trial is part of the overall CopenHeart project, which is designed to develop evidence-based knowledge on rehabilitation among patients with complex cardiac conditions.29
trial is a multicentre, multidisciplinary, randomised clinical trial designed to examine the effects of a comprehensive cardiac rehabilitation programme compared with usual care for patients treated for IE. In addition to this, the CopenHeartIE
trial includes two complementary studies, aimed at investigating the postdischarge experiences and rehabilitation needs of patients treated for IE, and a qualitative postintervention study to explore the meaning of the CopenHeartIE
rehabilitation programme from the patient's perspective. Accordingly, the trial combines quantitative and qualitative research methods. The premise of mixed methods research is that the use of qualitative and quantitative approaches in combination provides a better understanding of the research problems than either approach alone, because different types of questions require different types of data and that mixed methods research provides strengths that offset the weaknesses of both qualitative and quantitative research.30
The methods are integrated by applying the mixed method embedded experimental design and include qualitative data to develop the intervention and to examine the process of the intervention and the results of the trial (see ).30
The rationale for this approach is that the quantitative findings provide a general understanding of the research problem through statistical results, and qualitative findings refine and explain the results by exploring participants’ views in greater detail. Evaluation using qualitative research methods is increasingly promoted in evidence-based rehabilitation.32–35
Qualitative research alongside randomised controlled trials can contribute in several ways to the development and evaluation of complex healthcare interventions and may be particularly useful in evaluating interventions that involve social and behavioural processes that are difficult to explore or capture using quantitative methods alone.36
As patient participation is paramount to the efficacy of the rehabilitation,37
we find it highly valuable to include the patients’ perspective in the development and evaluation of the intervention. This paper presents the study protocol for the CopenHeartIE
randomised clinical trial. The complementary studies are briefly described in a separate section.
The CopenHeartIE study. Mixed method—embedded experimental model.
Study population and eligibility criteria
Consecutive patients treated for left-sided (native or prosthetic valve) or cardiac device endocarditis at the tertiary referral heart centres in Copenhagen, Denmark (Rigshospitalet and Gentofte Hospital) will be screened for inclusion and approached for study participation. The patients aged 18 years or older, having completed treatment for IE based on the Duke Criteria,38
speaking and understanding Danish and providing written informed consent will be considered eligible for participation. The patients unable to understand study instructions, with a cardiac ischaemic event within the past 6 months, who are pregnant or breastfeeding, with reduced ability to follow the planned programme due to, for example, substance abuse problems or other somatic illness, with considerable illness in the musculoskeletal system or with physical disability which complicates exercise training or patients whose physician advise against participation, will be excluded.
Study procedure, randomisation and follow-up
Patients eligible for participation will be approached by a nurse or a physician from the research group during the expected last week of their treatment for IE. A brief oral introduction is initially given together with written information describing the study and implications for the patient in detail. The patient is given ample time to read the information and if necessary involve a relative in the decision making. The enrolling nurse or physician will return within 2–3 days or at a planned time to answer any questions the patient or their relative might have. The patient should subsequently be able to provide informed consent or reject participation. When the informed consent form is signed attained, baseline data will be collected including the baseline questionnaire package, demographic variables and clinical characteristics. After baseline data collection, central randomisation is conducted by telephoning the trial coordinating centre, Copenhagen Trial Unit (http://www.ctu.dk/
), for randomised allocation. The allocation sequence will be computer-generated with varying block sizes, blinded to investigators, randomising patients 1
1 to either the experimental intervention versus usual care. Thus, neither investigators nor patients or relatives can influence to which group the patients are allocated. The patients will be stratified according to sex and the treating heart centre. For both groups, the follow-up assessment will take place at 1 month (T1
), 4 months (T4
), 6 months (T6
) and 12 months (T12
) postdischarge and a register-based follow-up assessment will be conducted at 24 months (T24
; see ). In the event of complications arising after study enrolment, cases will be handled individually (see Intervention deviation section).
The patients answer questionnaires independently of the researchers, and before randomisation. All questionnaires are distributed electronically, thus data management is handled independently from the researchers who interpret data. All data entry is doubled and stored electronically in a coded database, and in an independent spread sheet, only accessible for the CopenHeart group.
Personal information about potential and enrolled patients will be collected electronically and shared in a database only accessible to those within the project group responsible for patient recruitment, to protect confidentiality before, during and after the trial.
Experimental intervention group
Patients in the intervention group will follow the integrated rehabilitation programme, consisting of a psychoeducational component and an exercise training component as well as usual care (see below). The intervention has been developed and tested in two clinical trials; the DANREHAB trial including patients with ischaemic heart disease and HF,39
and the COPE-ICD trial including patients with an implantable cardioverter defibrillator.26
The blood work and clinical control described for the control group (see below) are incorporated in the follow-up of the intervention group.
The aim of the psychoeducational intervention is to provide emotional support and improve coping skills and illness appraisal in order for the patient to respond appropriately to physical and psychological symptoms. Education and information about the disease prepare the patient for expected symptoms and sensations. Dialogue and shared reflection facilitate strategies for coping with symptoms and experiences associated with the condition, for example, anxiety and fear. Cardiac care nurses with specific training will perform the psychoeducational intervention. Some of the most commonly reported concerns of patients treated for IE, such as fatigue, gastrointestinal function and concerns about work life are outlined in an inspiration guide for the nurses to address when and if relevant (see ). Information given will also be based on national guidelines and standard treatment of patients with IE, and on the findings of the qualitative study on postdischarge experiences described in the complementary studies section of this paper. The consultations focus on managing life after IE by establishing a joint approach to disease management and coping strategies, using a holistic view. The psychoeducational intervention is inspired by RR Parse's Human Becoming Practice Methodologies Three Dimensions.40
These are interpreted as (1) discuss and give meaning to the past, present and future, (2) explore and discuss events and possibilities and (3) move along with envisioned possibilities. According to this theory, there are three ways of changing health: creative imaging, that is to see, hear and feel what a situation might be like if lived in a different way, affirming personal patterns and value priorities and shedding light on paradoxes, that is, looking at the incongruence in a situation and changing the view held of something. The nurse is truly present in the process through discussions, silent immersion and reflection. The human becoming practise methodology was chosen to apply a holistic patient approach, focusing on the coping and transformation process of the individual person. Furthermore, the method is extensively used in the outpatient heart clinics at the heart centre at Rigshospitalet, such as for patients with inherited heart diseases and adults with congenital heart disease and finally documented in the COPE-ICD trial.26
The consultations take place in a quiet setting at the outpatient clinic and will last for approximately 1 h. The nurse is able to facilitate contact with or seek advice from a physician if needed. The first consultation will be approximately 1 week after discharge, and then once every 4–6 weeks, with a total of five consultations. Consultations can be done by telephone, according to the patient's wishes. The primary investigator will attend the consultations regularly to ensure protocol compliance.
Inspiration guide for nursing consultations/psychoeducational intervention
Physical exercise training component
The main objective of the exercise training is to improve the patient's physical capacity and facilitate lifestyle/behavioural changes, which will subsequently result in physical and psychological health benefits for the patient. However, the exercise training programme is also targeted at relieving the fear and uncertainty that the patient may feel in relation to physical activity. The intervention is based on the European guidelines for physical training in cardiac rehabilitation16
and complies with the recommendations on physical activity of the Danish National Board of Health.42
The intervention consists of three components (1) individual planning of the exercise training, (2) 12 weeks of high-intensity exercise training and (3) continuous moderate daily physical exercise.
Individually planned physical exercise by a specialised cardiac rehabilitation physiotherapist
Integrating detailed information regarding the specific type of IE, comorbidities, hospitalisation, activities of daily living (ADL) and level of physical activity prior to IE, the physiotherapist conducts a patient consultation of up to 30 min. The consultation is based on the initial testing of the patient, including the cardiopulmonary exercise testing, described in the outcome measures section, a 6 min walk test and a ‘sit to stand’ test. For all patients an individual training diary is prepared, and all patients are instructed in the use of a HR monitor integrated into Polar watches, provided by Rigshospitalet. The HR monitor and diary is essential to ensure CopenHeart training protocol compliance and are returned for data collection at the end of the exercise training intervention.
Intensive exercise training programme
The initial training sessions take place in a physiotherapist-supervised setting at the primary investigating hospital, Rigshospitalet, to ensure the quality, intensity and safety of training. Training is started 4 weeks postdischarge to ensure optimum postsurgery healing after heart valve surgery or cardiac device implantation. Using wireless electrodes integrated into t-shirts (Corus-Fit, CardioCardio and Corus Exercise Assistant, CEA, vs 2.0.16, Finland) potential cardiac arrhythmias, electrocardiographic abnormalities such as ST-depression, ST-elevation, Q-wave or T-wave altering, atrial fibrillation and ventricular arrhythmias and training intensity level are monitored. After 1–3 exercise training sessions at Rigshospitalet, the patient continues the programme at a local CopenHeart certified training facility supervised by physiotherapists or as supervised home-based training. Supervised home-based exercise training has shown similar results as hospital-based exercise training,43
and has been confirmed in a Danish setting.44
The physical exercise training continues for 12 weeks, comprising 3 sessions weekly of 60 min, with a total of 36 sessions. The training protocol consists of aerobic and anaerobic exercise to accommodate endurance and muscle strength.
An exercise training session consists of 10 min warm up, 20 min of bicycling, 20 min of resistance training and 10 min stretching and cool-down period. Using the results from the cardiopulmonary exercise test performed prior to the initial training session, in combination with the Borg scale measuring subjective exhaustion, the aerobic exercise is performed with a gradually increasing intensity throughout the exercise intervention period, corresponding to 13–17 at the Borg Scale and 50–80% of the maximum HR. The anaerobic resistance training is initiated at 30–40% of one repetition maximum (RM) for the upper body, and 40–50% of one RM for the lower body, with an increasing work load during the training sessions. To achieve cardiovascular adjustment and reduce the risk of malignant cardiac arrhythmias and ischaemia, the training session is initiated and terminated with a warm-up and a cool-down period to gradually increase and decrease training intensity and HR. This cardiovascular adjustment has been proven to reduce the risk of ischaemia and arrhythmia in relation to exercise training.45
Training is predominantly performed in the upright position to reduce left ventricle preload (diastolic volume) and the risk of ischaemia and arrhythmias due to HF.46
Sustained moderate daily physical exercise
Participants are instructed to perform moderate physical exercise at least 30 min/day during the intervention period, for example, bicycling, walking, gardening, jogging or recreational sports. Daily moderate physical exercise is encouraged to be continued throughout life.
Both components of the intervention will be supervised regularly by the primary investigator to ensure protocol compliance. Modification of the allocated intervention due to surgery complications, rehospitalisation or emerging comorbidities (eg, pneumonia, pericardial exudation and musculoskeletal problems) will be individually assessed, and the time of the primary outcome assessment at 4 months (described in section below) will be corrected in accordance with changes in the intervention.
Usual care control group
Patients in the control group will follow standard follow-up for patients treated for IE, with one to two visits within the first month postdischarge, including blood work and clinical assessment. Haemoglobin level, infection variables, kidney function and, on indication, liver status is assessed, and blood cultures are drawn on suspicion of IE relapse. Blood pressure, pulse and temperature parameters are obtained. If results give cause for concern, the patient will see a specialist physician during the follow-up visit. A transthoracic echocardiogram will be performed within the first year postdischarge, typically between 1 and 6 months postdischarge and again at 12 months, depending on whether the individual patient has had heart valve surgery and on the status of the native or replaced valve. These patients will be contacted at 1, 4, 6, 12 and 24 months for outcome assessment, including functional test, questionnaires and clinical data collection (see ).
Outcomes and data collection
Numerous data will be collected to evaluate the effect and meaning of the intervention. The primary and the secondary outcome reflect the primary modifiable factors of the intervention. Since almost no evidence exists, a number of explorative outcomes will also be collected.
MH will be measured by the Mental Component Subscale (MCS) of the Medical Outcome Study Short Form 36 (SF-36) questionnaire47
after 1 month (T1
), 4 months (T4
), 6 months (T6
), 12 months (T12
) and 24 months (T24
). The SF-36 questionnaire is a measure of self-rated health. It is a validated multipurpose health survey comprised of 36 items that address the following eight dimensions: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE) and MH. The first four scales (PF, RP, BP and GH) are then combined into a physical component scale and the latter four (VT, SF, RE and MH) into an MSC.47
The instrument was chosen for its ability to detect changes in self-rated health within domains that could potentially be influenced by the CopenHeartIE
intervention. MH was chosen as the primary outcome as other studies have shown that MH is affected in patients with IE compared to healthy controls13
and the rehabilitation intervention focuses on this modifiable factor.
Physical capacity will be measured by peak VO2
using cardiopulmonary exercise testing (Ergo-Spiro CS-200, Schiller, Switzerland) by investigators blinded to the intervention group. The test will be performed according to current guidelines for ergospirometry testing,48–50
using an ergometer bicycle with spirometry, monitoring heart rhythm, blood pressure, ECG and measuring gas exchange during workload and in the following recovery period. Average test duration is 10–15 min including pretestand post-test phase without work load. Before each session, calibration will be performed to address changes in room temperature, humidity and air O2
content. A standardised ramp protocol will be used with an initial work load of 25 or 50 W, increasing gradually by 12.5 W/min until peak exhaustion. Peak exhaustion is evaluated by a respiratory exchange ratio (RER)≥1.10 or subjective exhaustion of the patient. To encourage patients equally, independent of the tester, a standardised guide has been developed. During the test, clinical manifestations, ECG abnormalities (ST depression, ST elevation, q-wave and t-wave changes, supraventricular or ventricular arrhythmias), blood pressure response and several physiological parameters will be observed and documented. The test will be performed by either a cardiac care nurse or a physician. For safety reasons, preset criteria for initiation and/or termination of the test have been defined. The test will be performed prior to the exercise training programme (T1
), after 12 weeks of exercise training (T4
) and at 12 months follow-up (T12
). Physical capacity was chosen as the secondary outcome measure, as studies indicate that patients treated for IE are physically deconditioned after long-term illness and hospitalisation.14
A more extensive evaluation of the physical and psychological status of the patients over time will be performed, exploring demographic, clinical, paraclinical and imaging variables, as well as additional physical capacity tests and additional questionnaires exploring, for example, fatigue, sleep quality and anxiety and depression (see ).
CopenHeartIE—exploratory quantities subjected to post hoc analysis
Data collected from official national registers regarding mortality, hospitalisation, emergency room visits, outpatient visits, medication, employment status and payment of welfare benefits (sick leave payment and early retirement pension) will be collected at 24 months to assess the long-term effects of the intervention. The Danish official national registers are well functioning with a small percentage of lost data.64
Consequently, the method is well suited as an outcome measure in small patient populations. Data will be collected from the Danish National Patient Register,65
the Danish National Health Service Register,66
the Danish National Prescription Registry,67
the Danish National Causes of Death Register68
and registers on transfer payments and labour market affiliation.69
An economic evaluation will be conducted alongside the trial to assess the cost utility of comprehensive cardiac rehabilitation compared with usual care in the study population. The economic evaluation will compare the costs to QALYs (quality-adjusted life years) and take a societal perspective as recommended nationally. QALYs and costs will be assessed at the end of the intervention, 6 months from randomisation and later after 24 months from randomisation using register-based follow-up.
QALYs will be estimated using the self-completed EQ-5D instrument, which is a standardised instrument assessing five dimensions of self-reported health status (mobility, self-care, usual activities, pain/discomfort and anxiety/depression).71
The estimated calculations will be evaluated using Danish preference weights.73
Information on costs will only include costs that are expected to differ between the intervention and usual care group.59
Included costs in the evaluation are health costs associated with the rehabilitation programme, other healthcare costs (healthcare utilisation apart from rehabilitation), patient costs and costs of productivity losses. Information on costs will be collected by a mixture of activity-based costing, surveys, patient diaries and by the use of registers.
Results from the analysis will be reported as an incremental cost-effectiveness analysis (ICER). Sensitivity analysis will be conducted to express uncertainty in the estimates.74
The reporting of ICER is presented using Bayesian methods, including bootstrapping and presented as cost-effectiveness acceptability curves.75
Sample size, power calculations and interim analysis
We will perform a randomised trial with a continuous response variable from independent control and intervention group participants with one control per intervention group participant. A previous study on an IE population found that the MSC was normally distributed with a SD of 13.13
If the true difference between the intervention and control group means is six points, we will need to include 75 participants in each study group (a total of 150 participants) to be able to reject the null hypothesis, stating that the mean in the intervention and the control groups are the same with a power of 80%. The type I error probability associated with this test of this null hypothesis is 5%.
For the secondary outcome, VO2
, we will be able to reject the null hypothesis that the population means of the experimental and control groups are equal with a probability (power) of 75.4%, assuming the VO2
is normally distributed with an SD of 6.9,27
and the true difference in the experimental and control means is 3 ml/kg/min.
A data monitoring and safety committee will be informed, every 9 months, of all serious adverse events occurring in the two study groups. An interim analysis meeting will be held by the data monitoring and safety committee to review data relating to intervention efficacy, participant safety and quality of trial conduct. The committee will evaluate data on the primary and secondary outcome measures; MH (SF-36)/peak VO2 (efficacy) and all serious adverse events (safety/tolerability). After the interim analysis meeting, the committee will make a recommendation to the steering committee whether to continue, hold or terminate the trial. This recommendation will be based primarily on safety and efficacy considerations and will be guided by statistical monitoring guidelines defined by the trial safety charter.
Data will be pseudoanonymised and analysed, blinded by a trial-independent statistician using intention-to-treat analyses and a mixed model with repeated measures (MMRM) for continuous outcome measures.76
Using MMRM ensures that missing data values (in the case of the primary and secondary outcome) will not create bias as long as the missing values are random. Two-sided tests will be performed. The level of significance is set at 5%. Dealing with multiplicity, gate keeping will be used to adjust the observed p values for primary and secondary outcomes.77
Both original and adjusted p values will be reported.
For the primary and secondary outcomes, we will conduct sensitivity analysis to assess the potential impact of non-random missing values. For each intervention group (A and B) some quantities (imputing quantities) will be computed to be used to impute missing values in a group (A or B) as explained below. A comparison between groups A and B where missing values in group A are imputed using imputing quantities obtained from group A and missing values from group B are imputed using imputing quantities obtained from group B is referred to as a best-case analysis. If missing values in group A are imputed using imputing quantities obtained from group B and vice versa the comparison is called a worst-case analysis. The imputed quantities for the primary outcome would be the group mean at T1 (X1-bar), the group mean at T4 (X4-bar), the group mean at T6 (X6-bar), the mean difference between the value measured at T4 and that measured at T1 (delta 1), and the mean difference between the value measured at T6 and that measured at T4 (delta-2). explains how the quantities will be used to impute missing values in a group (either the same group or the other intervention group).
If the SE of a parameter estimate calculated using imputed data is smaller than that of the corresponding parameter calculated using complete case data it will be replaced by the latter SE when the p value is calculated.
Long-term register-based outcomes will be analysed by two different models: non-negative count outcomes (eg, number of contacts to the hospital or number of visits to general practitioners) will be analysed by a Poisson model or a zero-inflated Poisson model if the number of zeros are large, and time-to-event data (eg, cause-specific mortality and leaving the labour market) will be analysed with survival methods (Kaplan-Meier estimator and Cox regression model). Especially for socio-economic outcomes, competing risk due to mortality will be considered if a large proportion of patients die during follow-up.
Explorative data will be analysed using appropriate statistical methods according to type of data (see ). SPSS V.19.0 and SAS V.9.3 will be used.