© 2005 European Society of Cardiology
Baseline characteristics of patients recruited into the CARE-HF study
Department of Cardiology, Castle Hill Hospital Castle Road, Cottingham, University of Hull Kingston upon Hull, UK HU16 5JQ
* Corresponding author. Tel.: +44 1482 624084; fax: +44 1482 624085. E-mail address: J.G.Cleland{at}hull.ac.uk
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Abstract |
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 Top Abstract 1. Introduction2. Patients and methods3. Results4. DiscussionReferences |
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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 >70 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 
150 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.
Key Words: Heart failure • Cardiac resynchronisation therapy • Dyssynchrony • Mortality and morbidity • Randomized or randomised
Received December 23, 2004; Accepted January 13, 2005
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1. Introduction |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionReferences |
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Despite improvements in the pharmacological management 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 dyssynchrony, anaemia or renal dysfunction.
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 >120 ms of which 74% had major left ventricular systolic dysfunction [4]. Thus, 26% of patients with suspected heart failure will have both QRS >120 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 dyssynchrony 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 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 manipulating pharmacological therapy, that improvement in symptoms 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 randomised in CARE-HF are reported here.
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2. Patients and methods |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionReferences |
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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 pharmacological 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 subsequently to optimise this in both treatment groups. The objective was for patients randomised to cardiac resynchronisation 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 <35% (usually by echocardiography) with evidence of LV dilatation (LV end diastolic dimension 30 mm/height in metres) and a QRS interval >120 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 >150 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 >140 ms measured from the start of the QRS to the onset of aortic flow using pulsed wave Doppler; (b) interventricular mechanical delay >40 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 questionnaire 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, electrocardiography 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.
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 therefore 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 <60 years, 60–70 years and >70 years. Also, as the characteristics and outcome of patients with a QRS 150 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 according 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).
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3. Results |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionReferences |
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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
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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.
Few patients had a low body mass index (BMI), an indication of advanced cardiac cachexia. Twenty-three percent of patients were obese with a BMI>30. 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) 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 150 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 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 
12.4 g/dl. The median serum sodium was 139 mmol/l but 25% of patients had values 136 mmol/l indicating a high prevalence of hyponatraemia. The median value of serum creatinine was 106 µmol/l but 25% of patients had values 133 µmol/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 80 mg/day of furosemide (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
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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 haemoglobin and a past history of atrial arrhythmias were also more common in older patients. Older patients tended to report a similar severity of symptoms and quality of life. Ventricular function appeared similar across all three age groups (Table 5).
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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 <60 years were receiving a beta-blocker but only 64% of those aged >70 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 dysfunction. 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 cardiomyopathy. 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 glomerular 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 150 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.
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4. Discussion |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionReferences |
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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 dysfunction. The requirement for a reduced LV ejection fraction accounts for the younger age of the patients and preponderance of men recruited compared to epidemiological studies [13]. Older patients and women with heart failure are more likely to have preserved LV systolic function. Current pharmacological therapy had not adequately addressed the symptomatic needs of the majority of these patients and further effective interventions 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 somewhat 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 >90% of patients having an LVEF <30% and one quarter an LVEF <22%.
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 therapy in both arms of the study. If CRT can improve symptoms to a greater extent than pharmacological treatment 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 ‘soft,— often trivial end-point. The ‘harder— 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 preferred [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.
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 U. C. Hoppe, N. Freemantle, J. G.F. Cleland, M. Marijianowski, and E. Erdmann Effect of Cardiac Resynchronization on Morbidity and Mortality of Diabetic Patients With Severe Heart Failure Diabetes Care, March 1, 2007; 30(3): 722 - 724. [Full Text] [PDF]
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M. Schmidt, J. Bromsen, C. Herholz, K. Adler, F. Neff, C. Kopf, and M. Block Evidence of left ventricular dyssynchrony resulting from right ventricular pacing in patients with severely depressed left ventricular ejection fraction Europace, January 1, 2007; 9(1): 34 - 40. [Abstract] [Full Text] [PDF]
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S. Ghio, N. Freemantle, A. Serio, G. Magrini, L. Scelsi, M. Pasotti, J. G.F. Cleland, and L. Tavazzi Baseline echocardiographic characteristics of heart failure patients enrolled in a large European multicentre trial (CArdiac REsynchronisation Heart Failure study) Eur J Echocardiogr, October 1, 2006; 7(5): 373 - 378. [Abstract] [Full Text] [PDF]
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J. G.F. Cleland, J.-C. Daubert, E. Erdmann, N. Freemantle, D. Gras, L. Kappenberger, L. Tavazzi, and on behalf of The CARE-HF Study Investigators 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., August 2, 2006; 27(16): 1928 - 1932. [Abstract] [Full Text] [PDF]
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U. C. Hoppe, J. M. Casares, H. Eiskjaer, A. Hagemann, J. G.F. Cleland, N. Freemantle, and E. Erdmann Effect of Cardiac Resynchronization on the Incidence of Atrial Fibrillation in Patients With Severe Heart Failure Circulation, July 4, 2006; 114(1): 18 - 25. [Abstract] [Full Text] [PDF]
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J. G.F. Cleland, A. Charlesworth, J. Lubsen, K. Swedberg, W. J. Remme, L. Erhardt, A. Di Lenarda, M. Komajda, M. Metra, C. Torp-Pedersen, et al. A Comparison of the Effects of Carvedilol and Metoprolol on Well-Being, Morbidity, and Mortality (the "Patient Journey") in Patients With Heart Failure: A Report From the Carvedilol Or Metoprolol European Trial (COMET) J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1603 - 1611. [Abstract] [Full Text] [PDF]
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J. G.F. Cleland, K. Goode, O. Khaleva, and N. Khan How many patients need cardiac resynchronization therapy? Eur. Heart J., February 1, 2006; 27(3): 251 - 252. [Full Text] [PDF]
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J. G.F. Cleland, A. P. Coletta, M. Lammiman, K. K. Witte, H. Loh, M. Nasir, and A. L. Clark Clinical trials update from the European Society of Cardiology meeting 2005: CARE-HF extension study, ESSENTIAL, CIBIS-III, S-ICD, ISSUE-2, STRIDE-2, SOFA, IMAGINE, PREAMI, SIRIUS-II and ACTIVE Eur J Heart Fail, October 1, 2005; 7(6): 1070 - 1075. [Abstract] [Full Text] [PDF]
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J. G.F. Cleland, A. P. Coletta, N. Freemantle, P. Velavan, L. Tin, and A. L. Clark Clinical trials update from the American College of Cardiology meeting: CARE-HF and the Remission of Heart Failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER Eur J Heart Fail, August 1, 2005; 7(5): 931 - 936. [Abstract] [Full Text] [PDF]
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 G. A. Kirkorian, H. Burri, J. G.F. Cleland, J.-C. Daubert, L. Tavazzi, and the CARE-HF Study Investigators Cardiac-Resynchronization Therapy in Heart Failure N. Engl. J. Med., July 14, 2005; 353(2): 205 - 206. [Full Text] [PDF]
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J. G.F. Cleland, J.-C. Daubert, E. Erdmann, N. Freemantle, D. Gras, L. Kappenberger, L. Tavazzi, and the Cardiac Resynchronization -- Heart Failure (CA The Effect of Cardiac Resynchronization on Morbidity and Mortality in Heart Failure N. Engl. J. Med., April 14, 2005; 352(15): 1539 - 1549. [Abstract] [Full Text] [PDF]
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