Heart Rehabilitation in patients awaiting Open heart surgery targeting to prevent Complications and to improve Quality of life (Heart-ROCQ): study protocol for a prospective, randomised, open, blinded endpoint (PROBE) trial

Introduction The rising prevalence of modifiable risk factors (eg, obesity, hypertension and physical inactivity) is causing an increase in possible avoidable complications in patients undergoing cardiac surgery. This study aims to assess whether a combined preoperative and postoperative multidisciplinary cardiac rehabilitation (CR) programme (Heart-ROCQ programme) can improve functional status and reduce surgical complications, readmissions and major adverse cardiac events (MACE) as compared with standard care. Methods and analysis Patients (n=350) are randomised to the Heart-ROCQ programme or standard care. The Heart-ROCQ programme consists of a preoperative optimisation phase while waiting for surgery (three times per week, minimum of 3 weeks), a postoperative inpatient phase (3 weeks) and an outpatient CR phase (two times per week, 4 weeks). Patients receive multidisciplinary treatment (eg, physical therapy, dietary advice, psychological sessions and smoking cessation). Standard care consists of 6 weeks of postsurgery outpatient CR with education and physical therapy (two times per week). The primary outcome is a composite weighted score of functional status, surgical complications, readmissions and MACE, and is evaluated by a blinded endpoint committee. The secondary outcomes are length of stay, physical and psychological functioning, lifestyle risk factors, and work participation. Finally, an economic evaluation is performed. Data are collected at six time points: at baseline (start of the waiting period), the day before surgery, at discharge from the hospital, and at 3, 7 and 12 months postsurgery. Ethics and dissemination This study will be conducted according to the principles of the Declaration of Helsinki (V.8, October 2013). The protocol has been approved by the Medical Ethical Review Board of the UMCG (no 2016/464). Results of this study will be submitted to a peer-reviewed scientific journal and can be presented at national and international conferences. Trial registration number NCT02984449.

y surgery, at time of discharge from the hospital, and at 3, 7, and 12 months after surgery.

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Study enrolment, randomization and registry 158 Figure 2 shows the flow chart of the Heart-ROCQ study. Patients on the waiting list of the thoracic 159 surgery department and meeting the study criteria for type of surgery are asked to participate by their 160 cardiologist. The cardiologist provides the patients with study information and an invitation to meet 161 the researcher at the preoperative consultation. At the preoperative consultation, the researcher will 162 obtain informed consent and conduct the baseline measurements. Eligible patients who have signed 163 informed consent and performed the baseline measurements, are randomised to the Heart-ROCQ 166 replacement or repair of part of aortic or valve], 2 procedures or 3 procedures), gender, and age (≥65 167 and <65 years). Prior to the start of the study, the randomization lists were created (using the 'ralloc' 172 Patients who are not willing to participate are asked to give written consent for using data that 173 are collected during routine care. These data are collected in the Heart-ROCQ study registry to get 174 more insight in potential differences between patients who participated in the study and patients who 175 did not. The Heart-ROCQ registry will thus provide more insight in the generalizability of the results.

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The scores of all events are summed up to calculate a total score. Only the most serious 208 complication is counted per event (e.g. when a percutaneous coronary intervention [score 1] is 209 complicated by a stroke [score 2], the score will be 2 and not 3 [1 + 2]).

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions ___7, 8______ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned ___7, 8______ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions ____7, 8_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how ____7, 8_____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial ___NA________

Data collection methods 18a
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols __NA_________ Methods for any additional analyses (eg, subgroup and adjusted analyses) ___15________ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) ____15_______

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed ___13________ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ___15________ Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct ___13________ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor ___13________

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The aim of the Heart-ROCQ study is to determine the effect of a comprehensive pre-and to the Standard Care CR program. To assess who will benefit from CR and why the CR programs 112 are effective, moderator and mediator analyses are performed.   increase insight into-potential differences between patients who participated in the study and patients 171 who did not. The Heart-ROCQ registry will thus provide more insight into the generalizability of the 172 results. Data from this registry are not used for the primary statistical analyses.

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Heart-ROCQ group 176 The Heart-ROCQ group receives a CR program at the Centre of Rehabilitation of the UMCG

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(location Beatrixoord, which is located 6 km from the hospital of the UMCG) consisting of 3 phases.

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The first phase is an outpatient preoperative optimization phase during the waiting period (3 times 179 per week, minimum of 3 weeks). The second phase is a post-operative inpatient CR phase (3 weeks, 180 weekdays only) followed by the third phase, an outpatient CR phase (2 times per week, for 4 weeks).

181
During each phase, all participants receive physical therapy including group sessions of inspiratory The primary outcome is a composite weighted score of functional status, post-operative surgical 201 complications, readmissions to the hospital, and MACE. Each event is scored (ranging from 1 to 3 202 points), separately. Table 1 shows an overview of the primary outcome and the scoring system.

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The scores of all events are combined to calculate a total score. Only the most serious complication 204 is counted per event (e.g. when a percutaneous coronary intervention [score 1] is complicated by a 205 stroke [score 2], the score will be 2 and not 3 [1 + 2]).

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The concept of the composite weighted score is adapted from the African-American Heart    3) able to perform basic activity of daily living (ADL)-activities (i.e. going independently to the toilet).

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Previous preoperative CR studies were primarily focused on short-term effects; only one 367 preoperative CR study and a few post-operative CR studies have determined long-term

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The Heart-ROCQ program is expected to be cost-effective in the long-term, which is also of 381 interest for policymakers and health care providers. Therefore, an economic evaluation is performed     Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) ____6-14___

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions ___7, 8______ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned ___7, 8______ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions ____7, 8_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how ____7, 8_____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial ___NA________

Data collection methods 18a
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

__11-14_______
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols __NA_________  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol __13_________ Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol ___15, 16_____ 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ___15________ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) ____15_______

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed ___13________ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ___15________ Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct ___13________ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor ___13________  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46 F o r p e e r r e v i e w o n l y 5 Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32) __7, 8_______

Ethics and dissemination
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable __7, 8_______

Confidentiality 27
How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial __13_________

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operative CR program is more beneficial when compared to a separate preoperative CR program or 106 a single post-operative CR program.

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The aim of the Heart-ROCQ study is to determine the effect of a comprehensive pre-and to the Standard Care CR program. To assess who will benefit from CR and why the CR programs 114 are effective, moderator and mediator analyses are performed.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59      Patients who are not willing to participate are asked to give written consent for using data that 171 are collected during routine care. The data are collected in the Heart-ROCQ study registry to 172 increase insight into-potential differences between patients who participated in the study and patients 173 who did not. The Heart-ROCQ registry will thus provide more insight into the generalizability of the 174 results. Data from this registry are not used for the primary statistical analyses.

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Heart-ROCQ group 178 The Heart-ROCQ group receives a CR program at the Centre of Rehabilitation of the UMCG

179
(location Beatrixoord, which is located 6 km from the hospital of the UMCG) consisting of 3 phases.

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The first phase is an outpatient preoperative optimization phase during the waiting period (3 times 181 per week, minimum of 3 weeks). The second phase is a post-operative inpatient CR phase (3 weeks, 182 weekdays only) followed by the third phase, an outpatient CR phase (2 times per week, for 4 weeks).

183
During each phase, all participants receive physical therapy including group sessions of inspiratory  The primary outcome is a composite weighted score of functional status, post-operative surgical 203 complications, readmissions to the hospital, and MACE. Each event is scored (ranging from 1 to 3 204 points), separately. Table 1 shows an overview of the primary outcome and the scoring system.

205
The scores of all events are combined to calculate a total score. Only the most serious complication 206 is counted per event (e.g. when a percutaneous coronary intervention [score 1] is complicated by a 207 stroke [score 2], the score will be 2 and not 3 [1 + 2]).

Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained ___6________ Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

___7________
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered ___9________ 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease) ___NA______ 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

___13______
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ___7_______ Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended ___10-14___ Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) ____6-14___

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions ___7, 8______ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned ___7, 8______ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions ____7, 8_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how ____7, 8_____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial ___NA________

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol __11-14_______ 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols __NA_________  Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol __13_________ Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol ___15, 16_____ 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ___15________ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) ____15_______

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed ___13________ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ___15________ Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct ___13________ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor ___13________ How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial __13_________