Ankle Arterial Doppler Waveform Assessment For Surveillance Following Lower Limb Revascularisation
Conditions: Peripheral Arterial Disease
Sponsor: Imperial College London

 
                                          
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Ankle Arterial Doppler Waveform 
Assessment For Surveillance 
Following Lower Limb 
Revascularisation: WAVE study 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
    Protocol version: 4.0 
    Date: 01/03/2024 
 
MAIN SPONSOR: Imperial College London  
FUNDERS: Government of Saudi Arabia and NIHR Clinical Lectureship 
STUDY COORDINATION CENTRE: Department of Surgery and Cancer, Imperial College London, London 
Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London 
IRAS Project ID:  339909 
REC reference: 24SM8819 
 
Protocol authorised by: 
 
Name & Role 
 
Principal investigator: Pasha 
Normahani 
 
  
Date 
 
01/03/2024 
Signature 
 
 
 
 

 
                                          
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Study Management Group 
 
Chief Investigator: Pasha Normahani 
Principal Investigator: Pasha Normahani 
 
 
Co-investigators:  
Hamidah Alodayni 
Professor Alun H Davies 
Professor Usman Jaffer  
Professor Danilo Mandic 
Professor Athansiois Saratzis 
Mr Joseph Shalhoub 
Mr Adam Gwozdz  
 
Statistician:       
Mr Nicholas Johnson 
 
Study Management:       
 
Miss Sasha Smith 
Miss Sepideh Pushpas 
Miss Kelly Swagel 
Mr Carlos Pinho 
 
Study Coordination Centre  
 
For general queries, supply of study documentation, and collection of data, please 
contact: 
 
Study Coordinator: Hamidah Alodayni 
Address: 4N13, 4th Floor, Charing Cross Hospital, Charing Cross Campus 
Tel: 07587534716   
 
 
 
 
 
 
E-mail:  h.alodayni23@imperial.ac.uk 
 
 
 
 
 
 
 
 
Clinical Queries 
Clinical queries should be directed to Hamidah Alodayni, who will direct the query to 
the appropriate person 
 
 
 
 
 
 

 
                                          
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Revision summary 
 
Protocol 
version 
Date 
Revision summary 
V.1 
15/11/2023 
N/A – Original protocol 
V.2 
18/12/2023 
-Primary outcome measure clarifications 
-Further details on statistical analyses  
- Addition of co-investigators 
-Additional secondary objectives 
-Create the study flowchart 
V.3 
07/02/2023 
-Include sample size calculations 
-Addition of study statistician Mr Nicholas 
Johnson 
-Expanded on procedures and 
Assessments 
-Clarification of study visits 
V.4 
01/03/2024 
-Additional secondary objectives 
-Updated background section 
with additional literature 
-Updated study flowchart 
 
 
Sponsor 
Imperial College London the main research Sponsor for this study.  For further 
information regarding the sponsorship conditions, please contact the Head of 
Regulatory Compliance at: 
 
 
 
Research Governance and Integrity Team 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 1862 
Imperial College - Research Governance and Integrity Team (RGIT) Website 
 
This protocol describes the Ankle Arterial Doppler Waveform Assessment For 
Surveillance Following the Lower Limb Revascularisation study and provides 
information about procedures for entering participants.  Every care was taken in its 
drafting, but corrections or amendments may be necessary. These will be circulated 
to investigators in the study.  Problems relating to this study should be referred, in the 
first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Frame Work for Health 
and Social Care Research. It will be conducted in compliance with the protocol, the 
Data Protection Act and other regulatory requirements as appropriate.  

 
                                          
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Table of Contents 
1. 
INTRODUCTION ................................................................................................. 8 
1.1. 
Background ................................................................................................ 8 
1.2. 
Rationale for current study ......................................................................... 9 
2. 
STUDY OBJECTIVES ...................................................................................... 10 
2.1. 
Primary objective ..................................................................................... 10 
2.2. 
Secondary objectives ............................................................................... 10 
3. 
STUDY DESIGN AND SETTING ...................................................................... 11 
4. 
STUDY OUTCOME MEASURES ..................................................................... 11 
4.1. 
Primary outcome ...................................................................................... 11 
4.2. 
Secondary outcomes ............................................................................... 11 
5. 
PARTICIPANT ENTRY ..................................................................................... 12 
5.1. 
Inclusion criteria ....................................................................................... 12 
5.2. 
Exclusion criteria ...................................................................................... 12 
5.3. 
Withdrawal criteria ................................................................................... 12 
6. 
ADVERSE EVENTS ......................................................................................... 13 
6.1. 
Definitions ................................................................................................ 13 
6.2. 
Reporting procedures .............................................................................. 13 
7. 
INTERVENTION AND FOLLOW-UP ................................................................ 14 
7.1. 
Index test technique ................................................................................. 14 
7.2. 
Index test diagnostic criteria and analysis ................................................ 15 
7.3. 
Data collection ......................................................................................... 16 
7.5. 
Repeating index test ................................................................................ 16 
7.6. 
Reference test.......................................................................................... 16 
7.7. 
Repeating reference test .......................................................................... 16 
8. 
STATISTICS AND DATA ANALYSIS .............................................................. 17 
8.1. 
Sample size ............................................................................................. 17 
8.2. 
Statistical plan and data analysis ............................................................. 17 
8.3. 
Cost-effectiveness analysis ..................................................................... 18 
8.4. 
Machine learning...................................................................................... 18 
9. 
RECRUITMENT AND PARTICIPANT TIMELINE ............................................. 19 
9.1. 
Visit 0 (Pre-screening) ............................................................................. 19 
9.2. 
Routine visit 1(Planned clinical admission for revascularisation) ............. 19 
9.3. 
Routine visit 2,3,4 (3,6,12 months surveillance, respectively) .................. 20 
9.4. Blinding .......................................................................................................... 20 
10. 
REGULATORY ISSUES ................................................................................ 21 
10.1. 
Ethics approval ........................................................................................ 21 
10.2. 
Consent ................................................................................................... 21 
10.3. 
Confidentiality .......................................................................................... 21 
10.4. 
Indemnity ................................................................................................. 21 
10.5. 
Sponsor ................................................................................................... 21 
10.6. 
Funding .................................................................................................... 22 
10.7. 
Audits ....................................................................................................... 22 
11. 
STUDY MANAGEMENT ................................................................................ 22 
12. 
PUBLICATION POLICY ................................................................................. 22 
13. 
REFERENCES ............................................................................................... 23 

 
                                          
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14. 
APPENDICES ................................................................................................ 24 
Appendix 1. Participants visits schedule ............................................................... 24 
 

 
                                          
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TITLE 
STUDY SUMMARY 
 
Ankle Arterial Spectral Waveform Assessment For Surveillance Following Lower Limb Revascularisation 
DESIGN 
Single centre, prospective, observational, diagnostic accuracy study 
AIM 
 
OBJECTIVES 
To evaluate the feasibility and accuracy of using ankle arterial spectral waveform assessment for surveillance following lower 
limb revascularisation    
 
Primary objective 
The primary objective of this study is to determine the diagnostic performance of serial ankle visual arterial Doppler waveform 
assessment (using a handheld continuous-wave Doppler device) for the detection of significant arterial restenosis, as a 
method of post revascularisation surveillance, as determined by a full arterial lower limb Duplex Ultrasound (DUS).  
Secondary objectives 
• 
To determine the cost-effectiveness of serial visual handheld Doppler ankle waveform assessment over an 
appropriate time horizon of five years 
• 
To determine the diagnostic performance of serial visual focused ankle duplex ultrasound waveform assessment 
(visual waveform assessment using pulsed-wave Doppler) 
• 
To determine the cost-effectiveness of point of care duplex ultrasound waveform assessment over an appropriate 
time horizon of five years 
• 
To determine the diagnostic performance of serial visual waveform assessment using exploratory diagnostic 
thresholds  
• 
To evaluate the patient's acceptability of the test  
• 
To evaluate the effect of confounding patient characteristics (e.g., neuropathy and ulceration) on diagnostic 
performance  
• 
To evaluate the performance of the test for establishing the severity of stenosis 
• 
To evaluate inter- and intra-rater reliability of index tests and  evaluate inter- rater reliability of reference test 
• 
To determine the prognostic value of serial visual waveform assessment in predicting lower limb events (e.g. 
secondary revascularisation, wound healing, major lower limb amputation) 
• 
To evaluate the use of serial visual waveform assessment as a surrogate measure of technical revascaulrisation 
success  
• 
To evaluate the application of machine learning and signal processing methods to classify arterial waveforms 
 
OUTCOME MEASURES 
 
Primary outcome measure 
The primary outcome is the sensitivity of index tests as compared to the reference test of a full lower limb arterial 
DUS.  
Secondary outcome measures 
• 
Specificity, likelihood ratios, predictive values and diagnostic odds ratio.  
• 
Health economic outcomes: Cost of the test, quality-adjusted life and Incremental Cost-Effectiveness Ratio 
(ICER) at five years 
• 
Patient acceptability of index tests (Likert scale) 
• 
Inter- and intra-rater reliability of index tests  and inter-rater reliability of reference test 
• 
To establish optimal visual waveform criteria for the diagnosis of restenosis   
ELIGIBILITY 
Inclusion 
• 
≥18 years or older (no upper age limit) 
• 
Diagnosis of peripheral arterial disease based on duplex ultrasound, CTA, MRA or intra-arterial digital subtraction 
angiography  
• 
Patients presenting with symptomatic peripheral arterial disease (short distance claudication or chronic limb-
threatening ischaemia) who are planned to undergo primary lower limb arterial revascularisation  
• 
Patients presenting to vascular services (inpatient or outpatient settings) 
Exclusion 
• 
Patients undergoing primary major lower limb amputation  
• 
Patients with no revascaulrisation option 
• 
Patients with total distal ankle vessel (posterior tibial artery,PTA; anterior tibial artery, ATA; peroneal artery, PA) 
occlusion precluding ankle waveform assessment 
• 
Patients with acute lower limb ischemia 
• 
 
DURATION             24 months: 12 months recruitment and 12 months follow up.  
 

 
                                          
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                Reference diagram

 
                                          
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1. INTRODUCTION  
1.1. Background 
Peripheral Artery Disease (PAD) represents a prevalent global health issue, 
particularly among the ageing population. Roughly one in five individuals aged 60 and 
above in the UK is estimated to be affected by PAD, with this demographic facing a 2 
to 4 times higher risk of myocardial infarction, stroke, and coronary artery disease(1).  
Peripheral Artery Disease (PAD) in the lower extremities is a prevalent manifestation 
of systemic atherosclerosis. It could manifest as claudication, rest pain, and/or 
gangrene(2). PAD can significantly impact an individual's quality of life, particularly due 
to symptoms like limb claudication. This can limit mobility and daily activities. Detecting 
Peripheral Artery Disease (PAD) at an early stage facilitates the initiation of treatment 
and the adjustment of risk factors, thereby reducing the cardiovascular disease risks 
associated with the condition(3). In addition, it empowers healthcare providers to 
monitor PAD progression and conduct regular follow-up appointments for continuous 
management and preventive actions(4). 
Treatment for Peripheral Artery Disease (PAD) involves a comprehensive approach to 
address symptoms and minimise cardiovascular risks. Crucial interventions such as 
revascularisation procedures, encompassing angioplasty and bypass surgery, have 
become pivotal in reinstating blood flow and alleviating symptoms among individuals 
suffering from lower limb PAD(3). Individualised treatment plans necessitate 
collaboration with healthcare professionals to ensure comprehensive and 
personalised care. 
Surveillance post-revascularization refers to the ongoing monitoring and assessment 
of individuals who have undergone a revascularisation procedure to treat Peripheral 
Artery Disease (PAD) or other vascular conditions. The main objective of follow-up is 
to identify clinically important issues before clinical signs and symptoms become 
apparent, at an early stage when they can be managed most safely and effectively. 
This is essential for evaluating the effectiveness of the intervention, detecting potential 
complications such as restenosis, and ensuring long-term vascular health(5).  
Routine clinical assessments, encompassing physical examinations and ankle-
brachial index measurements, are commonly utilised to assess disease progression. 
Non-invasive imaging modalities like Doppler ultrasound or magnetic resonance 
angiography are mostly employed to visualise blood flow and identify any arterial 
blockages or irregularities(4). Additionally, despite these different surveillance 
strategies, rates of lower limb amputation , morbidity , mortality following lower limb 
revascularisation remain similar(6,7). The frequency and duration of post-
revascularization surveillance depend on various factors, including the type of 
intervention, the severity of the disease, and the individual patient's risk profile(8). The 
optimal follow-up strategy for individual patients should strive to reduce, potential risks, 
associated costs, and any interference with the patient's daily life. However, the 

 
                                          
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optimal form and frequency of structured follow-up programmes have remained 
controversial, mostly due to a lack of definitive evidence(9). 
1.2. Rationale for current study 
Non-invasive approaches are the most favoured diagnostic and monitoring methods 
for Peripheral Artery Disease (PAD)(5). Individuals presenting with a medical history 
and physical examination consistent with PAD undergo initial assessment using 
arterial Duplex ultrasonography (DUS). DUS is advantageous as it doesn't involve 
contrast or radiation exposure and generates portable and reproducible images. DUS 
offers two-dimensional structural images to assess for visual arterial stenosis and 
haemodynamic information from Doppler signals(9). These signals are analysed 
through spectrum analysis and colour flow velocity mapping. Spectrum analysis 
involves quantitative and qualitative interpretation of the visual arterial spectral 
waveform. It precisely identifies the location and severity of arterial stenosis along the 
lower limb, distinguishing between different grades of stenosis and occlusion(5). DUS 
offers essential anatomic and hemodynamic information vital for strategic 
revascularisation planning. Moreover, DUS serves as a valuable tool for post-
procedural surveillance, including cases involving angioplasty, stent placement, and 
bypass grafting. 
Full lower limb DUS for surveillance following lower limb revascularisation is 
technically challenging and must be carried out in specialised vascular 
departments(10). It is therefore costly to perform and unwell-liked by patients, resulting 
in high dropout rates(11). Previous studies have demonstrated that a focused 
assessment of the visual arterial waveform at the ankle is highly accurate and cost-
effective for the diagnosis of PAD(12). Changes in the quality of blood flow at the ankle 
reflect upstream steno-occlusive arterial disease.  However, this technique has not 
been yet evaluated for the purpose of surveillance following lower limb 
revascularisation. If serial assessment of visual ankle arterial waveforms was accurate, 
it could potentially allow for cheaper, more regular surveillance outside of the hospital 
setting.  
The primary aim of this study is to determine the diagnostic performance of serial 
visual handheld Doppler ankle waveform assessment for the detection of significant 
arterial stenoses as a method of post-revascularisation surveillance, as determined by 
a full arterial lower limb Duplex Ultrasound. 
 
 
 
 
 
 
 
 

 
                                          
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2. STUDY OBJECTIVES 
 
2.1. Primary objective 
The primary objective of this study is to determine the diagnostic performance of 
serial ankle visual arterial Doppler waveform assessment (using a handheld 
continuous-wave Doppler and pulsed-wave Doppler device) for the detection of 
significant arterial restenosis as a method of post-revascularisation surveillance, 
as determined by a full arterial lower limb Duplex Ultrasound (DUS). 
 
2.2. Secondary objectives 
• To determine the cost-effectiveness of serial visual handheld Doppler 
ankle waveform assessment over an appropriate time horizon of five 
years. 
• To determine the diagnostic performance of serial visual focused ankle 
duplex ultrasound waveform assessment (visual waveform assessment 
using pulsed-wave Doppler). 
• To determine the cost-effectiveness of point-of-care duplex ultrasound 
waveform assessment over an appropriate time horizon of five years. 
• To determine the diagnostic performance of serial visual waveform 
assessment using exploratory diagnostic thresholds.  
• To evaluate the patient's acceptability of the test. 
• To evaluate the effect of confounding patient characteristics (e.g., 
neuropathy and ulceration) on diagnostic performance. 
• To evaluate the performance of the test for establishing the severity of 
stenosis. 
• To evaluate inter- and intra-rater reliability of index test tests. 
• To evaluate inter-rater reliability of reference test  
• To determine the prognostic value of serial visual waveform 
assessment in predicting lower limb events (e.g. secondary 
revascularisation, wound healing, major lower limb amputation). 
• To evaluate the use of serial visual waveform assessment as a 
surrogate measure of technical revascularisation success.  
• To evaluate the application of machine learning and signal processing 
methods to classify arterial waveforms. 
 
 
 
 
 
 

 
                                          
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3. STUDY DESIGN AND SETTING  
 
▪ Prospective observational study of hospitalised and non-hospitalised 
patients with peripheral arterial disease post-revascularisation.  
▪ The study aims to recruit 121 individuals.  
▪ The study will run for 24 months. 
▪ 
This study is open to all patients (Outpatient and Inpatient settings) at 
NHS Trust, meeting specific inclusion and exclusion criteria.  
 
4. STUDY OUTCOME MEASURES  
 
4.1. Primary outcome 
The primary outcome is the sensitivity of index tests compared to the 
reference test of a full lower limb arterial DUS. 
4.2. Secondary outcomes 
• Specificity, likelihood ratios, predictive values and diagnostic odds ratio.  
• Health economic outcomes: Cost of the test, quality-adjusted life and 
Incremental Cost-Effectiveness Ratio (ICER) at five years 
• Patient acceptability of index tests (Likert scale) 
• Inter- and intra-rater reliability of index tests 
• inter-rater reliability of the reference test 
• To establish optimal visual waveform criteria for the diagnosis of restenosis   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                                          
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5. PARTICIPANT ENTRY  
 
5.1. Inclusion criteria  
• ≥18 years or older (no upper age limit) 
• Diagnosis of peripheral arterial disease based on duplex ultrasound, CTA, 
MRA or intra-arterial digital subtraction angiography.  
• Patients presenting with symptomatic peripheral arterial disease (short 
distance claudication or chronic limb-threatening ischaemia) who are planned 
to undergo primary lower limb arterial revascularisation. 
• Patients presenting to vascular services (inpatient or outpatient settings). 
5.2. Exclusion criteria  
• Patients undergoing primary major lower limb amputation.  
• Patients with no revascaulrisation option. 
• Patients with total distal ankle vessel (posterior tibial artery, PTA; anterior 
tibial artery, ATA; peroneal artery, PA) occlusion precluding ankle waveform 
assessment. 
• Patients with acute lower limb ischemia. 
 
5.3. Withdrawal criteria 
Upon enrolment, the clinical trial site will make diligent efforts to maintain 
communication with participants throughout the 24-month study duration. 
Participants will be provided with a study helpline to address any concerns. 
However, an anticipated 15% of participants may be lost to follow-up. Participants 
retain the freedom to withdraw from any aspect of the study without impacting their 
regular medical care. 
 
TheChief Investigator (CI) has the authority to withdraw participants from the study to 
safeguard their safety or if participants are unwilling to adhere to the protocol. In the 
event of withdrawal or discontinuation, all participants will be considered off the study 
tests but on study and will continue to be monitored until the study concludes (24 
months), unless they explicitly withdraw consent for further follow-up. Any changes in 
their status and the study procedures or assessments from which they have 
withdrawn will be documented in the Case Report Form (CRF)/electronic CRF and, if 
provided by the participant, in their medical records. 
 

 
                                          
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6. ADVERSE EVENTS  
6.1. Definitions  
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward medical occurrence or effect that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
 
• 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
 
6.2. Reporting procedures  
All adverse events should be reported. Depending on the nature of the event the reporting 
procedures below should be followed. Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded  
 
5.3.2 Serious AEs 
An SAE form should be completed and emailed to the principal Investigator within 24 hours.  
However, relapse and death and hospitalisations for elective treatment of a pre-existing 
condition do not need reporting as SAEs. 
 
All SAEs should be reported to the < name of REC>where in the opinion of the Chief 
Investigator, the event was: 
• 
‘related’, ie resulted from the administration of any of the research procedures; 
and 
• 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all related and unexpected SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 

 
                                          
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Contact details for reporting SAEs 
RGIT@imperial.ac.uk 
Please send SAE forms to: Pasha Normahani 
Tel: 07983402262 (Mon to Fri 09.00 – 17.00) 
E-mail: p.normahani@imperial.ac.uk 
 
7. INTERVENTION AND FOLLOW-UP  
 
7.1. Index test technique  
Visual ankle arterial waveform assessment will be performed by the researcher (who 
is a trained vascular scientist) or clinical vascular scientist assessing the patient as 
part of their routine clinical assessment. Visual ankle arterial waveform assessment 
(index test) will be conducted using two different methods: with a handheld 
continuous-wave Doppler device (CWD) and using Duplex ultrasound pulsed-wave 
Doppler (PWD)  (Figure 1).  
 
 
 
 
 
 
 
 
 
 
 
 
                                                  
 
 
 
The test will be performed in one or both lower limbs, depending on whether the 
patient has undergone unilateral or bilateral revascularisation. The anterior tibial, 
posterior tibial, and peroneal arteries will be interrogated at the ankle using a 
standard technique. Before the procedure, the patient is typically positioned in a 
supine position with the ankle to be examined exposed and rested for at least 10 
minutes prior to the test. The examination will be conducted in a standard room 
temperature between 20°C to 22°C to avoid the influence of temperature on 
peripheral vessels. 
 
Figure 1.Illustration for the ankle doppler 
waveforms test devices. Left: Ultrasound 
Machine probe (PWD). Right : the handheld 
doppler device (CWD). 

 
                                          
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The procedure involves applying ultrasound gel to the ankle, followed by the 
placement of a Doppler ultrasound (PWD) or handheld (CWD) probe over specific 
locations on the ankle to assess blood flow in the arteries. For the handheld Doppler, 
the probe will be placed at a 45° angle to the ankle vessels, and the vascular 
scientist may make adjustments to the position of the probe to optimise the clarity of 
the continuous Doppler signals. Then, the visual and audio signals will be generated 
and optimised by the device algorithms. 
 
When using Doppler ultrasound, arterial spectral waveforms will be sampled from 
each vessel's centre using a Doppler angle of <60°. Waveforms will be optimised for 
interpretation by adjusting sample volume, sample size, Doppler scale, Doppler gain, 
and wall thump filter settings. The entire scanning process usually takes 
approximately 10 to 15 minutes for both tests. 
. 
 
7.2. Index test diagnostic criteria and analysis  
 
By comparing Doppler waveforms recorded at different time intervals, changes that 
indicate restenosis can be detected , such as changes in waveform morphology or 
velocity. The patterns and properties of the Doppler waves produced during the tests 
will be analysed. Doppler waveforms will be analysed according to their auditory 
and/or visual characteristics, which undergo alterations in the presence of stenosis. 
In analyses of audio signals, non-pathological Doppler waveforms will be regarded 
as multi-phasic, encompassing both bi-phasic (two) and tri-phasic (three) sounds 
Conversely, a monophasic waveform, representing a single sound, will be 
considered pathological, indicating the potential presence stenosis. During the visual 
analysis of Doppler waveforms, non-pathological waveforms will continue to exhibit a 
distinct shape indicative of high resistance and diastolic flow reversal, falling into the 
category of multiphasic (bi or tri-phasic). Conversely, pathological waveforms are 
expected to display low resistance, slow systolic acceleration, and the absence of 
diastolic flow reversal, classifying them as monophasic. 
 
 
 
 
 
 
 
 
 
 
 
 

 
                                          
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7.3. Data collection 
 
Visual waveform signals will be collected and saved on a Micro SD card from the 
handheld Doppler device. For visual waveforms obtained by the Duplex ultrasound 
machine, screenshot images of the visual waveform output will be collected and 
saved, or the data will be saved directly to external media, such as USB drives or SD 
memory cards. Then, data will be collected on portable storage devices and promptly 
will be transferred to more secure storage systems after each session.To allow for 
the collection of the Doppler audio signal, which will be used in later phases of this 
research, the handheld Doppler device will be connected to a computer  device 
using a rig set-up that converts the stereo output to digital audio  
 
7.4. Incidental findings 
Incidental findings may potentially be identified during study assessments for 
example, lesions detected on ultrasound exam. These will be reported to the local 
clinical team and the GP. 
7.5. Repeating index test 
To assess both inter- and intra-observer reliability, the index test will be repeated on 
the same day by the same operator as well as by different operators. This will be 
performed across 50 episodes or visits involving volunteer patients during the three 
follow-up visits (visits 2, 3, and 4). We anticipate that this additional procedure will 
extend the duration of each episode by approximately 30 minutes. 
7.6. Reference test 
Patients will undergo a full departmental arterial DUS at their respective hospitals on 
the same day as the index tests by one vascular scientist. The study will assess the 
inter-observer reliability of the reference test by having it repeated by different vascular 
scientists. This reference scan is part of the standard care they will receive as part of 
follow up program following lower limb revascaularisation present in each clinic. All 
lower limb arterial segments (Iliac, femoral, popliteal and tibial) will be assessed using 
a combination of B-mode, Colour Doppler and Spectral Doppler ultrasound in 
transverse and longitudinal planes. Peak Systolic Velocity (PSV) will be selectively 
sampled throughout the segments and at areas of suspected stenosis. Peak systolic 
velocity ratio (PSVR) will be calculated as the ratio of PSV at the site of stenosis to 
where the lowest pre- or post-stenotic PSV value will be measured. All reference scans 
will be performed using departmental duplex ultrasound machines. 
7.7. Repeating reference test 
 
In addition to the index test, the reference test will be repeated on the same day by a 
different operator to assess inter-rater reliability. This will be performed during the 
three follow-up visits (visits 2, 3, and 4) in 50 episodes or visits with some 

 
                                          
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volunteering patients. We anticipate that this will extend the usual procedure by 
approximately 30 minutes. 
8. STATISTICS AND DATA ANALYSIS 
 
8.1. Sample size 
The calculations considered a 95% confidence level (equivalent to a 5% margin of 
error), an assumed restenosis rate of 44.05%, and an anticipated sensitivity of 90% 
for the visual Doppler waveform assessment (index test) based on our prior 
investigations. The determined sample size was calculated to be 314. Accounting for 
an expected attrition rate of 15% derived from previous research(12), the target 
recruitment for this study is set at 362 episodes or visits.  
However, as we treat the three surveillance periods as independent episodes (patients 
with diagnosed restenosis will go on to have treatment), and given that each recruited 
patient will have three episodes or visits of surveillance during the follow-up, the actual 
number of participants who will need to be recruited is 121 patients. 
 
8.2. Statistical plan and data analysis 
 
Any missing data will be appropriately justified, documented, and excluded from the 
analysis. The results of the index test will be cross-tabulated with those of the 
reference test. Uncertainty will be measured by calculating 95% confidence intervals 
using R package ‘epiR’. Sensitivity, specificity, negative predictive value (NPV), 
positive predictive value (PPV), positive likelihood ratio (PLR), and negative likelihood 
ratio (NLR) will be computed for different cut-off values of the index test. 
  
Comparison of diagnostic performance between the index tests and the reference test 
will be conducted using the 'DTComPair' R package. Sensitivity will be compared 
between the index test and the reference test through the application of McNemar and 
exact Binomial tests. Likelihood ratios will be compared between the index test and 
the reference test using a regression model approach. 
 
The Cohen’s Kappa test will be employed to evaluate the agreement between the two 
approaches of index test and the reference test. The interpretation of Kappa values 
will be as follows: K values in the range of 0.21-0.40 will indicate fair agreement, K 
values in the range of 0.41-0.60 will signify moderate agreement, K values in the range 
of 0.61-0.80 will represent substantial agreement, and K values in the range of 0.81-
1.00 will suggest almost perfect agreement. 
 
The potential impact of confounding patient characteristics (such as age, gender, 
intervention procedure and minor amputation history) on the performance of the index 
test will be evaluated using a logistic regression approach. This method involves a 

 
                                          
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modified formulation of logistic regression that facilitates the computation of likelihood 
ratios for the index test, considering selected covariates. The technique entails 
estimating logistic regression models for both the prior and posterior odds of disease. 
The model for prior odds is based on patient characteristics, while the model for 
posterior odds incorporates the diagnostic test under consideration. 
Data and all appropriate documentation will be stored for a minimum of 10 years 
after the completion of the study, including the follow-up period.   
 
 
 
8.3. Cost-effectiveness analysis  
 
A discrete-time state-transition (Markov) model will be employed in the study to 
compare the health service costs and quality-adjusted life years (QALY) associated 
with different index tests methods. The objective is to determine which method 
offered the greatest mean net benefit. The construction of the model will be involved 
extensive discussions among an interdisciplinary team of health economists and 
clinicians. The decision model have a time horizon of 5 years, with costs and QALYs 
discounted at a rate of 3.5% per year. The reference price-year is 2022/23, and the 
perspective adopted is that of the United Kingdom (UK) National Institute for Health 
and Care Excellence (NICE) and Personal and Social Services. The study adheres 
to the reporting standards outlined in the Consolidated Health Economic Evaluation 
Reporting Standards. 
 
8.4. Machine learning   
 
Following the completion of the primary study, we will evaluate whether arterial 
waveform signals can be automatically classified using the application of signal 
processing and machine learning methodologies. Index test signals will be labelled 
using the results of the reference test and different machine learning methodologies 
deployed and compared for accuracy of classification.   
 
 
 
 
 
 
 
 
 
 
 

 
                                          
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9. RECRUITMENT AND PARTICIPANT TIMELINE  
Recruitment will be primarily from vascular outpatient clinics as well as inpatient 
wards.  We estimate that the study will be completed within 24 months of 
commencement where one year for recruitment and one year follow up. To recruit  
121 patients evenly across 12 months, aiming for approximately 10 patients per 
month. The end of the study is defined as the last recruited patient completing the 
follow-up at 12 months. 
 
9.1. Visit 0 (Pre-screening) 
 
Adults with PAD will be pre-screened at least 74 hours prior to their routine (visit 1A) 
by a member of the direct care team. If eligible for recruitment and willing to speak to 
a research nurse. If the patient is willing, the study will be explained. If the patient 
gives verbal consent to receiving study information material, these will be provided 
on visit 1A, which coincides with a routine/planned visit. They will be told that if they 
agree to partake in the study and that if they choose not to participate, this will not 
affect their usual clinical care. 
 
9.2. Routine visit 1(Planned clinical admission for revascularisation) 
Patients undergoing lower limb revascularisation may be admitted for a day-case 
procedure (most endovascular procedures) or longer inpatient admission (all open 
surgical procedures). All patients will have study assessments prior to (visit 1A) and 
shortly after their procedure (visit 1B). This is to assess for immediate changes in the 
arterial waveform following revascularisation. Additionally, for those who are planned 
day cases, a baseline waveform will be established for later study visits so that serial 
waveform comparisons can be made. Patients who are planned for a longer 
admission will also have a later assessment (visit 1C) prior to discharge. This is 
because they may undergo further revascularisation procedures, resulting in further 
changes to the arterial waveform.  
 
Visit 1-A 
 
On visit 1A, informed consent will be obtained before the participant undergoes 
revascularisation procedures. Following this, demographic data will be collected, and 
then clinical assessment such as medical, intervention and drug history will be 
obtained as well as in the next routine visits. Then, patients will undergo the index 
tests (visual waveform assessment using continuous-wave handheld Doppler and 
pulsed-waved Doppler focused DUS). The visit schedule is summarised in a table 
(Appendix 1).   
 
 
 
 

 
                                          
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Visit 1-B 
Following the revascularisation, patients will be expected to have their index test in 
both approaches after several hours. 
 
 
 
Visit 1-C 
Prior to hospital discharge, patients will undergo the index test in both approaches. 
This criterion is applicable exclusively to patients undergoing non-day case 
procedures, who will be discharged subsequent to a period of several days.  
 
9.3. Routine visit 2,3,4 (3,6,12 months surveillance, respectively) 
Patients will be followed up at 3, 6 and 12 months as per standard national and local 
policies. At these visits, they will undergo routine surveillance with a full lower limb 
DUS performed by a clinical vascular scientist, as per current practice. In addition, 
they will undergo the index tests on the same day. We expect that this will add an 
additional 15 minutes to the usual episode. In 50 episodes or visits , some 
volunteering patients will undergo repeated index tests and reference test to assess 
the tests reliability. 
 
 
9.4. Blinding 
The researcher or the vascular scientists who performing the index tests will be 
blinded to the results of the reference test. Additionally, the vascular scientist 
performing the reference test will be blinded to the results of the index test. In 
addition, the independent findings of the researcher, vascular scientist and clinician 
including history, examination and referenced Duplex ultrasound test will be kept 
blinded from one another. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                                          
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10. REGULATORY ISSUES  
 
10.1. Ethics approval  
The Study Coordination Centre has obtained approval from the Head of the 
department and Research Ethics Committee (REC) and Health Research Authority 
(HRA). The study must also receive confirmation of capacity and capability from each 
participating NHS Trust before accepting participants into the study or any research 
activity is carried out. The study will be conducted in accordance with the 
recommendations for physicians involved in research on human subjects adopted by 
the 18th World Medical Assembly, Helsinki 1964 and later revisions. 
 
10.2. Consent   
Consent to enter the study must be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration. Signed participant consent should be obtained. The right of the 
participant to refuse to participate without giving reasons must be respected.  After the 
participant has entered the study, the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the 
participant’s best interest, but the reasons for doing so should be recorded.  In these 
cases, the participants remain within the study for the purposes of follow-up and data 
analysis.  All participants are free to withdraw from the protocol treatment at any time 
without giving reasons or prejudicing further treatment. 
 
10.3. Confidentiality  
The Chief Investigator will preserve the confidentiality of participants taking part in the 
study and is registered under the Data Protection Act. Data will be pseudonymised  
Data will not be transferred to a third party. 
 
10.4. Indemnity 
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study 
 
10.5. Sponsor  
Imperial College London will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.Travel 
expenses for study visits will be reimbursed as required.Individual researchers do not 
receive any personal payment beyond their normal salary or other benefits for 
participating in this research. This policy helps maintain the integrity of the research 

 
                                          
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by avoiding potential conflicts of interest that could arise from financial incentives for 
researchers. 
 
10.6. Funding  
Hamidah Alodayni is funded by the Government of  Saudi Arabia (Royal Embassy of 
Saudi Arabia in London). Pasha Normahani is funded by an NIHR Clinical 
Lectureship. Infrastructure support for this research was provided by the NIHR 
Imperial Biomedical Research Centre (BRC). The funders play no role in shaping the 
study's design and are not involved in any aspect of data collection, data analysis, or 
the formulation of the study protocol and manuscript.  
 
10.7. Audits   
The study may be subject to audit by Imperial College London under their remit as 
sponsor and other regulatory bodies to ensure adherence to GCP and the UK Policy 
Frame Work for Health and Social Care Research.  
11. STUDY MANAGEMENT  
 
The day-to-day management of the study will be co-ordinated through Hamidah 
Alodayni.   
12. PUBLICATION POLICY  
 
All publications and presentations relating to the study will be authorised by the CI. 
Terms of authorship will be agreed with all contributors. Authorship of parallel studies 
initiated will be according to the individuals involved in the project but must 
acknowledge the contribution of the study. The study will be published in a peer 
reviewed journal, and available from the researchers on request. We also intend to 
create an internal report for IC, summarizing the methodology, results, and 
implications of the study for internal use and reference. A lay summary of the results 
will be provided to participants. 
 
 
 
 
 
 
 

 
                                          
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13. REFERENCES  
 
1. R. BJ, R. AE, P. B, D. PA, J. BM, S. BRW, et al. A Best Practice Clinical Care Pathway for 
Peripheral Arterial Disease. J Vasc Soc Gt Br Irel [Internet]. 2022;1. Available from: 
http://doi.org/10.54522/jvsgbi.2022.017 
2. Venermo M, Sprynger M, Desormais I, Björck M, Brodmann M, Cohnert T, et al. Follow-up of 
patients after revascularisation for peripheral arterial diseases: a consensus document from the 
European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the 
European Society for Vascular Surgery. European Journal of Preventive Cardiology. 2019 Dec 
1;26:1971–84. 
3. Sobieszczyk P, Eisenhauer A. Management of patients after endovascular interventions for 
peripheral artery disease. Circulation. 2013 Aug 13;128:749–57. 
4. Aboyans V, Ricco JB, Bartelink MLEL, Björck M, Brodmann M, Cohnert T, et al. Editor’s Choice – 
2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in 
collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg. 
2018;55(3):305–68. 
5. Zierler RE, Jordan WD, Lal BK, Mussa F, Leers S, Fulton J, et al. The Society for Vascular Surgery 
practice guidelines on follow-up after vascular surgery arterial procedures. J Vasc Surg. 
2018;68(1):256–84. 
6. Sarpe AK, Flumignan CD, Nakano LC, Trevisani VF, Lopes RD, Neto HJG, et al. Duplex ultrasound 
for surveillance of lower limb revascularisation. Cochrane Database Syst Rev. 2021;(1). 
7. Davies AH, Hawdon AJ, Sydes MR, Thompson SG, Participants V. Is Duplex Surveillance of Value 
After Leg Vein Bypass Grafting? Circulation. 2005;112(13):1985–91. 
8. Eid MA, Mehta KS, Goodney PP. Epidemiology of peripheral artery disease. Semin Vasc Surg. 
2021;34(1):38–46. 
9. Olin JW, Sealove BA. Peripheral artery disease: Current insight into the disease and its diagnosis 
and management. In Elsevier Ltd; 2010. p. 678–92. 
10. Hodgkiss-Harlow KD, Bandyk DF. Arterial Duplex Imaging of Lower-Extremity Arteries and 
Interventions. J Vasc Ultrasound. 2012;36(2):143–51. 
11. Venermo M, Sprynger M, Desormais I, Björck M, Brodmann M, Cohnert T, et al. Follow-up of 
patients after revascularisation for peripheral arterial diseases: a consensus document from the 
European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the 
European Society for Vascular Surgery. Eur J Prev Cardiol. 2019;26(18):1971–84. 
12. Normahani P, Poushpas S, Alaa M, Bravis V, Sounderajah V, Aslam M, et al. Diagnostic Accuracy 
of Point-of-care Tests Used to Detect Arterial Disease in Diabetes: TEsting for Arterial Disease in 
Diabetes (TrEAD) Study. Annals of Surgery. 2022 Nov 1;276:E605–12. 
  
 

 
                                          
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14. APPENDICES 
Appendix 1. Participants visits schedule  
 *Only relevant in the first consenting 50 (out of 362 total) visits. 
 
                      
PROCEDURES 
AND 
ASSESSMENTS 
VISIT 0 
PRESCREENING 
/ 
IDENTIFICATION 
ROUTINE VISIT 1 
                      REVASCULISATION DAY 
ROUTINE VISIT 2 
3 MONTHS 
SURVEILLANCE 
ROUTINE VISIT 3 
6 MONTHS 
SURVEILLANCE 
ROUTINE VISIT 4 
12 MONTHS 
SURVEILLANCE  
Visit 1-A 
(Before the 
procedure) 
Visit 1-B 
(within 
hours after 
procedure) 
Visit 1-C 
(Before hospital 
discharge, only  
for non-day 
case 
procedures) 
Pre-screening 
X 
Inclusion & exclusion criteria X 
Informed Consent 
  
 X 
Demographics 
  
X 
Index test with handheld 
doppler  
X 
X 
X 
 X 
 X 
  X 
Index test with Ultrasound 
machine 
X 
X 
X 
 X 
 X 
 X 
Repeat of index tests (same 
operator) 
 
 
X 
X 
X 
Repeat of index tests 
(different operator) * 
 
 
X 
X 
X 
Reference test DUS 
 
X 
X 
X 
Repeat of reference test 
DUS (same operator)* 
 
X 
X 
X