BMJ Open · High intensity interval training (HIIT) appears to be a safe and effective alternative, resulting in greater improvements in peak oxygen uptake (VO2 peak). To date, HIIT

For peer review only

High intensity interval training versus moderate intensity steady state training in UK cardiac rehabilitation

programmes (HIIT or MISS UK): study protocol for a multi-centre randomised controlled trial and economic evaluation.

Journal: BMJ Open

Manuscript ID bmjopen-2016-012843

Article Type: Protocol

Date Submitted by the Author: 26-May-2016

Complete List of Authors: McGregor, Gordon; University Hospitals Coventry and Warwickshire NHS Trust, Cardiac Rehabilitation; Cardiff Metropolitan University, Centre for Exercise & Health Nichols, Simon; University of Hull, Department of Sport, Health & Exercise Science Hamborg, Tom; University of Warwick Warwick Medical School, Statistics and Epidemiology, Division of Health Sciences Bryning, Lucy; Bangor University, Centre for Health Economics and Medicines Evaluation Edwards, Rhiannon; Bangor University, Centre for Health Economics &

Medicines Evaluation Markland, David; Bangor University, School of Sport, Health & Exercise Sciences Mercer, Jenny; Cardiff Metropolitan University, Centre for Exercise & Health Birkett, Stefan; University of Hull, Department of Sport, Health & Exercise Science Ennis, Stuart; University Hospitals Coventry and Warwickshire NHS Trust, Cardiac Rehabilitation; Cardiff Metropolitan University, Centre for Exercise & Health Powell, Richard; University Hospitals Coventry and Warwickshire NHS Trust, Cardiac Rehabilitation Begg, Brian; Cardiff Metropolitan University, Centre for Exercise & Health;

Aneurin Bevan University Health Board, Cardiac Rehabilitation Haykowsky, Mark; University of Texas, College of Nursing and Health Innovation Banerjee, Prithwish; University Hospitals Coventry and Warwickshire NHS Trust, Department of Cardiology; Coventry University, Health & Life Sciences Ingle, Lee; University of Hull, Department of Sport, Health & Exercise Science Shave, Rob; Cardiff Metropolitan University, Centre for Exercise & Health Backx, Karianne; Cardiff Metropolitan University, Cardiff Centre for Exercise & Health

<b>Primary Subject Heading</b>:

Sports and exercise medicine

Secondary Subject Heading: Health economics, Qualitative research, Rehabilitation medicine, Cardiovascular medicine

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Keywords: Coronary heart disease < CARDIOLOGY, Myocardial infarction < CARDIOLOGY, HEALTH ECONOMICS

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High intensity interval training versus moderate intensity steady state training in UK

cardiac rehabilitation programmes (HIIT or MISS UK): study protocol for a multi-

centre randomised controlled trial and economic evaluation.

Gordon McGregor1,2 *

, Simon Nichols3, Thomas Hamborg

4, Lucy Bryning

5, Rhiannon Tudor-

Edwards5, David Markland

6, Jenny Mercer

2, Stefan Birkett

3, Stuart Ennis

1,2, Richard Powell

1,

Brian Begg2,7

, Mark J. Haykowsky8, Prithwish Banerjee

1,9, Lee Ingle

3, Rob Shave

2 and

Karianne Backx2

*Corresponding Author:

Department of Cardiac Rehabilitation, Office ADX10032, Cardiac Services Office Suite

Level 1, East Wing, University Hospital, Clifford Bridge Road, Coventry, CV2 2DX.

Email: [email protected]

Tel: 02476 234 570

1 Department of Cardiac Rehabilitation, Centre for Exercise & Health, University Hospital,

Coventry, UK

2 Cardiff Centre for Exercise & Health, Cardiff Metropolitan University, Cardiff, UK

3 Department of Sport, Health & Exercise Science, University of Hull, Hull, UK

4 Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School,

University of Warwick, Warwick, UK

5 Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK

6 School of Sport, Health & Exercise Sciences, Bangor University, Bangor, UK

7 Aneurin Bevan University Health Board, Gwent, Wales, UK

8 College of Nursing and Health Innovation,

University of Texas at Arlington, Arlington,

Texas, USA

9School of Health & Life Sciences, Coventry University, Coventry, UK

Key words: Cardiac rehabilitation, high intensity interval training, coronary heart disease

Word count: 3858

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Abstract

Introduction: Current international guidelines for cardiovascular rehabilitation (CR)

advocate moderate intensity exercise training (MISS, moderate intensity steady state). This

recommendation predates significant advances in medical therapy for coronary heart disease

(CHD) and may not be the most appropriate strategy for the ‘modern’ patient with CHD.

High intensity interval training (HIIT) appears to be a safe and effective alternative, resulting

in greater improvements in peak oxygen uptake (VO2 peak). To date, HIIT trials have

predominantly been proof of concept studies in the laboratory setting and conducted outside

the United Kingdom (UK). The purpose of this multi-centre randomised controlled trial is to

compare the effects of HIIT and MISS training in patients with CHD attending UK CR

programmes.

Methods and analysis: This pragmatic study will randomly allocate 510 patients with CHD

to 8 weeks of twice weekly HIIT or MISS training at 3 centres in the UK. HIIT will consist of

10 high intensity (85-90% peak power output (PPO)) and 10 low intensity (20-25% PPO)

intervals, each lasting 1 minute. MISS training will follow usual care recommendations,

adhering to currently accepted UK guidelines (i.e. >20 mins continuous exercise at 40-70%

heart rate reserve). Outcome measures will be assessed at baseline, 8 weeks and 12 months.

The primary outcome for the trial will be change in VO2 peak as determined by maximal

cardiopulmonary exercise testing. Secondary measures will assess physiological,

psychosocial and economic outcomes.

Ethics and dissemination: The study protocol v.1.0, dated 1st February 2016 was approved

by the NHS Health Research Authority, East Midlands - Leicester South Research Ethics

Committee (16/EM/0079). Recruitment will commence in July 2016 and will be completed in

April 2018. Results will be published in peer-reviewed journals, presented at national and

international scientific meetings and are expected to inform future national guidelines for

exercise training in UK CR.

Trial registration number: this study is registered with ClinicalTrials.gov: NCT02784873

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Introduction

Coronary heart disease (CHD) accounts for one third of all deaths globally, totaling 7.4

million in 2013.[1] In the United Kingdom (UK) alone, approximately 175,000 myocardial

infarctions (MI) are recorded annually.[2] Whilst this is a significant number, advances in

preventative therapy and medical treatment have contributed to an overall reduction in CHD

mortality in the UK[3]. An estimated 2.3 million people are now living with the disease,[2]

and with a growing population of CHD survivors, the need for comprehensive and cost

effective chronic disease management is ever more apparent.

Integral to the long-term management of CHD is the provision of cardiovascular

rehabilitation (CR) programmes.[4 5] Exercise training is considered a key component

alongside risk factor management and facilitation of long-term behavioural change.[4]

Compelling evidence exists for CR programmes, with meta-analyses historically highlighting

a favourable effect on functional capacity, health related quality of life (HR-QoL), hospital

admissions, and mortality.[6-8] The most recent data, however, do not confirm a survival

benefit from participation in CR.[9] This may relate to the ability of contemporary medical

care, both interventional cardiology and secondary prevention pharmacotherapy, to achieve

much of what was previously attributed to CR. However, CR does improve HR-QoL and, as

such, strategies to maximise long-term physical functioning (i.e. optimised, personalised

exercise training programmes) should be pursued in patients with CHD. Tangible benefits are

realistic for both the individual and an overburdened healthcare system and CR programmes

have a vital role to play in this regard.

In addition to improved medical care, the prescribed intensity of the exercise training

interventions included in the recent meta-analysis by Anderson et al.[9], may help explain the

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lack of improvement in mortality rates with CR. Exercise intensity ranged from 50-95% of

peak oxygen uptake (VO2 peak), with the vast majority of protocols at the lower end of this

range. This is in line with current international exercise guidelines for CHD which advocate

moderate intensity training (< 80% VO2 max) prescribed as either interval or steady state

(MISS, moderate intensity steady state).[10] It is well known that greater improvements in

VO2 peak can be expected with exercise training of a higher intensity, and that a higher VO2 peak

is associated with an improvement in mortality risk.[11 12] Given that current guidelines

predate significant advances in interventional cardiology and medical therapy, moderate

intensity exercise may be considered conservative and suboptimal for the ‘modern’ patient

with CHD.[13] Greater benefit may be attained by participating in high intensity interval

training (HIIT) involving repeated bursts of harder exercise interspersed with periods of

recovery.[14 15] High intensity, in this context, describes exercise performed above moderate

intensity as opposed to the maximal or supramaximal exercise specified in some protocols in

healthy individuals.[16]

Meta-analyses have indicated the superiority (approximately 1.7 ml·kg-1

·min-1

) of HIIT over

MISS for improvements in VO2 peak in patients with CHD.[14 15 17] These analyses,

however, are limited by small sample sizes and the significant heterogeneity of study

populations and HIIT protocols. High intensity interval training protocols can be modified in

numerous ways (e.g. modality, intensity, interval duration) to suit the population or intended

outcome,[18] but there is no consensus as to the optimal configuration for the CHD

population.[17] One option; low-volume, high intensity interval training, utilises 1-minute

intervals of harder exercise to provide intermittent metabolic stimulus with non-sustained

cardiovascular stress. This appears to be safe and well tolerated in addition to being effective

at improving VO2 peak in patients with CHD.[19 20] The benefit of this approach in ‘real

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world’ CR programmes in the UK, however, cannot be confirmed. Previous studies have

generally been proof of concept studies conducted under controlled ‘laboratory’ conditions

with non-UK populations, questioning both their ecological validity and applicability to CR

in the UK.

The High Intensity Interval Training versus Moderate Intensity Steady State Training in UK

Cardiac Rehabilitation trial (HIIT or MISS UK) is a pragmatic multi-centre randomised

controlled trial and economic evaluation comparing two CR exercise interventions. The

primary objectives of the trial are:

1. To assess the effect of HIIT on VO2 peak and cardiovascular health.

2. To assess the palatability of HIIT and the psychological and motivational factors

associated with compliance and adherence.

3. To assess the effect of HIIT on lifestyle physical activity, HR-QoL.

4. To conduct an economic evaluation of HIIT compared with MISS in CR programmes

in the UK.

5. To assess the safety of HIIT.

In patients attending CR programmes in the UK, we hypothesise that HIIT will improve VO2

peak to a greater extent than MISS training. We also hypothesise that HIIT will: 1) be more

palatable than MISS and demonstrate greater patient compliance and adherence; 2) improve

cardiovascular health to a greater extent than MISS; 3) improve HR-QoL to a greater extent

than MISS; 4) lead to more positive motivation and attitudes to exercise than MISS; 5) increase

short and medium-term participation in lifestyle physical activity to a greater extent than

MISS; 6) be a cost effective alternative to MISS; 7) be as safe as MISS.

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Methods and analysis

The HIIT or MISS UK study is a pragmatic, single-blind, multi-centre, longitudinal,

randomised controlled trial and economic evaluation. Participants will be randomly allocated

to 8 weeks of HIIT or MISS training (usual care). Outcomes will be measured at baseline, 8

weeks and 12 months by assessors blinded to group allocation. Study interventions will be

delivered by clinical (not research) staff. The study is pragmatic in nature in that it will be

conducted in existing CR programmes. As such, it is accepted that some variation in the

delivery of usual care will be evident between study sites. This will ensure generalisability of

the findings to UK CR programmes. The trial protocol adheres to the Standard Protocol

Items: Recommendations for Clinical Trials (SPIRIT) guidelines.[21]

Setting

The HIIT or MISS study will be conducted at three community CR centres; 1) Atrium Health,

Centre for Exercise & Health, Coventry, 2) The Department of Sport, Exercise & Health

Science, University of Hull and Hull Royal Infirmary, Kingston-upon-Hull and 3) Ystrad

Fawr Hospital, Ystrad Mynach, South Wales. Programmes are commissioned by University

Hospitals Coventry & Warwickshire NHS Trust, City Health Care Partnership CIC, (Hull)

and Aneurin Bevan University Health Board (South Wales) respectively. Commencing July

2016, 510 CR patients will be recruited over a 2-year period.

Participants

The study will recruit patients with established coronary artery disease (CAD) referred for

CR exercise training. Patients with myocardial infarction (MI), coronary artery bypass graft

(CABG) surgery, angiographically documented CAD and elective percutaneous coronary

intervention (PCI) will be eligible.

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General inclusion criteria:

1. Successfully revascularised following PCI or CABG

2. Angiographically documented non-obstructive CAD

3. Left ventricular ejection fraction > 40%

4. Clinically stable (symptoms and medication) for > 2 weeks

5. 18 – 75 yr of age

General exclusion criteria:

1. Symptoms of ischemia

2. Significant left main stem stenosis

3. NYHA class III-IV symptoms

4. Compromising ventricular arrhythmia

5. Significant valvular heart disease

6. Inability to comply with guidelines for participation in exercise testing and

training [22-24]

7. Significant limiting comorbidities that would prevent full participation

Additional exclusion criteria:

Further to the analysis of cardiopulmonary exercise test (CPET) and resting

echocardiography by the research team at baseline, and prior to randomisation, patients will

be prevented from continuing their involvement in the study if there is indication of:

1. Exercise-induced ischaemia or significant haemodynamic compromise

2. Left ventricular ejection fraction < 40%

3. Clinical instability in accordance with CR guidelines [22 24]

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training [23 24]

Study Procedures

An outline of the participant pathway for the study is presented in Figure 1. Eligibility will be

assessed by the research team at each site under the supervision of the local principal

investigator (PI). Potential participants will be approached at their first outpatient CR

appointment by a member of the study team: verbal and written information will be provided.

A subsequent phone call (at least 48 hours later) will confirm those who wish to participate.

Informed consent will be attained at the baseline assessment visit, which will coincide with

an outpatient CR appointment. Baseline procedures will include, CPET, echocardiogram,

venipuncture, arterial oscillometry, and clinical examination. Instruments to assess HR-QoL,

health and social care use, and the psychological and motivational factors associated with

compliance and adherence will be administered and a lifestyle physical activity monitor will

be fitted (removed 1 week later). Further to the analysis of CPET and echocardiography at

baseline, the local research team will rescreen potential participants for eligibility. Those who

are ineligible will take no further part in the study but will continue with usual care CR.

Eligible participants will subsequently be randomised to 8 weeks of twice weekly HIIT or

MISS training. All measures completed at baseline will be repeated at 8 weeks and 12

months.

Interventions

The study will compare high intensity interval training (HIIT) with current usual care -

moderate intensity steady state (MISS) training. Table 1 provides a summary of both

interventions and Table 2 details the standardised progression of the HIIT intervention.

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Participants will attend twice weekly CR exercise sessions for 8 weeks, performing either

HIIT or MISS training for the cardiovascular component of their programme. In accordance

with current guidelines,[24] a muscular strength and endurance training programme will also

be completed by both study groups and participation in additional home-based exercise

recommended as standard. Participants who are unable/unwilling to comply with the HIIT

protocol will be permitted to cease involvement in the HIIT intervention and continue with

usual care CR (not as part of the trial). Where two or more consecutive training sessions are

missed, the intervention period can be extended to 10 weeks. As is commonplace for CR

programmes in the UK, there will be some variation in the structure and delivery of the MISS

intervention at each of the study sites. This is in keeping with the pragmatic nature of the

trial. Each centre will, however, adhere to current UK guidelines.[24]

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Table 1. Comparison of HIIT and MISS training interventions

HIIT MISS

� Exercise sessions conducted as follows:

1. Warm up: 15 min total, 10 min <40%

HRR, 5 min <70% HRR.

2. Cardiovascular component: exercise cycle

ergometer interval training (Wattbike

Trainer (Wattbike, Notingham, UK):

high = 85-90% PPO from CPET, low = 20-

25% PPO (exercise intensity will not to be

prescribed from gas exchange data i.e.

%VO2 peak). Change in intensity from low to

high achieved by altering cadence (rpm).

3. Cool down: 10 min, <40% HRR

� Duration of intervals and total programme

duration increased in a standardised fashion

(Table 2).

� Workload increased bi-weekly in response to

participant reported RPE (only after the full 10

x 1 protocol has been achieved). If RPE < 17

then workload will be increased.

� Exercise sessions conducted in accordance

with BACPR/ ACPICR guidelines[24],

adhering to the following key principles:

1. Warm up: 15 min, < 40% HRR

2. Cardiovascular component: progress

towards 20 - 40 min continuous

cardiovascular exercise at 40-70% HRR.

3. Cool down: 10 min, < 40% HRR

� Initial duration based on participant’s

previous and current PA levels and CPET

performance.

� Duration and workload of cardiovascular

component adjusted, as tolerated, within the

above parameters, in response to exercising

HR, participant reported RPE and symptoms.

HRR, heart rate reserve; PA, physical activity; CPEX, cardiopulmonary exercise test; HR, heart rate;

RPE, rating of perceived exertion; PPO, peak power output; VO2 peak, peak oxygen uptake

Table 2. Breakdown of HIIT training programme by week

Week High intensity

intervals

(number x time

in min)

Low intensity

intervals

(number x time

in min)

Total high

intensity

exercise (min)

Total low

intensity

exercise (min)

Total exercise

time (min)

1 5 x 0.5 5 x 1 2.5 5 7.5

2 5 x 1 5 x 1 5 5 10

3 7 x 1 7 x 1 7 7 14

4-8 10 x 1 10 x 1 10 10 20

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The following exercise training criteria must be satisfied for participants to be regarded as

having sufficiently adhered to the treatment protocol:

• A minimum of 80% of sessions completed (13 of 16)

• HIIT – 10 x 1 min protocol achieved by week 4

• MISS – 20 min continuous CV exercise achieved by week 4

The number of participants who do not meet the above criteria will be recorded.

Randomisation and blinding:

Trial participants will be randomised to HIIT or MISS on a 1:1 basis. The random allocation

sequence will be generated by the trial statistician using a random number generator, and

implemented by a central telephone registration and randomisation service at Warwick

Clinical Trials Unit. Randomisation will be stratified by site using random permuted blocks

randomisation within each site to ensure approximately equal numbers of patients are

allocated to HIIT and MISS. To ensure allocation concealment, researchers will request

randomisation on completion of all baseline assessments. Outcome assessors will be blinded

to group allocation, as will the trial statistician. Clinical staff delivering the interventions

cannot be blinded, however, they will not be involved in data analysis or reporting.

Study outcome measures:

The primary outcome measure is the change in peak oxygen uptake (VO2 peak) at 8 weeks. A

number of secondary outcome measures will also be assessed, namely 1) palatability and the

motivational and attitudinal factors associated with compliance and adherence; 2) HR-QoL;

3) service and resource use; 4) lifestyle physical activity; 5) cardiovascular reserve; 6) cardiac

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remodelling; 7) arterial remodelling; 8) cardiovascular health; 9) safety. Table 3 provides the

complete schedule for outcome assessment.

Table 3. Outcome measures and assessment schedule

Measure Instrument Assessment time point

Primary outcome

VO2 peak

CPET

Baseline, 8 weeks, 12 months

Secondary outcomes

Compliance, adherence

Compliance/adherence/drop-

out rates

Continuous

MSES Baseline, 8 weeks, 12 months

BREQ-2 Baseline, 8 weeks, 12 months

PNSES Baseline, 8 weeks, 12 months

Bipolar adjectival rating scale Baseline, 8 weeks, 12 months

SC-IAT Baseline, 8 weeks, 12 months

Palatability Semi-structured interviews 8 weeks

HR-QOL EQ-5D Baseline, 8 weeks, 12 months

Service and resource use CSRI Baseline, 8 weeks, 12 months

Lifestyle physical activity Physical activity monitor Baseline, 8 weeks, 12 months

Cardiovascular reserve CPET Baseline, 8 weeks, 12 months

Cardiac remodelling Echocardiography Baseline, 8 weeks, 12 months

Arterial remodelling Arterial oscillometry Baseline, 8 weeks, 12 months

Cardiovascular health Clinical examination Baseline, 8 weeks, 12 months

Blood sampling Baseline, 8 weeks, 12 months

Safety Adverse event monitoring Continuous

VO2 peak, peak oxygen uptake; CPET, cardiopulmonary exercise test; MSES, Multidimensional Self-

Efficacy for Exercise Scale; BREQ-2, Behavioural Regulation in Exercise Questionnaire-2; PNSES,

Psychological Need Satisfaction in Exercise Scale; SC-IAT, Single-Category Implicit Association

Test; HR-QoL, health related quality of life; EQ-5D, 5 item EuroQol; CSRI, client service receipt

inventory.

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Cardiopulmonary exercise testing will be performed to measure VO2 peak and other parameters

representative of cardiovascular reserve. Tests will be conducted using a standard bicycle

ramp protocol in accordance with American Thoracic Society guideline.[25] Participants will

be encouraged to maintain a cadence of 70 rpm until symptom limited volitional fatigue

prevents continuation. A peak respiratory exchange ratio (RER) of >1.10 will be considered

indicative of maximal effort.[26]

Compliance and adherence will be determined by recording the number of training sessions

attended and successfully completed in accordance with the exercise protocol. Drop-out from

the programme will also be documented for both study groups in addition to reason for drop-

out, where provided voluntarily by participants. To assess the psychological and motivational

factors associated with compliance and adherence to the exercise training interventions, the

predictive effects of self-efficacy, motivation, need satisfaction and implicit and explicit

attitudes and, reciprocally, the effects of training on self-efficacy, motivation, need

satisfaction and implicit and explicit attitudes, will be quantitatively measured using validated

tools: 1) the Multidimensional Self-Efficacy for Exercise Scale (MSES)[27]; 2) the

Behavioural Regulation in Exercise Questionnaire-2 (BREQ-2)[28]; 3) the Psychological

Need Satisfaction in Exercise Scale (PNSES)[27]; 4) Courneya and Bobick’s 7-point bipolar

adjectival rating scale[29]; and 5) a Single-Category Implicit Association Test (SC-IAT)[30].

Semi-structured interviews will qualitatively evaluate palatability in a sub-group of 40

patients, representative of completers and drop-outs in both intervention groups. Verbatim

transcripts will be thematically analysed.[31]

Health-related quality of life will be assessed with the five-item EuroQoL (EQ-5D-5L)[32],

as recommended by the National Institute for Health and Care Excellence in the UK for

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economic evaluation in clinical trials.[33] General population preference based tariffs for the

UK allow for the comparison of EQ-5D index scores with population norms and other health

conditions[34] An adapted client service receipt inventory (CSRI), based on examples in the

DIRUM database,[35] will be administered at each time point to capture participant health

and social care service use since the last time point (plus a retrospective two month period at

baseline).

Lifestyle physical activity will be recorded over a seven day period with an ActiGraph GT9X

Link (Actigraph, Pensacola, Florida, USA) worn on the wrist. Comprehensive evaluation of

participants’ daily physical activity patterns will be derived from the unit’s 3-axis

accelerometer, magnetometer and gyroscope. The Actigraph GT9X Link is considered the

gold standard in non-invasive research grade physical activity monitoring and has been

extensively validated.

To quantify cardiac remodelling, echocardiographic images will be obtained and analysed as

recommended in current guidelines.[36 37] To assess cardiac structure and function (systolic

and diastolic), standard techniques will be utilised including 2D, M-mode, pulse wave

Doppler and tissue Doppler echocardiography. To investigate arterial remodelling, pulse

wave velocity, will be determined through the non-invasive method of brachial oscillometry

(Mobil-O-Graph PWA Monitor, I.E.M. GmbH, Stolberg, Germany). A blood pressure cuff

will be placed upon the participant’s upper left arm, and will inflate and deflate

automatically. Mobil-O-Graph PWA has been validated against internationally recognised

invasive and non-invasive gold standards.[38]

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Standard clinical examination will include past medical history, stature, body mass and

cardiovascular risk factor assessment i.e. resting blood pressure, diabetes, family history of

premature CHD, smoking status. Blood sampling will be performed to allow the

measurement of biomarkers of cardiovascular and metabolic health. Routine testing will

include full blood cell count, liver function, urea and electrolytes, glycaemic control and a

full lipid profile. Serum and plasma will be stored for the analysis of current and emerging

biochemical markers of cardiovascular and metabolic health relating to inflammation, cardiac

remodeling, pro-thrombosis, endocrine function and lipids.[39 40]

To verify the safety of HIIT and MISS training performed in CR, adverse and serious adverse

events will be carefully monitored, recorded and reported. In line with the principles of Good

Clinical Practice, the nature and severity of the event, in addition to its potential association

with the exercise training intervention, will be ascertained by the local principal investigator

and ratified by the trial clinician.[41]

Sample size

Given the pragmatic nature of the trial, a 1.5 ml.kg.-1

min-1

larger improvement of VO2 peak in

the HIIT group compared to the MISS group is considered a clinically relevant difference.

Keteyian and colleagues reported a reduction of approximately 15% in all-cause mortality for

each 1 ml.kg.-1

min-1

increase in VO2 peak in a large CR cohort with revascularised coronary

disease.[42] In the present study, a sample size of 191 patients in each group will be

sufficient to detect this difference assuming a standard deviation of 4.5 ml·kg-1

·min-1

, a

power of 90%, and a significance level of 5%. The assumed standard deviation is based on

observations from Conraads and co-workers.[43] This trial is similar to HIIT or MISS and

reported a loss to follow-up from baseline to post intervention of 13%. A conservative drop-

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out of approximately 25% yields a required sample size of 510 patients (255 per group) to be

randomised. Should the drop-out rate at 12 months be 50%, then the study would retain

power of 76% to detect a difference of 1.5 ml·kg-1

·min-1

in the primary outcome at this time

point using the aforementioned assumptions.

Data collection and management

Study data will be collected on a case report form by the research team at baseline, 8 weeks

and 12 months. Each participant will be allocated a unique study ID number; a list of

participants will be stored electronically by UHCW NHS Trust. Data will be anonymously

entered into REDCap (Research Electronic Data Capture),[44] a secure, web-based

application designed to support data capture for research studies. This will be hosted by

Cardiff Metropolitan University.

Statistical analysis

The primary endpoint for the statistical analysis is the mean change in VO2 peak (ml·kg-1

·min-

1) from baseline to 8 weeks of follow-up. The primary endpoint will be compared between

intervention arms using a general linear model with treatment group and baseline VO2 peak

fitted as covariates, and 8-week VO2 peak as the dependant variable. The linear model will be

adjusted for the continuous covariate age, and the categorical covariates sex and study site.

Further adjustment variables may be investigated as part of the exploratory analysis. The

robustness of the primary outcome analysis will be investigated using three standard multiple

imputation methods (monotone regression, fully conditional specification regression and

MCMC).

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The secondary outcome measures will be analysed using the same covariates as the primary

outcome analysis. Likewise, the differences between groups in terms of continuous secondary

outcome measures will be assessed with the same statistical model as the primary outcome

analysis. Differences between treatment arms for binary, unordered categorical and ordinal

secondary outcome variables will be analysed using logistic regression, multinomial logistic

regression and proportional odds models, respectively.

The primary and secondary outcome analyses will be conducted at the conventional (two-

sided) 5% level. To reduce the risk of false positive claims, all secondary analyses will be

considered as exploratory if a non-significant result is obtained from the primary analysis

and, whenever reported, the failure to achieve a significant result in the primary analysis will

be declared. It is not proposed to formally adjust for multiple testing amongst the secondary

endpoints as these are likely to be correlated so that standard adjustment techniques such as

the Bonferroni method would be conservative. All analyses will be performed on an

intention-to-treat basis. A per protocol analysis will be conducted as an exploratory analysis,

as will subgroup analyses (for sub-groups pre-specified in the protocol) and repeated

measures mixed models.

All data will be summarised and reported in accordance with the Consolidated Standards of

Reporting Trials (CONSORT) guideline.[45] No formal interim analyses are anticipated.

Economic evaluation

In line with the National Institute for Health and Clinical Excellence (NICE) guidance on the

economic evaluation of public health interventions, [46] from a societal perspective, a cost

consequence analysis of HIIT (embedded within CR) compared with MISS training

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(representing usual care) will be undertaken. Within the cost-consequence analysis there will

be an embedded cost-utility analysis, using Quality Adjusted Life Years (QALYs) gained

with HR-QoL weights drawn from EQ-5D-5L. This approach has been chosen because

QALYs allow comparison with the value for money of other medical and public health

interventions but do not capture the full range of relevant outcomes in public health

prevention.[46] We will use STATA 14 to bootstrap (5,000 replications) the differences in

cost and outcomes, to produce a 95% confidence interval, cost-effectiveness planes, and cost-

effectiveness acceptability curves (CEAC), to present to healthcare policymakers and local

commissioners the probability that the intervention is cost-effective at different payer

thresholds.

The health economics component of the study will be written up in accordance with the

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement for the

reporting of published economic evaluations.[47]

Patient and public involvement

Patient and public involvement has been integral to protocol development. A formal

consultation event was attended by a representative sample of current CR participants in

August 2015. Participants were introduced to various different approaches to exercise

training and asked to comment on their suitability. A range of opinions and views were

recorded with the overriding sentiment being that participants would be prepared to engage in

HIIT with minimal concern. Close supervision by experienced CR exercise professionals was

considered essential. The only significant negative comment related to the fact that HIIT

would be performed solely on an exercise bike as opposed to a range of cardiovascular

exercise equipment. However, participants confirmed that they would be prepared to tolerate

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this in the short term. Two CR participants will sit on the trial steering group for the duration

of the trial.

Ethics

The study protocol v1.0, dated 1st February 2016, was approved by the NHS Health Research

Authority, East Midlands - Leicester South Research Ethics Committee on 4th

March 2016

(16/EM/0079).

Dissemination and impact

Throughout the trial, media outlets (including social media) will be informed of progress, and

the experiences gained will be presented at national conferences and non-academic outlets

such as national governing body publications. On completion, the study results will be

published in peer-reviewed journals and presented at scientific meetings. The results will also

be disseminated in newsletter form throughout the UK via national governing bodies and at

local research and patient conference events. It is anticipated that the results of the study will

inform future national guidelines for exercise training in UK CR.

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Contributions: GM is the Chief Investigator for the trial, leading on protocol writing, ethics

application and manuscript preparation. GM, KB, RS, SN, LI, SE, RP, SB, MH, BB, TH and

PB all contributed fully to study design. TH (statistics), RT-E, LB (health economics), DM

(quantitative psychology) and JM (qualitative psychology) provided expertise in their

respective discipline and authored the relevant section of the protocol and manuscript. KB,

RS and SN edited the manuscript. All authors read and approved the final version of the

manuscript.

Funding: This research received no specific grant from any funding agency in the public,

commercial or not-for-profit sectors.

Competing interests: none.

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37. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by

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38. Luzardo L, Lujambio I, Sottolano M, et al. 24-h ambulatory recording of aortic pulse wave velocity

and central systolic augmentation: a feasibility study. Hypertens Res 2012;35(10):980-7

39. Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations.

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41. ICH Harmonised Tripartite guideline - guideline for good clinical practice E6 (R1).

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42. Keteyian SJ, Brawner CA, Savage PD, et al. Peak aerobic capacity predicts prognosis in patients

with coronary heart disease. Am Heart J 2008;156(2):292-300

43. Conraads VM, Pattyn N, De Maeyer C, et al. Aerobic interval training and continuous training

equally improve aerobic exercise capacity in patients with coronary artery disease: the

SAINTEX-CAD study. Int J Cardiol 2015;179:203-10

44. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture

(REDCap)--a metadata-driven methodology and workflow process for providing translational

research informatics support. Journal of biomedical informatics 2009;42(2):377-81

45. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated

guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869

46. NICE. Methods for the development of NICE public health guidance (third edition). NICE article

[pmg4]. https://www.nice.org.uk/article/pmg4/chapter/1%20introduction, 2012.

47. Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting

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Figure 1: Study flowchart

Screen/recruit CR patients

Exclusion – not eligible

Baseline assessment

Exclusion – not eligible

CPET, bloods, echocardiogram, oscillometry, questionnaires,

physical activity monitor, clinical examination

8 week assessment


physical activity monitor, clinical examination, interviews

8 week assessment


physical activity monitor, clinical examination, interviews

12 month assessment



12 month assessment



8 week MISS programme 8 week HIIT programme

Randomise n = 510

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1

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______�_______

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______�______

2b All items from the World Health Organization Trial Registration Data Set ______�______

Protocol version 3 Date and version identifier ______�_______

Funding 4 Sources and types of financial, material, and other support ______�_______

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ______�_______

5b Name and contact information for the trial sponsor ______�_______

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

______�_______

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

______�_______

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

______�_______

6b Explanation for choice of comparators ______�_______

Objectives 7 Specific objectives or hypotheses ______�_______

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

______�_______

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

______�_______

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)

______�_______

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

______�_______

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)

______�_______

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

______�_______

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ______�_______

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

______�_______

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)

______�_______

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3

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

______�_______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______�_______

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

______�_______

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

______�_______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

______�_______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

______�_______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

______�_______

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

_______�______

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

_______�______

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4

Data management 19 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

______�_______

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

______�_______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ______�_______

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)

______�_______

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

______�_______

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

______�_______

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

______�_______

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

______�______

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ______�_______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

______�_______

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5

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

_____�________

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

______N/A_____

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

_______�______

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site ______�_______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

______�_______

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

______�_______

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

______�_______

31b Authorship eligibility guidelines and any intended use of professional writers ______N/A_____

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ______N/A_____

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates ______�_______

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

______�_______

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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High intensity interval training versus moderate intensity steady state training in UK cardiac rehabilitation

programmes (HIIT or MISS UK): study protocol for a multi-centre randomised controlled trial and economic evaluation.

Journal: BMJ Open

Manuscript ID bmjopen-2016-012843.R1

Article Type: Protocol

Date Submitted by the Author: 12-Sep-2016

Complete List of Authors: McGregor, Gordon; University Hospitals Coventry and Warwickshire NHS Trust, Cardiac Rehabilitation; Cardiff Metropolitan University, Centre for Exercise & Health Nichols, Simon; University of Hull, Department of Sport, Health & Exercise Science Hamborg, Thomas; University of Warwick Warwick Medical School, Statistics and Epidemiology, Division of Health Sciences Bryning, Lucy; Bangor University, Centre for Health Economics and Medicines Evaluation Edwards, Rhiannon; Bangor University, Centre for Health Economics &

Medicines Evaluation Markland, David; Bangor University, School of Sport, Health & Exercise Sciences Mercer, Jenny; Cardiff Metropolitan University, Centre for Exercise & Health Birkett, Stefan; University of Hull, Department of Sport, Health & Exercise Science Ennis, Stuart; University Hospitals Coventry and Warwickshire NHS Trust, Cardiac Rehabilitation; Cardiff Metropolitan University, Centre for Exercise & Health Powell, Richard; University Hospitals Coventry and Warwickshire NHS Trust, Cardiac Rehabilitation Begg, Brian; Cardiff Metropolitan University, Centre for Exercise & Health;

Aneurin Bevan University Health Board, Cardiac Rehabilitation Haykowsky, Mark; University of Texas, College of Nursing and Health Innovation Banerjee, Prithwish; University Hospitals Coventry and Warwickshire NHS Trust, Department of Cardiology; Coventry University, Health & Life Sciences Ingle, Lee; University of Hull, Department of Sport, Health & Exercise Science Shave, Rob; Cardiff Metropolitan University, Centre for Exercise & Health Backx, Karianne; Cardiff Metropolitan University, Cardiff Centre for Exercise & Health

<b>Primary Subject Heading</b>:

Sports and exercise medicine

Secondary Subject Heading: Health economics, Qualitative research, Rehabilitation medicine, Cardiovascular medicine


BMJ Open on O

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Keywords: Coronary heart disease < CARDIOLOGY, Myocardial infarction < CARDIOLOGY, HEALTH ECONOMICS

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High intensity interval training versus moderate intensity steady state training in UK

cardiac rehabilitation programmes (HIIT or MISS UK): study protocol for a multi-

centre randomised controlled trial and economic evaluation.

Gordon McGregor1,2 *

, Simon Nichols3, Thomas Hamborg

4, Lucy Bryning

5, Rhiannon Tudor-

Edwards5, David Markland

6, Jenny Mercer

2, Stefan Birkett

3, Stuart Ennis

1,2, Richard Powell

1,

Brian Begg2,7

, Mark J. Haykowsky8, Prithwish Banerjee

1,9, Lee Ingle

3, Rob Shave

2 and

Karianne Backx2

*Corresponding Author:

Department of Cardiac Rehabilitation, Office ADX10032, Cardiac Services Office Suite

Level 1, East Wing, University Hospital, Clifford Bridge Road, Coventry, CV2 2DX.

Email: [email protected]

Tel: 02476 234 570

1 Department of Cardiac Rehabilitation, Centre for Exercise & Health, University Hospital,

Coventry, UK

2 Cardiff Centre for Exercise & Health, Cardiff Metropolitan University, Cardiff, UK

3 Department of Sport, Health & Exercise Science, University of Hull, Hull, UK

4 Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School,

University of Warwick, Warwick, UK

5 Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK

6 School of Sport, Health & Exercise Sciences, Bangor University, Bangor, UK

7 Aneurin Bevan University Health Board, Gwent, Wales, UK

8 College of Nursing and Health Innovation,

University of Texas at Arlington, Arlington,

Texas, USA

9School of Health & Life Sciences, Coventry University, Coventry, UK

Key words: Cardiac rehabilitation, high intensity interval training, coronary heart disease

Word count: 3858

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Abstract

Introduction: Current international guidelines for cardiovascular rehabilitation (CR)

advocate moderate intensity exercise training (MISS, moderate intensity steady state). This

recommendation predates significant advances in medical therapy for coronary heart disease

(CHD) and may not be the most appropriate strategy for the ‘modern’ patient with CHD.

High intensity interval training (HIIT) appears to be a safe and effective alternative, resulting

in greater improvements in peak oxygen uptake (VO2 peak). To date, HIIT trials have

predominantly been proof of concept studies in the laboratory setting and conducted outside

the United Kingdom (UK). The purpose of this multi-centre randomised controlled trial is to

compare the effects of HIIT and MISS training in patients with CHD attending UK CR

programmes.

Methods and analysis: This pragmatic study will randomly allocate 510 patients with CHD

to 8 weeks of twice weekly HIIT or MISS training at 3 centres in the UK. HIIT will consist of

10 high intensity (85-90% peak power output (PPO)) and 10 low intensity (20-25% PPO)

intervals, each lasting 1 minute. MISS training will follow usual care recommendations,

adhering to currently accepted UK guidelines (i.e. >20 mins continuous exercise at 40-70%

heart rate reserve). Outcome measures will be assessed at baseline, 8 weeks and 12 months.

The primary outcome for the trial will be change in VO2 peak as determined by maximal

cardiopulmonary exercise testing. Secondary measures will assess physiological,

psychosocial and economic outcomes.

Ethics and dissemination: The study protocol v.1.0, dated 1st February 2016 was approved

by the NHS Health Research Authority, East Midlands - Leicester South Research Ethics

Committee (16/EM/0079). Recruitment will commence in August 2016 and will be

completed in June 2018. Results will be published in peer-reviewed journals, presented at

national and international scientific meetings and are expected to inform future national

guidelines for exercise training in UK CR.

Trial registration number: this study is registered with ClinicalTrials.gov: NCT02784873

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Strengths and limitations of this study

• To ensure the findings are applicable to the ‘real world’, this study will adopt a

pragmatic, multi-centre approach to assessing the efficacy of HIIT in UK CR

programmes.

• This study will conduct an holistic, multi-disciplinary investigation into the

physiological, psychosocial and economic value of HIIT in patients with CHD.

• As a limitation, participants will only attend supervised exercise twice weekly for

eight weeks. This is suboptimal in relation to published data recommending

three times per week for 12 weeks.

Introduction

Coronary heart disease (CHD) accounts for one third of all deaths globally, totaling 7.4

million in 2013.[1] In the United Kingdom (UK) alone, approximately 175,000 myocardial

infarctions (MI) are recorded annually.[2] Whilst this is a significant number, advances in

preventative therapy and medical treatment have contributed to an overall reduction in CHD

mortality in the UK[3]. An estimated 2.3 million people are now living with the disease,[2]

and with a growing population of CHD survivors, the need for comprehensive and cost

effective chronic disease management is ever more apparent.

Integral to the long-term management of CHD is the provision of cardiovascular

rehabilitation (CR) programmes.[4 5] Exercise training is considered a key component

alongside risk factor management and facilitation of long-term behavioural change.[4]

Compelling evidence exists for CR programmes, with meta-analyses historically highlighting

a favourable effect on functional capacity, health related quality of life (HR-QoL), hospital

admissions, and mortality.[6-8] The most recent data, however, do not confirm a survival

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benefit from participation in CR.[9] This may relate to the ability of contemporary medical

care, both interventional cardiology and secondary prevention pharmacotherapy, to achieve

much of what was previously attributed to CR. However, CR does improve HR-QoL and, as

such, strategies to maximise long-term physical functioning (i.e. optimised, personalised

exercise training programmes) should be pursued in patients with CHD. Tangible benefits are

realistic for both the individual and an overburdened healthcare system and CR programmes

have a vital role to play in this regard.

In addition to improved medical care, the prescribed intensity of the exercise training

interventions included in the recent meta-analysis by Anderson et al.[9], may help explain the

lack of improvement in mortality rates with CR. Exercise intensity ranged from 50-95% of

peak oxygen uptake (VO2 peak), with the vast majority of protocols at the lower end of this

range i.e. equivalent to moderate intensity exercise (approx. 46-64% VO2 peak).[10] This is in

line with current international exercise guidelines for CHD which advocate moderate

intensity training (< 80% VO2 peak) prescribed as either interval or steady state (MISS,

moderate intensity steady state).[10] It is well known that greater improvements in VO2 peak

can be expected with exercise training of a higher intensity, and that a higher VO2 peak is

associated with an improvement in mortality risk.[11 12] Given that current guidelines

predate significant advances in interventional cardiology and medical therapy, moderate

intensity exercise may be considered conservative and suboptimal for the ‘modern’ patient

with CHD.[13] Greater benefit may be attained by participating in high intensity interval

training (HIIT) involving repeated bursts of harder exercise interspersed with periods of

recovery.[14 15] High intensity, in this context, describes exercise performed above moderate

intensity (i.e. >64% VO2 peak) as opposed to the maximal or supramaximal exercise specified

in some protocols in healthy individuals.[16]

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Meta-analyses have indicated the superiority (approximately 1.7 ml·kg-1

·min-1

) of HIIT over

MISS for improvements in VO2 peak in patients with CHD.[14 15 17] These analyses,

however, are limited by small sample sizes and the significant heterogeneity of study

populations and HIIT protocols. High intensity interval training protocols can be modified in

numerous ways (e.g. modality, intensity, interval duration) to suit the population or intended

outcome,[18] but there is no consensus as to the optimal configuration for the CHD

population.[17] In a landmark European study, high intensity intervals lasting four minutes

were deemed unfeasible in patients with CHD, and offered no additional benefit over

continuous training.[19] As an alternative, low-volume HIIT, utilises one-minute intervals to

provide intermittent metabolic stimulus with non-sustained cardiovascular stress. This

appears to be safe and well tolerated in addition to being effective at improving VO2 peak in

patients with CHD.[20 21] The benefit of this ‘low-volume HIIT’ approach in ‘real world’

CR programmes in the UK, however, cannot be confirmed. Previous studies have generally

been proof of concept studies conducted under ‘laboratory’ conditions. Carefully selected

populations, tightly controlled exercise protocols and researcher led interventions may limit

the ecological validity of such studies. Likewise, substantial international variation in the

provision and implementation of exercise based CR may reduce the extent to which non-UK

data can be applied to CR programmes in the UK.

The High Intensity Interval Training versus Moderate Intensity Steady State Training in UK

Cardiac Rehabilitation trial (HIIT or MISS UK) is a pragmatic multi-centre randomised

controlled trial and economic evaluation comparing two CR exercise interventions. The

primary objectives of the trial are:

1. To assess the effect of HIIT on VO2 peak and cardiovascular health.

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2. To assess the acceptability of HIIT and the psychological and motivational factors

associated with compliance and adherence.

3. To assess the effect of HIIT on lifestyle physical activity, HR-QoL.

4. To conduct an economic evaluation of HIIT compared with MISS in CR programmes

in the UK.

5. To assess the safety of HIIT.

In patients attending CR programmes in the UK, we hypothesise that HIIT will improve VO2

peak to a greater extent than MISS training. In this population, data relating to the effects of

HIIT (particularly low-volume HIIT) on clinical, physiological, psychosocial and economic

outcomes are limited, but appear to indicate at least an equivalent effect.[22-24] As such, we

also hypothesise that HIIT will: 1) be more acceptable than MISS and demonstrate greater

patient compliance and adherence; 2) improve cardiovascular health to a greater extent than

MISS; 3) improve HR-QoL to a greater extent than MISS; 4) lead to more positive motivation

and attitudes to exercise than MISS; 5) increase short and medium-term participation in

lifestyle physical activity to a greater extent than MISS; 6) be a cost effective alternative to

MISS; 7) be as safe as MISS.

Methods and analysis

The HIIT or MISS UK study is a pragmatic, single-blind, multi-centre, longitudinal,

randomised controlled trial and economic evaluation. In line with the median UK CR

programme duration of 8.5 weeks,[25] participants will be randomly allocated to 8 weeks of

HIIT or MISS training (usual care). Outcomes will be measured at baseline, 8 weeks and 12

months by assessors blinded to group allocation. Study interventions will be delivered by

clinical (not research) staff. The study is pragmatic in nature in that it will be conducted in

existing CR programmes. It is, therefore, accepted that some variation in the delivery of usual

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care will be evident between study sites. This will ensure generalisability of the findings to

UK CR programmes. The trial protocol adheres to the Standard Protocol Items:

Recommendations for Clinical Trials (SPIRIT) guidelines.[26]

Setting

The HIIT or MISS study will be conducted at three community CR centres; 1) Atrium Health,

Centre for Exercise & Health, Coventry, 2) Department of Sport, Health & Exercise Science,

University of Hull and Hull Royal Infirmary, Kingston-upon-Hull and 3) Ystrad Fawr

Hospital, Ystrad Mynach, South Wales. Programmes are commissioned by University

Hospitals Coventry & Warwickshire NHS Trust, City Health Care Partnership CIC, (Hull)

and Aneurin Bevan University Health Board (South Wales) respectively. Commencing

August 2016, 510 CR patients will be recruited over a 2-year period.

Participants

The study will recruit patients with established coronary artery disease (CAD) referred for

CR exercise training. Patients with myocardial infarction (MI), coronary artery bypass graft

(CABG) surgery, angiographically documented CAD and elective percutaneous coronary

intervention (PCI) will be eligible.

General inclusion criteria:

1. Successfully revascularised following PCI or CABG

2. Angiographically documented non-obstructive CAD

3. Left ventricular ejection fraction > 40%

4. Clinically stable (symptoms and medication) for > 2 weeks

5. 18 – 75 yr of age

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General exclusion criteria:

1. Symptoms of ischemia

2. Significant left main stem stenosis

3. NYHA class III-IV symptoms

4. Compromising ventricular arrhythmia

5. Significant valvular heart disease


training [27-29]

7. Significant limiting comorbidities that would prevent full participation

Additional exclusion criteria:

Further to the analysis of cardiopulmonary exercise test (CPET) and resting

echocardiography by the research team at baseline, and prior to randomisation, patients will

be prevented from continuing their involvement in the study if there is indication of:

1. Exercise-induced ischaemia or significant haemodynamic compromise

2. Left ventricular ejection fraction < 40%

3. Clinical instability in accordance with CR guidelines [27 29]


training [28 29]

Study Procedures

An outline of the participant pathway for the study is presented in Figure 1. Eligibility will be

assessed by the research team at each site under the supervision of the local principal

investigator (PI). Potential participants will be approached at their first outpatient CR

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appointment by a member of the study team: verbal and written information will be provided.

A subsequent phone call (at least 48 hours later) will confirm those who wish to participate.

Informed consent will be attained at the baseline assessment visit, which will coincide with

an outpatient CR appointment. Baseline procedures will include, CPET, echocardiogram,

venipuncture, arterial oscillometry, and clinical examination. Instruments to assess HR-QoL,

health and social care use, and the psychological and motivational factors associated with

compliance and adherence will be administered and a lifestyle physical activity monitor will

be fitted (removed 1 week later). Further to the analysis of CPET and echocardiography at

baseline, the local research team will rescreen potential participants for eligibility. Those who

are ineligible will take no further part in the study but will continue with usual care CR.

Eligible participants will subsequently be randomised to 8 weeks of twice weekly HIIT or

MISS training. All measures completed at baseline will be repeated at 8 weeks and 12

months.

Interventions

The study will compare high intensity interval training (HIIT) with current usual care in the

UK – i.e. moderate intensity interval training progressing towards moderate intensity steady

state (MISS) training.[29] Table 1 provides a summary of both interventions and Table 2

details the framework within which the HIIT intervention will be progressed. Participants

will attend twice weekly CR exercise sessions for 8 weeks, performing either HIIT or MISS

training for the cardiovascular component of their programme. In accordance with current

UK standards,[29] a muscular strength and endurance training programme will also be

completed by both study groups, and participation in additional home-based exercise

recommended as standard. Participants who are unable/unwilling to comply with the HIIT

protocol will be permitted to cease involvement in the HIIT intervention and continue with

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usual care CR (not as part of the trial). Where two or more consecutive training sessions are

missed, the intervention period can be extended to 10 weeks. As is commonplace for CR

programmes in the UK, there will be some variation in the structure and delivery of the MISS

intervention at each of the study sites. This is in keeping with the pragmatic nature of the

trial. Each centre will, however, adhere to current UK standards.[29]

Table 1. Comparison of HIIT and MISS training interventions

HIIT MISS

� Exercise sessions conducted as follows:

1. Warm up: 15 min total, 10 min <40%

HRR, 5 min <70% HRR.

2. Cardiovascular component: exercise cycle

ergometer interval training (Wattbike

Trainer (Wattbike, Notingham, UK):

high = 85-90% PPO from CPET, low = 20-

25% PPO (exercise intensity will not to be

prescribed from gas exchange data i.e.

%VO2 peak). Change in intensity from low to

high achieved by altering cadence (rpm).

Exercise HR will not exceed HRmax from

CPEX.

3. Cool down: 10 min, <40% HRR

� Duration of intervals and total programme

duration increased within a standardised

framework (Table 2).

� Workload increased bi-weekly in response to

participant reported RPE (only after the full 10

x 1 protocol has been achieved). If RPE < 17

during the last 2 high intensity intervals, then

workload will be increased.

� Exercise sessions conducted in accordance

with BACPR/ ACPICR standards [29],

adhering to the following key principles:

1. Warm up: 15 min, < 40% HRR

2. Cardiovascular component: moderate

intensity interval training progressing

towards 20 - 40 min continuous

cardiovascular exercise at 40-70% HRR

and RPE 12-14

3. Cool down: 10 min, < 40% HRR

� Initial duration based on participant’s

previous and current PA levels and CPET

performance.

� Duration and workload of cardiovascular

component adjusted, as tolerated, within the

above parameters, in response to exercising

HR, participant reported RPE and symptoms.

As per current practice, priority given to

increasing duration until 20 mins of

continuous exercise has been achieved.

Thereafter, workload can be increased in

conjunction with duration.

HRR, heart rate reserve; PA, physical activity; CPEX, cardiopulmonary exercise test; HR, heart rate;

RPE, rating of perceived exertion; PPO, peak power output; VO2 peak, peak oxygen uptake

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Table 2. Breakdown of HIIT training programme by week

Week High intensity

intervals

(number x time

in min)

Low intensity

intervals

(number x time

in min)

Total high

intensity

exercise (min)

Total low

intensity

exercise (min)

Total exercise

time (min)

1 5 x 0.5 5 x 1 2.5 5 7.5

2 5 x 1 5 x 1 5 5 10

3 7 x 1 7 x 1 7 7 14

4-8 10 x 1 10 x 1 10 10 20

The following exercise training criteria must be satisfied for participants to be regarded as

having sufficiently adhered to the treatment protocol:

• A minimum of 80% of sessions completed (13 of 16)

• HIIT – 10 x 1 min protocol achieved by week 4

• MISS – 20 min continuous CV exercise achieved by week 4

The number of participants who do not meet the above criteria will be recorded.

Randomisation and blinding:

Trial participants will be randomised to HIIT or MISS on a 1:1 basis. The random allocation

sequence will be generated by the trial statistician using a random number generator, and

implemented by a central telephone registration and randomisation service at Warwick

Clinical Trials Unit. Randomisation will be stratified by site using random permuted blocks

randomisation within each site to ensure approximately equal numbers of patients are

allocated to HIIT and MISS. To ensure allocation concealment, researchers will request

randomisation on completion of all baseline assessments. Outcome assessors will be blinded

to group allocation, as will the trial statistician. Clinical staff delivering the interventions

cannot be blinded, however, they will not be involved in data analysis or reporting.

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Study outcome measures:

The primary outcome measure is the change in peak oxygen uptake (VO2 peak) at 8 weeks. A

number of secondary outcome measures will also be assessed, namely 1) acceptability and

the motivational and attitudinal factors associated with compliance and adherence; 2) HR-

QoL; 3) service and resource use; 4) lifestyle physical activity; 5) cardiovascular reserve; 6)

cardiac remodelling; 7) arterial remodelling; 8) cardiovascular health; 9) safety. Table 3

provides the complete schedule for outcome assessment.

Table 3. Outcome measures and assessment schedule

Measure Instrument Assessment time point

Primary outcome

VO2 peak

CPET

Baseline, 8 weeks, 12 months

Secondary outcomes

Compliance, adherence

Compliance/adherence/drop-

out rates

Continuous

MSES Baseline, 8 weeks, 12 months

BREQ-2 Baseline, 8 weeks, 12 months

PNSES Baseline, 8 weeks, 12 months

Bipolar adjectival rating scale Baseline, 8 weeks, 12 months

SC-IAT Baseline, 8 weeks, 12 months

Acceptability Semi-structured interviews 8 weeks

HR-QOL EQ-5D Baseline, 8 weeks, 12 months

Service and resource use CSRI Baseline, 8 weeks, 12 months

Lifestyle physical activity Physical activity monitor Baseline, 8 weeks, 12 months

Cardiovascular reserve CPET Baseline, 8 weeks, 12 months

Cardiac remodelling Echocardiography Baseline, 8 weeks, 12 months

Arterial remodelling Arterial oscillometry Baseline, 8 weeks, 12 months

Cardiovascular health Clinical examination Baseline, 8 weeks, 12 months

Blood sampling Baseline, 8 weeks, 12 months

Safety Adverse event monitoring Continuous

VO2 peak, peak oxygen uptake; CPET, cardiopulmonary exercise test; MSES, Multidimensional Self-

Efficacy for Exercise Scale; BREQ-2, Behavioural Regulation in Exercise Questionnaire-2; PNSES,

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Psychological Need Satisfaction in Exercise Scale; SC-IAT, Single-Category Implicit Association

Test; HR-QoL, health related quality of life; EQ-5D, 5 item EuroQol; CSRI, client service receipt

inventory.

Cardiopulmonary exercise testing will be performed to measure VO2 peak and other parameters

representative of cardiovascular reserve. Tests will be conducted using a standard bicycle

ramp protocol in accordance with American Thoracic Society guideline.[30] Participants will

be encouraged to maintain a cadence of 70 rpm until symptom limited volitional fatigue

prevents continuation. Criteria for the assessment of a good participant effort will include

peak respiratory exchange ratio (RER) >1.10, peak HR ≥ 85% predicted, and RPE ≥ 18.[31]

Compliance and adherence will be determined by recording the number of training sessions

attended and successfully completed in accordance with the exercise protocol. Drop-out from

the programme will also be documented for both study groups in addition to reason for drop-

out, where provided voluntarily by participants. To assess the psychological and motivational

factors associated with compliance and adherence to the exercise training interventions, the

predictive effects of self-efficacy, motivation, need satisfaction and implicit and explicit

attitudes and, reciprocally, the effects of training on self-efficacy, motivation, need

satisfaction and implicit and explicit attitudes, will be quantitatively measured using validated

tools: 1) the Multidimensional Self-Efficacy for Exercise Scale (MSES)[32]; 2) the

Behavioural Regulation in Exercise Questionnaire-2 (BREQ-2)[33]; 3) the Psychological

Need Satisfaction in Exercise Scale (PNSES)[32]; 4) Courneya and Bobick’s 7-point bipolar

adjectival rating scale[34]; and 5) a Single-Category Implicit Association Test (SC-IAT)[35].

Semi-structured interviews will qualitatively evaluate acceptability in a sub-group of 40

patients, representative of completers and drop-outs in both intervention groups. Verbatim

transcripts will be thematically analysed.[36]

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Health-related quality of life will be assessed with the five-item EuroQoL (EQ-5D-5L)[37],

as recommended by the National Institute for Health and Care Excellence in the UK for

economic evaluation in clinical trials.[38] General population preference based tariffs for the

UK allow for the comparison of EQ-5D index scores with population norms and other health

conditions[39] An adapted client service receipt inventory (CSRI), based on examples in the

DIRUM database,[40] will be administered at each time point to capture participant health

and social care service use since the last time point (plus a retrospective two month period at

baseline).

Lifestyle physical activity will be recorded over a seven day period with an ActiGraph GT9X

Link (Actigraph, Pensacola, Florida, USA) worn on the wrist. Comprehensive evaluation of

participants’ daily physical activity patterns will be derived from the unit’s 3-axis

accelerometer, magnetometer and gyroscope. The Actigraph GT9X Link is considered the

gold standard in non-invasive research grade physical activity monitoring and has been

extensively validated.

To quantify cardiac remodelling, echocardiographic images will be obtained and analysed as

recommended in current guidelines.[41 42] To assess cardiac structure and function (systolic

and diastolic), standard techniques will be utilised including 2D, M-mode, pulse wave

Doppler and tissue Doppler echocardiography. To investigate arterial remodelling, pulse

wave velocity, will be determined through the non-invasive method of brachial oscillometry

(Mobil-O-Graph PWA Monitor, I.E.M. GmbH, Stolberg, Germany). A blood pressure cuff

will be placed upon the participant’s upper left arm, and will inflate and deflate

automatically. Mobil-O-Graph PWA has been validated against internationally recognised

invasive and non-invasive gold standards.[43]

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Standard clinical examination will include past medical history, stature, body mass and

cardiovascular risk factor assessment i.e. resting blood pressure, diabetes, family history of

premature CHD, smoking status. Blood sampling will be performed to allow the

measurement of biomarkers of cardiovascular and metabolic health. Routine testing will

include full blood cell count, liver function, urea and electrolytes, glycaemic control and a

full lipid profile. Serum and plasma will be stored for the analysis of current and emerging

biochemical markers of cardiovascular and metabolic health relating to inflammation, cardiac

remodeling, pro-thrombosis, endocrine function and lipids.[44 45]

To verify the safety of HIIT and MISS training performed in CR, adverse and serious adverse

events will be carefully monitored, recorded and reported. In line with the principles of Good

Clinical Practice, the nature and severity of the event, in addition to its potential association

with the exercise training intervention, will be ascertained by the local principal investigator

and ratified by the trial clinician.[46]

Sample size

Given the pragmatic nature of the trial, a 1.5 ml.kg.-1

min-1

larger improvement of VO2 peak in

the HIIT group compared to the MISS group is considered a clinically relevant difference.

Keteyian and colleagues reported a reduction of approximately 15% in all-cause mortality for

each 1 ml.kg.-1

min-1

increase in VO2 peak in a large CR cohort with revascularised coronary

disease.[47] In the present study, a sample size of 191 patients in each group will be

sufficient to detect this difference assuming a standard deviation of 4.5 ml·kg-1

·min-1

, a

power of 90%, and a significance level of 5%. The assumed standard deviation is based on

observations from Conraads and co-workers.[19] This trial is similar to HIIT or MISS and

reported a loss to follow-up from baseline to post intervention of 13%. A conservative drop-

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out of approximately 25% yields a required sample size of 510 patients (255 per group) to be

randomised. Should the drop-out rate at 12 months be 50%, then the study would retain

power of 76% to detect a difference of 1.5 ml·kg-1

·min-1

in the primary outcome at this time

point using the aforementioned assumptions.

Data collection and management

Study data will be collected on a case report form by the research team at baseline, 8 weeks

and 12 months. Each participant will be allocated a unique study ID number; a list of

participants will be stored electronically by UHCW NHS Trust. Data will be anonymously

entered into REDCap (Research Electronic Data Capture),[48] a secure, web-based

application designed to support data capture for research studies. This will be hosted by

Cardiff Metropolitan University.

Statistical analysis

The primary endpoint for the statistical analysis is the mean change in VO2 peak (ml·kg-1

·min-

1) from baseline to 8 weeks of follow-up. The primary endpoint will be compared between

intervention arms using a general linear model with treatment group and baseline VO2 peak

fitted as covariates, and 8-week VO2 peak as the dependant variable. The linear model will be

adjusted for the continuous covariate age, and the categorical covariates sex and study site.

Further adjustment variables may be investigated as part of the exploratory analysis. The

robustness of the primary outcome analysis will be investigated using three standard multiple

imputation methods (monotone regression, fully conditional specification regression and

MCMC).

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The secondary outcome measures will be analysed using the same covariates as the primary

outcome analysis. Likewise, the differences between groups in terms of continuous secondary

outcome measures will be assessed with the same statistical model as the primary outcome

analysis. Differences between treatment arms for binary, unordered categorical and ordinal

secondary outcome variables will be analysed using logistic regression, multinomial logistic

regression and proportional odds models, respectively.

The primary and secondary outcome analyses will be conducted at the conventional (two-

sided) 5% level. To reduce the risk of false positive claims, all secondary analyses will be

considered as exploratory if a non-significant result is obtained from the primary analysis

and, whenever reported, the failure to achieve a significant result in the primary analysis will

be declared. It is not proposed to formally adjust for multiple testing amongst the secondary

endpoints as these are likely to be correlated so that standard adjustment techniques such as

the Bonferroni method would be conservative. All analyses will be performed on an

intention-to-treat basis. A per protocol analysis will be conducted as an exploratory analysis,

as will subgroup analyses (for sub-groups pre-specified in the protocol) and repeated

measures mixed models.

All data will be summarised and reported in accordance with the Consolidated Standards of

Reporting Trials (CONSORT) guideline.[49] No formal interim analyses are anticipated.

Economic evaluation

In line with the National Institute for Health and Clinical Excellence (NICE) guidance on the

economic evaluation of public health interventions, [50] from a societal perspective, a cost

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consequence analysis of HIIT (embedded within CR) compared with MISS training

(representing usual care) will be undertaken. Within the cost-consequence analysis there will

be an embedded cost-utility analysis, using Quality Adjusted Life Years (QALYs) gained

with HR-QoL weights drawn from EQ-5D-5L. This approach has been chosen because

QALYs allow comparison with the value for money of other medical and public health

interventions but do not capture the full range of relevant outcomes in public health

prevention.[50] We will use STATA 14 to bootstrap (5,000 replications) the differences in

cost and outcomes, to produce a 95% confidence interval, cost-effectiveness planes, and cost-

effectiveness acceptability curves (CEAC), to present to healthcare policymakers and local

commissioners the probability that the intervention is cost-effective at different payer

thresholds.

The health economics component of the study will be written up in accordance with the

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement for the

reporting of published economic evaluations.[51]

Patient and public involvement

Patient and public involvement has been integral to protocol development. A formal

consultation event was attended by a representative sample of current CR participants in

August 2015. Participants were introduced to various different approaches to exercise

training and asked to comment on their suitability. A range of opinions and views were

recorded with the overriding sentiment being that participants would be prepared to engage in

HIIT with minimal concern. Close supervision by experienced CR exercise professionals was

considered essential. The only significant negative comment related to the fact that HIIT

would be performed solely on an exercise bike as opposed to a range of cardiovascular

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exercise equipment. However, participants confirmed that they would be prepared to tolerate

this in the short term. Two CR participants will sit on the trial steering group for the duration

of the trial.

Ethics

The study protocol v1.0, dated 1st February 2016, was approved by the NHS Health Research

Authority, East Midlands - Leicester South Research Ethics Committee on 4th

March 2016

(16/EM/0079).

Dissemination and impact

Throughout the trial, media outlets (including social media) will be informed of progress, and

the experiences gained will be presented at national conferences and non-academic outlets

such as national governing body publications. On completion, the study results will be

published in peer-reviewed journals and presented at scientific meetings. The results will also

be disseminated in newsletter form throughout the UK via national governing bodies and at

local research and patient conference events. It is anticipated that the results of the study will

inform future national guidelines for exercise training in UK CR.

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Contributions: GM is the Chief Investigator for the trial, leading on protocol writing, ethics

application and manuscript preparation. GM, KB, RS, SN, LI, SE, RP, SB, MH, BB, TH and

PB all contributed fully to study design. TH (statistics), RT-E, LB (health economics), DM

(quantitative psychology) and JM (qualitative psychology) provided expertise in their

respective discipline and authored the relevant section of the protocol and manuscript. KB,

RS and SN edited the manuscript. All authors read and approved the final version of the

manuscript.

Funding: This research received no specific grant from any funding agency in the public,

commercial or not-for-profit sectors.

Competing interests: none.

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46. ICH Harmonised Tripartite guideline - guideline for good clinical practice E6 (R1).

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47. Keteyian SJ, Brawner CA, Savage PD, et al. Peak aerobic capacity predicts prognosis in patients

with coronary heart disease. Am Heart J 2008;156(2):292-300

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Figure 1. Study Flowchart

210x297mm (300 x 300 DPI)

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1_______

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______1______

2b All items from the World Health Organization Trial Registration Data Set __throughout__

Protocol version 3 Date and version identifier ______all_______

Funding 4 Sources and types of financial, material, and other support ______1_______

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ______2,3______

5b Name and contact information for the trial sponsor ______1,3______

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

______1_______

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

______2,3,21___

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

______5-7______

6b Explanation for choice of comparators ______5-7______

Objectives 7 Specific objectives or hypotheses ______7_______

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

______8_______

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

______8_______

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)

______8_______

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

______12_______

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)

______13_______

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 ______13_______

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

______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)

______10_______

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

______12_______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______12_______

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

______12_______

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

______12_______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

______12_______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

______7_______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

______7_______

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

_______9______

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

_______9,14___

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Data management 19 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

______21_______

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

______18_______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ______19_______

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)

______18_______

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

______N/A_____

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

______N/A_____

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

______21_______

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

______N/A______

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ______1_______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

______X_______

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

_____9________

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

______N/A_____

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

_______21______

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site ______1_______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

______21_______

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

______ethics___

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

______22_______

31b Authorship eligibility guidelines and any intended use of professional writers ______N/A_____

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ______N/A_____

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates __Site file/ethics__

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

______N/A_____

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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BMJ Open · High intensity interval training (HIIT) appears to be a safe and effective alternative, resulting in greater improvements in peak oxygen uptake (VO2 peak). To date, HIIT