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The European Journal of Heart
Baseline characteristics of patients recruited into the CARE-HF study
J.G.F. ClelandT, J.C. Daubert, E. Erdmann, N. Freemantle, D. Gras,
L. Kappenberger, W. Klein, L. Tavazzi
On behalf of the CARE-HF study Steering Committee and Investigators
Department of Cardiology, Castle Hill Hospital, Castle Road, Cottingham, University of Hull, Kingston upon Hull, UK HU16 5JQ
Received 23 December 2004; accepted 13 January 2005
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Abstract
Background: Cardiac resynchronisation therapy (CRT) is a promising new treatment for patients with heart failure and cardiac dyssynchrony.
The CARE-HF study is a morbidity/mortality trial designed to provide conclusive evidence of the effects of CRT in patients with moderate to
severe heart failure.
Methods: A description of the baseline characteristics of patients randomised in the CARE-HF trial.
Results: 813 Patients with predominantly NYHA class III (94%) heart failure were randomised in 82 centres. Their mean age was 65
(interquartile range [IQR] 59 to 72) years, 34% were aged N70 years and 27% were women. Thirty-eight percent of the patients had
ischaemic heart disease. Mean heart rate was adequately controlled at 70 (IQR 60 to 78) bpm consistent with the use of beta-blockers. Supine
systolic blood pressure was low at 117 (IQR 105 to 130) mm Hg. Eighty-eight percent of patients had a QRS z150 ms. Mean LV ejection
fraction was 26% (IQR 22 to 29) and end-diastolic dimension was 7.2 (IQR 6.4 to 7.8) cm. Ninety-four percent of patients were receiving
loop diuretics, 95% an ACE inhibitor or angiotensin receptor blocker (ARB), 72% a beta-blocker and 56% were taking spironolactone.
Conclusions: The patients enrolled in CARE-HF had moderately severe heart failure and cardiac dysfunction with evidence of cardiac
dyssynchrony. The population appears at high risk of events despite pharmacological therapy and therefore appropriate for a trial of CRT.
D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Heart failure; Cardiac resynchronisation therapy; Dyssynchrony; Mortality and morbidity; Randomized or randomised
1. Introduction
Despite improvements in the pharmacological manage-
ment of heart failure, the prognosis of patients with major
left ventricular systolic dysfunction remains poor and
morbidity high [1]. Moreover, many patients only survive
with severe and persistent symptoms. More effective
interventions are required to add or exchange for existing
therapy. Efforts may be directed at finding interventions that
work for all patients or ones that are effective for a specific
subgroup of patients, such as those with cardiac dyssyn-
chrony, anaemia or renal dysfunction.
1388-9842/$ - see front matter D 2005 European Society of Cardiology. Publishe
doi:10.1016/j.ejheart.2005.01.010
T Corresponding author. Tel.: +44 1482 624084; fax: +44 1482 624085.
E-mail address: J.G.Cleland@hull.ac.uk (J.G.F. Cleland).
Cardiac dyssynchrony is common in patients with
heart failure due to LV systolic dysfunction and QRS
prolongation is a proposed simple ECG marker [2,3]. In a
large epidemiological study, approximately 35% of
patients with suspected heart failure had a QRS N120
ms of which 74% had major left ventricular systolic
dysfunction [4]. Thus, 26% of patients with suspected
heart failure will have both QRS N120 ms and major left
ventricular systolic dysfunction. However, a wide QRS,
especially if in the range 120–150 ms, is a relatively
crude marker of echocardiographic ventricular dyssyn-
chrony and therefore the ECG should only be used as an
approximate guide to its existence and prevalence and as
a screening tool [2,5].
Cardiac resynchronisation therapy (CRT), using atrio-
biventricular pacing, has been shown to improve symptoms
and delay the time to first hospitalisation in patients with
Failure 7 (2005) 205–214
d by Elsevier B.V. All rights reserved.
J.G.F. Cleland et al. / The European Journal of Heart Failure 7 (2005) 205–214206
cardiac dyssynchrony who have persistent, severe heart
failure despite conventional pharmacological therapy [6–9].
It is a potentially unique intervention for heart failure not
only because it can improve cardiac synchrony but also
because this may lead to marked improvement in mitral
regurgitation and, unlike pharmacological therapy, may be
especially effective for hypotensive patients [9].
Although there is already powerful evidence that CRT is
of benefit in selected patients with heart failure it is not yet
clear that CRT is superior to further attempts at manipulat-
ing pharmacological therapy, that improvement in symp-
toms is associated with a reduction in major morbidity or
mortality or that this intervention is cost-effective and
therefore a wise use of resources [10,11]. The CARE-HF
study was designed to determine the effects of CRT on long-
term, major morbidity and mortality in patients with
moderate to severe heart failure and markers of cardiac
dyssynchrony in order to address the above outstanding
issues. The baseline characteristics of the patients rando-
mised in CARE-HF are reported here.
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2. Patients and methods
2.1. CARE-HF study design
The design of this international, multi-centre study has
been reported in detail elsewhere [3]. Briefly, patients with
moderate to severe chronic heart failure despite pharmaco-
logical therapy, major left ventricular systolic dysfunction
and markers of cardiac dyssynchrony were randomised,
unblinded, to receive an atrio-biventricular stimulation
device or not. If medical treatment with ACE inhibitors,
beta-blockers and aldosterone antagonists was not already
optimal at the time of randomisation (for instance due to
intolerance of target doses) attempts were made subse-
quently to optimise this in both treatment groups. The
objective was for patients randomised to cardiac resynch-
ronisation therapy (CRT) to be implanted within 5 days of
randomisation. The primary end-point of the study is the
time to first event for the composite outcome of all-cause
mortality or hospitalisation for a major cardiovascular event,
which could include worsening heart failure, myocardial
infarction, stroke or sustained, new-onset, symptomatic
arrhythmia, adjudicated by a blinded end-point committee.
The study will be analysed on an intention-to-treat basis.
2.2. Inclusion and exclusion criteria
In order to be included, consenting patients had to have
heart failure for at least 6 weeks, be in New York Heart
Association (NYHA) class III or IV despite diuretic therapy
and other optimal treatment for heart failure and have a left
ventricular (LV) ejection faction b35% (usually by echo-
cardiography) with evidence of LV dilatation (LV end
diastolic dimension z30 mm/height in metres) and a QRS
interval N120 ms in at last two ECG leads. Additionally,
patients with a QRS 120–150 ms, in whom cardiac
dyssynchrony may be less common than in patients with
QRS N150 ms, had to have echocardiographic evidence of
dyssynchrony as evidenced by at least two of the following
three criteria assessed in a core laboratory; (a) aortic pre-
ejection delay N140 ms measured from the start of the QRS
to the onset of aortic flow using pulsed wave Doppler; (b)
interventricular mechanical delay N40 ms measured from
the onset of pulmonary ejection and aortic ejection using
pulsed wave Doppler; (c) delayed activation of the postero-
lateral left ventricular wall, defined as the maximal postero-
lateral wall inward movement, using M-mode or tissue
Doppler echo, occurring later than the start of left
ventricular filling, measured from the trans-mitral Doppler
flow signal.
Patients with permanent or persistent atrial fibrillation or
flutter were excluded, as these patients cannot benefit from
the atrio-ventricular component of resynchronisation.
Patients with a myocardial infarction, revascularisation or
other major cardiovascular event in the 6 weeks prior to
randomisation were excluded. Any patient who had received
or who had a conventional indication for a pacemaker or an
implantable defibrillator at the time of randomisation was
excluded. A complete list of other detailed entry criteria has
previously been published [3].
2.3. Methods of data collection
The data presented were recorded by the investigators in
the CARE-HF study case report form, which was designed
specifically for this study. The EuroHeart Failure question-
naire was used to assess the severity of symptoms and as a
measure of general and health related quality of life. In
addition, individual patient data were collected by three core
laboratories focusing on echocardiography, electrocardiog-
raphy and neuro-endocrine variables. However, neuro-
endocrine assays will not be conducted until the study is
complete and therefore no data can be presented at this time.
2.4. Time course of the CARE-HF study
The planning phase of the CARE-HF study began in
2000. The first implantation took place in the first quarter of
2001 and enrolment was completed in March 2003. The
original study design required a minimum follow-up of 18
months. However, in March 2004, the Data Safety and
Monitoring Board recommended the trial be extended until
May 2005. The Steering Committee was not given the
reason for this recommendation but knew that this was not
due to an insufficient number of primary outcome events.
The Steering Committee decided to close follow-up in the
main study on 30th September 2004 as planned in the
protocol. However, an extension phase with follow-up until
May 2005 with mortality as the outcome of primary interest
is planned.
J.G.F. Cleland et al. / The European Journal of Heart Failure 7 (2005) 205–214 207
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2.5. Recruitment sites
Patients were recruited from 82 centres in 12 countries
(Austria, Belgium, Denmark, Finland, France, Germany,
Italy, Netherlands, Spain, Sweden, Switzerland and United
Kingdom).
2.6. Patient subgroups
Clinicians have to manage individual patients and there-
fore the characteristics of subgroups of patients, which may
explain differences in outcome, baseline therapy received or
the effects of randomised therapy, is of interest. Accordingly,
data are presented according to age and sex. Patient age
groups were arbitrarily divided into b60 years, 60–70 years
and N70 years. Also, as the characteristics and outcome of
patients with a QRS z150 ms compared to those with QRS
120–149 ms may be of interest, data are presented for these
subgroups. For the purposes of this paper, the QRS width
reported by the core laboratory analysis was used.
2.7. Diagnostic issues
Usually, several factors conspire to induce heart failure in
an individual patient. The CARE-HF case report form
(CRF) was designed to capture this information and
encouraged the investigator to report factors contributing
to the development of heart failure or complicating its
management in addition to the primary diagnosis.
The CRF also requested information with which to
substantiate a stated diagnosis of dilated cardiomyopathy.
Conflicting definitions of dilated cardiomyopathy exist,
which renders such a diagnosis reported by an investigator
particularly open to interpretation. Accordingly, the CRF
requested information on coronary arteriography, when
available, in all patients.
Glomerular filtration rate was calculated using the
Modification of Diet in Renal Disease (MDRD) study
equation [12].
2.8. Statistics
Descriptive statistics were applied as appropriate accord-
ing to the distribution of variables. Categorical data were
reported as incidence (percent), and non-categorical data
were reported as mean/median and interquartile range. All
analyses were conducted in SAS version 9.1 (SAS Institute
Inc. Cary, NC, USA).
3. Results
834 Potentially suitable patients had information sent to
the core echo laboratory by investigators for possible
inclusion in the study. 13 Patients were rejected on the
basis of lack of dyssynchrony and 8 patients were not
randomised because they died during the run-in phase. 813
Patients were randomised in the CARE-HF study. Details of
these patients’ demographic and clinical characteristics are
shown in Tables 1–4.
3.1. Demography (Table 1)
The mean age of the patients was 65 (IQR 59 to 72) years
and 27% were women.
3.2. Aetiology and co-morbidity (Table 1)
The commonest reported aetiology of heart failure by
investigators was dilated cardiomyopathy (46% of patients).
Eighty percent of these patients were reported to have had a
coronary arteriogram and only 10 of these patients were
reported to have major coronary disease. Slightly more than
half of these patients had a history of either diabetes (22%)
or hypertension (36%). Accordingly, 148 patients (18% of
the total study population) had conclusive evidence of
idiopathic dilated cardiomyopathy as the only cause of heart
failure (Table 2). The primary cause of heart failure was
coronary artery disease in 38% of patients, most of who had
a past history of myocardial infarction and of prior coronary
revascularisation. A minority of patients had heart failure
and left ventricular systolic dysfunction due primarily to
hypertension, prior alcohol abuse or subsequent to valve
replacement or repair.
Hypertension (43%), diabetes (21%), a past history of
atrial arrhythmias (21%), renal dysfunction (18%) and
pulmonary disease (19%) were all common concomitant
conditions. Five percent of patients had a history of
sustained ventricular tachycardia or cardiac arrest, although
this may have occurred in the acute post-infarction setting.
Thirteen percent of patients had a history of syncope or
blackouts. No specific investigations for cardiac arrhythmias
were required by the protocol.
3.3. Symptoms and clinical signs (Table 3)
Although investigators reported that most patients (94%)
were in NYHA class III and only 6% in NYHA IV, direct
questioning of the patient using the EuroHeart Failure
Questionnaire identified a higher proportion in NYHA IV
(10%), whilst 22% of patients reported themselves to be in
NYHA class I or II at baseline. However, most patients
(64%) self-reported symptom severity was consistent with
NYHA class III heart failure.
Using the EuroHeart Failure Questionnaire, 49% of
patients reported severe or very severe breathlessness and
43% severe or very severe fatigue limiting their activities of
daily living, whilst 9% reported severe or very severe
breathlessness at rest. Chest pains, oedema and blackouts
were less frequently reported as severe or very severe.
Twenty-eight percent of patients rated their overall health
and 23% their quality of life as poor or very poor.
Table 1
Demography*
All b60
Years
60–70
Years
N70
Years
Male Female QRS
b150 msaQRS
z150 msa
Total recruitment, n (%) 813 (100%) 219 (27%) 315 (39%) 277 (34%) 596 (73%) 215 (27%) 92 (11%) 721 (89%)
Age (years), mean (IQR) 65 (59 to 72) 65 (59 to 72) 66 (61 to 74) 64 (59 to 70) 66 (59 to 73)
Female, n (%) 215 (27%) 50 (23%) 78 (25%) 87 (31%) 20 (22%) 195 (27%)
Primary diagnosis (only one choice is possible)
Coronary artery disease, n (%) 309 (38%) 54 (25%) 121 (38%) 134 (49%) 259 (44%) 50 (23%) 38 (42%) 271 (38%)
Myocardial infarction,
n (%)**249 (31%) 46 (21%) 100 (32%) 103 (37%) 214 (36%) 35 (16%) 33 (36%) 216 (30%)
Previous CABG, n (%)** 145 (18%) 22 (10%) 66 (21%) 57 (21%) 133 (22%) 12 (6%) 26 (28%) 119 (17%)
Previous angioplasty,
n (%)**237 (29%) 40 (18%) 89 (28%) 108 (39%) 194 (33%) 43 (20%) 31 (34%) 206 (29%)
Angina in last year, n (%)** 84 (10%) 16 (7%) 30 (10%) 38 (14%) 66 (11%) 18 (8%) 13 (14%) 71 (10%)
Hypertension, n (%) 73 (9%) 14 (6%) 31 (10%) 28 (10%) 48 (8%) 25 (12%) 10 (11%) 63 (9%)
Dilated cardiomyopathy
(by investigator), n (%)b370 (46%) 127 (58%) 143 (45%) 99 (36%) 242 (41%) 127 (59%) 36 (40%) 334 (46%)
Alcohol related 19 (2%) 11 (5%) 7 (2%) 0 17 (3%) 1 (0%) 2 (2%) 16 (2%)
Valve related, n (%) 19 (2%) 6 (3%) 7 (2%) 6 (2%) 16 (3%) 3 (1%) 1 (1%) 18 (3%)
Aetiology: other, n (%) 22 (3%) 7 (3%) 6 (2%) 9 (3%) 13 (2%) 9 (4%) 3 (3%) 19 (3%)
Associated diagnoses (more than one choice is possible)
Past history of paroxysmal
or persistent AF
169 (21%) 17 (8%) 80 (25%) 71 (26%) 134 (22%) 34 (16%) 28 (30%) 141 (20%)
Non-sustained ventricular
tachycardia
92 (11%) 17 (8%) 39 (12%) 36 (13%) 80 (13%) 12 (6%) 9 (10%) 83 (12%)
Sustained VT or
prior cardiac arrest
43 (5%) 5 (2%) 16 (5%) 22 (8%) 33 (6%) 10 (5%) 2 (2%) 41 (6%)
History of hypertension,
n (%)
353 (43%) 78 (36%) 144 (46%) 131 (47%) 256 (43%) 97 (45%) 35 (38%) 318 (44%)
Valve replacement or
repair (past or current)
38 (5%) 7 (3%) 19 (6%) 12 (4%) 30 (5%) 8 (4%) 1 (1%) 37 (5%)
Previous stroke or TIA,
n (%)
101 (12%) 22 (10%) 34 (11%) 45 (16%) 79 (13%) 22 (10%) 14 (15%) 87 (12%)
Syncope or blackouts 108 (13%) 27 (12%) 40 (13%) 41 (15%) 86 (14%) 22 (10%) 15 (16%) 93 (13%)
Renal dysfunction 146 (18%) 15 (7%) 62 (20%) 66 (25%) 111 (19%) 35 (16%) 21 (23%) 125 (17%)
Asthma or other chronic
lung disease
157 (19%) 32 (15%) 65 (21%) 60 (22%) 117 (20%) 40 (19%) 13 (14%) 144 (20%)
Diabetes on insulin or oral
hypoglycaemic therapy
171 (21%) 37 (17%) 85 (27%) 49 (18%) 118 (20%) 53 (25%) 25 (27%) 146 (20%)
a Data reported are the evaluation of the central therapy delivery core laboratory rather than from the investigator. Minor differences were recorded.b See Table 2 for further analysis.* Minor discrepancies in patient numbers reflect incomplete data at time of writing.** Components of coronary artery disease.
J.G.F. Cleland et al. / The European Journal of Heart Failure 7 (2005) 205–214208
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Few patients had a low body mass index (BMI), an
indication of advanced cardiac cachexia. Twenty-three
percent of patients were obese with a BMIN30. Mean heart
Table 2
Investigator reported DCMa
N %
1 Investigator report of DCM 370 100%
2 Coronary angiography not done 75 20%
3 Coronary angiography showing CAD 10 3%
4 Coexistent hypertension 133 36%
5 Coexistent diabetes 83 22%
6 Heart muscle disease with known
potential aetiology (any of 3–5 apply)
182 49%
7 Proven idiopathic dilated cardiomyopathy
(none of 2–6 apply)
148 40%
a DCM—dilated cardiomyopathy.
rate was adequately controlled at 70 (IQR 60 to 78) bpm
consistent with the use of beta-blockers. Supine systolic
blood pressure was low at 117 (IQR 105 to 130) and fell to
113 (IQR 100 to 125) mm Hg on standing, consistent with a
population of patients with moderately severe heart failure
and a poor prognosis. Peripheral oedema, a 3rd heart sound,
an elevated jugular venous pressure and pulmonary rales
were reported in only a minority of cases suggesting a low
rate of congestion and clinical stability of the patients when
enrolled into the trial.
3.4. Investigation (Table 4)
Eighty-nine percent of patients had a QRS z150 ms. The
overall mean QRS width was 165 (IQR 152 to 180) ms and
the mean PR interval was 196 (IQR 178 to 208) ms. Mean
Table 3
Signs and symptoms
All b60 Years 60–70 Years N71 Years Male Female QRS b150 ms QRS z150 ms
Height (cm), mean (IQR) 170 (163 to 176) 172 (168 to 178) 169 (162 to 176) 168 (162 to 174) 173 (168 to 178) 160 (156 to 165) 170 (165 to 177) 170 (163 to 176)
Weight (kg), mean (IQR) 78 (67 to 88) 82 (71 to 92) 79 (67 to 90) 74 (64 to 83) 81 (71 to 90) 69 (58 to 79) 80 (68 to 90) 78 (67 to 88)
BMI, mean (SD) 27 (24 to 30) 28 (25 to 31) 28 (24 to 30) 26 (23 to 29) 27 (24 to 30) 27 (23 to 31) 28 (24 to 31) 27 (24 to 30)
BMIN30, n (%) 191 (23%) 67 (31%) 80 (25%) 44 (16%) 131 (22%) 60 (28%) 28 (30%) 163 (23%)
BMIb20, n (%) 65 (8%) 9 (4%) 22 (7%) 32 (12%) 43 (7%) 20 (9%) 4 (4%) 61 (8%)
Heart rate (bpm), mean (SD) 70 (60 to 78) 70 (60 to 77) 72 (62 to 80) 69 (60 to 78) 70 (60 to 77) 72 (62 to 81) 71 (58 to 79) 70 (61 to 78)
Lying systolic BP (mm Hg),
mean (SD)
117 (105 to 130) 115 (102 to 125) 117 (104 to 129) 121 (110 to 130) 117 (105 to 130) 119 (106 to 130) 116 (110 to 125) 118 (105 to 130)
Lying diastolic BP (mm Hg),
mean (SD)
70 (60 to 80) 71 (65 to 80) 71 (60 to 80) 69 (60 to 80) 71 (61 to 80) 69 (60 to 80) 71 (60 to 80) 70 (60 to 80)
Standing systolic BP
(mm Hg), mean (SD)
113 (100 to 125) 112 (100 to 120) 112 (100 to 125) 116 (100 to 126) 113 (100 to 125) 114 (100 to 125) 111 (100 to 120) 114 (100 to 125)
Standing diastolic BP
(mm Hg), mean (SD)
70 (60 to 80) 72 (65 to 80) 70 (60 to 80) 68 (60 to 78) 70 (60 to 80) 69 (60 to 78) 68 (60 to 80) 70 (60 to 80)
Pulmonary rales, n (%) 96 (12%) 10 (5%) 39 (12%) 47 (17%) 65 (11%) 31 (14%) 15 (16%) 81 (11%)
Peripheral oedema, n (%)
dmore than noneT150 (18%) 29 (13%) 60 (19%) 61 (22%) 103 (17%) 47 (22%) 16 (17%) 134 (19%)
3rd Heart sound, n (%) 162 (20%) 36 (16%) 64 (20%) 62 (22%) 118 (20%) 44 (20%) 21 (23%) 141 (20%)
JVP elevated, n (%) 145 (18%) 30 (14%) 56 (18%) 59 (21%) 107 (18%) 38 (18%) 17 (18%) 128 (18%)
Patient-reported symptom severity
NYHA I 42 (5%) 13 (6%) 13 (4%) 16 (6%) 33 (6%) 9 (4%) 9 (10%) 33 (5%)
NYHA II 133 (16%) 50 (23%) 50 (16%) 33 (12%) 101 (17%) 32 (15%) 13 (15%) 120 (17%)
NYHA III 523 (64%) 138 (63%) 203 (64%) 181 (65%) 389 (65%) 132 (62%) 59 (64%) 464 (64%)
NYHA IV 85 (10%) 14 (6%) 34 (11%) 37 (13%) 59 (9%) 32 (15%) 5 (5%) 80 (11%)
Proportion rating symptoms as severity 5 or 6 on a 6 point scale
Swelling of ankles or legs 93 (11%) 26 (10%) 40 (13%) 32 (12%) 58 (10%) 35 (16%) 8 (9%) 85 (12%)
Breathlessness at rest 72 (9%) 16 (7%) 31 (10%) 25 (9%) 47 (8%) 25 (12%) 11 (12%) 61 (8%)
Breathlessness limiting ADL 399 (49%) 98 (45%) 170 (54%) 131 (47%) 269 (45%) 130 (60%) 35 (38%) 364 (50%)
Fatigue limiting ADL 346 (43%) 79 (36%) 149 (47%) 118 (43%) 234 (39%) 101 (52%) 31 (34%) 315 (44%)
Chest pain with ADL 94 (12%) 28 (13%) 34 (11%) 32 (12%) 68 (11%) 26 (12%) 6 (7%) 88 (12%)
Proportion reporting severity 6 or 7 on a 7 point scale
Rating of overall health 229 (28%) 68 (31%) 91 (29%) 70 (25%) 162 (27%) 67 (31%) 26 (28%) 203 (28%)
Rating of quality of life 183 (23%) 58 (27%) 70 (22%) 55 (20%) 129 (22%) 54 (25%) 20 (22%) 163 (23%)
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Table 4
Investigations
All b60 Years 60–70 Years N71 Years Male Female QRSb 150 ms QRSz150 ms
PR Interval (ms),
mean (IQR)
196 (178 to 208) 189 (168 to 200) 196 (180 to 210) 201 (180 to 215) 200 (180 to 212) 186 (165 to 200) 193 (170 to 200) 196 (180 to 208)
QRS width (ms) ,
mean (IQR)
165 (152 to 180) 164 (152 to 180) 165 (150 to 180) 166 (154 to 178) 165 (152 to 180) 165 (154 to 177) ~ ~
Tests of cardiac function
LVEF (%), mean (IQR) 26 (22 to 29) 26 (21 to 29) 25 (21 to 29) 26 (22 to 30) 26 (22 to 29) 25 (21 to 29) 28 (24 to 31) 25 (21 to 29)
LVEDD (mm),
mean (IQR)
7.2 (6.4 to 7.8) 7.2 (6.5 to 7.8) 7.5 (6.5 to 8.1) 6.9 (6.1 to 7.5) 7.3 (6.4 to 8.0) 6.9 (6.2 to 7.7) 6.8 (6.2 to 7.4) 7.3 (6.4 to 7.9)
LVEDD/Height
(mm/m), mean (IQR)
4.3 (3.8 to 4.6) 4.2 (3.8 to 4.6) 4.4 (3.9 to 4.9) 4.1 (3.7 to 4.4) 4.2 (3.8 to 4.6) 4.3 (3.9 to 4.8) 4.0 (3.7 to 4.4) 4.3 (3.8 to 4.7)
Angiography
performed, n (%)
622 (77%) 187 (85%) 252 (80%) 182 (66%) 466 (78%) 155 (72%) 72 (78%) 550 (76%)
Laboratory blood tests
Haemoglobin (g/dl),
median (IQR)
13.5 (12.4 to 14.7) 14.0 (13.1 to 15.1) 13.6 (12.6 to 14.8) 13.0 (11.9 to 14.2) 13.8 (12.8 to 14.9) 12.8 (11.8 to 13.7) 13.3 (12.7 to 14.3) 13.5 (12.4 to 14.7)
White blood cell
count (�109/L)
median (IQR)
7.6 (6.2 to 9.1) 7.5 (6.3 to 9.2) 7.6 (6.3 to 9.0) 7.5 (6.1 to 9.1) 7.6 (6.2 to 9.2) 7.6 (6.3 to 8.7) 7.3 (6.1 to 8.9) 7.6 (6.2 to 9.1)
C Reactive protein
(mg/l) , median
(IQR)
6 (1 to 14) 6 (1 to 13) 6 (1 to 13) 8 (1 to 17) 6 (1 to 13) 7 (1 to 17) 7 (1 to 14) 6 (1 to 14)
Sodium (mmol/l),
median (IQR)
139 (136 to 141) 138 (136 to 140) 138 (136 to 141) 139 (137 to 141) 138 (136 to 141) 139 (137 to 141) 139 (137 to 141) 139 (136 to 141)
Potassium (mmol/l),
median (IQR)
4.4 (4.1 to 4.7) 4.2 (3.9 to 4.6) 4.4 (4.1 to 4.7) 4.5 (4.1 to 4.8) 4.4 (4.1 to 4.7) 4.3 (4.1 to 4.7) 4.4 (4.1 to 4.8) 4.4 (4.1 to 4.7)
Urea (mmol/l),
median (IQR)
10.9 (7.1 to 17.8) 8.4 (5.9 to 15.0) 11.7 (7.4 to 19.3) 11.8 (8.4 to 18.9) 11.2 (7.2 to 17.8) 10.0 (6.8 to 17.5) 12.5 (7.5 to 18.7) 10.8 (7.0 to 17.5)
Creatinine (Amol/l),
median (IQR)
106 (88 to 133) 94 (80 to 111) 106 (90 to 133) 118 (99 to 147) 111 (94 to 138) 94 (80 to 115) 112 (96 to 137) 106 (88 to 133)
Glomerular filtration
rate (ml/min*),
median (IQR)
60 (46 to 73) 72 (59 to 87) 60 (48 to 71) 49 (40 to 62) 62 (47 to 76) 55 (44 to 67) 58 (46 to 70) 60 (46 to 73)
=* Actually mL/min per 1.73m2.
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J.G.F. Cleland et al. / The European Journal of Heart Failure 7 (2005) 205–214 211
LV ejection fraction was depressed at 26 (IQR 22 to 29)%
and end-diastolic dimension was increased at 7.2 (IQR 6.4
to 7.8) mm. Seventy-seven percent of patients had had a
coronary arteriogram. The median haemoglobin was 13.5 g/
dl but 25% of patients had a value V12.4 g/dl. The median
serum sodium was 139 mmol/l but 25% of patients had
values V136 mmol/l indicating a high prevalence of
hyponatraemia. The median value of serum creatinine was
106 lmol/l but 25% of patients had values z133 lmol/l,
indicating a high prevalence of renal dysfunction. These
laboratory features are all consistent with a patient
population with moderately severe heart failure.
3.5. Baseline treatment (Table 5)
Ninety-four percent of patients were receiving loop
diuretics and 46% were taking z80 mg/day of furosemide
Table 5
Medication
All b60 Years 60–70 Years z7
Diuretic ALL, n (%) 806 (99%) 216 (99%) 314 (99%) 27
Loop diuretics, n (%) 766 (94%) 196 (90%) 300 (95%) 26
Proportion taking z80 mg
of furosemide or equivalent
352 (46%) 80 (37%) 144 (46%) 12
Thiazide (or related) diuretic,
n (%)
117 (14%) 36 (16%) 51 (18%) 3
Proportion on loop/thiazide
combination
94 (12%) 25 (11%) 44 (14%) 2
Spironolactone, n (%) 457 (56%) 138 (63%) 179 (57%) 13
Spironolactone at least
25 mg daily, n (%)
406 (50%) 131 (60%) 154 (49%) 12
Other diuretics, n (%) 44 (5%) 13 (6%) 21 (7%) 1
ACE inhibitor, n (%) 647 (80%) 187 (85%) 255 (81%) 20
ACE inhibitor at least half
target dose n, (%)
309 (38%) 110 (50%) 120 (38%) 7
Angiotensin-II receptor
antagonist, n (%)
136 (17%) 28 (13%) 57 (18%) 5
ACE or angiotensin-II, n (%) 770 (95%) 213 (97%) 302 (96%) 25
Beta-blockers, n (%) 586 (72%) 184 (84%) 223 (71%) 17
Beta-blocker at least half
target dose, n (%)
321 (39%) 116 (53%) 112 (36%) 9
Digitalis (digoxin), n (%) 346 (43%) 107 (49%) 148 (47%) 9
Amiodarone, n (%) 141 (17%) 27 (12%) 60 (19%) 5
Other anti-arrhythmic
agents, n (%)
4 (0%) 3 (1%) 0
Nitrate, n (%) 256 (31%) 44 (20%) 103 (33%) 10
Calcium channel
blocker, n (%)
42 (5%) 8 (4%) 13 (4%) 2
Insulin, n (%) 85 (10%) 18 (8%) 43 (14%) 2
Oral hypoglycaemic, n (%) 90 (11%) 20 (9%) 44 (14%) 2
Insulin+oral
hypoglycaemic, n (%)
13 (2%) 2 (1%) 7 (2%)
Statins, n (%) 321 (39%) 85 (39%) 128 (41%) 10
Other lipid lowering
agents, n (%)
62 (8%) 20 (9%) 19 (6%) 2
Anticoagulants, n (%) 277 (34%) 90 (41%) 112 (36%) 7
Aspirin, n (%) 360 (44%) 73 (33%) 133 (42%) 15
Other antiplatelet
agents, n (%)
55 (7%) 8 (4%) 24 (8%) 2
Other NSAIDS, n (%) 20 (2%) 2 (1%) 7 (2%) 1
Allopurinol 148 (18%) 35 (16%) 63 (20%) 5
(or equivalent of another diuretic). Twelve percent were
taking loop and thiazide diuretics in combination. Fifty-six
percent were taking spironolactone, 95% an ACE inhibitor
or angiotensin receptor blocker (ARB) and 72% a beta-
blocker. Only 13 patients were on a combination of ACE
inhibitor and ARB. Digoxin was used in 43% of patients
and amiodarone in 17%. Nitrates, statins, anti-coagulants
and aspirin were also commonly prescribed.
3.6. Influence of age (Tables 1–5)
Older patients were more often women and were more
likely to have ischaemic heart disease. Older patients had
more co-morbidities, a higher systolic blood pressure and a
substantially lower BMI. Renal dysfunction, low haemo-
globin and a past history of atrial arrhythmias were also
more common in older patients. Older patients tended to
1 Years Male Female QRS b150 ms QRS z150 ms
5 (99%) 590 (99%) 215 (100%) 91 (99%) 715 (99%)
9 (97%) 564 (95%) 201 (93%) 86 (94%) 680 (94%)
8 (46%) 266 (45%) 86 (40%) 36 (39%) 316 (44%)
0 (11%) 82 (14%) 36 (16%) 16 (17%) 101 (14%)
5 (9%) 66 (11%) 28 (13%) 13 (14%) 81 (11%)
9 (50%) 330 (55%) 126 (59%) 42 (46%) 415 (58%)
0 (43%) 288 (48%) 117 (54%) 38 (41%) 368 (51%)
0 (4%) 33 (6%) 11 (5%) 9 (10%) 35 (5%)
4 (74%) 475 (80%) 171 (80%) 72 (78%) 575 (80%)
8 (28%) 220 (37%) 88 (41%) 37 (40%) 272 (38%)
1 (18%) 101 (17%) 35 (16%) 14 (15%) 122 (17%)
4 (92%) 567 (95%) 202 (94%) 84 (91%) 686 (95%)
8 (64%) 424 (71%) 161 (75%) 70 (76%) 516 (72%)
3 (34%) 225 (38%) 96 (45%) 37 (40%) 284 (39%)
1 (33%) 244 (41%) 102 (47%) 34 (37%) 312 (43%)
3 (19%) 121 (20%) 19 (9%) 18 (20%) 123 (17%)
1 (0%) 4 (1%) 0 0 4 (1%)
9 (40%) 190 (32%) 66 (31%) 40 (43%) 216 (30%)
1 (8%) 32 (5%) 10 (5%) 2 (2%) 40 (6%)
4 (9%) 56 (9%) 29 (13%) 13 (14%) 72 (10%)
6 (9%) 62 (10%) 28 (13%) 15 (16%) 75 (10%)
4 (1%) 9 (2%) 4 (2%) 1 (1%) 12 (2%)
8 (39%) 248 (42%) 73 (34%) 40 (43%) 281 (39%)
3 (8%) 49 (8%) 13 (6%) 9 (10%) 53 (7%)
5 (27%) 216 (36%) 61 (28%) 30 (33%) 247 (34%)
3 (55%) 269 (45%) 90 (42%) 46 (50%) 314 (44%)
3 (8%) 44 (7%) 11 (5%) 7 (8%) 48 (7%)
1 (4%) 14 (2%) 6 (3%) 2 (2%) 18 (3%)
0 (18%) 127 (21%) 21 (10%) 15 (16%) 133 (18%)
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Table 6
Comparisons between trials
Miracle
(8)
Miracle-ICD
(7)
Companion
(9)
Care-HF
Number of patients
assigned to
control group
225 141 308 404
Number of patients
assigned to CRT
228 NA 617 409
Number of patients
assigned to
CRT-D
NA 142 595 NA
Duration (months) 6 6 11.9–16.5a 29.4
Mean age (years) 64 67 67 65
Women (%) 10 23 33 27
Ischaemic heart
disease (%)
54 70 55 38
NYHA III (%)b 90 89 86 94
Minnesotac 59 56 NA 45
LVEF (%) 22 24 22 26
LVEDD (cm) 70 76 67 7.2
QRS (ms) 166 164 160 165
Heart rate (bpm) 74 71 72 70
Systolic BP
(mm Hg)
115 114 111 117 (L)/
113 (S)
Diuretics (%) 94 94 95
(loop)
99
(94 loop)
Digoxin (%) 79 NA NA 43
ARB/ACEi (%) 92 91 89 95
Beta-blockers (%) 59 60 68 72
Spironolactone 54 56d
NA=not available.
(L)= lying and (S)=standing.
Loop= loop diuretics.a Significantly different lengths of follow-up depending on treatment
group and endpoint assessed. Shortest duration was for death or hospital-
isation in the control group (11.9 months) and the longest for mortality
alone in the CRT group (16.5 months).b Investigator reported.c Score ranges from 0 to 105 with higher scores indicating more severe
impairment. Derived from reference [18].d Does not include patients on canrenoate.
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report a similar severity of symptoms and quality of life.
Ventricular function appeared similar across all three age
groups (Table 5).
Over 90% of patients in each age group were receiving
an ACE inhibitor or ARB. Older patients were slightly more
likely to receive an ARB, but this did not appear to be due to
the higher proportion of women among older subjects.
Eighty-four percent of patients aged b60 years were
receiving a beta-blocker but only 64% of those aged N70
years. Some of this difference could be accounted for by the
higher reported prevalence of pulmonary disease among
older patients. Older patients were also less likely to receive
spironolactone, but this may be explained by their higher
serum potassium and a higher prevalence of renal dysfunc-
tion. Despite a more frequent history of atrial arrhythmias,
older patients were less likely to receive digoxin, possibly
due to the greater fear of toxicity, higher prevalence of renal
dysfunction and lower prevalence of dilated cardiomyop-
athy. Older patients were less likely to receive oral
anticoagulants and more likely to receive aspirin, reflecting
differences in the aetiology of heart failure and fears about
the safety of anti-coagulants in elderly patients.
3.7. Differences between men and women (Tables 1–5)
Women tended to be slightly older and were less likely to
have ischaemic heart disease. The proportion of men and
women with co-morbid medical conditions was generally
similar, although the prevalence of diabetes tended to be
higher in women. Symptoms and signs of heart failure and
ECG measurements were generally similar in men and
women. LV ejection fraction and end-diastolic dimensions
were also similar even after correction for height. Although
almost all the women in this study were post-menopausal,
haemoglobin was about 1 g/dl lower than in men. Although
serum creatinine was lower in women, calculated glomer-
ular filtration rate, which is corrected for body surface area,
was similar in men and women. Treatment patterns in men
and women, including spironolactone, beta-blockers, ACE
inhibitors, ARBs and digoxin, were also similar.
3.8. Impact of QRS width (Tables 1–5)
Relatively few patients with QRS 120–149 ms were
recruited and therefore caution should be applied to any
apparent differences. In general, patient characteristics and
treatment were similar in patients with QRS above or below
150 ms by core laboratory assessment. Patients with QRS
z150 ms had greater left ventricular dimension and lower
ejection fraction but did not report worse symptoms or
quality of life.
3.9. Comparisons with other studies (Table 6)
A comparison between key characteristics of patients in
CARE-HF and COMPANION are shown in Table 6. The
patients randomised in CARE-HF are similar to those in
other recent large trials of CRT.
4. Discussion
The CARE-HF study has successfully recruited a large
cohort of patients with major left ventricular systolic
dysfunction and cardiac dyssynchrony who generally had
persistent troublesome symptoms of heart failure despite
conventional pharmacological therapy. The patients
recruited had many other adverse prognostic features
including a low arterial pressure and a high proportion
of patients had anaemia, hyponatraemia and renal dys-
function. The requirement for a reduced LV ejection
fraction accounts for the younger age of the patients and
preponderance of men recruited compared to epidemio-
logical studies [13]. Older patients and women with heart
failure are more likely to have preserved LV systolic
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function. Current pharmacological therapy had not
adequately addressed the symptomatic needs of the
majority of these patients and further effective interven-
tions are required.
Subgroup analysis of baseline characteristics identified
few clinically relevant differences between men and women
or between those with QRS duration above or below 150
ms. However, there were major differences in characteristics
according to age. Older patients were more likely to have
ischaemic heart disease and other adverse prognostic
markers such as low BMI, anaemia and renal dysfunction.
They were also less likely to receive either a beta-blocker or
spironolactone. The lower likelihood of receiving effective
treatment despite expert care and a worse prognostic profile
suggest that more elderly patients were intolerant of
pharmacological interventions due to pulmonary disease,
hypotension or renal dysfunction. CRT may provide an
effective treatment for these patients where pharmacological
therapy is not tolerated.
Patients in CARE-HF appear, on average, to be some-
what less symptomatic than in the MIRACLE trials [7,8].
This suggests that investigators in CARE-HF may already
have been extrapolating the results of trials in severe heart
failure to recruit patients with milder symptoms and were,
perhaps, already implanting CRT devices in some sicker
patients in their usual clinical practice, thereby excluding
such patients from the randomised study. If CRT proves
effective in CARE-HF, this may provide evidence of benefit
in a broader symptomatic group than previously studied.
However, cardiac function was markedly depressed in this
population with N90% of patients having an LVEF b30%
and one quarter an LVEF b22%.
This population would be expected to obtain symptom
benefit from CRT. The CARE-HF study should be able to
confirm an effect on symptoms, although as the study is
open-label, this outcome cannot be measured as robustly as
in the MUSTIC [6] and MIRACLE [8] trials in which
blinded evaluations were conducted. Nonetheless, unlike
previous shorter term studies, investigators have been
encouraged to optimise continuously pharmacological ther-
apy in both arms of the study. If CRT can improve
symptoms to a greater extent than pharmacological treat-
ment alone, despite the strenuous efforts of investigators,
this will provide further evidence of a unique role for CRT.
It is also possible that CRT will increase the proportion of
patients in whom ACE inhibitors, beta-blockers, aldosterone
antagonists and ARBs can be introduced or titrated to the
target dose by preventing excessive bradycardia and
increasing systolic blood pressure [9] and therefore renal
perfusion pressure.
The COMPANION trial suggested that CRT could delay
hospitalisation, especially for heart failure, and the trend to
reduced mortality came close to statistical significance.
However, the data presented on the COMPANION study
so far must be interpreted with caution for several reasons
[9]. Firstly, all-cause hospitalisation is a dsoft,T often trivial
end-point. The dharderT end-point of hospitalisation for
heart failure reported in the paper was combined with
cause-specific rather than all-cause mortality. The outcome
of all-cause mortality and hospitalisation for heart failure
has not been reported, although would almost certainly be
positive. CRT combined with a defibrillator (CRT-D) did
reduce mortality compared to medical therapy but the
effect was clearly not superior to CRT only. If CRT and
CRT-D exert similar effects on mortality then the less
expensive, lower morbidity intervention should be pre-
ferred [14]. Finally, the robustness of the result of a trial is
related, among other factors, to the sample size. The
randomisation design of the COMPANION trial allocated
only one patient to the control group for every two
assigned to the other two groups. Thus only 308 patients
or 20% of patients were assigned to control, reducing the
power of the study. A number of flawed meta-analyses of
CRT have been published and criticised [10,15–17].
Robust meta-analysis does not yet confirm a benefit of
CRT on either hospitalisation for worsening heart failure or
death [10,15–17]. The CARE-HF study will resolve
whether the trends to effects of CRT on major morbidity
and mortality suggested by the trials that have reported so
far have occurred by chance or represent an important
therapeutic advance.
References
[1] Cleland JGF, Clark AL. Delivering the cumulative benefits of triple
therapy for heart failure. Too many cooks will spoil the broth. J Am
Coll Cardiol 2003;42:1226–33.
[2] Baldasseroni S, et al, on behalf of the Italian Network on Congestive
Heart Failure Investigators. Left bundle-branch block is associated
with increased 1-year sudden and total mortality rate in 5517
outpatients with congestive heart failure: a report from the Italian
network on congestive heart failure. Am Heart J 2002;143:398–405.
[3] Cleland JGF, Kappenberger LJ, Tavazzi L, Klein W, Erdmann E.
Design and methodology of the CARE-HF trial. A randomised trial of
cardiac resynchronisation in patients with heart failure and ventricular
dyssynchrony. Eur J Heart Fail 2001;3:481–9.
[4] Khan N, et al, on behalf of the EuroHeart Failure Investigators. The
EuroHeart failure survey: the value of the ECG in the evaluation of
heart failure. Eur Heart J 2002;23:707 [Suppl].
[5] Cleland JGF, Ghosh J, Freemantle N, Kaye GC, Nasir M, Clark AL,
et al. Clinical trials update and cumulative meta-analyses from the
American College of Cardiology: WATCH, SCD-HeFT, DINAMIT,
CASINO, INSPIRE, STRATUS-US, RIO-LIPIDS and cardiac
resynchronisation therapy in heart failure. Eur J Heart Fail 2004;
6:501–8.
[6] Cazeau S, et al, Multisite stimulation in cardiomyopathies (MUSTIC)
study investigators. Effects of multisite biventricular pacing in patients
with hear failure and intraventricular conduction delay. N Engl J Med
2001;344:873–80.
[7] Young J, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff
B, et al. Combined cardiac resynchronisation and implantable
cardioversion defibrillation in advanced chronic heart failure. The
MIRACLE ICD trial. JAMA 2003;289:2685–94.
[8] Abraham WT, et al, for the MIRACLE Study Group. Cardiac
resynchronisation in chronic heart failure. N Engl J Med 2002;
346(24):1845–53.
J.G.F. Cleland et al. / The European Journal of Heart Failure 7 (2005) 205–214214
[9] Bristow MR, for the comparison of medical therapy pacing and
defibrillation in heart failure (COMPANION) investigators. Cardiac-
resynchronization therapy with or without an implantable defibrillator
in advanced chronic heart failure. N Engl J Med 2004;350:2140–50.
[10] Calvert M, et al. Cardiac Resynchronisation in patients with
symptomatic heart failure. Ann Int Med [in press].
[11] Cleland JGF, Ghosh J, Khan NK, Ghio S, Tavazzi L, Kaye G. Multi-
chamber pacing: a perfect solution for cardiac mechanical dyssyn-
chrony? Eur Heart J 2003;24(5):384–90.
[12] Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al.
National kidney foundation practice guidelines for chronic kidney
disease: evaluation, classification, and stratification. Ann Intern Med
2003;139(2):137–47.
[13] Cleland JGF, et al, for the Study Group on Diagnosis of the Working
Group on Heart Failure of the European Society of Cardiology. The
EuroHeart failure survey programme: survey on the quality of care
among patients with heart failure in Europe: Part 1. Patient character-
istics and diagnosis. Eur Heart J 2003;24:422–63.
[14] Moss AJ, et al, for the Multicenter Automatic Defibrillator Implanta-
tion Trial II ((MADIT-II) Research Group. Long-term clinical course
of patients after termination of ventricular tachyarrhythmia by an
implanted defibrillator. Circulation 2004;110:3760–5.
[15] Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H,
Goodman SN, et al. Cardiac resynchronization and death from
progressive heart failure: a meta-analysis of randomized controlled
trials. JAMA 2003;289(6):730–40.
[16] McAlister FA, et al. Systematic review: cardiac resynchronization in
patients with symptomatic heart failure. Ann Intern Med 2004;141:
381–90.
[17] Cleland JG, Freemantle N. Cardiac resynchronization for progressive
heart failure. JAMA 2003;290:36–7.
[18] Calvert M, Freemantle N, Cleland JGF. The Impact of chronic heart
failure on health-related quality of life data acquired in the baseline
phase of the CARE-HF study. Eur J Heart Fail 2005;7(2):243–51.
by guest on May 14, 2011
eurjhf.oxfordjournals.orgD
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