Heart Failure With Preserved Ejection Fraction Treated by Cardiac Resynchronisation Therapy Versus Rate Responsive Pacing: A Mechanistic Study
Phase: NA
Conditions: Diastolic Heart Failure
Sponsor: Cardiff and Vale University Health Board

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The PREFECTUS Study: Heart Failure
with Preserved Ejection Fraction
Treated by Cardiac Resynchronisation
Therapy Versus Rate Responsive
Pacing: A Mechanistic Study
Study Reference Numbers:
Clinicaltrials.org: pending
Ethics: 17/WA/0004 (Wales REC 3)
IRAS: 190938
Chief Investigator:
Dr Zaheer Yousef, Consultant Cardiologist, University Hospital of Wales, Heath Park,
Cardiff, CF14 4XW
yousefz@cf.ac.uk
Principal Investigator:
Dr Freya Lodge, Clinical Research Fellow, Wales Heart Research Institute, Heath
Park, Cardiff, CF14 4XW
freyalodge@doctors.org.uk
029 2074 4936
Other Project Collaborators:
Prof Robert Shave, Professor of Sport and Exercise Physiology, Cardiff School of
Sport, Cardiff Metropolitan University, Cyncoed Campus, Cyncoed Road, Cardiff, CF23 6XD
rshave@cardiffmet.ac.uk
Prof Tim Rainer, Professor of Emergency Medicine, Wales Heart Research Institute,
Heath Park, Cardiff, CF14 4XW
thrainer@cuhk.edu.hk

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Mr Andrew Penney, Cardiac Device Services Manager/Senior Chief Cardiac
Physiologist, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW
Andrew.penney@wales.nhs.uk
Study sponsor:
Cardiff and Vale University Health Board
Sponsor’s Representative:
Mrs Lee Hathaway, Registrations and Permissions Improvement Manager, R&D Office, 2nd
Floor TB2, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW
This study is funded by an educational grant from St Jude Medical (now Abbott). Abbott have
no influence on study design, patient recruitment, analysis of results or publication of
findings.

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Contents
Abbreviations.................................................................................................................4
1.0 Project Summary......................................................................................................5
1.1 Background and Rationale.......................................................................................5
2. Study Design...............................................................................................................8
2.1 Objectives........................................................................................................................ 8
2.2 Setting and Participants.................................................................................................. 8
2.3 Endpoints: ....................................................................................................................... 8
2.4 Planned interventions:.................................................................................................... 9
2.5 Rationale for use of crossover design........................................................................... 10
3. Study Procedures.....................................................................................................12
3.1 Assessments and Reprogramming:............................................................................... 13
3.2 Study Extension: Targeted Multipoint Pacing............................................................... 13
4. Criteria for Evaluation..............................................................................................13
5. Statistical Analysis Plan............................................................................................14
6. Study Administration ...............................................................................................15
6.1 Resources...................................................................................................................... 15
6.2 Ethical Considerations................................................................................................... 15
6.3 Safety............................................................................................................................. 16
6.4 Data Handling................................................................................................................ 16
6.5 Dissemination of Results............................................................................................... 17
6.6 Arrangements for supervision ...................................................................................... 17
Appendix: Exercise Echocardiography Protocol ..........................................................18
Study Diagram..............................................................................................................19
Schedule of Evaluations...............................................................................................20
References ...................................................................................................................21

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Abbreviations
6MWT
6-minute walk test
AAIR
Atrial inhibited mode with rate response
APMHR
Age-predicted maximum heart rate
Ar
Duration of pulmonary venous A-wave reversal
AV
Atrio-ventricular
CI
Chronotropic incompetence
CPEX
Cardiopulmonary exercise
CRT
Cardiac resynchronisation therapy
DDDR
Dual chamber, dual response mode with rate response
DT
Deceleration time
ECG
Electrocardiogram
EF
Ejection Fraction
FEV1
Forced expiratory volume over 1 second
GLS
Global longitudinal strain
HFpEF
Heart failure with preserved ejection fraction
HFrEF
Heart failure with reduced ejection fraction
IVCT
Isovolumic contraction time
IVRT
Isovolumic relaxation time
LVOT VTI
Left ventricular outflow tract velocity time integral (a measure of the volume
of blood ejected from the heart with each heart beat)
MEDIA
Metabolic road to diastolic heart failure (study)
MLHFQ
Minnesota living with heart failure questionnaire
MVI
Myocardial velocity imaging
NYHA
New York Heart Association
RER
Respiratory exchange ratio
RRP
Rate responsive pacing
SAE
Serious adverse event
VE-VCO2
Rate of increase of minute ventilation per unit of carbon dioxide production
VO2 max
Peak oxygen consumption
Vp
Peak diastolic suction velocity

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1.0 Project Summary
Half of patients with heart failure have normal heart pumping function (Heart failure with
Preserved Ejection Fraction, HFpEF), most commonly characterised by breathlessness on
exercise. A number of mechanisms are responsible, but frequently patients are unable to
raise their heart rate on exercise. This can be treated by a ‘rate-responsive pacemaker’
(RRP), which detects exercise and increases the heart rate accordingly. Some beneficial
effects on echocardiographic parameters have been reported with exercise programmes.
However, evidence based treatment options are limited in this group and therapy mainly
relies on water tablets and treatment of blood pressure.
Cardiac resynchronisation therapy (CRT) is a technique using specialised ‘biventricular’
pacemakers that is well established in heart failure with reduced pump function. Patients
who respond to this treatment have lower risk of death and hospitalisation and usually feel
better. CRT is not currently used in HFpEF. The PROSPECT trial showed that some patients
with relatively preserved heart function exhibited similar benefits to those with poor pump
function, but this has not been formally tested. CRT aims to make the heart beat in a more
synchronised way. Patients with HFpEF commonly have evidence of reduced heart
synchronisation.
We plan to investigate the feasibility of using a prospective crossover study to assess the
incremental benefit of CRT over and above RRP in patients with HFpEF. We will recruit 10
patients with HFpEF and insufficient heart rate and perform exercise testing, heart scanning
and symptom questionnaires. A biventricular pacemaker will be implanted the patients will
be randomised in a 1:1 ratio to receive either CRT or RRP for 12 weeks and the functional
tests will be repeated. The groups will then be swapped so that each patient receives the
alternative programming function for the next 12 weeks and the assessments performed
again. If incremental benefit is shown with CRT we will study the echocardiograms to
determine the mechanism of change. We will then invite study participants to participate in
a study extension. This will involve non-invasively programming the pacemakers to optimise
their function guided by the results of the echocardiograms in the first two phases of the
study. After a further 12 weeks, the functional assessments will be repeated. If no benefit is
seen with CRT after initial analysis, the participant involvement will end.
1.1 Background and Rationale
Half of patients with the clinical syndrome of heart failure have normal ejection fraction.
Their cardiovascular mortality is similar to those with reduced ejection fraction (including
26% sudden cardiac death, 14% heart failure and 5% myocardial infarction). 1
The hallmark of Heart Failure with Preserved Ejection Fraction (HFpEF) is exercise
intolerance. The mechanisms for this include impaired left ventricular active relaxation,
impaired untwisting and torsion, reduced left ventricular suction, increased passive stiffness,
dyssynchrony, impaired systolic and diastolic reserve, increased arterial stiffness and
impaired peripheral oxygen utilisation, among others. Chronotropic incompetence is a
contributor to this, affecting up to 63% of patients.2 Despite the prevalence of impaired
chronotropy, it is little recognised in clinical practice.
Exercise endurance training has been shown to increase peak heart rate in patients with
chronotropic incompetence and heart failure by an average of 12 beats per minute.3
Additionally, such training programmes improved peak oxygen utilisation on exercise testing

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by 38% and self-reported physical functioning score by 50% in HFpEF.4 However, in practice
exercise programmes are difficult to coordinate and maintain. Use of rate-responsive pacing
improved peak oxygen consumption by 18% in heart failure patients with proven
chronotropic incompetence undergoing cardiac resynchronisation therapy (with reduced
ejection fraction).5 The RESET trial is currently recruiting and aims to evaluate the effect of
rate responsive pacing on patients with HFpEF; 6 currently, chronotropic incompetence is a
Class IIb indication for dual-chamber pacing.
No trial of drug therapy in HFpEF has yet shown symptomatic or outcome benefit, although
there is some evidence of improved diastolic and longitudinal function with valsartan
(VALIDD),7 amlodipine (ASCOT),8 nebivolol (ENESYS)9 and spironolactone (TOPCAT);10 all
except the latter were conducted in hypertensive patients rather than HFpEF.
Analyses of patients with HFpEF have suggested that mechanical dyssynchrony is present in
up to 60% of patients with HFpEF and that it may also play a significant pathophysiological
role in the disease process. 11, 12 A PARAMOUNT sub-study found that dyssynchrony was
significantly more common than in age-matched healthy controls, even in patients with
narrow QRS complexes and ejection fraction >55%.13 This relationship persisted when
corrected for age, left ventricular mass, gender and blood pressure and was associated with
reduced global longitudinal strain and markers of diastolic dysfunction such as e’, a marker
of early diastolic relaxation. However, some trials have suggested that dyssynchrony in
HFpEF is relatively uncommon, as low as 18% for systolic dyssynchrony, unless the QRS
duration is prolonged.14, 15
Another notable abnormality in HFpEF is that of twisting and untwisting. The left ventricle
does not simply squeeze inwards during systole; rather, the complex arrangement of
myofibrils in three separate layers of differing orientation means that the heart
demonstrates a wringing motion during contraction with untwisting during diastole. This
twist can be measured using speckle tracking, an echocardiographic method by which
individual acoustic ‘speckles’ within the myocardium can be traced between frames and
therefore throughout the cardiac cycle. This technique can be performed in short and long-
axis imaging planes, allowing the precise motion of the myocardium to be approximated.
Prior studies in HFpEF have found that systolic torsion and diastolic untwisting rate are
significantly reduced in patients compared to healthy controls.16 The overall untwisting was
not significantly reduced at rest, but became so on exercise in these patients; however, early
diastolic untwisting was markedly reduced at rest. Reduction in systolic twisting was noted
at rest compared with controls, but was more marked on exercise.
Cardiac Resynchronisation Therapy (CRT) is a well-established therapy in Heart Failure with
reduced Ejection Fraction (HFrEF), but there is little evidence regarding its use in HFpEF. A
PROSPECT sub-study demonstrated benefit with CRT for patients with ejection fraction
>35%.17 In this group, functional class and 6-minute walk test times appeared to predict
response to CRT rather than ejection fraction, and CRT was associated with a significant
reduction in end-systolic volumes. These findings were confirmed by a second study
examining CRT in pure diastolic dysfunction using pressure-volume loops and
echocardiography to demonstrate a reduction in dyssynchrony, although markers of
symptomatic and physiological improvement were not examined.18
Several studies have looked at markers of diastolic dysfunction and dyssynchrony in patients
with broad QRS undergoing CRT implantation. 19-24 Diastolic dyssynchrony has been found to
be more prevalent in prospective CRT candidates than systolic dyssynchrony (74% vs 49%),
but the two often occur together and both appear to predict response to CRT.24

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Additionally, there is evidence that dyssynchrony is present in a significant number of
patients with QRS duration <120 ms, and one study suggested that diastolic dyssynchrony is
more prevalent than systolic (44% diastolic, 33% systolic dyssynchrony). 23, 24
Patients undergoing CRT for classical indications typically exhibit an improvement in diastolic
parameters such as peak mitral E wave velocity, E/A ratio and diastolic filling time, left
ventricular filling pressure and overall grade of diastolic dysfunction. 20-24 Moreover,
relatively load-insensitive markers of diastolic function such as peak lateral and septal e’
velocity, and E/e’ have also been seen to improve in some studies. 20-22 Propagation velocity
(Vp), a marker of diastolic suction, improved in one study,20 but was unchanged in another.23
In another study, deactivation of CRT in patients with HFrEF resulted in delayed early
diastolic vortex development and immature vortex at aortic valve opening. These vortices
are thought to reduce left ventricular shear stress and improve energy conservation by
allowing channelling of blood towards the left ventricular outflow tract. These findings
reversed on reactivation of CRT.25 Improvements in left ventricular torsion have been
demonstrated following CRT implantation and torsion is increasingly recognised as a marker
of overall left ventricular systolic function.26, 27 Little work has been done looking at left
ventricular diastolic untwisting in this patient population. However, given the continuum of
myocardial function that involves sequential contraction and relaxation, it is likely that CRT
involves improvements in untwisting as well as twisting. More research is required in this
area.
Furthermore, improvement in diastolic parameters is seen in some patients who experience
clinical response to CRT without demonstrating echocardiographic response (i.e. reduction
in left ventricular end-systolic volume or increase in ejection fraction).22, 24
To our knowledge, there has been no previous comparison of rate-responsive pacing (RRP)
and cardiac resynchronisation therapy in HFpEF. We therefore propose to compare these
treatments in a population of HFpEF patients with proven chronotropic incompetence.

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2. Study Design
This is an exploratory single-centre, prospective, single-blinded, randomised crossover study
comparing rate responsive pacing (RRP) with CRT in patients with confirmed HFpEF and
chronotropic incompetence.
2.1 Objectives
The Primary Objective of this study is:

To evaluate the feasibility and acceptability of using a randomised crossover trial
design to assess efficacy of CRT versus rate-responsive pacing in patients with HFpEF
The Secondary Objectives of this study are:

To evaluate the use of diastolic and systolic reserve index as end-points in a trial
design comparing CRT with RRP in patients with HFpEF

To establish appropriate secondary end-points for future studies into the effect of
CRT on:
i.
Longitudinal and global longitudinal strain, torsion and untwisting, and
diastolic dyssynchrony at rest and on exercise echocardiography,
ii.
Exercise duration and oxygen carrying capacity measured by
cardiopulmonary exercise (CPEX) testing,
iii.
Distance walked in a 6-minute walk test,
iv.
New York Heart Association (NYHA) functional class,
v.
Quality of life using the Minnesota Living with Heart Failure Questionnaire
(MLHFQ)

To establish the likely drop-out rate following recruitment for the trial in terms of
failed implantation and patient disengagement

To establish the number of participants required to appropriately power a further
randomised trial of CRT versus RRP in patients with HFpEF

To identify possible confounders and covariates to inform sample size calculations
for future studies
2.2 Setting and Participants
2.2.1 Setting:
The study will be conducted in Cardiff and Vale University Health Board, with
patients drawn from Cardiology clinics and inpatient wards. Follow-up assessments
will be conducted at Cardiff School of Sport, a research facility at a university
campus close to the main hospital.
2.2.2 Number of subjects planned:
10 patients. This will be sufficient to establish estimates of variability in the diastolic
reserve index (see below), allow estimation of treatment difference and gauge
acceptability.
2.2.3 Target population:
Subjects with HFpEF and chronotropic incompetence
2.3 Endpoints:
Systolic and diastolic longitudinal reserve index are calculated by the following formulae:

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Systolic reserve
= Δs’ x [1-(1/s’rest)]
Diastolic reserve
= Δe’ x [1-(1/e’rest)]
These are known to be impaired in patients with HFpEF and are a marker of
adaptation to exercise in terms of filling pressures and left ventricular relaxation.
Tan et al report a significant difference between the results seen with 56 patients
with HFpEF and 27 control subjects on exercise echocardiography with semi-supine
bicycle.16 Patient characteristics were similar to those of our proposed study group
(EF >50%, NYHA II, HFpEF according to Vasan and Levy criteria).28
We will therefore investigate diastolic and systolic reserve index as possible
endpoints of a future study into the efficacy of CRT versus RRP in HFpEF patients.
2.4 Planned interventions:
Visit 1 – Baseline Assessments: Patients will undergo initial assessment of baseline
characteristics by echocardiography, cardiopulmonary exercise testing, 6MWT and
MLHFQ. (Visit length: approx. 4 hours)
Visit 2 - Device Implantation (≤7 days after baseline assessments completed):
Eligible subjects will undergo implantation of a biventricular pacemaker under
normal laboratory conditions. Patients will be randomised in a 1:1 ratio to receive
either rate-responsive pacing (DDDR) or CRT. Patients will be blinded to their
treatment allocation. They will return to pacing clinic a week later for a
programming check; during this visit, they will also undergo a chest x-ray according
to local protocol to ensure correct lead placement (Visit length: 1 day + 2 hours)
Visit 3 – Assessments and Device Reprogramming
After 12 weeks, the baseline parameters will be reassessed and patients will then
have their device non-invasively reprogrammed to the remaining treatment
allocation. (Visit length: approx. 4 hours)
Visit 4 – Assessments
After a further 12 weeks, the baseline assessments will be repeated. The pacemaker
will be non-invasively reprogrammed to DDDR mode and the patient will go home.
(Visit length: approx. 4 hours)
Optional extension (pending analysis of results)
Visit 5 – Reprogramming
If incremental benefit has been demonstrated with CRT above the benefit of RRP,
the echocardiograms will be examined to establish the mechanism of improvement.
Subjects will be invited to participate in a study extension using multisite
technology. The device will be non-invasively reprogrammed to optimise the CRT
settings targeted specifically for the mechanism identified. (Visit length: approx. 3
hour)
Visit 6 – Assessments
12 weeks after the final reprogramming, patients will attend for a final set of
assessments as per baseline. Participant involvement will then cease. (Visit length:
approx. 4 hours)

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Total contact time with research team: Approximately 27 hours (22 hours without
extension)
2.5 Rationale for use of crossover design
HFPEF subjects are known to have similar mortality rates to HFREF subjects. However, they
tend to be clinically stable for fairly long periods of time. A crossover design has been
employed in preference to a cohort study to minimise the effects of natural disease
progression on the measurement of each treatment effect. The period length is designed to
allow effects of the pacing modes to be well-established without a high likelihood of
significant change in the subject’s overall wellbeing, cardiac function or functional status.
Previous studies using similar pacing protocols have found no carry-over effects in
haemodynamic parameters such as e’ (and therefore diastolic and systolic reserve index),
which demonstrate beat-to-beat change; however, end-systolic and end-diastolic volumes
are more slow to change.6, 29, 30 Previous studies, most notably the MUSTIC trial, have
employed similar 3-month blocks as in our study design with no washout period.31 The study
involved 48 patients and found no carry-over effect for the stated haemodynamic
parameters.
Covariates and confounders may include the subject’s baseline demographic,
echocardiographic and functional parameters. Full characterisation of each subject will be
undertaken at baseline with respect to possible confounders such as comorbidity, baseline
diastolic function and baseline exercise ability. In this exploratory study, we are aiming to
identify possible confounders and will not make statistical corrections for them due to the
small sample size.
2.6 Device Characteristics:
The device implanted will be a St Jude Quadra Allure MPTM CRT device with St Jude
QuartetTM quadripolar left ventricular lead, and standard compatible right
ventricular and right atrial leads. These components comprise a standard CRT device
implanted at University Hospital of Wales (UHW). Quadripolar leads have 4 sites
along the lead from which pacing can be performed, including in combination or
sequence. This is called multisite pacing. In comparison to the traditional style leads,
which pace only from the lead tip, this offers a far greater array of options for
optimising pacing. For example, where the lead is stimulating the phrenic nerve
(resulting in uncomfortable hiccups for the patient) or where the pacing lead is
placed over a patch of scar on the heart, a different site can be selected on the lead,
allowing the clinician or physiologist to pace around these issues.
All CRT devices are able to deliver conventional pacing as well as biventricular pacing
and this will be utilised for the first stage of the study, where RRP only is needed.
2.7 Pacing Modes:
Whilst programmed to DDDR mode, the pacemakers will be programmed to a base
rate of 30 min-1 with a prolonged atrio-ventricular delay of 350 ms. This will mean
that the patient’s own intrinsic atrio-ventricular (AV) conduction is favoured over
pacing. The purpose of this is to avoid right ventricular pacing, which can be
detrimental. Abbott pacemakers include technology known as VIP (ventricular

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intrinsic preference) which will also be switched on with the same aim. DDDR mode
allows for rate response, meaning that if the pacemaker detects the onset of
exercise, it will increase the atrial rate in order to maintain an adequate heart rate.
This is a treatment for chronotropic incompetence and has been shown to be
beneficial in HFrEF with CI.5
CRT will be programmed to maximise biventricular pacing as close to 100% of the
time as possible. A short AV delay will therefore be selected, with a ventricular base
rate of 30 min-1 to favour intrinsic atrial rate and AV conduction. The AV delay will be
tailored to the individual patient according to the interval that gives greatest left
ventricular outflow tract velocity time integral (LVOT VTI) as measured on
echocardiography. Ventriculo-ventricular delay (VV delay, the time difference
between the stimulation of the left and right ventricles) will be programmed to
optimise cardiac output according to LVOT VTI once optimal AV delay has been
determined. Maximum tracking rate will be programmed according to heart rate
achieved on exercise testing, but nominally at 120 min-1. Atrial mode switching
algorithms will be included as despite atrial arrythmias being an exclusion criterion
in this group, they have multiple risk factors for developing atrial fibrillation.
These settings have an evidence base when programmed in HFREF. Although cardiac
output is not significantly impaired at rest in HFPEF, settings which reduce cardiac
output would potentially have a deleterious effect on patient symptoms and
therefore this has been selected as the target of device programming.
2.8 Duration of Treatment:
12 weeks in each period followed by full symptomatic and physiological evaluation.
Total study participation will be up to 40 weeks from baseline visit. We will gain
written consent from the participants to contact them by telephone up to study
completion in order to gain outcome information.
2.9 Diagnosis of HFpEF:
All subjects will be recruited according to the criteria recommended by the
European Society of Cardiology consensus statement for the diagnosis of HFpEF.32
Previously defined criteria included symptoms of heart failure in the absence of
reduced ejection fraction, and no evidence of cardiac (valvular disease, coronary
artery disease or significant arrhythmia) or non-cardiac (chronic lung disease, central
causes of breathlessness or haematological abnormality) cause, with parameters
consistent with HFpEF on echocardiographic and biomarker profiling.
2.10 Diagnosis of Chronotropic incompetence:
Chronotropic incompetence (CI) is a Class IIb recommendation for pacemaker
implantation. CI is defined by failure to achieve 80% of expected heart rate reserve
on maximal exercise testing, according to the following formula:
Heart rate reserve
x 100
APMHR – Rest HR
(APMHR = age-predicted maximum heart rate; heart rate reserve = change in heart
rate from rest to peak exercise; APMHR will be defined by 208 – 0.7 x age [Tanaka et
al],33 or for patients on beta blockers 164-0.7(age) [Brawner et al]34)

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2.11 Cardiopulmonary exercise testing
Cardiopulmonary exercise testing on an upright bicycle will be used to assess the
presence of CI. This initial test will also serve as a familiarisation test for the
subsequent study assessments. The exercise will be performed according to
standard hospital protocol. Expired gas analysis will be conducted to assess the
Respiratory Exchange Ratio (RER). Maximal exercise will be deemed to have
occurred if this is greater than 1.05. Data regarding ventilator efficiency will be
gathered to explore whether a cardiac cause for breathlessness exists. 12-lead
electrocardiogram monitoring will be performed throughout the test until at least 3
minutes after exercise completion.
Patients with a Class I indication for beta blocker therapy will continue the
treatment (namely prior history of ventricular tachyarrhythmia or myocardial
infarction; those with significant angina or recent arrhythmia will be excluded).
Inclusion Criteria:
1.
Confirmed HFpEF as described above
2.
Chronotropic incompetence as described above
3.
Ongoing exertional breathlessness of NYHA Grade II or worse
4.
Ability to understand and sign written consent form
5.
Males and females, age >18 years
6.
Ability to participate in follow-up appointments at 3 and 6 months post-
implantation
7.
Ability to complete a cardiopulmonary exercise test
Exclusion criteria
1.
Any contraindication to implantation of permanent pacemaker, namely
unresolved infective process or sepsis, vascular access difficulties, advanced
neoplastic process, expected lifespan less than 1 year or patient choice
2.
Ejection fraction <50%
3.
Known valvular disease graded severe or moderate-to-severe
4.
Cardiac arrhythmia (paroxysmal or persistent) within 1 year of recruitment
5.
Exertional chest pain suggestive of angina or personal history of coronary artery
disease without subsequent revascularisation, or coronary angiogram within the
past 5 years demonstrating >50% stenosis in ≥ 1 epicardial coronary artery
6.
Significant chronic lung disease (FEV1 <80%)
7.
Inability to complete follow-up process for any reason not defined above
3. Study Procedures
At baseline, the following assessments will be undertaken:

NYHA functional class assessment

6-minute walk test (6MWT)

MLHFQ

Echocardiographic assessment of systolic and diastolic parameters at rest, followed
by exercise echocardiography on semi-supine bicycle ergometer of the same
parameters. (Appendix).

Cardiopulmonary exercise testing on an upright bicycle according to standard local
protocol (see above).

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Study subjects will then undergo implantation of a biventricular pacemaker with leads in the
right ventricular apex, coronary sinus (aiming for posterolateral or lateral wall position
where anatomically possible), and right atrium.
Following successful device placement, subjects will be randomised in a 1:1 ratio (using
online computer randomisation software, https://www.randomizer.org/) to receive either
RRP (in DDDR mode) or CRT as described above. This will be performed whilst the subject is
still in the pacing laboratory and the device programmed by the attending physiologist
according to the parameters described above, tailored to the subject’s individual heart rate.
Patients will be blinded to the treatment allocation, but investigators will not as the pacing
mode will be evident on ECG traces.
3.1 Assessments and Reprogramming:
After 12 weeks, patients will be recalled for repeat assessment of the same modalities (rest
and exercise echocardiography, CPEX, 6MWT, NYHA functional class assessment, MLHFQ).
The pacemakers will be non-invasively reprogrammed (using a magnet placed over the
chest) to switch the treatment period so that subjects experience whichever mode they
have not yet received. After a further 12 weeks, the same assessments will be repeated. The
pacemaker will then be non-invasively programmed back to RRP.
3.2 Study Extension: Targeted Multipoint Pacing
Once all subjects have completed 12 weeks of RRP and 12 weeks of CRT (in either order),
provisional analysis of the data will be performed. If an incremental benefit is shown for CRT
above the benefit of RRP, analysis of echocardiograms before and after CRT will be
performed to elucidate the mechanisms. Subjects will be invited to participate in a study
extension. The pacemakers will then be non-invasively programmed using multisite
optimisation to administer optimised CRT targeted to the specific mechanism of action. Final
assessments will occur after 12 weeks, following which the participant involvement will end.
If no incremental benefit is shown for CRT at the initial analysis, the study will end at this
point (after 24 weeks).
Incremental benefit for CRT will be defined as a statistically significant difference between
average values for RRP and for CRT in paired t-tests in one or more of the following
parameters: a) echocardiographic: diastolic reserve index; systolic reserve index; left
ventricular end-systolic volume; left ventricular end-diastolic volume; tricuspid regurgitant
peak velocity; torsion and untwisting on strain imaging; global longitudinal strain; b)
cardiopulmonary exercise testing: peak oxygen consumption; exercise duration; VE-VCO2
slope; c) distance walked on 6-minute walk test.
Ongoing pacemaker function will be a clinical decision based on patient preference and
objective markers such as 6MWT. Long-term pacemaker follow-up will take place at
Professor Yousef’s CRT clinic at University Hospital of Wales. All medications can be
continued as prescribed for the duration of the study, but medication changes should be
noted during follow-up.
4. Criteria for Evaluation
At each 12-week stage, the following will be assessed:

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1.
Change in end-diastolic volume
2.
Change in end-systolic volume
3.
Change in ejection fraction (Simpson’s Biplane method)
4.
Change in left ventricular filling by pulsed-wave Doppler of mitral inflow (peak E and
A wave velocities, E wave deceleration time, A wave duration, diastolic filling time
(DFT))
5.
Change in pulmonary venous Ar (Atrial reversal) duration.
6.
Change in left and right ventricular isovolumic relaxation time (IVRT) and isovolumic
contraction time (IVCT)
7.
Change in peak diastolic suction velocity (Vp)
8.
Change in peak systolic twist (torsion) and in untwisting rate on speckle tracking
9.
Myocardial velocity imaging (MVI) in basal anterior, inferior, septal and lateral walls
to assess:
a.
Change in peak systolic velocity (s’)
b.
Change in peak early diastolic wave velocity (e’)
c.
Change in time from onset of QRS to onset of s’ wave
d.
Change in time from onset of QRS to peak e’ wave
10. Change in duration of pulmonary venous a wave
11. Change in peak longitudinal strain in 12 wall segments, and peak global longitudinal
strain (GLS) in 12-segment model
12. Change in pulmonary pressures as measured by tricuspid regurgitant jet peak
velocity
13. Change in above parameters on exercise echocardiography where feasible due to
image quality
14. Change in peak oxygen consumption (VO2 max) and slope of ventilation to carbon
dioxide production (VE-VCO2 slope) on exercise
15. Change in exercise capacity as defined by duration of exertion and work-level
achieved on cardiopulmonary exercise testing
16. Change in blood pressure response to exercise
17. Change in distance walked on 6-minute walk test
18. Change in New York Heart Association Functional Class
19. Change in Minnesota Living with Heart Failure Questionnaire score
5. Statistical Analysis Plan
Enrolled subjects will be analysed in a per protocol fashion. Estimates of period effects will
be made by performing an unpaired t-test on the mean difference between the two
treatment orders. Carryover effects will be estimated by performing a t-test comparing the
mean within patient score (the mean of the two period means for each patient) with the
mean between the treatment arms. If significant period or carry-over effects exist, then only
the first period will be analysed.
The change in exercise, echocardiographic, functional class and wellbeing parameters will be
evaluated using paired sample t-tests. A Wilcoxon signed rank test will be employed as a test
of robustness.
The settings in the study extension will be compared with the CRT programming during the
initial crossover period for each patient using paired sample t-tests (this may have taken
place in period 1 or period 2).

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Where normality of distribution is not found, attempts will be made to transform the data
using a suitable mathematical function. Where this is not possible, the Mann-Whitney U test
will be employed. Analysis of categorical data will be by Chi-squared tests. Normality will be
evaluated using visual assessment histograms and Q-Q plots. Significance will be tested at
the 95% confidence level for all analyses, including calculation of period and carry-over
effects.
An intention to treat analysis will be reported if the drop-out rate exceeds 10%. Corrections
for multiplicity will not be made due to the exploratory nature of this data. No subgroup
analysis is planned. Where data is missing, analysis will only be completed if 80% or more of
data is present. For each analysis performed, subjects with data missing will be excluded
from the individual parameter analysis, but will be included where data is present. Interim
analysis will not be performed, except in the event of study discontinuation. Study
discontinuation will occur only in the event of safety concerns, as detailed below, or in the
event of failure to recruit within the planned timeframe.
Drop-out rates and reasons will be recorded at each stage. This will be presented as a
CONSORT diagram in the publication of study results.
All statistical analysis will be double-checked by a statistician prior to dissemination of study
results.
6. Study Administration
6.1 Resources
The study will be carried out principally by Dr Freya Lodge, the principal investigator, who is
employed by the health board and funded by St Jude Medical (now Abbott). Eligibility
assessments required for the study are part of the usual care for patients with heart failure
and will therefore be conducted at University Hospital of Wales under the NHS.
Baseline assessments, follow-up appointments, echocardiography, cardiopulmonary exercise
testing, questionnaires and functional tests will be carried out by Dr Lodge and research staff
from the School of Sport, Cyncoed Campus, Cardiff Metropolitan University. This will be
overseen by prior agreement with Professor Robert Shave. Device implantation will be
conducted by Prof Yousef in the Pacing Theatre at University Hospital of Wales on normal
clinical lists, usually on a Tuesday. Abbott will pay for the difference in device cost between a
dual chamber and a biventricular device. A member of nursing staff from the coronary care
unit will be required to assist in these procedures and this will be arranged prior to
implantation. Patients recruited to the study will be under a consultant at the hospital and
will have a Class IIb indication for pacing.
6.2 Ethical Considerations
Patients recruited to this study will have an indication for a dual chamber pacemaker and
significant symptoms of breathlessness. Full written consent will be obtained prior to study
entry. Patients will be exposed to a small increase in risk due to implantation of a
biventricular rather than dual chamber pacemaker. This equates to an increase from 1% to
2% of serious complications requiring further hospital treatment. This risk is felt to be
acceptable in patients with reduced ejection fraction undergoing biventricular pacemaker
implantation. Additionally, there will be extra radiation exposure due to longer procedure

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time associated with CRT implantation compared with standard pacemakers. These risks
have been reviewed by experts in clinical radiology and nuclear physics. The overall
exposure to radiation is equivalent to 21 months of background radiation in the UK and
confers a low cancer risk of 1 in 5100. Exercise tests are low risk procedures conferring
overall risk of 1 in 10 000 of serious complication. Subjects will be counselled regarding
these procedures prior to recruitment.
6.3 Safety
Local procedures will apply to tests carried out at University Hospital of Wales, and to
pacemaker implantation. A local anticoagulant policy is in place. Patients will receive intra-
venous antibiotics prior to pacemaker implantation according to local policy (usually
Teicoplanin).
All investigations at Cardiff Metropolitan University will take place in the presence of an
experienced clinician. Other members of staff will be available who have been trained in
Intermediate Life Support. A cardiac defibrillator, supplemental oxygen and intravenous
adrenaline will be available. Additionally, there will be equipment for cannulation and airway
support that will be kept in an easily accessible bag within the department. These products
and medications will be checked on a monthly basis by study staff.
6.3.1 Adverse Events
Early termination will occur in the case of serious adverse events (SAE) related to study
interventions. If a SAE occurs (death or hospitalisation of study subject for heart failure or
related conditions, device related complications), the study team will meet at the earliest
possible juncture. A decision as to whether adverse events are related to study procedures
will be made according to clinical judgement by the study group, which includes several
experienced clinicians.
If the SAE is deemed to be due to the study intervention, the trial will be immediately
suspended pending further investigation and terminated if evidence emerges of causality. In
the event of study suspension, all participants will be contacted to explain the situation and
will be asked to attend for reprogramming of their pacemaker as appropriate.
In the event of early study termination, all participants will be contacted by telephone and
asked to attend for device reprogramming. Devices will be programmed to RRP on study
termination unless safety issues arise with this programming mode.
6.4 Data Handling
Case record forms will be created for each participant in the study; these will be stored in
the clinical research area of Cardiff Metropolitan University School of Sport. This is a secure
building protected by swipe-card access available only for approved university staff.
Data will be stored on personal computer databases (Excel, SPSS) in anonymised form.
Access to all computers is password-protected.
Echocardiographic images will be stored on a secure server in Cardiff Metropolitan
University and will be coded by the patient's record number but not by name.
No patient-identifiable data will be stored in data logs. After recruitment, patients will be
issued with a study number which will be used thereafter in place of identifiable details.
Only date of birth will be stored alongside the study number. Each patient will be assigned a

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folder with all study paperwork, investigations and data in. This will be kept in a swipe card-
accessed office within Cardiff Metropolitan University. All data collected will be stored by
study number only on computer databases on a locked computer. This computer will remain
in the possession of the Principal Investigator; however, no sensitive data or personal data
will be stored on this computer.
6.5 Dissemination of Results
The results from the study will be published in one or more articles in peer-reviewed
journals, and/or be presented at international cardiovascular meetings, either as abstracts
or oral presentations.  Patients will be notified of the study findings by post following the
termination of the study. This study will form part of a Medical Doctorate project for the
Principal Investigator, Dr Freya Lodge and as such will be published as a thesis.
6.6 Arrangements for supervision
The project is being overseen by Prof Yousef. Frequent meetings are arranged to review
protocols and progress with both Prof Yousef and the other project collaborators. This
protocol has undergone review by scientific staff at Cardiff and Vale University Health Board,
as well as by the scientific committee at Abbott. After recruitment begins, all study
personnel will meet every 6 months to review progress until termination of the study.

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Appendix: Exercise Echocardiography Protocol
Exercise:

Workload at anaerobic threshold will be calculated using results from the
introductory cardiopulmonary exercise test.

For echocardiography, a ramped stress protocol, aiming to achieve image acquisition
at baseline, and at 50% and 100% of anaerobic threshold (AT, also known as
ventilatory threshold) will be used.

A pedalling rate of 55–65 r.p.m. will be aimed for.

Ramp to 50% of AT workload will occur over one minute, with a further minute for
stabilisation of heart rate and vasculature.

Images will then be obtained over the following three minutes.

Once images have been obtained, a further ramp will occur to AT workload over one
minute with a further minute for stabilisation.

Images will be obtained at AT over three minutes.

Following image acquisition, the test will cease.

Should the subject be unable to maintain pedalling rate or exercise at AT, the
workload will be reduced by 25% to enable continued scanning until image
acquisition is complete.

Total exercise time for this test will be 10 minutes.

Workload at each stage will be kept the same for each test that a participant
performs.

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Study Diagram
Initial Data Analysis
Programme to rate-
responsive pacing
(AAIR)
Programme to
cardiac
resynchronisation
Implantation of
biventricular
pacemaker
Screening and
recruitment: n=10
End of Study*
Incremental benefit
shown with CRT
No incremental benefit
shown with CRT
Echocardiographic
analysis of mechanism
Device programmed
with targeted
multipoint pacing
End of Study*
* Pacemaker settings at end of study to be determined clinically based on patient preference and
objective measures such as 6MWT
Randomisation
1:1 ratio
Programme to
cardiac
resynchronisation
Programme to rate-
responsive pacing
(AAIR)
Assessment
Assessment
Assessment
Week 0
Week 12
Week 24
Assessment
+ 12weeks

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Schedule of Evaluations
Visit
Screening
Visit 1
Visit 2
Visit 3
Visit 4 c
Provisional Analysis: once data obtained from all subjects
Visit 5
Visit 6c
Day/Week/Month
≤-12 Weeks a
Day 0
Day 1
+/- 7 days
Week 12 b
Week 24 b
+0 weeks
+ 12 weeks
Informed consent
X
Demographic data
X
Medical history
X
Medical examination
X
X
X
X
X
Medication history
X
X
X
X
X
Height & weight
X
Inclusion and
exclusion criteria
X
X
12-lead ECG
X
X
X
X
X
NYHA Functional
Assessment
X
X
X
X
X
6-minute walk test
X
X
X
X
MLHFQ
X
X
X
X
Echocardiogram
X
X
X
X
Cardiopulmonary
exercise test
X
X
X
X
Implant CRT device
X
Randomisation a
X
Reprogram device
X
X
X
Abbreviations: CRT = cardiac resynchronisation therapy, NYHA = New York Heart Association, MLHFQ  = Minnesota Living with Heart Failure
Questionnaire, ECG = Electrocardiogram
a  Randomisation must occur within 12 weeks of screening visit; https://www.randomizer.org/
b  ±7 days permissible for follow-up visit
c Study termination occurs after Visit 4 if no incremental benefit for CRT seen and after Visit 6 if benefit seen

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