Baseline characteristics of patients recruited in the AREA IN-CHF study (Antiremodelling Effect of...

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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

by guest on May 14, 2011

eurjhf.oxfordjournals.orgD

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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: [email protected] (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.

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https://www.researchgate.net/publication/267394704_Baldasseroni_S_Opasich_C_Gorini_M_Lucci_D_Marchionni_N_Marini_M_et_al_Left_bundle-branch_block_is_associated_with_increased_1-year_sudden_and_total_mortality_rate_in_5517_outpatients_with_congestive_h?el=1_x_8&enrichId=rgreq-01dfe70b-6118-4059-92a0-d6adc7ff19ec&enrichSource=Y292ZXJQYWdlOzgwMzIyMDQ7QVM6MTAzMzY5ODU1MjA5NDk0QDE0MDE2NTY3MDM0MzU=

https://www.researchgate.net/publication/267394704_Baldasseroni_S_Opasich_C_Gorini_M_Lucci_D_Marchionni_N_Marini_M_et_al_Left_bundle-branch_block_is_associated_with_increased_1-year_sudden_and_total_mortality_rate_in_5517_outpatients_with_congestive_h?el=1_x_8&enrichId=rgreq-01dfe70b-6118-4059-92a0-d6adc7ff19ec&enrichSource=Y292ZXJQYWdlOzgwMzIyMDQ7QVM6MTAzMzY5ODU1MjA5NDk0QDE0MDE2NTY3MDM0MzU=

https://www.researchgate.net/publication/8523763_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_f?el=1_x_8&enrichId=rgreq-01dfe70b-6118-4059-92a0-d6adc7ff19ec&enrichSource=Y292ZXJQYWdlOzgwMzIyMDQ7QVM6MTAzMzY5ODU1MjA5NDk0QDE0MDE2NTY3MDM0MzU=

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.


https://www.researchgate.net/publication/10739591_Combined_Cardiac_Resynchronization_and_Implantable_Cardioversion_Defibrillation_in_Advanced_Chronic_Heart_Failure_The_MIRACLE_ICD_Trial?el=1_x_8&enrichId=rgreq-01dfe70b-6118-4059-92a0-d6adc7ff19ec&enrichSource=Y292ZXJQYWdlOzgwMzIyMDQ7QVM6MTAzMzY5ODU1MjA5NDk0QDE0MDE2NTY3MDM0MzU=

https://www.researchgate.net/publication/271235588_Systematic_Review_Cardiac_Resynchronization_in_Patients_with_Symptomatic_Heart_Failure?el=1_x_8&enrichId=rgreq-01dfe70b-6118-4059-92a0-d6adc7ff19ec&enrichSource=Y292ZXJQYWdlOzgwMzIyMDQ7QVM6MTAzMzY5ODU1MjA5NDk0QDE0MDE2NTY3MDM0MzU=

https://www.researchgate.net/publication/228693449_Cardiac_resynchronisation_therapy_in_chronic_heart_failure?el=1_x_8&enrichId=rgreq-01dfe70b-6118-4059-92a0-d6adc7ff19ec&enrichSource=Y292ZXJQYWdlOzgwMzIyMDQ7QVM6MTAzMzY5ODU1MjA5NDk0QDE0MDE2NTY3MDM0MzU=

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.




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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)


Standing systolic BP

(mm Hg), mean (SD)


Standing diastolic BP

(mm Hg), mean (SD)


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)


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)


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)


White blood cell

count (�109/L)

median (IQR)


C Reactive protein

(mg/l) , median

(IQR)


Sodium (mmol/l),

median (IQR)


Potassium (mmol/l),

median (IQR)


Urea (mmol/l),

median (IQR)


Creatinine (Amol/l),

median (IQR)


Glomerular filtration

rate (ml/min*),

median (IQR)


=* Actually mL/min per 1.73m2.

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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

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