© 2001 European Society of Cardiology
The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points
Department of Cardiology, Castle Hill Hospital Castle Road, Cottingham University of Hull Kingston upon Hull, HU16 5JQ, UK
* Corresponding author. Tel.: +44-1482-624084; fax: +44-1482-624085. E-mail addrss: j.g.cleland{at}hull.ac.uk (J.G.F. Cleland).
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Background: Cardiac resynchronisation is a promising new intervention for patients with heart failure, left ventricular systolic dysfunction and ventricular dyssynchrony.
Objective: The CARE-HF trial is designed to evaluate the long-term effects of cardiac (atrio-bi-ventricular) resynchronisation on the mortality and morbidity of patients with heart failure due to left ventricular systolic dysfunction already receiving diuretics and optimal medical therapy with ACE inhibitors and beta-blockers (where indicated and tolerated).
Methods and Results: Approximately 800 patients will be randomised to device therapy or control and followed for a minimum of 18 months. A pragmatic study design has been chosen that does not attempt to conceal allocation from investigators or patients because it is impossible to guarantee maintenance of blinding for the duration of the study. The end-points committee will adjudicate events in a blinded fashion. Since cardiac resynchronisation may alter other aspects of the management of the patient, as would occur in clinical practice, the study should be considered a comparison of strategies rather than simply of a device. The primary end-point is all-cause mortality or unplanned cardiovascular hospitalisation. The study should complete recruitment during 2002 and report in 2004.
Key Words: CARE-HF trial • Cardiac dyssynchrony • Beta-blockers • ACE inhibitors • Cardiac (atrio-bi-ventricular) resynchronisation
Received June 1, 2001; Accepted July 6, 2001
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Despite recent advances in pharmacological management, heart failure continues to exact a heavy toll in terms of debilitating symptoms, frequent hospitalisation and high mortality [1]. Indeed, improved therapy is likely to lead to an increase in the number of patients who suffer from heart failure, because prevalence is determined by incidence and patient longevity. Although treatment may delay the progression of heart failure, there is no evidence that it can prevent it. Despite treatment with ACE inhibitors and beta-blockers, many patients have persistent symptoms and most will still die from cardiovascular causes, often from progressive heart failure. Clearly, further therapeutic interventions to improve symptoms, reduce morbidity and decrease the risk of sudden death, arrhythmic or vascular, and death due to progressive heart failure are desirable.
It is likely that many new interventions for heart failure will be targeted at specific groups of patients rather than the whole population. Cardiac dyssynchrony, a complex multi-component syndrome, has recently been identified as one such target [2–4]. Atrio-ventricular, regional left ventricular and inter-ventricular dyssynchrony can all lead to a decline in global cardiac performance. Cardiac dyssynchrony leads to a reduction in systolic performance, impairs ventricular filling and contributes to systolic and diastolic mitral regurgitation. The decline in cardiac performance due to cardiac dyssynchrony may not only increase symptoms but may also impair prognosis. A prolonged PR interval on the surface ECG, a marker of atrio-ventricular conduction delay, and prolongation of the QRS complex, a surface ECG marker of left ventricular dyssynchrony, both predict worse outcome in patients with heart failure [5].
Recently, a series of single- or double-blind randomised controlled trials of patients with severe heart failure and prolonged QRS intervals on the surface ECG, has consistently demonstrated that cardiac (atrio-biventricular) resynchronisation improves patients’ symptoms [6–13]. These studies have also frequently shown improvement in other outcomes, including exercise capacity, ventricular function and quality of life. Although a reduction in the rate of hospitalisation with heart failure has been reported in some and trends to a reduction in mortality in others [6,9], the studies conducted so far have been of insufficient size or duration to determine whether cardiac resynchronisation can exert an important reduction in morbidity and/or mortality. The CARE-HF study has been set-up to address this issue.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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2.1. Study purpose
The CARE-HF trial is designed to evaluate the long-term effect of cardiac (atrio-biventricular) resynchronisation on the morbidity and mortality of patients with heart failure due to left ventricular systolic dysfunction already receiving diuretics and optimal medical therapy with ACE inhibitors and beta-blockers (where indicated and tolerated). If the intervention reduces morbidity and/or mortality, then the cost-effectiveness of this intervention will be evaluated.
2.2. Study design
Approximately 800 patients will be enrolled in approximately 100 European centres. Patients are randomised equally to control or resynchronisation therapy. Because blinding to the allocation of therapy would be immediately broken if the investigator saw the patients implantation scar or ECG, the study will be conducted open-label. Even attempted partial blinding would necessitate implanting but not activating a device, which could entail a morbidity and mortality in the control group that would not be incurred in real clinical practice. Also, investigators may be tempted to activate devices in patients who appeared to be deteriorating. A high rate of cross-over could jeopardise the validity of the trial. The End-point and Adverse Event Committee will be blinded during the classification of events.
2.3. Inclusion and exclusion criteria
Study inclusion and exclusion criteria are shown in Table 1. A QRS duration >150 ms on the surface ECG, usually associated with a left bundle branch block morphology, is generally accepted to indicate left ventricular dyssynchrony. Patients with less marked QRS prolongation (120–150 ms) must also have objective echocardiographic evidence for ventricular dyssynchrony verified by the echocardiography core laboratory. Mortality is high in the first 3 months after the onset of heart failure. In order not to exclude this high-risk period, but to ensure at the same time that it is unlikely that the patient will recover from heart failure, the minimum duration of heart failure has been set at 6 weeks. Patients with permanent or persistent atrial fibrillation or flutter are excluded, as these patients cannot benefit from the atrio-ventricular component of resynchronisation.
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3. End-points |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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3.1. Primary end-point
Neither morbidity nor mortality alone adequately describes the burden of illness in heart failure, nor does changing only one adequately describe the benefit of an intervention. A reduction in morbidity and mortality is the strongest justification for intervention. Cardiac resynchronisation improves cardiac function, which may reduce the risk of worsening heart failure and supra-ventricular and ventricular arrhythmias and thereby reduce the rate of hospitalisation, stroke and death. Accordingly, the primary end-point in the CARE-HF study is the composite of all-cause mortality or unplanned cardiovascular hospitalisation using a time to first event analysis (Table 2). Deaths occurring at any time after randomisation will count towards the primary end-point, even if they occur prior to device implantation. Patients who undergo emergency heart transplantation due to end-stage heart failure will be counted as deaths. Patients who undergo elective heart transplantation are censored 7 days post-transplant. Patients who undergo transplantation will have their vital status assessed for the duration of the study.
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Hospitalisation means admission to a hospital involving an overnight stay or resulting in death. Day-care admissions are not included in the primary end-point, although data on these will be collected for the health economic analysis. Cardiovascular hospitalisation includes hospitalisation for or with worsening heart failure, angina, myocardial infarction, syncope, arrhythmia, stroke, transient ischaemic attack, acute peripheral vascular emergencies, pulmonary embolism or other cardiovascular events. Hospitalisation for or with worsening heart failure includes heart failure induced by infection, supraventricular or ventricular arrhythmias, acute coronary syndromes or renal dysfunction due to drug effects or worsening cardiac function.
Admissions for initial device implantation are planned and do not count towards the primary end-point. Re-admissions within the first 10 days for device related re-interventions are considered as part of the same episode of care. In order to avoid bias in favour of the device, hospitalisations within 10 days of randomisation regardless of the treatment arm will be recorded, but will not contribute to the primary end-point. Planned admissions for diagnostic procedures, revascularisation or non-emergency arrhythmia management or non-emergency transplantation will be recorded but will not count towards the primary end-point. Re-admission for lead displacement that has not precipitated a cardiac emergency will be considered planned. All data will be adjudicated by an end-points committee in a blinded fashion.
3.2. Secondary end-points
All cause mortality is the outcome least subject to bias. Death will be classified according to place (in-hospital, out-of-hospital and in-transit to hospital), mode (sudden, circulatory failure, stroke, etc.) and relationship to preceding events (e.g. myocardial infarction, unstable angina, persistent NYHA class IV heart failure, renal failure, stroke, device-related complication, cardiovascular procedure, cancer, etc.). Sudden death is defined as death within 1 h of the onset of symptoms or unwitnessed death without any other obvious cause (Table 2).
For each hospital admission for or with worsening heart failure, the investigator will be requested to state whether or not the patient experienced worsening heart failure (a) at the time of admission or (b) during the admission, and if so, whether or not this was the primary reason for admission or secondary to an obvious precipitating factor such as infection, myocardial infarction or atrial fibrillation. The investigator will also be asked to state whether or not the patient received (a) intra-venous medication for heart failure (including diuretics, vasodilators or inotropic agents) or (b) a substantial increase in oral diuretic therapy for heart failure, defined as an increase of furosemide 
40 mg or equivalent, or the addition of a thiazide to a loop diuretic. Patients are generally expected to be on ACE inhibitors and beta-blockers at baseline and will often be receiving spironolactone; therefore, these therapies, directed principally at the improvement of prognosis rather than symptoms, are not used as supportive evidence of worsening heart failure. Only patients who are reported to have worsening heart failure and who have also undergone an intensification of therapy as outlined above will be deemed to have worsening heart failure. Patients who have an exacerbation of heart failure secondary to supra-ventricular or ventricular arrhythmia, myocardial ischaemia, myocardial infarction, renal dysfunction or infection may be included in this end-point. Final classification of hospital admission for or with heart failure will be made by a blinded end-points committee.
The end-point of days alive and not in hospital for unplanned cardiovascular cause over the first 500 days of follow-up uses the definitions for all-cause mortality and unplanned cardiovascular hospitalisations set out above. In this analysis, each patient has the same exposure to risk and a maximum possible score of 500. The number of days ‘lost’ due to death or days in hospital for unplanned cardiovascular cause will be deducted from this maximum score. Admissions days will be counted by the number of midnights in hospital. The whole period of any admission that fulfils the definition of the ‘unplanned cardiovascular hospitalisation’ component of the primary end-point will be counted as days in hospital. The end-point of days alive and not in hospital for any reason over the first 500 days is similar to the above, but includes non-cardiovascular hospitalisation, planned admissions and admissions for device implantation or revision. Patients lost to follow-up will be assumed to have died on the day after they were last known to be alive. These types of analyses take into account the competing effects of mortality, duration of hospital stay and frequency of hospital admission.
In order to prevent the confounding effects of a possible difference in long-term mortality between groups, the effect of therapy on symptoms will be assessed principally at 90 days. Symptoms will be assessed using the New York Heart Association (NYHA) classification. The worst status within the last week will be counted. Patients who have died will be assumed to be in NYHA class IV. Patients and investigators are aware of their treatment allocation. Accordingly, the patients rather than the investigators will decide which NYHA class most closely resembles their current status. Long-term effects on symptoms may be best gauged by composite measures including need for intensification of therapy and frequency and duration of hospitalisation for heart failure.
Quality of life, for the above reasons, will also be assessed at 90 days using three quality of life tools, two of which are completed by the patients and one by the investigator. Changes from baseline to 90 days will be assessed. The Minnesota Living with Heart Failure questionnaire is a well-validated but highly disease-specific tool that may be poorly responsive to change. It is completed by the patient. The EuroQoL is a simple, general quality of life tool that is completed by the patient. The EuroHeart Failure questionnaire is designed to assess both general and disease-specific quality of life in patients with heart failure. The investigator asks the patient a series of questions and records the answers given. It is currently undergoing validation.
Patients symptoms may follow a fluctuating clinical course. Increasing diuretic therapy may alleviate symptoms and mask progressive deterioration. Some patients may fair badly at first, but show late improvement. For these reasons, the long-term clinical status is of interest and will be evaluated at the end of the study. Patients who are alive, in the same NYHA class (or better) as at the start of the study and who are not receiving a substantial increase in diuretic therapy (see above) will be deemed to have benefitted. Patients who do not fulfil all of these criteria will be deemed to have deteriorated. As status may be confounded by differences in the duration of follow-up this analysis will also be assessed at 18 months for all patients.
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4. Mechanistic outcomes |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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It is desirable to try to understand how any clinical benefit observed is brought about and whether it is possible to predict more accurately which patients benefit most from CRT. Echocardiography will be used to assess dyssynchrony and to optimise the timing of cardiac resynchronisation. A decline in cardiac function is expected in the control group during the study, which may be attenuated or reversed due directly to the effects of resynchronisation or due to effects on remodelling. Accordingly, serial echocardiographic measurements of left ventricular volumes, contractility, filling and mass will be made at baseline 3, 9 and 18 months in both active and control groups. Systolic and/or diastolic mitral regurgitation, right ventricular function and changes in atrial dimensions will also be assessed. Neuroendocrine activation may be both a marker and mechanism for progressive deterioration in cardiac function. N-terminal pro-BNP and big-endothelin will be measured at baseline and at 3 and 18 months. The ability to deliver cardiac resynchronisation will be assessed from ECG templates, the diagnostic memory of the device and by echocardiography.
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5. Health economic outcome |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Heart failure is widely seen as a resource-intensive and costly chronic disease. Accordingly, a health–economic evaluation is planned. This outcome will describe the difference in frequency (rate), type and associated mean cost per patient attributable to the intervention, taking into account any reduction in hospitalisation or the use of other relevant health care resources that may offset these costs. The mean cost attributable to resynchronisation therapy for heart failure, with a 95% confidence interval, will be described alongside the clinical outcomes observed in the trial to inform clinicians and policy makers of the cost-effectiveness of the therapy. Components of relevant health care resource use for each patient will be translated to standardised treatment costs, expressed in Euros, based on UK cost structures. Where cost structures differ substantially in other health care systems, further analyses will be performed to develop mean cost per patient relevant to that health system. When necessary, sensitivity analyses will be conducted to describe important variations.
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6. Substudies |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Substudies are planned to investigate the effect of cardiac resynchronisation on three-dimensional echocardiographic imaging and on neurohormonal and other biochemical markers of cardiac dysfunction. Other sub-studies will be considered.
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7. Study conduct (Fig. 1) |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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This study will be conducted in compliance with Good Clinical Practice (GCP), including International Conference on Harmonisation (ICH) Guidelines, consistent with the most recent version of the Declaration of Helsinki. The study will be conducted with the approval of all appropriate national and local ethics committees. Patients who have given informed consent and who fulfil the inclusion/exclusion criteria will be entered in a screening log and asked to participate. If the patient subsequently decides or is advised not to participate in the trial, the reason will be documented on the screening log and the patient will be asked to participate in an event registry to determine mortality and clinical status at the termination of the trial. Optimal proven medical treatment, including ACE inhibitors and beta-blockers, unless contra-indicated or not tolerated, will be provided to all patients in both groups. Investigators are encouraged to use spironolactone in patients with advanced symptoms or receiving high doses of diuretics.
Following verification of the inclusion and exclusion criteria, and if necessary, approval of the Echo Core Laboratory (for patients with QRS between 120 and 150 ms), an admission date to perform the cardiac resynchronisation device implantation will be scheduled for all patients. At the randomisation visit, patients will be asked to reconfirm their consent, baseline investigations will be completed and patients will be allocated randomly subsequent to a fax-request to the central randomisation office. The target is to implant devices within 5 working days of randomisation, but patients who fail initial implantation may have further attempts at any time during the course of the study. Patients who are randomised to optimal medical therapy alone will have their admission cancelled.
Follow-up visits will occur at 1, 3, 6, 9, 12 and 18 months after randomisation, and every 6 months thereafter. At the end of the study, a final visit will be scheduled and the clinical status of the patients recorded. Patients will be followed until the last patient has been followed for 18 months. It is anticipated that exposure to the study therapy will be in excess of 30 months for some patients as accrual is expected to last approximately 15 months.
Medtronic's Field Clinical Monitoring Organisation in cooperation with the Heart Failure Management Clinical and Research department will supply devices, software, and if required, ensure that physician trainers are present to assist at the time of implant. An independent clinical trials organisation will provide administrative support and will check the data on the original case report forms against the subject's source documents at the study site.
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8. Core laboratories |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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8.1. Echocardiography
All investigators must obtain the approval of the core laboratory before participating in the study by sending a test tape (Super VHS) of adequate quality to the core laboratory. Patients with QRS between 120 and 150 ms can only be enrolled after the core laboratory have confirmed the echo inclusion criteria for dyssynchrony (Table 1). The laboratory is responsible for quantifying the echocardiographic effectiveness of resynchronisation and optimisation of atrio-ventricular delay and for assessing the echocardiographic outcomes, specified in the protocol.
8.2. Neurohormonal
The neurohormonal core laboratory is responsible for measuring N-terminal pro-BNP and big-endothelin-1 as specified in the main protocol as well as from possible substudies. Blood samples (20 ml) are taken after 15 min rest into pre-chilled EDTA tubes, cool centrifuged, then supernatant plasma is stored in aliquots at –70°C.
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9. Therapy delivery |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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This laboratory's role is to quantify and monitor therapy delivery using information from ECG templates collected at the time of implantation and follow-up, echocardiographic assessments and interrogation of the device for the frequency of stimulation prior to discharge and after 3, 9 and 18 months and at the end of study. Three possible outcomes are recognised:
- Resynchronisation pacing beats were not delivered frequently enough (<80% of time);
- Pacing beats and programmed timing failed to induce appropriate resynchronisation; and
- Satisfactory resynchronisation.
For patients who have evidence of failed bi-ventricular stimulation, it will be assumed that therapy delivery was inadequate from the time of the previous assessment. Investigators will be informed of the core laboratory's conclusions. The total percentage of time with bi-ventricular stimulation for the duration of the trial will be calculated for each patient.
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10. Cardiac resynchronisation system |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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The InSync® family of cardiac resynchronisation devices, the AttainTM family of left ventricular cardiac vein leads and appropriate programming software and devices will be used. Left ventricular leads will be placed through the coronary sinus into a lateral cardiac vein whenever possible and the right ventricular lead will generally be placed close to the apical septum to give the longest possible inter-ventricular conduction time. Bipolar leads will be used to minimise pectoral muscle or phrenic nerve stimulation.
Centres with little experience of cardiac resynchronisation will be assisted by an expert implanter. The assistance of an expert implanter is encouraged if a first attempt at implantation fails. If two attempts at device implantation have failed, further attempts are encouraged only if new technology becomes available. Trans-thoracic lead placement is discouraged. As the study will be analysed on an intention to treat basis, patients randomised to device remain in the resynchronisation arm for all efficacy end-points, whether or not implantation is successful.
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11. Optimisation of cardiac resynchronisation |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Devices are programmed to maximise bi-ventricular pacing throughout the range of expected patient activity and to minimise power output to prolong battery life. Further optimisation of atrio-ventricular delay will be performed using Doppler echocardiography of trans-mitral flow to provide the maximum left ventricular filling time without compromising cardiac resynchronisation. The AV delay is set at a value which provides maximum separation of the E and A waves, representing passive ventricular filling and atrial contraction, respectively. A short AV delay results in an earlier E-wave, and therefore, a longer left ventricular filling duration, but compromises the left atrial contribution to left ventricular filling due to early mitral valve closure. A long AV delay results in a delayed E-wave, and therefore, contributes to a fusion between the E- and A-wave and shortens left ventricular filling. The aim of the AV delay optimisation will be to select the shortest AV-delay without compromising the left atrial contribution to the left ventricular filling.
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12. Steering Committee |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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This committee is responsible for developing and monitoring the implementation of the protocol. The committee is supported by a statistician independent of the sponsor and is responsible for ensuring timely publication of the results.
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13. Adverse event and End-Point Committee |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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This committee is responsible for classifying all events that could potentially contribute to an end-point or adverse event. Events will be adjudicated in a blinded fashion. Where an adverse event possibly related to cardiac resynchronisation has occurred, causality will subsequently be re-adjudicated with details of the implant procedure revealed. Adverse events related to resynchronisation will be classified as procedure related (e.g. dissection, perforation, pocket infection, etc.) or device related (e.g. lead failure). The committee will classify the mode of death. Autopsy reports will be sought where relevant. Explanted systems will be interrogated. Investigators are encouraged to request explantation of systems if the patient dies.
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14. Data Safety Monitoring Board (DSMB) |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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The DSMB is responsible for monitoring patient safety and will recommend that the trial is stopped prematurely if a pre-defined increase in all-cause mortality occurs in the cardiac resynchronisation arm or if a three standard deviation benefit in all-cause mortality, on a log rank test, is observed. This is equivalent to an effect identified or the magnitude that would be identified by chance alone with a probability P<0.00135. The DSMB may request interim analyses should the safety data indicate that treatment is associated with important adverse events. The proceedings of each meeting will be recorded in minutes. Access to the minutes by the sponsor or study investigators will be prohibited until after the database for the trial has been locked.
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15. Randomisation |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Randomisation is through a centralised, concealed, minimisation process implemented by an independent statistician. Stratification is by NYHA class.
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16. Statistical power |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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Because of the increased initial risk of a primary event in the intervention group, due to the hazard associated with implantation, CARE-HF provides particular challenges for design and analysis. We assume a hazard ratio in the first month of 2.5, attributable to the intervention, a subsequent hazard ratio of 0.69 for the remaining months of follow up, the conventional one sided
value of 0.025, and power (1–β) of 0.8. We also assume accelerating rates of recruitment over 18 months, and a minimum follow up of 18 months. A cross-over rate of 1.8% is assumed for the control group for the overall period of the trial. Similarly, a failure to implant successfully of 20% is assumed. Given these conservative assumptions, the trial is powered to detect a 14% reduction in the risk of a primary event, expecting approximately 300 primary events [14]. |
17. Statistical analysis plan |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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The statistical analysis for the primary outcome, and other ‘time to event’ outcomes is by log rank test. The analyses for the continuous variables is by standard methods, unless there is good evidence of important deviation from assumptions of normality, in which case non-parametric ‘boot strap’ methods will be used to generate confidence intervals. An exploratory analysis considering a limited number of potentially important predictive factors (Table 3) will be examined through a Cox proportional hazards model, accounting for the negative effects of implantation as a time dependent covariate.
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18. Timelines |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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The first patient was randomised in March 2001, at the time of writing 100 patients have been randomised. Recruitment is expected to complete in the summer of 2002 and the study should close at the beginning of 2004.
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References |
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TopAbstract1. Introduction2. Methods3. End-points4. Mechanistic outcomes5. Health economic outcome6. Substudies7. Study conduct (Fig....8. Core laboratories9. Therapy delivery10. Cardiac resynchronisation...11. Optimisation of cardiac...12. Steering Committee13. Adverse event and...14. Data Safety Monitoring...15. Randomisation16. Statistical power17. Statistical analysis plan18. TimelinesReferences |
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