal dysfunction, prevalent and/or incident, reported in selected studies of vasodilators, angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers and aldosterone
receptor antagonists

Heart Fail Rev (2012) 17:133149

141

123

123
25
28

72
60

4,128
4.1 years

PEPCHF [101]

I-PRESERVE[102]

31

22

1.8 years
14%

69

69

2,737

23

55

41%

26.2

124

122
25.4

60

137

140

54

136

Sys BP
(mmHg)
LVEF (%)

WRF as an AE: 3%

GFR \60 mL/min in 33%

Mean GFR 71 mL/min

SCr mean change at

12 weeks ?0.114 mg/dl

WRF as an AE 3%

GFR \60 mL/min in 31%

Mean GFR 72 mL/min

Mean SCr 88 lmol/L

Unchanged at 1 year on
placebo : by 4 lmol/L
on perindopril

Mean SCr: 96 lmol/L

Incident: 5%

GFR \60 mL/min 35%

Renal dysfunction

NT-proBNP, age, recent hosp for

HF, DM, neutrophil count,
LVEF, COPD, eGFR, QoL, IHD,
HR

NT-proBNP, age, IHD, use of loop

diuretics

Strongest prognostic markers or

other comments

NR not reported, AF atrial fibrillation, BMI body mass index, urea serum urea - to convert to BUN multiply by 2.8, SCr serum creatinine in lmol/L (divide by 88.4 to convert to mg/dL), readm
readmission, eGFR estimated glomerular filtration rate, WRF worsening renal function, BNP brain natriuretic peptide, NT-proBNP amino-terminal pro-BNP, IHD ischaemic heart disease, DM
diabetes mellitus, hosp hospitalisation, LVEF left ventricular ejection fraction, QoL quality of life, HR heart rate, VO2 peak oxygen consumption during exercise, LVH left ventricular
hypertrophy, COPD chronic obstructive pulmonary disease, CTR cardiothoracic ratio, V-HeFT-II see list of study acronyms, NYHA New York heart association functional class, LVEDD left
ventricular end-diastolic dimension, CRP C-reactive protein, sys BP systolic blood pressure, S. Sod serum sodium concentration, CAD coronary artery disease, Hb haemoglobin

For acronyms please refer to relevant reference

Prevalent renal dysfunction are the rates reported by investigators

EMPHASIS [103]

62
19

214
2 years

55
23

39

76

16%
850

RALES [42]

28

40

21%

57

67

3,023
3.0 years

CHARM-preserved [99, 100]

CAD (%)
Diabetes (%)

Age (years)
Women (%)

N
FU
Mortality

Study
Year

Table 4 continued

142
Heart Fail Rev (2012) 17:133149

Heart Fail Rev (2012) 17:133149

143

Table 5 Renal dysfunction, prevalent and/or incident, in studies of heart rate lowering medicines and statins
Study
Year

Age (years)
Women (%)

CAD (%)
Diabetes (%)

Sys BP (mmHg)
LVEF (%)

Renal dysfunction

Strongest prognostic
markers #

DIG [104]

6,800

64

71

125

Prevalent 45%

3.1 years

22

29

29

Mean GFR 65 mL/min

Serum concentrations,
diuretics

Mean SCr: 106 lmol/L

35%

Incident: NR
MERIT-HF [105]

COPERNICUS [106]

3,991

64

35

130

Mean SCr 106 lmol/L

1.0 year

23

25

28

Mean GFR 67 mL/min

9%
2,289

63

67

123

Mean SCr 133 lmol/L

BNP, sys BP

0.9 year

21

HR, sys BP, BNP, NYHA,

anaemia

eGFR

19.9

14%
COMET [107]

3,029

62

52

126

Mean SCr 115 lmol/L

4.9 years

20

24

26

9.8% developed eGFR

\30 mL/min by
58 months

5,011

73

73

129

Mean SCr 115 lmol/L

2.7 years
30

24

29

31

eGFR \60 mL/min in 57%

Doubling SCr1%

6,558

60

68

122

Mean GFR 75 mL/min

1.9 years

24

31

29

37%
CORONA [76, 108]

SHIFT [109]

NT-proBNP, age, AF, DM

NR

17%
Prevalent renal dysfunction are the rates reported by investigators
For acronyms please refer to relevant reference
NR not reported, urea serum urea - to convert to BUN multiply by 2.8, SCr serum creatinine in lmol/L (divide by 88.4 to convert to mg/dL),
readm readmission, eGFR estimated glomerular filtration rate, WRF worsening renal function, BNP brain natriuretic peptide, NT-proBNP aminoterminal pro-BNP, IHD ischaemic heart disease, DM diabetes mellitus, hosp hospitalisation, LVEF left ventricular ejection fraction, QoL quality
of life, HR heart rate, VO2 peak oxygen consumption during exercise, CTR cardiothoracic ratio, V-HeFT-II see list of study acronyms, NYHA
New York heart association functional class, LVEDD left ventricular end-diastolic dimension, CRP C-reactive protein, sys BP systolic blood
pressure, S. Sod serum sodium concentration, Hb haemoglobin, AF atrial fibrillation, LVEF left ventricular ejection fraction

prognostic information is because they partly reflect renal

function. They might be elevated in renal dysfunction for at
least three reasons. Firstly, relative salt and water retention
could increase cardiac load. Secondly, patients with worse
renal function will tend to have worse cardiac function, either
reflecting damage from a common risk factors such as
hypertension and atherosclerosis or because of interplay
between the heart and the kidney. Finally, many peptides are
excreted by the kidney. Thus, when assessing the prognostic
value of any peptide, it is important to adjust for renal
function. In the future, this may be urea rather than creatinine, but for exploratory studies, it should be both, although
not simultaneously in the same model due to the problems of
collinearity described above.

The prevalenceincidence paradox of renal dysfunction

in heart failure
Remarkably, on average, patients with heart failure have a
similar annual rate of decline in GFR to the healthy ageing

population [72]. The reason why there are relatively few

patients with end-stage renal failure and heart failure is
because most patients die before they progress to the need
for dialysis. Those who do progress to end-stage renal
failure are often denied dialysis and have a very poor
prognosis, so the modest incidence of end-stage renal
failure in this population translates to a very small prevalence. Nonetheless, this is a difficult group of patients to
treat, and they typically spend a lot of time in hospital in
their final weeks and months of life. Improved management
of heart failure, which reduces the rate of sudden death and
death from worsening heart failure, will allow more
patients to survive to develop end-stage renal disease and
to survive longer with it. Clearly, this is a small but
important problem that is going to get bigger.
So, how can we explain the high prevalence of renal dysfunction combined with a rather normal rate of deterioration in
patients with heart failure? Treatments for heart failure may
have slowed the rate of worsening renal function to that of the
normal population, perhaps by controlling blood pressure and
other renal haemodynamic stresses. The obvious explanation

123

144

Heart Fail Rev (2012) 17:133149

Table 6 Renal dysfunction in trials of devices and monitoring

Study
Year

MADIT-II [110]

1,232

SCD-HeFT [111]

Age (years)
Women (%)

CAD (%)
Diabetes (%)

Sys BP
(mmHg)
LVEF (%)

Renal dysfunction

Strongest prognostic
markers #

65

100

NR

Urea [9 mmol/L 40%

16

36

23

SCr C124 lmol/L 34%

Age, NYHA, DM, AF,

BUN

eGFR \60 mL/min 46%

Mean SCr 97 lmol/L

2,521

60

52

119

3.8 years

24

31

25

1,520

66

58

113

1.2 years

35

44

22

813

67

38

3.0 years

27

21

26%
COMPANION
[112]

Prevalent 24%

H/o RD, HR, NYHA, IHD,

PVD, AF, LVEF, QRS,
sys BP

110

Prevalent 18%

25

Mean Urea 10.9 mmol/L

BNP, MR, IHD, NYHA,

CRT, IVMD

21%
CARE-HF
[113, 114]

Mean SCr 106 lmol/L

31%

Mean GFR 60 mL/min

TEN-HMS [115]

426

67

59

115

1.3 years

23

35

25

1,820

65

55

123

2.4 years

25

30

24

Mean SCr 136 lmol/L

Age, BNP, BMI, sys BP,

SCr, Hb, S. Sod

Mean Urea 7 mmol/L

(25% [9)

Female gender

24%
MADIT-CRT
[116]

Mean SCr: 106 lmol/L

(25% [115)
Mean eGFR 66 mL/min
RAFT [117]

1,798

66

67

NR

Mean eGFR 60 mL/min

3.3 years

17

34

23

eGFR \30 mL/min in 7%

23%

eGFR 3060 mL/min in 44%

Prevalent renal dysfunction are the rates reported by investigators

For acronyms please refer to relevant reference
NR not reported, urea serum urea - to convert to BUN multiply by 2.8, SCr serum creatinine in lmol/L (divide by 88.4 to convert to mg/dL),
readm readmission, eGFR estimated glomerular filtration rate, WRF worsening renal function, BNP brain natriuretic peptide, NT-proBNP aminoterminal pro-BNP, IHD ischaemic heart disease, DM diabetes mellitus, hosp hospitalisation, LVEF left ventricular ejection fraction, QoL quality
of life, HR heart rate, VO2 peak oxygen consumption during exercise, CTR cardiothoracic ratio, V-HeFT-II see list of study acronyms, NYHA
New York heart association functional class, LVEDD left ventricular end-diastolic dimension, CRP C-reactive protein, sys BP systolic blood
pressure, S. Sod serum sodium concentration, Hb haemoglobin, AF atrial fibrillation, QRS QRS duration on the surface electrocardiogram, LVEF
left ventricular ejection fraction

Fig. 3 Relationship between baseline SCr, WRF and death. WRF

is defined as an increase in SCr of [26.5 lmol/L (0.3 mg/dL): SCr
low B106 lmol/L (B1.2 mg/dL), medium = 106177 lmol/L (1.2
2.0 mg/dL) and high C177 lmol/L ([2.0 mg/dL)

123

for the high prevalence of renal dysfunction in heart failure is

that renal dysfunction usually precedes or coincides with the
onset of heart failure. If this is true, then the kidney can be
considered the egg and the heart the chicken in this relationship. There is a substantial body of evidence that people
with renal dysfunction have an increased risk of developing
heart failure [35, 36, 77, 78]. This may reflect common factors,
such as hypertension, diabetes and atherosclerosis, that
adversely affect both heart and renal function [13]. Alternatively, renal dysfunction may have adverse effects on cardiovascular, neuroendocrine and cytokine function that
promote the development of heart failure.
In conclusion, most patients with heart failure have mild
or moderate renal dysfunction, and in many cases, renal

Heart Fail Rev (2012) 17:133149

dysfunction precedes the onset of heart failure. Remarkably, with good treatment, the average rate of decline in
renal function is similar in patients with chronic heart
failure and healthy people of a similar age. Renal function
will improve in some and deteriorate in others, with a net
balance towards worsening renal function of about 5% of
patients/year. Urea appears to be a stronger marker of an
adverse prognosis than creatinine-based measures of renal
function. Recent evidence suggests that minor transient
increases in creatinine in the setting of acute heart failure
are not prognostically important but persistent deterioration
indicates a higher mortality. The poor prognosis of patients
with worsening renal function ensures that few require
renal dialysis, but this may change as methods to prevent
sudden death improve and new ways are found to control
fluid congestion.

References
1. Damman K, Navis G, Voors AA, Assmann SF, Smilde TDJ,
Cleland JG, Van Veldhuisen DJ, Hillege H (2007) Worsening
renal function and prognosis in heart failure: systematic review
and meta-analysis. J Card Fail 13:599608
2. House AA, Anand I, Bellomo R, Cruz D, Bobek I, Anker SD,
Aspromonte N, Bagshaw S, Berl T, Daliento L, Davenport A,
Haapio M, Hillege H, McCullough P, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A,
Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P,
Ronco C (2010) Definition and classification of cardio-renal
syndromes: workgroup statements from the 7th ADQI consensus
conference. Nephrol Dial Transplant 25(5):14161420
3. Smilde TDJ, Van Veldhuisen D, Navis G, Voors AA, Hillege
HL (2006) Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and
systolic dysfunction. Circulation 114:15721580
4. Lassus J, Harjola VP, Sund R, Siirila-Waris K, Melin J, Peuhkurinen K, Pulkki K, Nieminen MS (2007) Prognostic value of
cystatin C in acute heart failure in relation to other markers of
renal function and NT-proBNP. Eur Heart J 28(15):18411847
5. Alehagen U, Dahlstrom U, Lindahl TL (2009) Cystatin C and
NT-proBNP, a powerful combination of biomarkers for predicting cardiovascular mortality in elderly patients with heart
failure: results from a 10-year study in primary care. Eur J Heart
Fail 11(4):354360
6. Shenkman HJ, Zareba W, Bisognano JD (2007) Comparison of
prognostic significance of amino-terminal pro-brain natriuretic
peptide versus blood urea nitrogen for predicting events in patients
hospitalized for heart failure. Am J Cardiol 99(8):11431145
7. Filippatos G, Rossi J, Lloyd-Jones DM, Stough WG, Ouyang J,
Shin DD, OConnor C, Adams KF, Orlandi C, Gheorghiade M
(2007) Prognostic value of blood urea nitrogen in patients hospitalized with worsening heart failure: insights from the acute
and chronic therapeutic impact of a vasopressin antagonist in
chronic heart failure (ACTIV in CHF) study. J Card Fail
13(5):360364
8. Cauthen CA, Lipinski MJ, Abbate A, Appleton D, Nusca A,
Varma A, Goudreau E, Cowley MJ, Vetrovec GW (2008)
Relation of blood urea nitrogen to long-term mortality in
patients with heart failure. Am J Cardiol 101(11):16431647

145
9. Kazory A (2010) Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure. Am J
Cardiol 106(5):694700
10. Schrier RW (2008) Blood urea nitrogen and serum creatinine:
not married in heart failure. Circ Heart Fail 1(1):25
11. Lin HJ, Chao CL, Chien KL, Ho YL, Lee CM, Lin YH, Wu
YW, Hsu RB, Chou NK, Wang SS, Chen CY, Chen MF (2009)
Elevated blood urea nitrogen-to-creatinine ratio increased the
risk of hospitalization and all-cause death in patients with
chronic heart failure. Clin Res Cardiol 98(8):487492
12. Campbell CY, Clarke W, Park H, Haq N, Barone BB, Brotman
DJ (2009) Usefulness of cystatin C and prognosis following
admission for acute heart failure. Am J Cardiol 104(3):389392
13. de Silva R, Nikitin NP, Bhandari S, Nicholson A, Clark AL,
Cleland JGF (2005) Atherosclerotic renovascular disease in
chronic heart failure: should we intervene? Eur Heart J
26(16):15961605
14. Damman K, Voors AA, Hillege HL, Navis G, Lechat P, Van
Veldhuisen DJ, Dargie HJ (2010) Congestion in chronic systolic
heart failure is related to renal dysfunction and increased mortality. Eur J Heart Fail 2(9):974982
15. Damman K, van Deursen VM, Navis G, Voors AA, Van Veldhuisen DJ, Hillege HL (2009) Increased central venous pressure is associated with impaired renal function and mortality in a
broad spectrum of patients with cardiovascular disease. J Am
Coll Cardiol 53(7):582588
16. Magrini F, Niarchos AP (1983) Hemodynamic effects of massive peripheral edema. Am Heart J 105(1):9097
17. Niarchos AP, Magrini F (1982) Hemodynamic effects of
diuretics in patients with marked peripheral edema and mild
hypertension. Clin Pharmacol Ther 31(3):370376
18. Magrini F, Niarchos AP (1980) Ineffectiveness of sublingual
nitroglycerin in acute left ventricular failure in the presence of
massive peripheral edema. Am J Cardiol 45(4):841847
19. Doty JM, Saggi BH, Blocher CR, Fakhry I, Gehr T, Sica D,
Sugerman HJ (2000) Effects of increased renal parenchymal
pressure on renal function. J Trauma 48(5):874877
20. Doty JM, Saggi BH, Sugerman HJ, Blocher CR, Pin R, Fakhry I,
Gehr TW, Sica DA (1999) Effect of increased renal venous
pressure on renal function. J Trauma 47(6):10001003
21. Mullens W, Abrahams Z, Francis GS, Taylor DO, Starling RC,
Tang WH (2008) Prompt reduction in intra-abdominal pressure
following large-volume mechanical fluid removal improves
renal insufficiency in refractory decompensated heart failure.
J Card Fail 14(6):508514
22. Mullens W, Abrahams Z, Skouri HN, Francis GS, Taylor DO,
Starling RC, Paganini E, Tang WH (2008) Elevated intraabdominal pressure in acute decompensated heart failure: a
potential contributor to worsening renal function? J Am Coll
Cardiol 51(3):300306
23. Cleland JGF, Gillen G, Dargie HJ (1988) The effects of frusemide and angiotensin-converting enzyme inhibitors and their
combination on cardiac and renal haemodynamics in heart
failure. Eur Heart J 9(2):132141
24. Cleland JGF, Dargie HJ (1987) Heart failure, renal function, and
angiotensin converting enzyme inhibitors. Kidney Int 31:S220
S228
25. Cowburn PJ, Cleland JGF, McArthur JD, MacLean MR,
McMurray JV, Dargie HJ, Morton JJ (1999) Endothelin receptors are functionally important in mediating vasoconstriction in
the systemic circulation in patients with left ventricular systolic
dysfunction. J Am Coll Cardiol 33(4):932938
26. Cowburn P, Cleland JGF, McDonagh T, McArthur JD, Dargie
HJ, Morton JJ (2005) Comparison of selective ET(A) and
ET(B) receptor antagonists in patients with chronic heart failure.
Eur J Heart Fail 7(1):3742

123

146
27. Massie BM, OConnor CM, Metra M, Ponikowski P, Teerlink
JR, Cotter G, Davison Weatherley B, Cleland JGF, Givertz MM,
Voors AA, DeLucca PT, Mansoor GA, Salerno CM, Bloomfield
DM, Dittrich HC, for the PROTECT Investigators and Committees (2010) Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 363:14191428
28. Metra M, Cleland JG, Weatherley BD, Dittrich HC, Givertz
MM, Massie BM, OConnor C, Ponikowski P, Teerlink JR,
Voors AA, Cotter G (2010) Dyspnoea in patients with acute
heart failure: an analysis of its clinical course, determinants and
relationship to 60-day outcomes in the PROTECT pilot study.
Eur J Heart Fail 12(5):499507
29. de Boer RA, Voors AA, Muntendam P, van Gilst W, Van
Veldhuisen D (2009) Galectin-3: a novel mediator of heart
failure development and progression. Eur J Heart Fail 11:811
817
30. Good JM, Peters M, Wilkins M, Jackson N, Oakley CM, Cleland
JGF (1995) Renal response to candoxatrilat in patients with
heart failure. J Am Coll Cardiol 25(6):12731281
31. Cleland JG, Coletta AP, Buga L, Antony R, Pellicori P, Freemantle N, Clark AL (2011) Clinical trials update from the
American heart association meeting 2010: EMPHASIS-HF,
RAFT, TIM-HF, Tele-HF, ASCEND-HF, ROCKET-AF, and
PROTECT. Eur J Heart Fail 13(4):460465
32. Cleland JGF, John J, Houghton T (2001) Does aspirin attenuate
the effect of angiotensin-converting enzyme inhibitors in
hypertension or heart failure? Curr Opin Nephrol Hypertens
10:625631
33. Cleland JGF, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C,
Prentice C, Ford I, Trainer A, Poole-Wilson PA (2004) The
warfarin/aspirin study in heart failure (WASH): a randomized
trial comparing antithrombotic strategies for patients with heart
failure. Am Heart J 148:157164
34. Davie AP, Love MP, McMurray JJV (2000) Even low-dose
aspirin inhibits arachidonic acid-induced vasodilatation in heart
failure. Clin Pharm Ther 67:530537
35. Ix JH, Shlipak MG, Chertow GM, Whooley MA (2007) Association of cystatin C with mortality, cardiovascular events, and
incident heart failure among persons with coronary heart disease: data from the heart and soul study. Circulation 115(2):
173179
36. Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Jenny NS,
Psaty BM, Newman AB, Siscovick D, Shlipak MG (2005)
Cystatin C concentration as a risk factor for heart failure in older
adults. Ann Intern Med 142(7):497505
37. De Silva R, Loh PH, Rigby AS, Nikitin NP, Witte KK, Goode
K, Bhandari S, Nicholson A, Clark AL, Cleland JG (2007)
Epidemiology, associated factors and prognostic outcomes of
renal artery stenosis in chronic heart failure assessed by magnetic resonance angiography. Am J Cardiol 100(2):273279
38. Bourantas CV, Loh HP, Tweddel AC, de Silva R, Ettles DP,
Nikitin NP, Clark AL, Cleland JG (2011) Atherosclerotic disease of the aorta and its branches: prognostic implications in
patients with heart failure. Heart Fail Rev 56(34):123156
39. de Silva R, Nikitin NP, Witte KK, Rigby AS, Loh H, Nicholson
A, Bhandari S, Clark AL, Cleland JG (2007) Effects of applying
a standardised management algorithm for moderate to severe
renal dysfunction in patients with chronic stable heart failure.
Eur J Heart Fail 9:415423
40. The SOLVD Investigators (1992) Effect on enalapril on mortality and the development of heart failure in asymptomatic
patients with reduced left ventricular ejection fractions. N Engl J
Med 327:685691
41. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum
H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL,
Amann-Zalan I, DeMets DL, Carvedilol Prospective

123

Heart Fail Rev (2012) 17:133149

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

Randomized Cumulative Survival COPERNICUS) Study Group

(2002) Effect of carvedilol on the morbidity of patients with
severe chronic heart failure: results of the carvedilol prospective
randomized cumulative survival (COPERNICUS) study. Circulation 106(17):21942199
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A,
Palensky J, Witte J (1999) The effect of spironolactone on
morbidity and mortality in patients with severe heart failure.
N Engl J Med 341(10):709717
Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie
BM, OConnor CM, Rich MW, Stevenson LW, Wang Y, Young
JB, Krumholz HM (2004) Relationship between heart failure
treatment and development of worsening renal function among
hospitalized patients. Am Heart J 147:331338
Elkayam U, Mehra A, Cohen G, Tummala PP, Karalp IS, Wani
OR, Canetti M (1998) Renal circulatory effects of adenosine in
patients with chronic heart failure. JACC 32:211215
Cleland JG, Coletta AP, Buga L, Ahmed D, Clark AL (2010)
Clinical trials update from the American college of cardiology
meeting 2010: DOSE, ASPIRE, CONNECT, STICH, STOP-AF,
CABANA, RACE II, EVEREST II, ACCORD and NAVIGATOR. Eur J Heart Fail 12(6):623629
Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW,
Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO,
Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA,
Mascette AM, Braunwald E, OConnor CM (2011) Diuretic
strategies in patients with acute decompensated heart failure.
N Engl J Med 364(9):797805
Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA,
Teerlink JR, Jaski BE, Fang JC, Feller ED, Haas GJ, Anderson
AS, Schollmeyer MP, Sobotka PA, for the UNLOAD Trial
Investigators (2007) Ultrafiltration versus intravenous diuretics
for patients hospitalized for acute decompensated heart failure.
J Am Coll Cardiol 49:675683
Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang
J, Zimmer C, Orlandi C, Efficacy of Vasopressin Antagonism in
Heart Failure Outcome Study with Tolvaptan (EVEREST)
Investigators (2007) Short-term clinical effects of tolvaptan, an
oral vasopressin antagonist, in patients hospitalized for heart
failure: the EVEREST clinical status trials. JAMA 297(12):
13321343
Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K (2005)
Short-term risk of death after treatment with nesiritide for
decompensated heart failure: a pooled analysis of randomized
controlled trials. JAMA 293:19001905
Cleland JGF, Ghosh J, Tavazzi L, Freemantle N, Marijianowski
M, Kappenberger L, Gras D, Daubert J-C (2006) The effect of
CRT on blood pressure, renal function and anaemia in patients
with heart failure and cardiac dyssynchrony. Eur J Heart Fail
8(suppl):19
Al AZ, Abbas S, Moore E, Diallo O, Hauptman PJ, Bastani B
(2005) The natural history of renal function following orthotopic
heart transplant. Clin Transpl 19(5):683689
Demirozu ZT, Etheridge WB, Radovancevic R, Frazier OH
(2011) Results of heartmate II left ventricular assist device
implantation on renal function in patients requiring post-implant
renal replacement therapy. J Heart Lung Transpl 30(2):182187
Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ (2005) Risk stratification for in-hospital mortality in
acutely decompensated heart failure: classification and regression tree analysis. JAMA 293(5):572580
Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, OConnor CM, Sun JL, Yancy CW,
Young JB (2008) Predictors of in-hospital mortality in patients

Heart Fail Rev (2012) 17:133149

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

hospitalized for heart failure: insights from the organized program to initiate lifesaving treatment in hospitalized patients with
heart failure (OPTIMIZE-HF). J Am Coll Cardiol 52(5):
347356
Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV
(2003) Predicting mortality among patients hospitalized for
heart failure: derivation and validation of a clinical model.
JAMA 290(19):25812587
Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J (2007) High prevalence of renal dysfunction and its impact on outcome in 118,465 patients
hospitalized with acute decompensated heart failure: a report
from the ADHERE database. J Card Fail 13(6):422430
Cleland JGF, Swedberg K, Follath F, Komajda M, Cohen-Solal
A, Aguilar JC, Dietz R, Gavazzi A, Hobbs R, Korewicki J,
Madeira HC, Moiseyev VS, Preda I, Van Gilst WH, Widimsky
J, for the Study Group on Diagnosis of the Working Group on
Heart Failure of the European Society of Cardiology, Freemantle N, Eastaugh J, Mason J (2003) The EuroHeart failure
survey programme: survey on the quality of care among patients
with heart failure in Europe. Part 1: patient characteristics and
diagnosis. Eur Heart J 24:422463
Harjola VP, Follath F, Nieminen MS, Brutsaert D, Dickstein K,
Drexler H, Hochadel M, Komajda M, Lopez-Sendon JL, Ponikowski P, Tavazzi L (2010) Characteristics, outcomes, and
predictors of mortality at 3 months and 1 year in patients hospitalized for acute heart failure. Eur J Heart Fail 12(3):239248
Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, OConnor CM, Pieper K, Sun JL,
Yancy CW, Young JB (2008) Factors identified as precipitating
hospital admissions for heart failure and clinical outcomes:
findings from OPTIMIZE-HF. Arch Intern Med 168(8):847854
Kociol RD, Greiner MA, Hammill BG, Phatak H, Fonarow GC,
Curtis LH, Hernandez AF (2010) Long-term outcomes of medicare
beneficiaries with worsening renal function during hospitalization
for heart failure. Am J Cardiol 105(12):17861793
Smith GL, Vaccarino V, Kosiborod M, Lichtman JH, Cheng S,
Watnick SG, Krumholz HM (2003) Worsening renal function:
what is a clinically meaningful change in creatinine during
hospitalization with heart failure? J Card Fail 9(1):1325
Krumholz HM, Chen YT, Vaccarino V, Wang Y, Radford MJ,
Bradford WD, Horwitz RI (2000) Correlates and impact on
outcomes of worsening renal function in patients C65 years of
age with heart failure. Am J Cardiol 85(9):11101113
Forman DE, Butler J, Wang Y, Abraham WT, OConnor CM,
Gottlieb SS, Loh E, Massie BM, Rich MW, Stevenson LW,
Young JB, Krumholz HM (2004) Incidence, predictors at
admission, and impact of worsening renal function among
patients hospitalized with heart failure. J Am Coll Cardiol
43(1):6167
Kaminski K, Goode KM, Zhang J, Clark AL, Cleland JGF
(2009) The effect of transient deterioration of renal parameters
on distant mortality of patients hospitalized for heart failure. Eur
J Heart Fail 11:93
Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang
J, Zimmer C, Orlandi C, Efficacy of Vasopressin Antagonism in
Heart Failure Outcome Study with Tolvaptan (EVEREST)
Investigators (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial.
JAMA 297(12):13191331
Yilmaz MB, Gayat E, Salem R, Lassus J, Nikolaou M, Laribi S,
Parissis J, Follath F, Peacock WF, Mebazaa A (2011) Impact of
diuretic dosing on mortality in acute heart failure using a propensity-matched analysis. Eur J Heart Fail 13(11):12441252

147
67. De Silva R, Nikitin NP, Witte KK, Rigby AS, Goode K,
Bhandari S, Clark AL, Cleland JG (2006) Incidence of renal
dysfunction over 6 months in patients with chronic heart failure
due to left ventricular systolic dysfunction: contributing factors
and relationship to prognosis. Eur Heart J 27:569581
68. Cleland JGF, Goode K, Erhardt L, Remme WJ, Charlesworth A,
Poole-Wilson PA, Di Lenarda A, Hanrath P, Komajda M, Metra
M, Swedberg K, Torp-Pedersen C, on behalf of the COMET
Investigators (2004) A description of the clinical characteristics
at baseline of patients recruited into the carvedilol or metoprolol
European trial (COMET). Cardiovasc Drugs Ther 18(2):
139152
69. Cleland JGF, Armstrong P, Horowitz JD, Massie B, Packer M,
Poole-Wilson P, Ryden L (1999) Baseline clinical characteristics of patients recruited into the assessment of treatment with
lisinopril and survival study. Eur J Heart Fail 1(1):7379
70. Cleland JG, Daubert J-C, Erdmann E, Freemantle N, Gras D,
Kappenberger L, Tavazzi L, CARE-HF Study Steering Committee and Investigators (2005) Baseline characteristics of
patients recruited into the CARE-HF study. Eur J Heart Fail
7(2):205214
71. Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J (1999)
Predictors of decreased renal function in patients with heart
failure during angiotensin-converting enzyme inhibitor therapy:
results from the studies of left ventricular dysfunction
(SOLVD). Am Heart J 138(5 Pt 1):849855
72. Di Lenarda A, Charlesworth A, Cleland JG, et al (2004) Carvedilol better preserves renal function in heart failure than
metoprolol: COMET. Circulation 110(suppl):III-431
73. Shlipak MG, Katz R, Fried LF, Jenny NS, Stehman-Breen CO,
Newman AB, Siscovick D, Psaty BM, Sarnak MJ (2005)
Cystatin-C and mortality in elderly persons with heart failure.
J Am Coll Cardiol 45(2):268271
74. Arimoto T, Takeishi Y, Niizeki T, Takabatake N, Okuyama H,
Fukui A, Tachibana H, Nozaki N, Hirono O, Tsunoda Y, Miyashita T, Shishido T, Takahashi H, Koyama Y, Kubota I (2005)
Cystatin C, a novel measure of renal function, is an independent
predictor of cardiac events in patients with heart failure. J Card
Fail 11(8):595601
75. Komajda M, Anker S, Charlesworth A, Okonko D, Metra M, Di
Lenarda A, Remme W, Moullet C, Swedberg K, Cleland JGF,
Poole-Wilson PA (2006) The impact of new onset anaemia on
morbidity and mortality in chronic heart failure; results from
COMET. Eur Heart J 27(12):14401446
76. Cleland JG, McMurray JJ, Kjekshus J, Cornel JH, Dunselman P,
Fonseca C, Hjalmarson A, Korewicki J, Lindberg M, Ranjith N,
Van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J (2009)
Plasma concentration of amino-terminal pro-brain natriuretic
peptide in chronic heart failure: prediction of cardiovascular
events and interaction with the effects of rosuvastatin: a report
from CORONA (controlled rosuvastatin multinational trial in
heart failure). J Am Coll Cardiol 54(20):18501859
77. Moran A, Katz R, Smith NL, Fried LF, Sarnak MJ, Seliger SL,
Psaty B, Siscovick DS, Gottdiener JS, Shlipak MG (2008)
Cystatin C concentration as a predictor of systolic and diastolic
heart failure. J Card Fail 14(1):1926
78. Djousse L, Kurth T, Gaziano JM (2008) Cystatin C and risk of
heart failure in the physicians health study (PHS). Am Heart J
155(1):8286
79. OConnor CM, Abraham WT, Albert NM, Clare R, Gattis SW,
Gheorghiade M, Greenberg BH, Yancy CW, Young JB, Fonarow GC (2008) Predictors of mortality after discharge in patients
hospitalized with heart failure: an analysis from the organized
program to initiate lifesaving treatment in hospitalized patients
with heart failure (OPTIMIZE-HF). Am Heart J 156(4):662673

123

148
80. Mebazaa A, Pang PS, Tavares M, Collins SP, Storrow AB,
Laribi S, Andre S, Courtney DM, Hasa J, Spinar J, Masip J,
Peacock WF, Sliwa K, Gayat E, Filippatos G, Cleland JGF,
Gheorghiade M (2010) The impact of early standard therapy on
dyspnoea in patients with acute heart failure: the URGENTdyspnoea study. Eur Heart J 31:832841
81. Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R,
Gayat E, Burrows N, McLean A, Vilas-Boas F, Mebazaa A
(2011) Clinical presentation, management and outcomes in the
acute heart failure global survey of standard treatment
(ALARM-HF). Intensive Care Med 37(4):619626
82. Allen LA, Metra M, Milo-Cotter O, Filippatos G, Reisin LH,
Bensimhon DR, Gronda EG, Colombo P, Felker GM, Cas LD,
Kremastinos DT, OConnor CM, Cotter G, Davison BA, Dittrich HC, Velazquez EJ (2008) Improvements in signs and
symptoms during hospitalization for acute heart failure follow
different patterns and depend on the measurement scales used:
an international, prospective registry to evaluate the evolution of
measures of disease severity in acute heart failure (MEASUREAHF). J Card Fail 14(9):777784
83. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F,
Harjola VP, Hochadel M, Komajda M, Lassus J, Lopez-Sendon
JL, Ponikowski P, Tavazzi L (2006) EuroHeart failure survey
II (EHFS II): a survey on hospitalized acute heart failure
patients: description of population. Eur Heart J 27(22):
27252736
84. Cuffe MS, Califf RM, Adams KF, Benza R, Bourge R, Colucci
WS, Massie BM, OConnor CM, Pina I, Quigg R, Silver MA,
Gheorghiade M (2002) Outcomes of a prospective trial of
intravenous milrinone for exacerbations of chronic heart failure
(OPTIME-CHF) investigators. JAMA 287(12):15411547
85. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC,
Shah M, Yancy CW, Califf RM, Stevenson LW, Hill JA (2008)
Cardiorenal interactions: insights from the ESCAPE trial. J Am
Coll Cardiol 51(13):12681274
86. McMurray JJV, Teerlink JR, Cotter G, Bourge RC, Cleland JGF,
Jondeau G, Krum H, Metra M, OConnor C, Parker JD, Torre
Amione G, Van Veldhuisen D, Lewsey J, Frey A, Rainisio M,
Kobrin I, for the VERITAS Investigators (2007) Effects of tezosentan or symptoms and clinical outcomes in patients with
acute heart failure. The VERITAS randomized controlled trials.
JAMA 298(17):20092019
87. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber
FX, Pocock SJ, Thakkar R, Padley RJ, Poder P, Kivikko M, for
the SURVIVE Investigators (2007) Levosimendan versus
dobutamine for patients with acute decompensated heart failure:
the survive randomized trial. JAMA 297:18831891
88. Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J (2008) Noninvasive ventilation in acute cardiogenic
pulmonary edema. N Engl J Med 359(2):142151
89. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE,
Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH
(1986) Effect of vasodilator therapy on mortality in chronic
congestive heart failure: results of a veterans administration
cooperative study. N Engl J Med 314:15471552
90. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F,
Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S,
Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G,
Shabetai R, Haakenson C (1991) A comparison of enalapril with
hydralazine-isosorbide dinitrate in the treatment of chronic
congestive heart failure. N Engl J Med 325:303310
91. Swedberg K, Idanpaan Heikkila U, Remes J, for the CONSENSUS trial study group (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the
cooperative north Scandinavian enalapril survival study (CONSENSUS). N Engl J Med 316(23):14291435

123

Heart Fail Rev (2012) 17:133149

92. Ljungman S, Kjekshus J, Swedberg K (1992) Renal function in
severe congestive heart failure during treatment with enalapril
(the cooperative north Scandinavian enalapril survival study
[CONSENSUS] trial). Am J Cardiol 70:479487
93. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson
LW (2000) The prognostic implications of renal insufficiency in
asymptomatic and symptomatic patients with left ventricular
systolic dysfunction. J Am Coll Cardiol 35(3):681689
94. SOLVD Investigators (1991) Effect of enalapril on survival in
patients with reduced left ventricular ejection fractions adn
congestive heart failure. N Engl Med 325:303310
95. Packer M, Poole Wilson PA, Armstrong PW, Cleland JGF,
Horowitz JD, Massie B, Ryden L, Thygesen K, Uretsky B, on
behalf of the ATLAS investigators (1999) Comparative effects
of low and high doses of the angiotensin-converting enzyme
inhibitor, lisinopril, on morbidity and mortality in chronic heart
failure. Circulation 100:23122318
96. Taylor AL, Ziesche S, Yancy CW, Carson P, DAgostino RB,
Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M,
Cohn J, for the A-Heft trial investigators (2004) Combination of
isosorbide dinitrate and hydralazine in blacks with heart failure.
N Engl J Med 351:20492057
97. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial
Investigators (2001) A randomized trial of the angiotensinreceptor blocker Valsartan in chronic heart failure. N Engl J
Med 345(23):16671675
98. McMurray JJV, Ostergren J, Swedberg K, Granger CB, Held P,
Michelson EL, Olofsson B, Yusuf S, Pfeffer MA, for the Charm
Investigators and Committees (2003) Effects of candesartan in
patients with chronic heart failure and reduced left-ventricular
systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-added trial. Lancet 362(9386):767771
99. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P,
McMurray JJV, Michelson EL, Olofsson B, Ostergren J, for the
CHARM Investigators and Committees (2003) Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-preserved trial. Lancet 362:771781
100. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray
JJV, Swedberg K, Yusuf S, Granger CB, Michelson EL, Pocock
S, Pfeffer MA (2004) Effect of candesartan on cause-specific
mortality in heart failure patients. The candesartan in heart
failure assessment of reduction in mortality and morbidity
(CHARM) program. Circulation 110:21802183
101. Cleland JGF, Tendera M, Adamus J, Freemantle N, Polonski L,
Taylor J, on behalf of PEP-CHF Investigators (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF)
study. Eur Heart J 27:23382345
102. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie
R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C,
Ptaszynska A (2008) Irbesartan in patients with heart failure and
preserved ejection fraction. N Engl J Med 359:24562467
103. Zannad F, McMurray JJ, Krum H, Van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B (2011) Eplerenone in
patients with systolic heart failure and mild symptoms. N Engl J
Med 364(1):1121
104. The Digitalis Investigation Group (1997) The effect of digoxin
on mortality and morbidity in patients with heart failure. N Engl
J Med 336(8):525533
105. MERIT-HF Study Group (1999) Effect of metoprolol CR/XL in
chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet
353(9169):20012007
106. Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohasci
P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz
MK, DeMets DL, for the carvedilol prospective randomized

Heart Fail Rev (2012) 17:133149

107.

108.

109.

110.

111.

cumulative survival study group (2001) Effect of carvedilol on

survival in severe chronic heart failure. N Engl J Med
344:16511658
Poole-Wilson PA, Swedberg K, Cleland JGF, Di Lenarda A,
Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme
WJ, Torp-Pedersen C, Scherhag A, Skene A, for the COMET
investigators (2003) Comparison of carvedilol and metoprolol
on clinical outcomes in patients with chronic heart failure in the
carvedilol or metoprolol European trial (COMET): randomised
controlled trial. Lancet 362:713
Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JGF, Cornel
JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L,
Hjalmarson A, Hradec J, Janosi A, Kamensky G, Komajda M,
Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith
N, Schaufelberger M, Vanhaecke J, Van Veldhuisen D, Waagstein F, Wedel H, Wikstrand J, CORONA Group (2007) Rosuvastatin in older patients with systolic heart failure. N Engl J
Med 357(22):22482261
Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, DubostBrama A, Lerebours G, Tavazzi L (2010) Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebocontrolled study. Lancet 376(9744):875885
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS,
Daubert JP, Higgins SL, Brown MW, Andrews ML, for the
Multicenter Automatic Defibrillator Implantation Trial II
Investigators (2002) Prophylactic implantation of a defibrillator
in patients with myocardial infarction and reduced ejection
fraction. N Engl J Med 346(12):877883
Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R,
Domanski M, Troutman C, Anderson J, Johnson G, McNulty
SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein
DP, Lceri RM, Ip JH, for the Sudden Cardiac Death in Heart
Failure Trial (SCD-HeFT) Investigators (2005) Amiodarone or

149

112.

113.

114.

115.

116.

117.

an implantable cardioverter-defibrillator for congestive heart

failure. N Engl J Med 352:225237
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De
Marco T, Carson P, DiCarlo L, Demets D, White BG, DeVries
DW, Feldman AM, for the comparison of medical therapy
padihfCi (2004) Cardiac-resynchronization therapy with or
without an implantable defibrillator in advanced chronic heart
failure. N Engl J Med 350:21402150
Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D,
Kappenberger L, Tavazzi L, for the Cardiac ResynchronisationHeart Failure (CARE-HF) Study Investigators (2005) The effect
of cardiac resynchronization on morbidity and mortality in heart
failure. N Engl J Med 352(15):15391549
Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D,
Kappenberger L, Tavazzi L, on behalf of the CARE-HF study
investigators (2006) Longer-term effects of cardiac resynchronization therapy on mortality in heart failure {the cardiac resynchronization-heart failure (CARE-HF) trial extension
phase}. Eur Heart J 27(16):19281932
Cleland JGF, Louis AA, Rigby AS, Janssens U, Balk AHMM,
on behalf of the TEN-HMS investigators (2005) Noninvasive
home telemonitoring for patients with heart failure at high risk
of recurrent admission and death. The trans-European networkhome-care management system (TEN-HMS) study. J Am Coll
Cardiol 45(10):16541664
Moss AJ, Hall WJ, Cannom DS et al (2009) Cardiac-resynchronization therapy for the prevention of heart-failure events.
N Engl J Med 361(14):13291338
Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R,
Healey JS, Rouleau JL (2010) Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 363(25):
23852395

123

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