Controlled Trial of High-risk Coronary Intervention With Percutaneous Left Ventricular Unloading
Phase: PHASE3
Conditions: Ischemic Heart Disease, Coronary Artery Disease
Sponsor: Guy's and St Thomas' NHS Foundation Trust

 
 
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Controlled trial of High-risk coronary Intervention with 
Percutaneous left ventricular unloading 
 
(CHIP-BCIS3) 
 
 
Trial Protocol Version 1.4 
 
 
Sponsored by King’s College London 
 
 
This project is funded by the National Institute for Health Research (NIHR) HTA 
CET (130593). 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
1. 
Trial Summary ........................................................................................................... 5 
1.1 
Protocol Summary ......................................................................................................... 5 
1.2 
Trial Flowchart .............................................................................................................. 6 
1.3 
Trial Organisation .......................................................................................................... 7 
1.3.1 
NIHR HTA CET Grant Applicants ........................................................................................................ 7 
1.3.2 
Trial Steering Committee (TSC) ......................................................................................................... 7 
1.3.3 
Data Monitoring Committee (DMC) ................................................................................................. 7 
1.3.4 
Trial Management Group (TMG) ...................................................................................................... 7 
1.3.5 
Clinical Trials Unit (CTU) .................................................................................................................... 8 
1.3.6 
Clinical Events Committee (CEC) ....................................................................................................... 8 
1.3.7 
Recruiting Centres ............................................................................................................................ 8 
1.4 
List of Abbreviations and Definitions ............................................................................. 8 
2. 
Background ............................................................................................................. 10 
2.1 
High-Risk PCI ............................................................................................................... 10 
2.2 
LV Unloading ............................................................................................................... 10 
2.3 
Current Evidence ......................................................................................................... 12 
3. 
Hypothesis ............................................................................................................... 13 
4. 
Study Design ............................................................................................................ 13 
5. 
Health Technology ................................................................................................... 13 
6. 
Trial Population ....................................................................................................... 13 
6.1 
Target Population ........................................................................................................ 13 
6.2 
Inclusion Criteria ......................................................................................................... 13 
6.3 
Exclusion Criteria ......................................................................................................... 13 
7. 
Endpoints ................................................................................................................ 14 
7.1 
Primary Endpoint ........................................................................................................ 14 
7.2 
Major Secondary Endpoints ......................................................................................... 14 
7.3 
Other Secondary Endpoints ......................................................................................... 14 
7.4 
Endpoint Definitions .................................................................................................... 15 
8. 
Safety Reporting ...................................................................................................... 18 
8.1 
Definition .................................................................................................................... 18 
8.2 
Unexpected Serious Adverse Events ............................................................................ 18 
8.3 
Unexpected Non-Serious Adverse Events ..................................................................... 18 
8.4 
Reporting Unexpected Adverse Events ......................................................................... 18 
8.4.1 
Assessment of Intensity .................................................................................................................. 18 
8.4.2 
Assessment of Causality.................................................................................................................. 19 
8.5 
Notification ................................................................................................................. 19 
9. 
Ethical Considerations .............................................................................................. 19 

 
 
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9.1 
Consent ...................................................................................................................... 19 
9.2 
Declaration of Helsinki and Good Clinical Practice ........................................................ 19 
9.3 
Ethical Committee Review ........................................................................................... 20 
10. Statistical Considerations ......................................................................................... 20 
10.1 
Win Ratio .................................................................................................................... 20 
10.2 
Power Calculation ....................................................................................................... 21 
10.2.1 
Sample size extension ................................................................................................................ 21 
10.2.2 
Secondary Endpoints .................................................................................................................. 22 
10.3 
1-year feasibility review .............................................................................................. 22 
11. Screening ................................................................................................................. 23 
11.1 
Screening Population .................................................................................................. 23 
11.2 
Screening Log .............................................................................................................. 23 
12. Assessment of LVEF.................................................................................................. 23 
12.1 
Qualifying Ejection Fraction ......................................................................................... 23 
13. Viability Testing ....................................................................................................... 23 
14. Core Laboratories .................................................................................................... 23 
14.1 
Imaging Core Lab ......................................................................................................... 23 
14.2 
Vascular Core Lab ........................................................................................................ 24 
15. Randomisation ........................................................................................................ 24 
16. Percutaneous Coronary Intervention ........................................................................ 24 
16.1 
Pre-procedure workup ................................................................................................ 24 
16.2 
LV Unloading ............................................................................................................... 25 
16.3 
Adjunctive therapy and devices ................................................................................... 25 
16.4 
Bailout ........................................................................................................................ 25 
16.5 
Staged Procedures ...................................................................................................... 26 
16.6 
Completeness of Revascularisation .............................................................................. 26 
16.7 
Protocol adherence ..................................................................................................... 26 
17. Coronary physiology substudy ................................................................................. 26 
17.1 
Aim ............................................................................................................................. 26 
17.2 
Site selection ............................................................................................................... 26 
17.3 
Consent ...................................................................................................................... 27 
17.4 
Sample size ................................................................................................................. 27 
17.5 
Methods ..................................................................................................................... 27 
18. Medical Therapy ...................................................................................................... 27 
19. Data Collection and Follow-Up ................................................................................. 27 
19.1 
Data handling .............................................................................................................. 27 

 
 
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19.2 
NHS England ............................................................................................................... 28 
19.3 
Tests required for eligibility ......................................................................................... 28 
19.3.1 
Time limits for screening tests ................................................................................................... 28 
19.4 
Trial Checklist .............................................................................................................. 29 
19.5 
Definition of end of trial .............................................................................................. 31 
19.6 
Adverse Events ............................................................................................................ 32 
19.7 
Participant ID Log ........................................................................................................ 32 
20. Health Economic Analysis ........................................................................................ 32 
21. Version History Log .................................................................................................. 34 
22. References ............................................................................................................... 35 
Appendix 1 – EQ-5D-5L ................................................................................................... 37 
 
 
 

 
 
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1. Trial Summary 
1.1 Protocol Summary 
 
Study Title 
Controlled trial of High-risk coronary Intervention with Percutaneous 
left ventricular unloading (CHIP-BCIS3) 
Aim 
To establish whether, in patients undergoing high-risk percutaneous 
coronary intervention, a strategy of percutaneous left ventricular 
unloading is superior to standard care in terms of patient outcomes, 
quality of life and cost-effectiveness 
Trial Design 
Prospective randomised open-label multicentre trial 
Primary Outcome 
Composite hierarchical outcome of death, stroke, spontaneous 
myocardial infarction, cardiovascular hospitalisation or 
periprocedural myocardial infarction, analysed using a Win Ratio 
method 
Major Secondary Outcomes • 
Individual components of the primary outcome (as well as 
repeated occurrences of these events) 
• 
Completeness of revascularisation 
• 
Major bleeding (BARC 3 to 5) 
• 
Major vascular complication (VARC) 
• 
Procedural complication 
• 
Unplanned revascularisation 
• 
Health related quality of life/functional status 
• 
Resource utilisation and cost effectiveness 
• 
Length of stay 
Inclusion Criteria 
1. Extensive coronary disease (BCIS-JS ≥ 8) 
2. Severe Left Ventricular Dysfunction§ 
3. Scheduled to undergo complex PCI* 
Exclusion Criteria 
1. Cardiogenic shock or acute STEMI at randomisation 
2. Contraindication to pLVAD insertion 
Sample Size 
250 (125 in each group) would provide >80% power to detect a 
hazard ratio of 0.62, requiring approx. 150 first events during entire 
follow-up duration (equates to risk ratio ~0.70 at 12 months). The 
sample size was extended to 300 patients in May 2024 to further 
improve statistical power. 
 

 
 
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1.2 Trial Flowchart 
 
1. Extensive CAD (BCIS-JS ≥ 8)
2. Severe left ventricular dysfunction (LVEF ≤ 35%)§
3. Scheduled for complex PCI*
Randomise
Elective LV 
Unloading
No LV 
Unloading
Follow Up (minimum duration:12m) 
Primary Analysis: Win Ratio of Hierarchical Composite Outcome
PCI
PCI
§ LVEF ≤ 35% (or ≤ 45% with severe mitral regurgitation) 
* Complex PCI: at least one of the following 
• Unprotected left main intervention in the presence of 
• an occluded dominant right coronary artery or 
• a left dominant circulation or 
• disease involving the entire bifurcation (Medina 1,1,1 or 0,1,1) 
• Intended calcium modification (by rotational or orbital atherectomy, lithotripsy 
or laser) 
• in multiple vessels or 
• in the left mainstem or 
• in a final patent conduit or 
• where the anatomic SYNTAX score is ≥32 
• Target vessel is a chronic total occlusion with planned retrograde approach 

 
 
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1.3 Trial Organisation 
1.3.1 
NIHR HTA CET Grant Applicants 
Prof. Divaka Perera, King’s College London (Chief Investigator) 
Prof. Tim Clayton, London School of Hygiene and Tropical Medicine 
Prof. Peter Ludman, Queen Elizabeth Hospital, Birmingham 
Dr. Peter O’Kane, Royal Bournemouth Hospital, Bournemouth 
Dr James Spratt, St George’s Hospital, London 
Dr. Simon Walsh, Belfast Health and Social Care Trust, Belfast 
Dr. Ian Webb, King’s College Hospital, London 
Mr Richard Evans, London School of Hygiene and Tropical Medicine 
Assistant Prof. Zia Sadique, London School of Hygiene and Tropical Medicine 
Dr. Matthew Ryan, King’s College London 
1.3.2 
Trial Steering Committee (TSC) 
Prof. Nick Curzen, University of Southampton (Chair) 
Mrs Jacqueline Grudzinskas, PPI Representative 
Mr Hameed Khan, PPI Representative 
Dr. Rasha Al-Lamee, Imperial College London 
Dr. Adam De Belder, Royal Sussex County Hospital, Brighton 
Prof. Divaka Perera, King’s College London 
Prof. Tim Clayton, London School of Hygiene and Tropical Medicine 
Dr. Ly-Mee Yu, University of Oxford 
Prof. José Henriques, University of Amsterdam 
1.3.3 
Data Monitoring Committee (DMC) 
Prof. Rod Stables, University of Liverpool (Chair) 
Dr. Louise Brown, MRC Clinical Trials Unit at University College London 
Dr Miles Behan, Edinburgh Royal Infirmary 
The DMC is supported by Mr Matt Dodd, Statistician at the London School of Hygiene and Tropical 
Medicine CTU 
1.3.4 
Trial Management Group (TMG) 
Prof. Divaka Perera, King’s College London 
Prof. Tim Clayton, London School of Hygiene and Tropical Medicine 
Mr Richard Evans, London School of Hygiene and Tropical Medicine 
Dr Matthew Ryan, King’s College London 
Dr Saad Ezad, King’s College London 
Mrs Lynn Laidlaw, PPI Representative 

 
 
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Ms Megan Knight, London School of Hygiene and Tropical Medicine 
Mr Matthew Kwok, London School of Hygiene and Tropical Medicine 
1.3.5 
Clinical Trials Unit (CTU) 
The trial is managed by the UKCRC accredited CTU at London School of Hygiene and Tropical 
Medicine (Registration ID 44) 
1.3.6 
Clinical Events Committee (CEC) 
Dr Stephen Hoole, Royal Papworth Hospital (Chair) 
Dr Peter Henrikson, University of Edinburgh 
Dr Rong Bing, University of Edinburgh 
Dr Paul Bambrough, Royal Papworth Hospital 
Dr Heeraj Bulluck, Leeds General Infirmary 
Dr Natalia Briceno, Wexham Park Hospital 
Dr Nicholas Jenkins, Sunderland Royal Hospital 
Dr Abdul Mozid, Leeds General Infirmary 
1.3.7 
Recruiting Centres 
At each site; 
• 
Principal Investigator 
• 
Trial Coordinator 
A current list of sites is provided on the trial website http://chip-bcis3.lshtm.ac.uk/. 
1.4 List of Abbreviations and Definitions 
ACE 
angiotensin converting enzyme 
ACS 
acute coronary syndrome 
BARC 
Bleeding Academic Research Consortium 
BCIS-JS 
British Cardiovascular Intervention Society Jeopardy Score 
BNP 
brain natriuretic peptide 
CABG 
coronary artery bypass grafting 
CAD 
coronary artery disease 
CCS 
Canadian Cardiovascular Society 
CE 
certification for use in the European Union 
CEA 
cost-effectiveness analysis 
CEC 
clinical events committee 
CET 
clinical evaluation and trials 
CHIP 
Complex, high-risk and indicated percutaneous coronary intervention 
CNS 
central nervous system 
CT 
computed tomography 
CTO 
chronic total occlusion 
CTU 
clinical trials unit 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 

 
 
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EF 
ejection fraction 
EQ-5D-5L 
EuroQoL survey 
FBC 
full blood count 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
haemoglobin A1c 
HES 
hospital episode statistics 
HRQoL 
health related quality of life 
HSQ 
health service questionnaire 
HTA 
health technology assessment 
IABP 
intra-aortic balloon pump 
IPG 
Interventional procedures guidance 
IVUS 
Intravascular ultrasound 
JS 
jeopardy score 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KCL 
King’s College London 
LAD 
left anterior descending coronary artery 
LBBB 
left bundle branch block 
LSHTM 
London School of Hygiene and Tropical Medicine 
LV 
left ventricle 
LVEDP 
left ventricular end diastolic pressure 
LVEF 
left ventricular ejection fraction 
LVSD 
left ventricular systolic dysfunction 
MAE 
major adverse events 
MACE 
major adverse cardiovascular events 
MCS 
mechanical circulatory support 
MI 
myocardial infarction 
MICE 
multiple imputation using chained equations 
MRI 
magnetic resonance imaging 
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence 
NIHR 
National Institute for Health Research 
NSAE 
non-serious adverse event 
NT-proBNP 
n-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OCT 
optical coherence tomography 
PCI 
percutaneous coronary intervention 
PIC 
Participant Identification Centre 
pLVAD 
percutaneous left ventricular assist device 
QALY 
quality added life year 
RCT 
randomised controlled trial 
REC 
research ethics committee 
RI 
revascularisation index 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
STEMI 
ST-elevation myocardial infarction 
SYNTAX 
synergy between PCI with taxus and cardiac surgery 
TMG 
trial management group 
TSC 
trial steering committee 
TTE 
transthoracic echocardiogram 
UK 
United Kingdom 
URL 
upper reference limit 
VA-ECMO 
veno-arterial extra-corporeal membrane oxygenation 
VF 
ventricular fibrillation 
VT 
ventricular tachycardia 

 
 
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2. Background 
2.1 High-Risk PCI 
Coronary artery disease (CAD) is the top cause of death globally and a leading cause of morbidity 
and mortality in the UK[1]. Revascularisation, the process of restoring normal coronary blood flow 
through either coronary artery bypass grafting or percutaneous coronary intervention (angioplasty 
and stenting, PCI), is a cornerstone in the management of patients with CAD. In the context of an acute 
coronary syndrome (ACS), revascularisation is associated with improved mortality, freedom from heart 
failure and improved health related quality of life (HRQoL) when compared to medical therapy 
alone[2]. These benefits need to be balanced against the adverse events associated with the 
procedure itself which become more likely with increasing age, comorbidity and the complexity of 
coronary disease. This creates a conundrum; high-risk patients with comorbidities and extensive 
coronary disease are more likely to benefit from revascularisation, but safely delivering this treatment 
is challenging and associated with high rates of early adverse events including periprocedural 
myocardial infarction, pulmonary oedema, cardiogenic shock and cardiac arrest[3]. Because of these 
factors, high-risk patients are often under-treated with associated poor health outcomes[4].  
2.2 LV Unloading 
Several strategies have been developed in an attempt to prevent periprocedural adverse events 
during high-risk PCI procedures. Of these, percutaneous left ventricular (LV) unloading shows promise. 
Unloading involves the placement of a mechanical pump which draws blood from the left ventricle and 
returns it into the aorta at flow rates approaching native cardiac output. Unloading has favourable 
physiological effects, reducing cardiac work and pulmonary capillary wedge pressure whilst improving 
cardiac power output[5]. Whether these physiological effects translate into better clinical outcomes 
remains, however, unclear. 
There is a lack of robust evidence for the efficacy of LV unloading in complex PCI procedures. Despite 
this, usage has increased significantly in recent years and hence NICE published Interventional 
Procedures Guidance (IPG633) in November 2018[6]. The guideline noted the limited quality of 
evidence on efficacy and serious, infrequent, but well-recognised safety concerns related to LV 
unloading. Whilst permitting use within the NHS, they recommended this be limited to specialised 
centres with clinicians and teams who had specialised training and experience in complex PCI. The 
committee highlighted the urgent need for new data and recommended the following key efficacy 
outcomes; procedural success, completeness of revascularisation, haemodynamic stability, survival to 
hospital discharge, survival at 30 days and the rate of major adverse cardiac events.  
Recommendations for safety outcomes were vascular damage, bleeding, haemolysis and damage to 
the left ventricle.  

 
 
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The recent upsurge in LV unloading has been primarily driven by countries which have arrangements 
for reimbursement for use of this technology, including the USA, Germany and Japan. Our group have 
recently audited the use of LV unloading in high-risk PCI at the 4 largest volume centres since the 
technology was introduced to the UK, a little over a decade ago – the data demonstrate increasing 
use over time and confirmed the uncommon but significant bleeding and vascular complications (Figure 
1). Many other UK centres have recently started to utilise these devices. 
Figure 1: Cumulative Number of Impella Implantations (Blue), Bleeding Complications (Red) and 
Vascular Complications (Green). 
LV unloading could provide clinical benefit via two distinct mechanisms – firstly, by preventing major 
periprocedural complications, which in turn would be expected to reduce mortality, critical care 
admissions and length of stay; secondly, by allowing operators to undertake more complex and 
complete revascularisation, the latter having been shown to be associated with improved mortality, 
reduced rehospitalisation and subsequently improved health-related quality of life. If LV unloading 
during high-risk PCI is clinically effective, increased use may have significant positive implications both 
for patient outcomes and healthcare resource utilisation. Conversely, if ineffective, limiting use could 
reduce both clinical and fiscal costs. Bleeding and vascular complications have significant HRQoL and 
healthcare resource implications, including increased hospitalisation and critical care utilisation.  
The most widely adopted LV unloading device is the Impella (Abiomed, Danvers, MA, USA). Whilst it 
would be optimal for any new healthcare technology to be first evaluated in carefully designed 
clinical trials before being adopted widely and incorporated into guidelines, the unique set of 
circumstances surrounding the introduction of the device in the United States (where reimbursement far 
exceeded costs for many years) has meant that the FDA has approved use of the device based almost 
entirely on registry data. Consequently, no randomised trial of percutaneous LV unloading devices in 
high-risk PCI is planned or ongoing.  A single industry-funded RCT (DanGer-Shock, ClinicalTrials.gov 
identifier NCT01633502) is investigating the role of LV unloading in patients with cardiogenic shock: 
this is a wholly separate condition for which data cannot be translated into the high-risk PCI setting. 

 
 
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2.3 Current Evidence 
Whilst there is no universally accepted definition, to be considered high-risk the PCI would typically 
include a combination of complex coronary anatomy, impaired cardiac function, the likely duration of 
ischaemia during the procedure and patient frailty/comorbidity[7]. The indication for revascularisation 
may be either stable coronary disease or acute coronary syndrome, though the latter generally 
indicates a higher risk.  
Recent systematic reviews of the evidence for LV unloading in high-risk PCI have been conducted by 
NICE[6] and Health Quality Ontario[8]. Both concluded that there is currently inadequate data to 
make any strong recommendation as to the use of LV unloading in high-risk PCI.  
There are no randomised data on the safety and efficacy of LV unloading assisted PCI compared to 
the current standard of care (PCI without mechanical support). One randomised trial sought to compare 
the Impella versus intra-aortic balloon pump (IABP), the PROTECT II study[9]. Patients undergoing high-
risk PCI, defined as unprotected left main disease or last patent vessel with an LVEF ≤35%, or three-
vessel disease with an LVEF ≤30% were randomised 1:1 to receive an Impella 2.5 catheter or intra-
aortic balloon pump (IABP) before PCI. The planned sample size was 600 but the data and safety 
committee recommended premature termination due to likely futility (as no difference was observed 
after 300 patients completed primary follow-up) hence only 452 patients were enrolled. The trial 
demonstrated the expected high rates of early major adverse events (MAE), but no significant 
difference between arms at 30 days (40% vs. 35%, respectively, p = 0.277). Selected sub-analyses 
were published indicating benefit (as-treated, excluding the first case performed at each centre) 
adding to the ambiguous interpretation of the data, despite the negative primary endpoint. Key 
safety data including bleeding and vascular complications were also absent from the report.  
Methodological issues are apparent across both PROTECT II and many other previous trials of 
mechanical circulatory support and must be borne in mind in designing future studies if they are to 
provide definitive data.  
Firstly, prior trials have defined risk only by simple coronary anatomic characteristics and LVEF. The 
complexity of intervention is a key factor in determining procedural risk and the likelihood of adverse 
events. Defining the participant population based on such complexity will test the utility of LV 
unloading in the circumstances where it may be efficacious, with higher event rates reducing the 
necessary sample size to show benefit. In order to recruit a sufficient number of such characterised 
patients, a network of centres is required which has both appropriate clinical experience and a track 
record of recruitment to trials in high-risk PCI.  
Additionally, primary analyses were planned at early time-points; this limits the assessment to 
periprocedural events and complications. As patients undergoing high-risk PCI continue to accrue 
adverse events at significant rates, longer term follow-up provides large numbers of clinically 
important events[10]. Furthermore, most trials to date have used non-hierarchical composite endpoints 
with time-to-first-event analyses; whilst this approach is common in cardiovascular trials, it has 
significant weaknesses. Instead, considering these data in a hierarchy of clinical importance and 
capturing the impact of recurrent events by using innovative methods of statistical analysis will 
significantly increase power whilst focusing the assessment of outcomes on endpoints that are 
meaningful to both patients and healthcare providers. 
A recent registry, arising from the Premier Healthcare Database (representing 20% of acute 
hospitalisations in the USA per annum) highlights the increase in LV unloading for high-risk PCI.  The use 
of unloading increased from <5% of MCS supported procedures in 2010, to 33% of MCS procedure 
in 2016.  The registry also indicated an increased risk of death, bleeding and stroke in patients 
treated with LV unloading after propensity matching, highlighting the safety risks and need for 
randomised data.[11] 
This project therefore addresses a significant need for research, identified by the NICE Interventional 
Procedures Guideline Committee, and is being proposed at a critical time, where LV unloading use is 
not widely established in clinical practice, but is creeping into current practice in the absence of a 
significant evidence base and, were the American experience to be replicated, represents a 
substantial economic burden on the NHS. 

 
 
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3. Hypothesis 
In patients undergoing high-risk percutaneous coronary intervention, a strategy of percutaneous left 
ventricular unloading is superior to standard care in terms of patient outcomes, quality of life and cost-
effectiveness. 
4. Study Design 
A multicentre, open-label randomised controlled superiority trial. 
5. Health Technology 
The health technology being assessed is percutaneous left ventricular assist/unloading devices (pLVAD), 
specific to their use in high-risk PCI, as covered by NICE IPG 633.  The comparator will the current 
standard of care, high-risk PCI without elective mechanical circulatory support. 
6. Trial Population 
6.1 Target Population 
Patients undergoing high-risk PCI defined by 1: extensive coronary disease; 2: severe left ventricular 
systolic dysfunction; 3: scheduled to undergo complex PCI. 
6.2 Inclusion Criteria 
1. Extensive coronary disease defined by a British Cardiovascular Intervention Society (BCIS) Jeopardy 
Score ≥ 8* 
 
2. Severe left ventricular systolic dysfunction defined as a LVEF ≤ 35% (or ≤ 45% in the presence of 
severe mitral regurgitation)# 
 
3. Complex PCI defined by the presence of at least one of the following criteria: 
• 
Unprotected left main intervention in the presence of 
o an occluded dominant right coronary artery or 
o a left dominant circulation or  
o disease involving the entire bifurcation (Medina 1,1,1 or 0,1,1) 
• 
Intended calcium modification (by rotational or orbital atherectomy, lithotripsy or laser)  
o in multiple vessels or 
o in the left mainstem or 
o in a final patent conduit or 
o where the anatomic SYNTAX score is ≥32 
• 
Target vessel is a chronic total occlusion with planned retrograde approach 
 
* In general, patients who do not have bypass grafts will be eligible if they have at least proximal left 
anterior descending (LAD) disease or at least proximal 2 vessel disease. For patients with patent bypass 
grafts, or in cases where the extent of coronary artery disease (CAD) is uncertain, the BCIS-1 JS should 
be calculated. The maximum possible JS score is 12. N.B. The JS should be based on all coronary disease, 
not just the vessel subtending viable myocardium.  
#  Biplane/3D echocardiography or cardiac MRI can be used to assess the qualifying LVEF. 
6.3 Exclusion Criteria 
1. Cardiogenic shock or acute STEMI at randomisation (including current treatment with a mechanical 
circulatory support device) 
 
2. Contraindication to pLVAD insertion 

 
 
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3. Inability to give informed consent 
 
4. Previously enrolled in CHIP or current enrolment in another interventional study that may affect 
CHIP outcomes 
7. Endpoints 
An independent clinical events committee (CEC), who are blinded to treatment assignment, will centrally 
adjudicate and validate selected endpoints where validation is necessary. 
7.1 Primary Endpoint 
A combined hierarchical endpoint incorporating death, stroke, myocardial infarction and 
cardiovascular hospitalisation, analysed with the Win Ratio method (see section 10 below). 
7.2 Major Secondary Endpoints 
Combined primary endpoint analysed with a time-to-first-event method 
Individual components of the primary endpoint (as well as repeated occurrences of these events) 
7.3 Other Secondary Endpoints 
Major bleeding 
Vascular complication 
Procedural complication 
Acute kidney injury 
Unplanned revascularisation 
Completeness of revascularisation 
Health related quality of life/functional status 
Resource utilisation and cost effectiveness 
Serial cardiac troponin (T or I) levels 
Length of stay 
 
 
 

 
 
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7.4 Endpoint Definitions 
Disabling Stroke 
Stroke is defined as an acute episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or retinal vascular injury as a 
result of hemorrhage or infarction, resulting in persistent moderate 
disability (modified Rankin Scale ≥3) at the time of discharge from the 
acute hospital admission. 
Acute Myocardial 
Infarction 
1. Spontaneous MI (>48 hours after PCI/CABG) 
Detection of a rise and/or fall of cardiac Troponin I or T, with at least one 
value higher than the 99th percentile upper reference limit (URL) AND 
symptoms consistent with ischaemia OR dynamic electrocardiogram (ECG) 
changes (including ≥1mm ST elevation or ST depression, new left bundle 
branch block (LBBB) or >3mm T-wave inversion) OR imaging evidence of 
new loss of viable myocardium or new regional wall motion abnormality in 
a pattern consistent with an ischaemic aetiology. 
 
2. Peri-procedural MI (<48 hours after PCI/CABG) 
Following PCI:  Detection of a rise in cardiac troponin I or T, with the 
threshold of significance determined by the pre-procedure baseline value. 
 
Baseline ≤URL: At least one value higher than five times the URL 
 
Baseline > URL and stable or falling:  At least one value higher than 5xURL 
above the baseline value or 20% above the baseline value, whichever is 
greater.  
 
Baseline > URL and rising:  At least one value higher than 5xURL above the 
predicted value* or 20% above the predicted value, whichever is 
greater. 
 
*the predicted value will be calculated via linear extrapolation of the trend 
from at least two troponin values taken within 48 hours before the 
procedure. 
 
Following CABG:  As for PCI, but with a threshold of 10xURL.  
In addition to classifying patients dichotomously as having suffered a 
periprocedural MI or not, baseline and peak troponin I or T values measured 
within 24 hours of a procedure will be recorded.  This will provide a 
continuous measure for adjudication of ties in patients reaching the 
periprocedural myocardial infarction endpoint within the Win Ratio.                
 
Absolute values of troponin, ECGs and supporting information will be 
collected for all patients who experience a periprocedural MI, so that 
sensitivity analyses based on alternative definitions can be explored.               
Cardiovascular 
Hospitalisation 
Hospital or virtual ward admission (lasting ≥24 hours) with a primary 
diagnosis of heart failure or sustained ventricular arrhythmia. Prolonged 
hospitalisation for complications of the PCI procedure: acute heart failure, 
major bleeding and major vascular complication are included within the 
definition where the length of admission is extended by ≥24 hours from 
the expected time of discharge following the procedure and the 
associated endpoint definition has been met and was the primary reason 
for prolongation of the hospital admission. 
 
Heart failure hospitalisation will be defined as Hospital admission (lasting 
>24 hours) for deteriorating symptoms or signs of heart failure, where there 
is a documented diagnosis of heart failure and the patient receives initiation 
or intensification of treatment for heart failure. Initiation or intensification of 

 
 
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treatment includes at least one of the following: increase in oral diuretic dose 
or addition of another oral diuretic; intravenous diuretic therapy; intravenous 
vasoactive therapy (vasodilator, inotrope or vasopressor); mechanical 
circulatory support (MCS) (including intra-aortic balloon pump (IABP), 
pLVAD, extra-corporeal membrane oxygenation (ECMO)); or cardiac 
transplantation. 
 
Heart failure during or after the assigned PCI procedure itself is defined as 
prolongation of the planned admission by at least 24 hours due to acute 
heart failure requiring initiation or intensification of treatment as defined 
above (including continued use of pLVAD for >24hours after PCI in patients 
randomised to the elective pLVAD arm, for a clinical suspicion of heart 
failure).  Elective admission for implantation or revision of ICD/cardiac 
resynchronisation therapy (CRT) devices will NOT constitute an endpoint. 
 
Sustained ventricular arrhythmia is defined as Ventricular tachycardia or 
fibrillation persisting for more than 30 seconds and/or associated with 
haemodynamic compromise, and/or requiring cardioversion/defibrillation 
(external or via implantable cardioverter defibrillator).  Suspicion of 
arrhythmia without documentation on a recorded surface ECG or 
electrograms from an indwelling device will not constitute an endpoint. 
 
Elective admission for planned cardiac procedures (staged PCI, device 
insertion, cardioversion or catheter ablation) will not constitute an 
endpoint. 
Major Bleeding 
Major bleeding will be defined using the Bleeding Academic Research 
Consortium (BARC) categories below:  
 
Type 3: Major Bleeding 
Type 3a  
• 
Overt bleeding plus haemoglobin drop of ≥30 to <50g/L 
(provided haemoglobin drop is related to bleed)  
• 
Any transfusion with overt bleeding  
      Type 3b  
• 
Overt bleeding plus haemoglobin drop ≥50g/L (provided 
haemoglobin drop is related to bleed)  
• 
Cardiac tamponade  
• 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/haemorrhoid)  
• 
Bleeding requiring intravenous vasoactive drugs  
Type 3c  
• 
Intracranial haemorrhage (does not include microbleeds or 
haemorrhagic transformation; does include intraspinal)  
• 
Subcategories; confirmed by autopsy, imaging or lumbar 
puncture 
• 
Intra-ocular bleed compromising vision  
 
Type 4: CABG-Related Bleeding  
• 
Perioperative intracranial bleeding within 48 hours  
• 
Reoperation following closure of sternotomy for the purpose 
of controlling bleeding  
• 
Transfusion of ≥5 units of whole blood or packed red blood 
cells within a 48-hour period  
• 
Chest tube output ≥2L within a 24-hour period  
• 
If a CABG-related bleed is not adjudicated as at least a 
Type 3 severity event, it will be classified as ‘Not a bleeding 
event’  

 
 
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Type 5: Fatal Bleeding  
Type 5a  
• Probable fatal bleeding: no autopsy or imaging 
confirmation, but clinically suspicious  
Type 5b  
• Definite fatal bleeding: overt bleeding or autopsy or 
imaging confirmation  
Vascular Complication 
Vascular complications will be defined according to the valve academic 
research consortium (VARC) criteria below: 
 
Major complication 
• 
Aortic dissection or aortic rupture 
• 
Vascular (arterial or venous) injury# or compartment syndrome 
resulting in death, VARC type ≥2 bleeding, limb or visceral 
ischaemia, or irreversible neurologic impairment 
• 
Distal embolization (non-cerebral) from a vascular source resulting 
in death, amputation, limb or visceral ischaemia, or irreversible 
end-organ damage 
• 
Unplanned endovascular or surgical intervention resulting in death, 
VARC type ≥2 bleeding, limb or visceral ischaemia, or 
irreversible neurologic impairment 
• 
Closure device failure resulting in death, VARC type ≥2 bleeding, 
limb or visceral ischaemia, or irreversible neurologic impairment 
 
Minor complication 
• 
Vascular (arterial or venous) injury# not resulting in death, VARC 
type ≥2 bleeding, limb or visceral ischaemia, or irreversible 
neurologic impairment 
• 
Distal embolization treated with embolectomy and/or 
thrombectomy, not resulting in death, amputation, limb or visceral 
ischaemia, or irreversible end-organ damage 
• 
Any unplanned endovascular or surgical intervention, ultra-sound 
guided compression, or thrombin injection, not resulting in death, 
VARC type ≥2 bleeding, limb or visceral ischaemia, or 
irreversible neurologic impairment 
• 
Closure device failure not resulting in death, VARC type ≥2 
bleeding, limb or visceral ischaemia, or irreversible neurologic 
impairment 
Access related non-
vascular complication 
Non-vascular structure, non-cardiac structure perforation, injury, or 
infection resulting in death, VARC type ≥2 bleeding, irreversible nerve 
injury or requiring unplanned surgery or percutaneous intervention. 
Non-vascular access site (e.g. trans-apical left ventricular) perforation, 
injury, or infection resulting in death, VARC type ≥2 bleeding, irreversible 
nerve injury or requiring unplanned surgery or percutaneous intervention. 
 
 

 
 
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Major Procedural 
Complication  
VT/VF requiring defibrillation.  
Cardiorespiratory arrest or acute pulmonary oedema requiring assisted 
ventilation.  
Prolonged hypotension (Mean arterial pressure ≤75 mmHg for >10 min 
despite fluid resuscitation and/or vasoactive drugs and/or requirement of 
mechanical circulatory support). 
Acute Kidney Injury 
Acute kidney injury defined as prolongation hospital admission or 
readmission ≥ 24 hours with rise in creatinine to 200% of baseline value 
or need for new renal replacement therapy within 30 days of procedure. 
Completeness of 
Revascularisation 
Change in anatomic BCIS-JS and anatomic SYNTAX score between the 
time of randomisation and the completion of the final planned PCI 
procedure. 
Unplanned 
Revascularisation 
Any unplanned target vessel or non-target vessel revascularisation by PCI 
or CABG, excluding staged PCI (with plan documented at the index 
procedure). 
Length of stay 
Duration of admission in complete days following the index PCI procedure 
and any subsequent planned staged PCI procedure 
8. Safety Reporting  
8.1 Definition  
Unexpected events that have not been defined as endpoints (section 7) or expected complications of 
the PCI procedure (listed in section 7.4) should be reported as either a serious adverse event (SAE) or 
non-serious adverse event (NSAE) depending on their severity.  
8.2 Unexpected Serious Adverse Events  
SAEs should be reported to the Clinical Trials Unit (CTU) within 7 days of the site becoming aware of 
the event. The report should include an assessment of causality by the Principal Investigator at each site 
(see section 5.4.2). The Chief Investigator will be responsible for the prompt notification of findings that 
could adversely affect the health of patients or impact on the conduct of the trial.  
8.3 Unexpected Non-Serious Adverse Events  
Unexpected NSAEs should be evaluated by the Principal Investigator. This should include an assessment 
of intensity (see section 8.4.1) and causality (see section 8.4.2) and reports made within 14 days of the 
site becoming aware of the event. The CTU will keep detailed records of all unexpected adverse 
events reported. Reports will be reviewed by the Chief Investigator to consider intensity, causality and 
expectedness.  
8.4 Reporting Unexpected Adverse Events  
Investigators will make their reports of all unexpected adverse events, whether serious or not, to the 
CTU at the London School of Hygiene & Tropical Medicine.  
8.4.1 
Assessment of Intensity  
Mild: The patient is aware of the event or symptom, but the event or symptom is easily tolerated.  

 
 
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Moderate: The patient experiences sufficient discomfort to interfere with or reduce his or her usual 
level of activity.  
Severe: Significant impairment of functioning; the patient is unable to carry out usual activities and/or 
the patient’s life is at risk from the event.  
8.4.2 
Assessment of Causality  
Probable: A causal relationship is clinically / biologically highly plausible and there is a plausible time 
sequence between onset of the adverse event and the trial intervention. 
Possible: A causal relationship is clinically / biologically plausible and there is a plausible time 
sequence between onset of the adverse event and the trial intervention. 
Unlikely: A causal relationship is improbable and another documented cause of the adverse event is 
most plausible.  
Unrelated: A causal relationship can definitely be excluded and another documented cause of the 
adverse event is most plausible.  
8.5 Notification 
The Sponsor, the Research Ethics Committee (REC) and the Data Monitoring Committee (DMC) will be 
notified by the CTU when reported SAEs have been classified by the Chief Investigator as both 
unexpected and given a causality classification of either Probable or Possible.  
9. Ethical Considerations 
9.1 Consent 
Only patients that give written consent will be included in the trial. If fully informed consent is not 
possible, the patient will not be recruited into the trial. The patient should be given sufficient time to 
consider the trial following which informed consent will be taken. Consent may be taken once all 
requirements for inclusion have been met. 
 
Staff at site may telephone potential patients with information about the trial before scheduled 
hospital appointments. If a patient is interested, then the site can post them the information sheet to 
read prior to their appointment and follow this up with a further telephone call within a reasonable 
time frame. 
 
Patients at Participant Identification Centres (PICs) who meet the required eligibility criteria may be 
given the Participant Information Sheet (a localised version from the associated recruiting trial site). The 
review of eligibility and initial approach to the patient must be made by a member of their direct care 
team. It is then dependent on the patient to contact the relevant trial site to undergo informed consent 
and any further study procedures.      
 
A patient may decide to withdraw from the trial at any time without prejudice to their future care.  
9.2 Declaration of Helsinki and Good Clinical Practice 
The trial will conform to the spirit and the letter of the Declaration of Helsinki, and in accordance with 
Good Clinical Practice (GCP) Guidelines. 

 
 
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9.3 Ethical Committee Review 
The National Research Ethics Service Committee London - Bloomsbury have reviewed and approved 
the trial (REC reference 21/LO/0287). Copies of the letters of approval are to be filed in the trial site 
files at each centre. 
10. 
Statistical Considerations 
10.1 
Win Ratio 
The analysis will be undertaken by use of the Win Ratio, an increasingly recognised approach to allow 
for the hierarchy of events as well incorporating repeat events such as myocardial infarctions or 
hospitalisations[12,13]. The Win Ratio is the ratio of “winners” on the intervention compared to “losers” 
thus a value above 1 indicated a benefit of the intervention. Confidence intervals can be calculated as 
well as p-values and the process extended for repeat component events. 
 
The combined hierarchical endpoint is all-cause death, stroke, spontaneous myocardial infarction (MI), 
cardiovascular hospitalisation and peri-procedural MI. The outcome hierarchy is as follows: 
 
(1) All-cause death 
(2) Stroke (defined as disabling stroke thus not including transient ischaemic attacks) 
(3) Spontaneous MI 
(4) Cardiovascular hospitalisation 
(5) Peri-procedural MI 
 
The Win Ratio will use an unmatched pairs approach with each individual in the intervention arm 
compared to each individual in the standard care arm, using the stepwise sequence below, to 
adjudicate a winner/loser or declare a tie. For each comparison the common follow-up is defined in 
which follow-up is censored at the duration of the shorter follow-up interval. For example, if one 
patient has been followed for 1 year and the second patient for 2 years then for that specific 
comparison events up to one year will be considered. 
 
• Step 1: Compare all-cause mortality – if one has died, the survivor is the winner, if both have 
died, the patient who survives longer is the winner and if neither has died (or both die at the 
same interval from randomisation) proceed to step 2 
• Step 2: Compare time to occurrence of disabling stroke, as above. If no winner, proceed to 
step 3. 
• Step 3: Compare time to occurrence of spontaneous MI (as per Universal Definition) as above. 
If no winner, proceed to step 4. 
• Step 4: Compare the number of cardiovascular hospitalisations (as defined in the trial 
protocol). The patient with the least number of hospitalisations occurring within the common 
follow-up period is the winner. If the same number of hospitalisations have occurred, the patient 
who survives longer before the first hospitalisation is the winner. If neither have had a 
cardiovascular hospitalisation in this period, proceed to step 5. 
• Step 5: Compare periprocedural MI. If only one has had a periprocedural MI, the patient who 
does not have a MI is the winner. If both have had a periprocedural MI, the patient with the 
smaller infarct size, as measured by peak Troponin level (expressed as a multiple of the 99th 
centile, to allow comparison of different Troponin assays) is the winner, unless the difference in 
increase in troponin level between patients is ≤5x the URL, in which case a tied will be declared. 
If neither patient has had a periprocedural MI, the stepwise comparison is concluded and the 
result declared a tie. 
 
This approach is designed to optimise the impact of individual components of a composite endpoint, by 
allocating greater weight to more important events, increasing the range of events considered and 
allowing capture of recurrent events. The requirement for a ≥ 5x URL difference in troponin level in 
determining wins based upon peri-procedural MI is designed to ensure a clinically meaningful 

 
 
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difference in all declared wins.  When analyses of recurrent events has been applied to simulated 
data and major contemporary heart failure trials precision has been shown to improve when treatment 
discontinuation is low following the first event[14]. Since the intervention is high-risk PCI and not drug 
therapy crossover rates are expected to be negligible allowing a smaller sample size whilst 
maintaining power. In contrast, a traditional composite endpoint trial using time to first event analysis 
weights each event equally and only incorporates the first event hence many more serious outcomes, 
such as death, may not included and no account is taken of later events. The sample size using such an 
approach would require a larger treatment difference to be detected (as illustrated below) or require 
a prohibitively large and expensive trial and would not be able to complete recruitment in a 
reasonable timeframe. 
10.2 
Power Calculation 
Based on an accrual period of 3 years and minimum follow-up of 12 months major events will be 
recorded for a minimum of 12 months and a maximum of 4 years. Major events over this duration can 
easily be incorporated into the Win Ratio analysis to maximise power and more appropriately account 
for the impact of more serious clinical outcomes.  Calculations for the unmatched pairs Win Ratio 
analysis are not well established at present and require many underlying assumptions. Hence, we have 
first calculated sample size using a conventional approach (incorporating modest power). 
 
In the PROTECT II trial the composite endpoint comparable to that proposed in CHIP was 40% at 30 
days and 50% at 90 days. Assuming a more conservative event rate of 50% at 12 months in the 
control arm a trial of 250 (125 in each group) would have well in excess of 80% power to detect a 
hazard ratio of 0.62 requiring approximately 150 first events using all follow-up time (which, at these 
event rates, represents a risk ratio of 0.70 at 12 months) allowing for 5% losses. Whilst this rate may 
appear to be high at first, it is based on published data from high risk intervention. Given the 
established superior statistical power of a Win Ratio analysis and other secondary analyses accounting 
for repeated events in trials with low crossovers, a sample size of 250 patients was expected to 
provide good power to detect important clinical differences between the treatment groups. Crossovers 
will be evaluated throughout the trial. 
 
10.2.1 Sample size extension 
Due to successful recruitment, the opportunity arose for the investigators to extend recruitment and 
increase the sample size to 300 participants. The decision to design and conduct CHIP-BCIS was 
largely influenced by the position taken by NICE in 2018, when it was felt that there was insufficient 
evidence to support routine use of this strategy in the NHS and that more research on its safety and 
efficacy was a priority. Whilst a 30% relative risk reduction would enable NICE to issue clear 
guidelines on the use of LV unloading in the UK, increasing the sample size would allow an even 
smaller treatment effect to be assessed and hence provide NICE (as well as other healthcare systems 
and international guideline committees) with more definitive evidence on which to base their 
recommendations.  
 
A further advantage of extending the accrual period is that the follow-up period of the 250 
patients first recruited to the trial would be extended by the duration of the additional recruitment 
period. In total, we estimate that the proposed changes would lead to an increase in total follow-up by 
approximately 140 patient-years, which would allow capture of more clinical events, hence increasing 
statistical power. Given that the additional events captured will be those occurring later following 
randomisation, this will also potentially lead to more pairwise comparisons in the primary (win ratio) 
analysis being determined by components higher-up the hierarchy than peri-procedural MI, thereby 
also increasing clinical impact. 
 
The TSC initially considered an increase in sample size in July 2023, subject to satisfactory progress in 
recruitment over the following 6 months. Accordingly, the TSC reviewed recruitment rates again in 
February 2024 and recommended an increase in the sample size to 300. An application to the funder 
was made in March 2024 and approved in May 2024.  

 
 
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10.2.2 Secondary Endpoints 
Individual components of the hierarchical combined primary endpoint as well as repeated occurrences 
of these events, health-related quality of life, New York Heart Association (NYHA) functional class, 
completeness of revascularisation and resource utilisation at 90 days, yearly and at the end of the 
trial. The combined outcome and individual components will also be analysed using Cox proportional 
hazard models for the time-to-first event over the follow-up period.  Other analyses such as sensitivity 
and per-protocol analyses will be detailed in the statistical analysis plan. 
10.3 
1-year feasibility review 
A review of recruitment and pooled event rates was performed approximately one year after the first 
patient was recruited to inform the feasibility of completing the trial within the initial projected period. 
As the number of patients randomised was still relatively small and length of follow-up short, it was felt 
that the expected number of events at this stage of the trial was too low for meaningful assessment. 
Recruitment and the pooled event rate will continue to be monitored as the trial progresses.  
 
An independent DMC has been established and a separate DMC charter developed which includes 
details of the meeting schedule and stopping guidelines. The DMC is expected to meet at least 
annually.  
 
 

 
 
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11. 
Screening 
11.1 
Screening Population 
All patients undergoing PCI should be screened for eligibility at the time of listing.  They may come 
from the following sources: 
 
• 
Patients referred to the Heart Team for consideration of revascularisation 
• 
Patients seen in outpatient clinics for consideration of PCI 
• 
Patients referred for advanced imaging to plan complex revascularisation 
• 
Patients currently admitted with acute coronary syndromes or acute heart failure, either at the 
site or planned for transfer from a referring centre. 
• 
Following coronary angiography in patients who are known to have poor resting LV function 
• 
Participant Identification Centres (PICs) 
11.2 
Screening Log 
Detailed screening logs of all patients with extensive CAD and EF ≤35% considered for the trial will 
be completed at sites. Details of all patients who undergo pLVAD supported high-risk PCI at the site 
will also be collected at the same time as the screening log. 
 
The CTU will collect screening logs from the recruiting sites each month. Once recruitment is established, 
and if the TSC agrees it is appropriate, screening information may be collected less frequently.  
12. 
Assessment of LVEF 
12.1 
Qualifying Ejection Fraction 
To determine eligibility for the trial, LVEF can be determined by the following modalities:  
 
•  Transthoracic echocardiogram (TTE) (Simpson’s biplane on 2D or 3D echocardiography)  
•  The resting stage of a stress echocardiogram  
•  Cardiac MRI  
 
The qualifying assessment must have been carried out less than 1 year before randomisation. 
Estimation of LVEF and adjudication of eligibility for enrolment in will be done by each participating 
centre, using locally agreed protocols.  
13. 
Viability Testing 
Viability testing is not mandated.  However, as per current international guidelines, formal testing for 
myocardial viability is strongly recommended for all patients undergoing PCI with severely impaired 
left ventricular function. 
14. 
Core Laboratories 
14.1 
Imaging Core Lab 
All trial echocardiograms should be performed in accordance with the minimum standard set out by the 
British Society of Echocardiography.  Viability studies should be carried out in accordance with the 
relevant national and international society guidelines, dependent on modality. 

 
 
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If the qualifying echocardiogram study was performed less than 6 months before randomisation, this 
study can also be submitted to the core lab to calculate baseline LVEF.  If the qualifying 
echocardiogram was done more than 6 months before randomisation, or the qualifying LVEF was 
assessed using MRI, a further transthoracic echocardiogram should be carried out soon after 
randomisation and this study submitted to the core lab to calculate baseline LVEF.  Any viability study 
performed in the 12 months prior to randomisation should be submitted to the core laboratory. 
 
Baseline echocardiograms and viability studies will be anonymised and submitted to an imaging core 
laboratory which will determine LV volumes and EF using a Simpson’s biplane method and segmental 
myocardial viability and (where available) ischaemia from the viability study. The core laboratory will 
be blinded to treatment assignment as well as to the timing of the studies in relation to randomisation. 
 
The core laboratory will subsequently provide the relevant data to the Sponsor and CTU at the London 
School of Hygiene & Tropical Medicine for analysis against the data held in the eCRF.  
14.2 
Vascular Core Lab 
Both pre-randomisation and trial procedure coronary angiogram, coronary angioplasty images, 
intracoronary imaging and peripheral vascular imaging will be transferred to a vascular core 
laboratory. Each participant’s pre-randomisation BCIS JS and PCI procedural success will be 
independently validated by the core laboratory. The core laboratory will calculate a number of other 
scores reflecting the anatomic complexity of coronary disease, the extent of effective revascularisation 
and the complexity of CTO lesions.  
 
This data will be used to conduct a number of sub-analyses to identify predictors of benefit for the 
primary and secondary outcomes. The core laboratory will subsequently provide the relevant data to 
the Sponsor and CTU at the London School of Hygiene & Tropical Medicine for analysis against the 
data held in the eCRF.  
15. 
Randomisation 
Potential patients will be reviewed by the Principal Investigator before randomisation with all 
available tests/notes to confirm eligibility.  
 
Once the eligibility of a patient is confirmed by the trial coordinators and written informed consent 
obtained, randomisation will be carried out via an online web-based system. Randomisation of the 
treatment assignment will be stratified by centre using randomly permuted blocks of varying size, with 
1:1 allocation between the LV-unloading and non-LV unloading arms.  
 
There is no time limit from randomisation to PCI. However, it is recommended that index PCI be carried 
out as close as possible to randomisation to minimise the incidence of events prior to the assigned 
treatment. Clinical events that occur after randomisation but before planned PCI will be attributed to 
the assigned treatment on an intention-to-treat basis.  
16. 
Percutaneous Coronary Intervention 
16.1 
Pre-procedure workup 
Cross-sectional imaging of the peripheral vasculature with computed tomography (CT) angiography is 
strongly recommended in all patients prior to enrolment.  Where significant peripheral vascular 
disease or access issues are identified, cases should be discussed in a multidisciplinary meeting with 
vascular surgeons and/or interventional radiologists to develop a safe access and closure plan prior to 
randomisation. 

 
 
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16.2 
LV Unloading 
The choice of pLVAD device is at the discretion of the operator: any CE marked device intended for 
the purpose of LV unloading during high-risk PCI may be used.  Device placement should be 
performed prior to the start of the PCI and used according to the manufacturer’s instructions.  Femoral 
arterial access is preferred, but alternative routes of access (e.g. axillary, transcaval may be utilised 
where local expertise permits).  Use of ultrasound and/or fluoroscopy to guide femoral arterial 
puncture is mandated; the micro puncture technique is strongly advised where expertise permits.  
Device position should be documented fluoroscopically and if required, by echocardiography during 
the procedure.  The maximal amount of haemodynamic support should be provided throughout the 
procedure. 
 
At the end of the PCI procedure device support should be weaned and an assessment made of 
suitability for removal. Where possible, the device should be removed on-table prior to transfer of the 
patient. Otherwise, weaning of the device in the recovery area is recommended. The method of 
vascular closure is at the discretion of the operator and vascular surgical/interventional radiology 
experts. If ongoing haemodynamic support is required, the patient should be transferred to a critical 
care environment for ongoing monitoring and management.  
 
Elective mechanical circulatory support is not permitted in the no-unloading arm, but may be used for 
bail-out following complications of the procedure (see 16.4 below) 
16.3 
Adjunctive therapy and devices 
PCI will be performed according to local protocols.  Measurement of LV end-diastolic pressure should 
be performed in all patients prior to PCI; right heart catheterisation for periprocedural haemodynamic 
monitoring may be used at the clinicians discretion.  Dual antiplatelet therapy should be given in all 
cases, with pre-loading, and the post-PCI duration based on the individuals bleeding risk and 
local/national guidelines.  Radial access is preferred for the PCI procedure.  Drug-eluting stents are 
recommended.  Intracoronary imaging (OCT or IVUS) is mandated for left mainstem PCI and strongly 
recommended for all other PCI procedures: a final intracoronary imaging acquisition following final 
balloon inflations is strongly recommended to assess the adequacy of PCI 
16.4 
Bailout 
In patients assigned to receive no LV unloading, bail-out use of mechanical circulatory support will be 
permitted only in specific circumstances; 
 
• 
Cardiogenic shock (persistent hypotension systolic blood pressure (SBP) <90mmHg for > 15 
minutes and signs of organ hypoperfusion without response to vasoactive drugs) 
• 
Profound hypotension (SBP <60mmHg) for > 3 minutes 
• 
Significant pulmonary oedema requiring high-flow oxygen therapy or refractory to initial 
medical management 
• 
Incomplete resolution of mechanical complication of PCI with persistently reduced angiographic 
flow and/or symptoms or signs of ischaemia 
• 
Cardiac arrest requiring CPR 
 
In such situations, the permitted mechanical circulatory support strategies will be IABP and/or veno-
arterial extracorporeal membrane oxygenation (VA-ECMO).  These events will be captured as pre-
specified secondary outcome events.  Crossover to pLVAD is not permitted and will be considered a 
protocol violation. 

 
 
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16.5 
Staged Procedures 
Where a second stage is required, this must be specified at the end of the first procedure and the 
second stage should be completed within the subsequent 6 weeks.  In patients assigned to LV-
unloading, use of an unloading device in the second stage is at the operator’s discretion.  In the no LV-
unloading arm, elective mechanical circulatory support is not permitted, unless the procedure is a re-
attempt following a prior failed PCI due to haemodynamic instability, in which case an IABP may be 
utilised. 
16.6 
Completeness of Revascularisation 
It is strongly recommended that PCI is considered and, if feasible, attempted on all significant coronary 
lesions in major proximal coronary vessels (or side branches >2.5mm in diameter) subtending viable 
myocardium. Lesion significance is defined as >70% diameter stenosis on angiography or for lesions 
between 50 and 70% diameter stenosis, when accompanied by demonstrable reversible ischaemia on 
invasive or non-invasive testing. Planned target lesions will need to be identified by the operator and 
recorded by the trial coordinator before the procedure.  
 
The coronary disease burden at baseline and the degree of final revascularisation will be 
characterised by the BCIS-1 JS and SYNTAX scores and revascularisation index (RI), where RI = (JSpre – 
JSpost)/JSpre. 
16.7 
Protocol adherence 
Every effort should be made to adhere to the assigned treatment strategy. 
 
In cases where, following randomisation to no LV-unloading, it is decided PCI cannot safely be 
performed without LV unloading (either due a change in clinical status or a failed attempt), 
consideration should be given to revascularisation with CABG; otherwise the patient should not 
undergo revascularisation. 
 
In cases where, following randomisation to LV-unloading, it is decided pLVAD insertion cannot safely 
be performed, PCI may be performed with an alternative MCS device or without device support. 
17. 
Coronary physiology substudy 
17.1 
Aim 
One of the proposed beneficial mechanisms of action for the pLVAD is to improve coronary flow and 
to potentially protect the coronary microvasculature during PCI. Post PCI physiology measurements 
have failed to show an improvement in flow with a pLVAD however, pre-PCI where autoregulation is 
likely to be disabled an improvement in flow may be seen but this is yet to be investigated. This 
substudy therefore aims to establish whether LV unloading with pLVAD leads to an improvement in 
coronary flow pre PCI and a greater improvement in coronary flow reserve from before to after PCI, 
than standard high-risk PCI without pLVAD.  The results of the substudy will give a deeper mechanistic 
understanding of how a pLVAD impacts on myocardial oxygen supply and therefore could potentially 
help explain the findings of the main CHIP-BCIS3 study.  
17.2 
Site selection 
Participation in the substudy is optional for trial sites participating in the main trial.  

 
 
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17.3 
Consent 
Patients approached to participate in the main trial at substudy sites will be invited to join the 
substudy. Participation in the substudy will be optional and patients may participate in the main trial 
without participating in the substudy.  
17.4 
Sample size 
We aim to recruit a minimum of 44 patients to detect a difference in post-PCI CFR of 0.5 (at a 
significance level of 5% and power of 90%) between the elective unloading and standard care 
groups. 
17.5 
Methods 
Measurements of coronary flow will be made pre- and post- PCI using a coronary pressure guidewire 
equipped with a temperature sensor (Abbot Pressurewire X), using standard clinical methods.  
In both groups transit time will be measured at rest and repeated with hyperaemia induced with 
intravenous adenosine.  
In the elective unloading group transit time will also be measured with the pLVAD active at maximal 
setting both before and after PCI. 
18. 
Medical Therapy 
It is recommended that all patients receive guideline directed medical therapy following the 
procedure.  Drug classes to be considered include: 
• 
Aspirin 
• 
P2Y12 inhibitor 
• 
High-potency statin 
• 
ACE inhibitor 
• 
Beta-blocker 
• 
Mineralocorticoid receptor antagonist 
• 
Anticoagulation where appropriate 
19. 
Data Collection and Follow-Up 
19.1 
Data handling 
Data will be collected via an electronic Case Report Form (eCRF), managed by Sealed Envelope Ltd. 
and hosted by Rackspace.  In accordance with GCP, the electronic data entry system will be validated 
and Working Practice Documents covering its use will be drafted and maintained. 
The eCRF will be accessed by users through a normal web browser (e.g. Internet Explorer).  Each user 
will have their own individual account and secure password.  Only personnel authorised by the LSHTM 
CTU will be granted access to the eCRF.  Centres will only be able to access data for participants 
recruited at their centre.  Direct access to the eCRF will be granted to authorised representatives from 
the Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections.  eCRFs should be completed within 2 weeks of each trial milestone where possible.  
Principal Investigators at each site have overall responsibility for the accuracy, completeness and 
legibility of the data entered onto the eCRF and associated reports. 
Trial participants will be identified by a unique trial specific number and/or code in any database.  
The name and any other identifying detail will not be included in any trial data electronic file.  Patient 
data will be kept confidential and managed in accordance with the Data Protection Act (2018), NHS 
Caldecott principles, the Research Governance Framework for Health and Social Care, and the 

 
 
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conditions of Research Ethics Committee Approval.  Personal patient data will be stored for a 
maximum of 8 years at the research sites. 
Data will be pseudonymised and will not contain any identifiable data, apart from NHS number which 
will be encrypted and stored separately from the other data.  This will be used to link patients to HES 
data through NHS England.  NHS numbers will be stored for up to 10 years following enrolment. 
19.2 
NHS England 
There will be two occurrences of data linkage with HES data through NHS England (formerly NHS 
Digital).  A list of trial IDs, date of randomisation, NHS numbers and dates of birth will be prepared 
and securely sent to NHS England.  In turn, NHS England will provide number of events of death, 
stroke, myocardial infarction and cardiovascular hospitalisation that occur between the date of 
randomisation and date the data linkage was run.  These data will be used to validate the main trial 
dataset and identify with high sensitivity any endpoints missed by traditional follow up methods. 
19.3 
Tests required for eligibility 
The following tests are required for identifying and screening patients.  These are all standard of care 
tests and must be performed before patient consent: 
• 
Demographics and medical history 
• 
Coronary angiogram 
• 
LVEF assessment 
19.3.1 Time limits for screening tests 
Eligibility criteria 
Test 
Time limit 
Extensive coronary disease 
Coronary angiogram 
Clinically valid 
Severe LV systolic dysfunction 
Echocardiogram, cardiac MRI 
1 year prior to randomisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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19.4 
Trial Checklist 
 
Tests required for 
eligibility 
Baseline 
Pre-PCI 
Peri-procedural 
Post-procedure (6   
hours) 
Post-procedure 
(24 hours) 
At discharge (up 
to 24 hours) post-
PCI
At 90 days post-
randomisation 
At 1-year post-
randomisation 
Yearly Follow-up 
End of trial follow-
up 
Clinical assessments (standard of care)  
Demographics and med. 
history 
X 
 
 
 
 
 
 
 
 
 
 
Coronary angio 
X 
 
 
 
 
 
 
 
 
 
 
LVEF assessment 
X 
 
 
 
 
 
 
 
 
 
 
Viability assessment 
 
X 
 
 
 
 
 
 
 
 
 
FBC 
X 
 
 
 
 
 
X 
 
 
 
 
Creatinine and electrolytes 
X 
 
X 
 
 
 
X 
 
 
 
 
HbA1C 
 
X 
 
 
 
 
 
 
 
 
 
Full lipid profile 
 
X 
 
 
 
 
 
 
 
 
 
Troponin T/I 
 
X 
X 
 
X 
X 
 
 
 
 
 
Haemodynamics 
 
 
 
X 
 
 
 
 
 
 
 
Procedural details including 
device insertion 
 
 
 
X 
 
 
 
 
 
 
 
Vasoactive medication 
 
 
 
X 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
X 
 
 
 
 
 
Intravascular imaging 
 
 
 
X 
 
 
 
 
 
 
 
Trial specific assessments 
LVEDP  
 
 
 
 
X 
 
 
 
 
 
 
 
BNP/NT-proBNP 
 
X 
 
 
 
 
 
 
 
 
 
NYHA/CCS 
 
X 
 
 
 
 
 
X 
X 
X 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
X 
X 
X 
X 
KCCQ 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Primary Endpoint 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Secondary Endpoints 
 
 
 
 
 
 
X 
X 
X 
X 
X 
SAEs 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Cardiac Medication 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 

 
 
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Baseline (up to 6 months prior to randomisation): 
• 
Coronary anatomy and planned PCI procedure 
• 
Viability study (If available) 
• 
Cross-sectional imaging of peripheral vasculature (If available) 
• 
LVEF 
• 
Full blood count 
• 
Creatinine and electrolytes 
• 
HbA1c 
• 
ECG 
• 
Troponin T or I 
• 
BNP/NT-proBNP 
• 
NYHA/CCS 
• 
EuroQoL EQ-5D-5L 
• 
KCCQ 
• 
Cardiac Medication 
 
Pre-PCI (within 24 hours of procedure): 
• 
Troponin T or I 
• 
Creatinine and electrolytes 
 
Peri-procedural 
• 
Haemodynamics 
• 
Procedural details including device insertion 
• 
Vasoactive medication 
• 
Intravascular imaging 
 
Post-procedure (6 hours after end of procedure) 
• 
Troponin T or I 
 
Post-procedure (24 hours after end of procedure if patient remains in hospital) 
• 
Troponin T or I 
• 
ECG 
 
At discharge – if PCI is staged please collect for each stage of the procedure: 
• 
Death 
• 
Stroke 
• 
MI 
• 
Cardiovascular Hospitalisation 
• 
Creatinine and electrolytes 
• 
Cardiac medication 
• 
SAE 
 
 
 

 
 
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90 days after randomisation (telephone follow-up, or in person if the participant is due to attend hospital for 
a clinical visit): 
• 
Death 
• 
Stroke 
• 
MI 
• 
Cardiovascular Hospitalisation 
• 
Major bleeding 
• 
Unplanned further revascularisation 
• 
NYHA/CCS 
• 
EuroQoL EQ-5D-5L 
• 
KCCQ 
• 
Cardiac medication 
• 
Acute Kidney Injury 
• 
SAE 
 
Yearly after randomisation (telephone follow-up, or in person if the participant is due to attend hospital for 
a clinical visit): 
• 
Death 
• 
Stroke 
• 
MI 
• 
Cardiovascular Hospitalisation 
• 
Major bleeding 
• 
Unplanned further revascularisation 
• 
NYHA/CCS 
• 
EuroQoL EQ-5D-5L 
• 
KCCQ 
• 
Cardiac medication 
• 
SAE 
 
End of trial follow-up (telephone follow-up, or in person if the participant is due to attend hospital for a 
clinical visit): 
• 
Death 
• 
Stroke 
• 
MI 
• 
Cardiovascular Hospitalisation 
• 
Major bleeding 
• 
Unplanned further revascularisation 
• 
NYHA/CCS 
• 
EuroQoL EQ-5D-5L 
• 
KCCQ 
• 
Cardiac medication 
• 
SAE 
 
19.5 
Definition of end of trial 
The end of trial is defined as the final lock of the trial database prior to unblinding and analysis.  
 

 
 
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19.6 
Adverse Events 
Expected adverse events (see section 7.4 for endpoint definitions) should be reported in the eCRF. An 
additional SAE form is not required.  
 
Unexpected adverse events (see section 8 for requirements) should be reported on the relevant SAE or 
NSAE forms and faxed/emailed to the CTU within 7 days of notification for SAE and 14 days of 
notification for NSAE. 
19.7 
Participant ID Log 
A list of all patients enrolled into the trial should be maintained by each centre, containing patient 
identification numbers, full names, dates of birth and dates of enrolment in the trial, which could be 
used for unambiguous identification of each patient if required. The patient’s enrolment in a trial must 
also be recorded in the patient’s medical record and the general practitioner notified accordingly. 
20. 
Health Economic Analysis 
The primary outcome for the cost-effectiveness analysis (CEA) will be incremental costs, quality-
adjusted life years (QALYs) and net monetary benefit at 12 months following randomisation. The CEA 
will take an NHS and personal social services perspective. Resource use data collected through trial 
CRFs and follow-up questionnaires will be combined with appropriate unit costs to report total costs. 
Health-related quality of life (HRQoL), assessed using the EuroQol EQ-5D-5L questionnaire, will be 
combined with survival data to report QALYs. Secondary outcomes for the cost-effectiveness analysis 
will include resource use, costs and QALYs at 90-days. 
 
The primary sources of the resource use data will be the eCRFs, and individual health service 
questionnaires (HSQs) on the use of personal health services administered to surviving patients at 
regular intervals. Resource use data from the index hospital stay will be taken from the eCRF. Use of 
hospital resources from readmissions since discharge from index hospital stay and use of resources in 
primary care and community health services will be assessed by HSQs. To minimise recall bias the HSQ 
will be administered at 90 days and 12 months following randomisation. Resource use data from the 
eCRFs and HSQs will be valued using unit costs from the NHS Payment by Results database and unit 
costs of health and social care (PSSRU) to report the total costs per patient at 90 days and 12 months 
for both randomised groups. Data on hospitalisations will be collected through NHS England, to 
minimise the effects of recall bias. HRQoL will be assessed at baseline, 90 days, yearly and end of 
trial follow-up using the EuroQol EQ-5D-5L questionnaire, with NICE recommended valuation set that 
maps EQ-5D-5L descriptive system data onto the EQ-5D-3L value set (Hernández Alava et al. 2017; 
Hernández Alava et al. 2020). HRQoL data will be combined with the survival data to report QALYs 
at 90 days and 12 months. Quality Added Life Years (QALY) will be calculated by valuing each 
patient’s survival time by their HRQoL at each time point according to the “area under the curve” 
approach. Baseline HRQoL and other baseline patient/site level variables will be adjusted for in 
estimating the adjusted effect of randomisation on incremental costs and QALYs.  The economic 
analysis will follow the intention-to-treat principle. Missing data in costs and EQ-5D score will be 
handled with multiple imputation, assuming the data are missing at random conditional on the observed 
data. Multiple imputation will be undertaken using the Multivariate Imputation using Chained Equations 
(MICE) algorithm, with the multiple imputation model including all baseline variables, resource use and 
outcome (costs and HRQoL) variables. The number of imputations will be determined according to level 
of missingness in the outcome variables. Multiple imputation model will follow the same structure as 
followed for the analysis model.  
 
The cost-effectiveness analysis will use Bivariate Seemingly Unrelated Regression model to allow for 
correlation between costs and QALYs and report the mean (95% confidence interval) incremental costs, 
and QALYs. We will also calculate the mean (95% confidence interval) net monetary benefits by 
valuing QALY gains at £20,000 per QALY and subtracting incremental costs. We will report the 

 
 
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probability that the intervention is cost-effective compared to current standard of care at different 
levels of willingness-to-pay for a QALY gain using the cost-effectiveness acceptability curves.  
 
The following sensitivity analyses will be performed to check the robustness of primary cost- 
effectiveness results at 12 months: 
 
(a) The costs and QALY could be highly skewed. Several distributions that can give a better fit of cost 
and QALY data will be considered. 
 
(b) The implications of potential double-counting of inpatient costs across the sources of resource data 
(eCRF and HSQ). 
 
 

 
 
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21. 
Version History Log 
 
Version Date Implemented 
Details of Key Changes 
1.0 
25/11/2020 
Not applicable 
1.2 
26/08/2022 
• 
Correction of trial flowchart to match protocol inclusion 
criteria 
• 
Change to membership and chair of the DMC 
• 
Change to membership of the TMG 
• 
Clarification of exclusion criteria to include current 
mechanical circulatory support 
• 
Clarification that prolongation of hospitalisation requires 
specific endpoint definitions to be met to be adjudicated 
as a primary endpoint. 
• 
Update to vascular complication secondary endpoint to 
align with VARC criteria 
• 
Change to protocol for bailout use of IABP or VA-ECMO 
when the patient has developed significant pulmonary 
oedema requiring high-flow oxygen therapy. 
• 
Coronary physiology substudy details added 
• 
Amendment to timing of post-PCI troponin and ECG testing 
• 
Amendment to criteria for determining wins on the basis of 
periprocedural MI 
• 
Corrections to typos and incorrect  
1.3 
22 May 2023 
• 
Added Participant Identification Centres (PICs) 
• 
Change to membership of the TSC 
• 
Clarification of inclusion criteria to include orbital 
atherectomy 
• 
Addition of yearly and end of trial follow-up 
• 
Change to post-PCI ECG testing 
• 
Update to trial checklist 
• 
Update to Health Economic Analysis 
1.4 
22 May 2024 
• 
Update to sample size from 250 to 300 participants 
• 
Update to trial flowchart to include orbital atherectomy 
• 
Update to membership of the Trial Management Group 
• 
Update to membership of the Clinical Events Committee  
• 
Update to Cardiovascular Hospitalisation definition to 
include virtual ward admission 
• 
Clarification that the planned 1-year feasibility review 
does not constitute a formal interim analysis 
• 
Update to organisation responsible for electronic health 
record data (now NHS England) 
• 
Addition of dates of birth to allow optimal data linkage 
via NHS England 
• 
Corrections to typographical errors 
 
 
 

 
 
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22. 
References 
 
1 
Townsend N, Bhatnagar P, Wilkins E, et al. Cardiovascular Disease Statistics, 2015. London: British 
Heart Foundation  2016.  
2 
Fox K, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional strategy in non-ST-
elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial. The 
Lancet 2005;366:914–20. doi:10.1016/S0140-6736(05)67222-4 
3 
Kirtane AJ, Doshi D, Leon MB, et al. Treatment of Higher-Risk Patients With an Indication for 
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4 
McAlister FA, Oreopoulos A, Norris CM, et al. Exploring the treatment-risk paradox in coronary 
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5 
Dixon SR, Henriques JPS, Mauri L, et al. A prospective feasibility trial investigating the use of the 
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Percutaneous insertion of a temporary heart pump for left ventricular haemodynamic support in 
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7 
Perera D, Stables R, Thomas M, et al. Elective intra-aortic balloon counterpulsation during high-
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doi:10.1001/jama.2010.1190 
8 
Health Quality Ontario. Percutaneous ventricular assist devices: a health technology assessment. 
Ont Health Technol Assess Ser 2017;17:1–97. 
9 
O'Neill WW, Kleiman NS, Moses J, et al. A prospective, randomized clinical trial of hemodynamic 
support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk 
percutaneous coronary intervention: the PROTECT II study. Circulation 2012;126:1717–27. 
doi:10.1161/CIRCULATIONAHA.112.098194 
10 
Perera D, Stables R, Clayton T, et al. Long-Term Mortality Data From the Balloon Pump–Assisted 
Coronary Intervention Study (BCIS-1). Circulation 2013;127:207–12. 
doi:10.1161/CIRCULATIONAHA.112.132209 
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Amin AP, Spertus JA, Curtis JP, et al. The Evolving Landscape of Impella® Use in the United States 
Among Patients Undergoing Percutaneous Coronary Intervention with Mechanical Circulatory 
Support. Circulation 2019;66:606–34. doi:10.1161/CIRCULATIONAHA.119.044007 
12 
Pocock SJ, Ariti CA, Collier TJ, et al. The win ratio: a new approach to the analysis of composite 
endpoints in clinical trials based on clinical priorities. European Heart Journal 2012;33:176–82. 
doi:10.1093/eurheartj/ehr352 
13 
Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with 
Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2018;379:1007–16. 
doi:10.1056/NEJMoa1805689 
14 
Claggett B, Pocock S, Wei LJ, et al. Comparison of Time-to-First Event and Recurrent-Event 
Methods in Randomized Clinical Trials. Circulation 2018;138:570–7. 
doi:10.1161/CIRCULATIONAHA.117.033065 

 
 
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15 
Ryan M, O’Gallagher K, Vetrugno V, et ak.  Does “real world” mechanical circulatory support 
match randomised clinical trials?  The United Kingdom Impella (UKpella) registry.  Heart 2020; 
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Appendix 1 – EQ-5D-5L 
 

 
 
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