Diagnosis of Heart Failure in the Post-COVID-19 Clinic, Primary Care and Hospital Setting Using a Digital Stethoscope With Artificial Intelligence (AI) Electrocardiogram (ECG)
Conditions: Heart Failure
Sponsor: Imperial College London

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DUO-EF-19 
 
 
 
 
Diagnosis of Heart Failure in the Post-COVID-19 Clinic, Primary Care 
and Hospital Setting Using a Digital Stethoscope with AI ECG  
 
 
 
v2.0 04/02/2021 
 
 
 
 
MAIN SPONSOR: Imperial College London 
FUNDERS: NIHR - Artificial Intelligence in Health & Social Care Award 
STUDY COORDINATION CENTRE: Connected Care Bureau, 4th Floor ICTEM Building, 
Hammersmith Hospital , London, W12 0HS 
 
IRAS Project ID: 285417 
REC reference: pending 
NCT number: NCT04601415 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol authorised by: 
 
Name & Role 
Signature 
Date 
Professor Nicholas Peters 
 
 
07/10/2020 
Dr Carla Plymen 
 
 
06/10/2020 
Dr Daniel Keene 
 
 
5.10.20 
Dr Alex Fragoyannis 
 
5.10.20 
Dr Patrik Bachtiger 
 
 
4.10.20 
 
 
Version Control 
 
 
Version Number 
Purpose/Change  
Author  
Date 
1.0 
First version 
Bachtiger et. al 
18/10/2020 
2.0 
Second version 
updating with REC 
feedback.  
Bachtiger et. al 
04/02/2021 
Study Management Group 

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Chief Investigator:       
Professor Nicholas Peters 
 
Co-investigators:       
Dr Carla Plymen, Dr Daniel Keene, Dr Patrik Bachtiger,  Dr Alex  
Fragoyannis 
 
Statistician:       
 
Dr Daniel Keene 
 
Study Management:     
Rhiannon Thomas (NHLI)  
 
 
Study Coordination Centre (may not be applicable) 
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Connected Care Bureau, ICTEM 4 TH Floor, NHLI, Hammersmith Hospital, London W12 0HS 
 
For general queries, supply of study documentation, and collection of data, please contact: 
Study Coordinator: Rhiannon Thomas      
Address:  NHLI, Hammersmith Hospital Registration:       
E-mail: rhiannon.thomas@imperial.ac.uk 
 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Patrik Bachtiger patrik.bachtiger@nhs.net who will direct 
the query to the appropriate person. 
 
 
Sponsor 
 
Imperial College London is the main research Sponsor for this study.  For further information 
regarding the sponsorship conditions, please contact the Head of Research Governance and 
Integrity 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 
https://www.imperial.ac.uk/research-and-innovation/research-office/research-governance-              
and-integrity/ 
 

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Funder 
 
Funding (£450,000) has been awarded from the 2020 NIHR Artificial Intelligence in Health and 
Care Award (AI award). Reference: AI_AWARD01849 
 
 
This protocol describes the DUO-EF-19 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 Framework 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                                                             Page No 
GLOSSARY OF ABBREVIATIONS 
6 
KEYWORDS 
6 
STUDY SUMMARY 
7 
1. INTRODUCTION 
12 
1.1 BACKGROUND 
12 
Heart Failure 
12 
Heart Failure and COVID-19 
13 
Eko DUO Digital Stethoscope with Artificial Intelligence Electrocardiogram (ECG) 
13 
Eko DUO Device Regulatory Approvals 
14 
2.  STUDY OBJECTIVES 
15 
PRIMARY OBJECTIVE: 
15 
Secondary Objectives: 
15 
3.  STUDY DESIGN & METHODS 
15 
Statistical Considerations 
15 
Sample Size 
16 
SAMPLE SIZE CALCULATION 
16 
Avoidance of bias for primary objective 
17 
Study Participant Population 
17 
Method for Single-Lead ECG Collection for DUO-EF 
18 
Data point collection: %LVEF echo, %LVEF cMRI, BNP 
19 
3.1 STUDY OUTCOME MEASURES 
20 
4. PARTICIPANT ENTRY 
20 
4.1 PRE-REGISTRATION EVALUATIONS 
20 
4.2 INCLUSION CRITERIA & EXCLUSION CRITERIA 
20 
4.4 WITHDRAWAL CRITERIA 
21 
5. ADVERSE EVENTS AND RISK 
21 
5.1 DEFINITIONS 
21 
5.3 REPORTING PROCEDURES 
22 
5.3.1 Non serious AEs 
22 
5.3.2 Serious AEs 
22 
6. ASSESSMENT AND FOLLOW-UP 
23 
8.1 ETHICS APPROVAL 
25 
8.2 CONSENT 
25 
8.3 CONFIDENTIALITY 
26 
8.4 INDEMNITY 
26 
8.5 SPONSOR 
26 
8.6 FUNDING 
26 

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8.7 AUDITS 
26 
9. STUDY MANAGEMENT 
26 
10. PUBLICATION POLICY 
27 
10. REFERENCES 
27 
 
GLOSSARY OF ABBREVIATIONS 
 
COVID-19 
coronavirus disease caused by SARS-CoV-2 
DUO-EF 
the prediction of ejection fraction above or below 40% 
based on the interpretation of a single-lead 
electrocardiogram using a machine learning algorithm 
ECG 
electrocardiogram 
LVEF 
left ventricular ejection fraction; the pumping function (in %) of 
the left ventricle of the heart, where >50% is normal 
(preserved); 40-49% is moderately reduced; and <40% is 
reduced 
Echo 
echocardiogram 
HF 
heart failure 
HFpEF 
heart failure with preserved ejection fraction (above 50%) 
HFmEF 
heart failure with moderately reduced ejection fraction 
(between 41 - 50%) 
HFrEF 
heart failure with reduced ejection fraction (below 40%) 
LVEF 
left ventricular ejection fraction 
cMRI 
cardiac magnetic resonance imaging 
 

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KEYWORDS 
- 
COVID-19 
- 
Heart failure 
- 
Ejection fraction 
- 
Machine learning 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SUMMARY 
 
TITLE 
DUO-EF-19: Diagnosis of Heart Failure in the Post-COVID-19 
Clinic, Primary Care and Hospital Setting Using a Digital 
Stethoscope with AI ECG 
  
DESIGN Prospective cross-sectional study       
 
AIMS 
 
 
 
 
 
 
 
Methods 
1. To validate detection of left ventricular ejection fraction (LVEF) above or 
below 40% using single-lead ECG interpreted by machine learning 
algorithm (DUO-EF) compared to gold-standard investigations for 
calculating LVEF (echocardiography [echo], and a subgroup in cardiac 
MRI [cMRI])  
2. To conduct a real-world evaluation of DUO-EF detection of LVEF above or 
below 40% in the primary care and COVID-19 follow up clinic setting; validated 
against subsequent gold standard investigations  
3. To evaluate the positive and negative-predictive value of DUO-EF at 24 months  
 
1. Head-to-head comparison of DUO-EF against gold standard investigation (echo 
and cMRI) for classifying LVEF<40%; in unselected patients attending for routine 
echocardiography (main study group) and cardiac MRI (subgroup) as part of their 
routine clinical care 
2. Point-of-care DUO-EF in patients where GP suspects new heart failure and 
comparison with: 
a. Subsequent DUO-EF at time of gold-standard investigation (if indicated 
as standard of care) 
b. Ejection fraction as calculated by gold-standard investigation 
3. Point-of-care DUO-EF in patients attending COVID-19 follow up clinic where 
clinician suspects new heart failure and comparison with: 
a. Subsequent DUO-EF at time of gold-standard investigation for HF  
b. Ejection fraction as calculated by gold-standard investigation 
Telephone call follow-up at 24 months for all patients with DUO-EF suggestive of HFrEF 
but normal gold standard investigations 
 
 

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OUTCOME 
MEASURES 
 
- 
1.) Primary: Sensitivity and specificity of DUO-EF for detecting LVEF 
above or below 40% 
- 
2.) Secondary: 
- 
DUO-EF performance against subgroup LVEF calculated by cardiac MRI  
- 
Consistency of DUO-EF result at point-of-care in GP practice (‘real 
world’ use where GP suspects new heart failure) against repeat DUO-EF 
at time of gold-standard investigation 
- 
Consistency of DUO-EF result at point-of-care in Covid-19 follow up 
clinic (‘real world’ use where clinician suspects new heart failure) against 
repeat DUO-EF at time of gold-standard investigation 
- 
Development of LVEF <40% at 24 months in participants with initial 
DUO-EF suggestive of LVEF <40% but gold standard investigations 
LVEF >40% i.e., can DUO-EF predict future development of LVEF <40% 
- 
DUO-EF point-of-care determination of LVEF<40% in comparison with 
the components of the established NICE pathway (BNP result) 
 
POPULATION 
- 
Group 1: All-comers to echocardiography and cardiac MRI departments across 
Imperial College Healthcare NHS Trust (echo n = 1,500, cMRI n = 100) 
- 
Group 2: Patients seen in primary care (GP) with symptoms newly suggestive of 
heart failure (n = 400); contributing to Group 1 if standard of care indicates need 
for referral to echo/cMRI 
- 
Group 3: Patients seen in the COVID-19 follow-up clinic with symptoms newly 
suggestive of heart failure (n = 400); contributing to Group 1 if standard of care 
indicates need for referral to echo/cMRI 
ELIGIBILITY       
Inclusion 
criteria for 
all  
- 
Age 18 years or above 
- 
Able to give informed consent 
 
Group 1 
Group 2  
Group 3 
Additional 
inclusion 
criteria 
- Patient 
attending for 
departmental 
echo or 
cardiac MRI  
- Attending for GP 
appointment; GP 
concerned about 
heart failure 
diagnosis and 
initiates patient onto 
routine NICE 
pathway  
- Attending COVID-19 
follow-up clinic; clinician 
concerned about heart 
failure diagnosis and 
initiates patient onto 
routine NICE pathway 

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Exclusion 
criteria 
Any chest wound, skin pathology or other feature that would 
prohibit routine stethoscope examination 
 
 
 
DURATION Start date 01/02/2021, duration 36 months    
 
 
 
 
 
 
 
 
 
 
STUDY WORKFLOW SUMMARY DIAGRAM ON NEXT PAGE 

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1. INTRODUCTION  
 
1.1 
BACKGROUND 
Heart Failure 
 
One million people in the UK are living with heart failure (HF), with more than 60,000 new cases 
annually. Consuming 2% of the entire NHS budget, HF has a worse prognosis — 50% mortality 
within five years — than most cancers. Furthermore, hospital admissions and demand for social 
care related to HF is expected to increase by 50% by 2040.1 Given this massively increasing 
prevalence of HF, the evidence for the benefits of early diagnosis and treatment coupled with the 
importance of accuracy and difficulty in diagnosis, HF is one of the biggest challenges facing the 
NHS, for which  better, early diagnostic and management strategies are urgently needed.  
HF is a clinical syndrome with a wide spectrum. The majority of patients with HF have heart failure 
with reduced ejection fraction (HFrEF), characterised by a reduction in blood pumped out of the 
left ventricle with each heartbeat, as seen on an echocardiogram (an ultrasound-based medical 
imaging tool, where above 50% is considered normal ejection fraction). HFrEF is defined as a left 
ventricular ejection fraction (LVEF) below 40%. The clinical syndrome of heart failure with 
preserved ejection fraction (HFpEF) features similar clinical symptoms (e.g. breathlessness, 
fatigue, ankle swelling) to HFrEF. However, it is difficult to diagnose and no treatment has been 
proven in pivotal clinical trials to be effective for HFpEF,2 the mortality from which is lower than 
treated HFrEF, even when optimally managed.   
There is strong and abundant evidence that early effective drug therapy can improve 
symptoms and prognosis in patients with HFrEF (LVEF <40%), where a substantial portion 
of increased morbidity and mortality is attributable to late initiation of therapies — caused 
by delayed diagnosis.3   
HF is poorly served in primary care, as it can be difficult to diagnose from non-specific symptoms. 
Delays in diagnosis lead to late initiation of life-prolonging therapies. Current clinical management 
guidelines from the National Institute for Health and Care Excellence (NICE) suggest performing a 
brain natriuretic peptide blood test (BNP) when HF is suspected. According to the NICE 
guidelines, if BNP is elevated, the GP makes a referral for specialist tests (echocardiogram) and 
assessments within six weeks - two weeks if BNP is especially high.1   
Only 4% of patients complete these NICE-recommended investigations in the recommended time 
frame,3  largely reflecting this unwieldy diagnostic pathway, limited resources, and HF being a 
common condition that is inherently difficult to diagnose.  
Consequently, although 40% of patients might previously have seen their GP with HF symptoms 
(including breathlessness, ankle swelling, fatigue), the diagnosis of HF is made in 80% of cases 

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when patients have advanced, severe (and life-threatening) worsening of symptoms, requiring 
hospital admission.4  HF is now the most common reason for acute hospital admission in those 
aged over 65 and and improving diagnosis in the community is listed as an explicit priority for the 
NHS Long Term plan.5   
 
Heart Failure and COVID-19 
It is now indisputable that patients with COVID-19 are at increased risk of cardiovascular 
complications, in many cases culminating in heart failure.6 As our understanding continues to 
develop, some studies have suggested myocardial involvement is present in as many as 78% of 
patients.7 Importantly, a substantial proportion of heart failure in need of treatment to prolong life is 
initially asymptomatic. Guidance from the British Thoracic Society8 recommends all patients who 
attended hospital with clinico-radiological findings of COVID-19 should be followed up as an 
outpatient within six weeks -- a huge challenge given the high volume of patients. 
 
Part of this care involves measurement of blood oxygen saturations and testing to screen for 
chronic lung disease. At present, despite the known cardiovascular complications, no routine 
screening for heart failure is being done for patients in this setting. This is partly due to the gold 
standard diagnostic for heart failure -- echocardiography -- being a limited, expensive and 
specialist resource.9 
 
Eko DUO Digital Stethoscope with Artificial Intelligence Electrocardiogram 
(ECG) 
The Eko DUO, is a stethoscope with an expanded acoustic “bell” 
with which heart sounds can be heard either through 
conventional rubber tubing (removable) with conventional ear 
pieces or via a connected mobile phone speaker. Eko DUO is 
also unique among stethoscopes in featuring a single-lead 
electrocardiogram (ECG). The Eko DUO and ECG capability are 
fully CE marked.  
With just 15 seconds of Eko DUO ECG data, a deep neural 
network (a form of artificial intelligence), developed at the Mayo 
Clinic in the US, can accurately predict low ejection fraction, 
abbreviated for this study as DUO-EF. Previous studies (n = 
100) have shown DUO-EF has high accuracy for achieving this (AUC 0.906 [CI: 0.831-0.955] for 
EF <=35%; 0.841 [CI: 0.754 - 0.906] for EF<50%).10 
Single-lead ECG requires only two contact points, as in the case of the two stainless steel 
electrodes on the body of the Eko DUO device, touched to the skin of the patient’s chest wall for 
instantaneous acquisition of ECG signal. Single-lead ECG is already well established to be 

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adequate for a machine learning algorithm that detects atrial fibrillation, now a standard feature of 
some of the biggest consumer wearable technologies (e.g. Apple Watch Series 4). The Eko DUO 
is able to give a DUO-EF reading at the clinically significant threshold of 40% using single-lead 
ECG alone -- a study of 100 patients at the Mayo Clinic showed an AUC of 0.89 for detection of 
LVEF above or below 40%.11 
 
Eko DUO Device Regulatory Approvals 
The Eko DUO device with ECG has full Conformite European (CE) marking. This study will seek 
approval both from the Health Research Authority research ethics committee for use of the DUO-
EF algorithm as a ‘medical device’..  
In the US, the Food and Drug Administration (FDA) has cleared Eko DUO and its AI-algorithms for 
heart sound interpretation and ECG detection of atrial fibrillation. The algorithm for detecting low 
EF recently received FDA Breakthrough Status and fast-track approval in the US. The 12-lead 
ECG algorithm has recently (May 2020) received Emergency Use Authorization for use during the 
COVID-19 pandemic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.  STUDY OBJECTIVES 
Primary objective: 
1. To test if the DUO-EF algorithm can achieve a sensitivity and specificity above 80% 
for detection of LVEF above or below 40% in comparison to gold-standard 
echocardiography  
Secondary Objectives: 
- 
To perform a subgroup analysis of DUO-EF against LVEF calculated by cardiac MRI 
(another gold standard investigation for calculating LVEF <40%) 
- 
To validate consistency of DUO-EF result at point-of-care in GP practice (‘real world’ use 
where GP suspects new heart failure) against repeat DUO-EF at time of gold-standard 
investigation 
- 
To validate consistency of DUO-EF result at point-of-care in Covid-19 follow up clinic (‘real 
world’ use where clinicians suspect new heart failure) against repeat DUO-EF at time of 
gold-standard investigation 
- 
To measure if participants with DUO-EF suggestive of LVEF <40% but with gold standard 
investigations where LVEF >40% are at increased risk of developing heart failure at 24 
months i.e. can DUO-EF predict future development of LVEF <40% at 24 months 
- 
To evaluate DUO-EF point-of-care determination of LVEF<40% in comparison with the 
components of the established NICE primary care pathway (e.g. BNP result) 
 
 
3.  STUDY DESIGN & METHODS 
 
Statistical Considerations 
 
Type of study: Prospective cross-sectional study comparing identification of LVEF above or 
below 40% by DUO-EF algorithm versus gold-standard methods. 
 
Duration: Start date 01/02/2021, duration 36 months 
 
Number and type of participants: across all settings 2,400 total  
 

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Sample Size  
Imperial College Healthcare NHS Trust performs over 20,000 echocardiograms per year across its 
three hospital and community sites, serving the most ethnically and socioeconomically diverse 
population in the UK.  
Based on established data and extensive clinical expertise of the investigators, around half of all 
patients who attend for echocardiography at the Trust are found to have LVEF <40%. The sample 
size calculation below addresses the primary objective: evaluating if the DUO-EF algorithm 
can achieve a performance of sensitivity and specificity above 80% for detection of LVEF 
above or below 40% – compared to gold-standard echocardiography.  
SAMPLE SIZE CALCULATION 
Primary Variable: Left Ventricular Ejection Fraction >/< 40% 
Null Hypothesis: DUO-EF DOES NOT detect with sensitivity and specificity exceeding 80% a 
LVEF greater or less than 40% 
Alternate Hypothesis: DUO-EF CAN detect with sensitivity and specificity exceeding 80% a 
LVEF greater or less than 40% 
Type 1 error 5% (5% 2 sided test) 
Type 2 error 20% (80% power) 
Based on the above parameters for sample size calculation (Ref: G*Power, proportion, difference 
from a constant [binomial test 1 sample test]) to address the primary objective, this study will 
recruit participants until at least 500 have been recruited with an LVEF above 40% and 500 with a 
LVEF below 40% i.e the minimum total required is 1000 patients.  
This will provide us with an ability to estimate sensitivity and specificity with a 95% CI ±3.3%, and 
assuming the underlying sensitivity and specificity are at least 85% provide us with 80% power at 
the 5 % significance level to detect that they exceed the pre-specified criterion of a sensitivity and 
specificity of 80%. 
Dropouts: Dropouts are unlikely within the context of the primary objective since consent and the 
entire data collection will occur within a short space of time during a single clinical visit (standard-
of-care attendance for echocardiography). 
Protocol Allowances: Although we require 466 patients with EF >40% and 466 patients with EF 
<40% we have rounded these up to 500 patients. Furthermore, we will likely need to recruit up to 
1,500 patients in total since it is unlikely that the first 1,000 patients will fulfil the exact breakdown 
of required LVEF above and below 40%. 
Controls: The ‘control’ population in this study are participants with LVEF>40%. Indications for 
referral to echocardiography are broad and include but are not limited to: suspected or known 

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ischaemic heart disease, suspected cardiomyopathy, pericardial disease, murmurs, assessment of 
valve disease, assessment of prosthetic valves, assessing chronic lung disease, neurological 
disease (stroke or transient ischaemic attack), arrhythmia (palpitations and/or loss of 
consciousness), high blood pressure (common) and as a standard investigation considered before 
surgery. Many of these referred patients are found to have no abnormalities on echo and are 
otherwise healthy. Therefore, the unselected approach of this study to include all-comers to echo 
will generate a population sample that can be evaluated for alignment with the type of population 
in whom a screening programme for heart failure may be beneficial.  
Performance characteristics: Eko Health (the ‘manufacturer’ of the algorithm) indicate a 
performance of 80% sensitivity and 80% specificity for the identification of LVEF above or 
below 40% 
Confounders: our study design precludes confounders 
Avoidance of bias for primary objective 
To avoid any biases in both the recording of DUO-EF readings by the member of the research 
team and this influencing calculation of %LVEF by the echocardiography team (sonographer), the 
following steps will be taken: 
 
- 
The member of the research team approaching patients in the echo department for 
consent will not be aware of the indication for referral at time-of-consent 
- 
DUO-EF readings can happen before or after the echo, with the member of the research 
team unaware of the echo-derived %LVEF until they check the electronic health record 
(after DUO-EF has already been recorded).  
- 
The sonographer will not be made aware of the results of DUO-EF, therefore not biasing 
any interpretation of %LVEF if borderline around 40% 
Study Participant Population 
All study participants will be approached to take part and have a DUO-EF reading during the 
course of their routine care (minimal disruption) in the echo or cardiac MRI setting, during their GP 
appointment, or while attending COVID-19 follow up clinic. This will result in a large, 
representative study population to meet the objectives of testing the hypothesis for DUO-EF as a 
screening tool.  
 
Group 1: Departmental Echocardiography and Cardiac MRI, Imperial College Healthcare 
NHS Trust 
 
Unselected patients attending for departmental echocardiography (n = 1,500) and subgroup in 
cardiac MRI (n = 100). Patients will be consented by a member of the research team while they 
wait for an echocardiogram/cMRI. Patients from group 2 (GP referrals) will also be attending for 
an echo as part of their routine care on the heart failure pathway; they will be re-consented by a 
member of the research team upon arrival in the department. 

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Researchers will perform and record DUO-EF readings on participants and subsequently review 
echocardiography and cardiac MRI reports and document the LVEF calculated by these 
modalities. 
 
 If echocardiography does not suggest heart failure with LVEF<40% but DUO-EF does, patients 
will be followed-up with a 24 month phone call (early evidence indicates the algorithm can 
identify low ejection fraction before being detectable on echo8). 
 
Group 2: Patients in Primary care (‘real world’ evaluation) 
 
NIHR North West London Primary Care Clinical Research Network (n = 10 GP practices). 
Patients attending GP with signs/symptoms of heart failure (n = 400 in total across all sites) will 
proceed with standard-of-care NICE heart failure pathway, with no change to standard of care 
through participation in study. GP’s will be asked to record DUO-EF in any patient where heart 
failure is suspected.  
 
Researchers will capture the point-of-care DUO-EF prediction from the GP: 
- 
Comparing this to repeat DUO-EF (‘agreement’ between two time points) at time 
of (group 1) echocardiography (if indicated by standard of care investigations: 
BNP and 12-lead ECG) 
- 
And comparing both of these DUO-EF measurements to echocardiography 
derived LVEF 
 
Group 3: COVID-19 Clinic, Imperial College Healthcare NHS Trust 
 
Patients attending COVID-19 follow up clinic (n = 400). Only patients who are being routinely 
referred onto the heart failure pathway for investigations will be invited to participate i.e. patients 
with clinical symptoms of heart failure, who would/should be referred onto routine NICE 
pathway. Researchers will capture the point-of-care DUO-EF prediction from the Covid-19 follow 
up clinic setting: 
- 
Comparing this to repeat DUO-EF (‘agreement’ between two time points) at time 
of (group 1) echocardiography  
- 
And comparing point-of-care and time-of-echo DUO-EF results  
 
Method for Single-Lead ECG Collection for DUO-EF 
 
For echo and cMRI, DUO-EF recordings will be made after these gold standard investigations so 
as not to bias interpretation of results. The protocol for DUO-EF recording for all patients in the 
COVID-19 follow up clinic, GP, echo and cMRI setting will be as follows: 
 

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1. Clinical user turns on Eko DUO device and confirms connection to secure app 
2. Participants sitting upright will have 15 second single-lead ECGs recorded by the Eko DUO 
from five different locations: 
a. Lead I position (holding the device’s electrodes between two hands) 
b. Clavicle 
c. Angled 
d. V2 position 
e. V5 position 
3. Five recordings of DUO-EF recorded by researchers 
 
The participant will be categorised as having a DUO-EF <40% if any of the five DUO-EF readings 
suggest this. 
 
Data point collection: %LVEF echo, %LVEF cMRI, BNP 
 
Recording %LVEF from echocardiography 
 
EF is routinely measured or estimated using well-established standardized methodologies. For the 
purpose of this study we draw on previous work by Attia et al (2019) to record the %LVEF value 
on echocardiography using the first available model in a standard hierarchical sequence:  
 
- 
EF determined using 3-D echocardiography12 
- 
Biplane approach using the Simpson method13 a 2-D method, or M-mode 
- 
In the absence of any of the preceding, the reported visually estimated EF 
 
If the estimation is a range, the midpoint as a single LVEF value will be used. LVEF will also be 
classified as low (≤40%), moderately depressed (41–49%), or normal (≥50%). 
 
Recording %LVEF from cardiac MRI 
 
As with echo, standard approaches to calculating EF also exist for cMRI. Calculated %LVEF 
(reported as standard) will be recorded alongside classification as low (≤40%), moderately 
depressed (41–49%), or normal (≥50%). 
 
Brain Natriuretic Peptide 
 
Where available, particularly in patients initiated onto the routine diagnostic heart failure pathway 
in the primary care and COVID-19 follow up clinic setting, BNP will also be recorded by 
researchers as an additional comparator to DUO-EF. BNP recorded longer than two months 
before or after DUO-EF will be excluded.  
 

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3.1 STUDY OUTCOME MEASURES 
 
The study will end after 36 months or at the point where the predetermined number of participants 
have been recruited; and 24-month follow up phone call has been completed for those with DUO-
EF suggestive of LVEF<40% but gold-standard LVEF >40%. 
 
Primary outcome measure: 
- 
Sensitivity, specificity for DUO-EF detecting LVEF above or below 40% 
 
Secondary outcome measures: 
- 
DUO-EF performance against subgroup %LVEF calculated by cardiac MRI  
- 
Consistency of DUO-EF result at point-of-care in GP practice (‘real world’ use where GP 
suspects new heart failure) against repeat DUO-EF at time of gold-standard investigation; 
similarly with patients attending Covid-19 follow up clinic with symptoms of LVEF <40% 
- 
Development of LVEF <40% at 24 months in participants with initial DUO-EF suggestive of 
LVEF <40% but gold standard investigations LVEF >40% i.e. can DUO-EF predict future 
development of LVEF <40% 
- 
DUO-EF point-of-care determination of LVEF<40% in comparison with the components of 
the established NICE pathway (BNP result) 
 
 
4. PARTICIPANT ENTRY  
 
4.1 PRE-REGISTRATION EVALUATIONS  
 
No pre-registration screening or tests are required.  
 
4.2 INCLUSION CRITERIA & EXCLUSION CRITERIA 
 

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Inclusion 
criteria for 
all  
- 
Age 18 years or above 
- 
Able to give informed consent 
 
Group 1 
Group 2  
Group 3 
Additional 
inclusion 
criteria 
- Patient attending 
for departmental 
echo or cardiac 
MRI  
- GP concerned about heart 
failure diagnosis and initiates 
patient onto routine NICE 
pathway  
- Attending COVID-19 
follow-up clinic and 
clinician concerned 
about heart failure 
diagnosis and initiates 
patient onto routine 
NICE pathway  
Exclusion 
criteria 
- 
Any chest wound, skin pathology or other feature that would prohibit 
routine stethoscope examination 
 
 
 
4.4 WITHDRAWAL CRITERIA 
 
Participants are free to withdraw their consent from the study at any point.  
 
 
5. ADVERSE EVENTS AND RISK 
False negative & False Positive Results 
 
This study poses minimal to no risk to participants. The Eko DUO device's capability to record 
ECG is fully CE marked and is already in mainstream clinical use. There are no ‘side-effects’ or 
contact hazards. There is a risk of a ‘false negative’ DUO-EF reading in those who in fact do have 
LVEF <40; however this is already accounted for in this study since DUO-EF is not interfering with 
the standard of care (e.g. echocardiography to definitively determine LVEF).  
 
5.1 DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 

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Serious Adverse Event (SAE): any untoward and unexpected 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. 
 
5.3 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 faxed to the Chief 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 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 
CI email (and contact details below) 
Fax: xxx, attention xxx 
Please send SAE forms to: xxx 
Tel: xxx (Mon to Fri 09.00 – 17.00) 
 
6. ASSESSMENT AND FOLLOW-UP  
 
Please see table below describing follow up procedures for different groups of the study. Describe 
how incidental findings will be identified, reviewed and reported, and to which individuals they will 
be reported to (i.e. GP, clinical care team).  
 
 
 
Group 1: All-comers to 
echo/cardiac MRI  
Group 2: GP patients 
Group 3: COVID-19 
follow-up clinic  
Follow-up 
Follow-up phone call at 24 months for all patients with positive DUO-EF but negative 
gold standard investigations for LVEF <40% (to evaluate if positive DUO-EF is an 
indicator of future risk for developing LVEF <40%) 
 
 
The recruitment for the study will end when the requisite number of participants has been 
achieved. For some groups, there will be a long-term follow up period as described above. The 
study will end upon completion of these follow up periods. 
 
In those patients where a 24 month follow up phone call is indicated, we will first attempt to 
confirm whether or not the participant is deceased by review of the NHS Spine, thereby avoiding 
unnecessary distress for relatives. 
Incidental Findings 
Incidental findings are highly unlikely in the course of this study since the process of having DUO-
EF would not identify anything additional to what would be found during standard of care. In the 
unlikely event of the study team making an incidental finding they will notify the team in charge of 
the patient’s care at the time-of-appointment.  
 
7. 
STATISTICS, DATA ANALYSIS, DATA SECURITY 
 

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Data Analysis 
 
Data will be analysed using a statistical package and platform (R Studio). Analysis will be 
completed by a clinical research fellow with appropriate access privileges (including honorary 
Imperial NHS contract) to study data. 
 
Data Protection, Security and Compliance 
 
This study has been reviewed and approved by the Imperial College Healthcare NHS Trust Data 
Protection Office (reference 20HH6360). 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.   
 
All study data will be collected using a REDCap (Research Electronic Data Capture) database, 
with a unique study ID for each participant (only identifiable by the principal investigator using an 
encrypted master key held in a password protected file on NHS servers) Patients will be allocated 
a de-identified study ID number, derived from a key that processes NHS numbers algorithmically. 
This key will be kept secure in a password encrypted file (accessible only to principal investigator). 
Study participant data will therefore not be identifiable unless researchers revert study ID’s to NHS 
number.  
 
The following data (where available) will be captured by researchers from the electronic health 
record (EHR): 
 
- 
Encrypted NHS number (master key held in password protected file on NHS server, only 
accessible to principal investigator) 
- 
Age 
- 
Ethnicity 
- 
Comorbidities 
- 
Classification into study group 1-3 
- 
BNP blood test result 
- 
Echocardiography calculated %LVEF and categorisation 
- 
Cardiac MRI calculated EF and categorisation 
 
Eko DUO Data Security 
 
The only data received by Eko Health will be digital ECG data. This will not be identifiable to the 
patient (i.e. not associated with an NHS number, date of birth or other identifier and Eko will not 
have access to the key for linkage with NHS numbers). This digital ECG data is uploaded to the 
Eko cloud via the mobile phone app (connected to the Eko DUO by bluetooth, no data stored on 
the device).   
 
The data can be freely retrieved and will only be accessed through and securely stored within 
Imperial College London computers and servers. At the end of the study, all digital ECG data will 
be retrieved from Eko’s servers and stored in accordance with Imperial College London policy on 
secure College computers.  

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No ECG or other data is stored on the mobile phone/on the app.  
 
Interim Analysis 
 
An interim analysis will be conducted (anticipated at 3 months) when the study has recruited n = 
400 patients with paired DUO-EF and echocardiography results. Based on the previous power 
calculation this should be sufficient to indicate with 90% power if we can reject a null hypothesis 
that the AUC <0.7 at the 0.05 level of significance.  
 
Missing Data 
 
The study design and nature of the variables collected makes missing data unlikely. In order to 
avoid introducing bias into the dataset by removal of participants with any missing data, all 
participants will be retained; missing of any variable will entail the affected participant not being 
included only in the analyses specifically relevant to that variable. Access to shared primary and 
secondary care electronic health records should make missing data retrievable in most cases. 
Details of any missing data will be explicitly described in any reports or publications.  
 
 
 
8. 
REGULATORY ISSUES 
 
8.1 ETHICS APPROVAL 
The Study Coordination Centre has obtained approval from the xxx 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. 
 
8.2 CONSENT  
 
Consent to enter the study will be sought from each participant only after a full explanation has been 
given, an information leaflet offered and time allowed for consideration. The right of the participant 
to refuse to participate without giving reasons will be respected.   
 
Consent will either be in the form of a standard paper consent form or, for those with access to the 
Imperial NHS Care Information Exchange electronic patient record, using a digital consent form that 
conforms to the HRA and MHRA’s joint statement on e-consent for research.   
 

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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 at any time 
from the protocol treatment without giving reasons and without prejudicing further treatment. 
 
8.3 CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and is 
registered under the Data Protection Act. 
 
8.4 INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance policies which 
apply to this study. 
 
8.5 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.   
 
8.6 FUNDING 
NIHR is funding this study. Participants will not be paid for joining the study. Investigators will 
receive no direct or indirect payments for conducting the study.   
 
8.7 AUDITS  
The study may be subject to inspection and audit by Imperial College London under their remit as 
sponsor and other regulatory bodies to ensure adherence to GCP and the UK Policy Framework for 
Health and Social Care Research.  
 
9. STUDY MANAGEMENT 
 
The day-to-day management of the study will be co-ordinated through the Imperial College & Trust 
Connected Care Bureau, 4th Floor ICTEM, Hammersmith Hospital, London, W12 0HS. 
 

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10. PUBLICATION POLICY 
 
Results from this study will be published in peer-reviewed journals and presented at relevant 
conferences with all named lead and co-investigators as authors.  
 
 
 
10. REFERENCES 
 
1. Al-Mohammad, A. & Mant, J. The diagnosis and management of chronic heart failure: review 
following the publication of the NICE guidelines. Heart 97, 411–416 (2011). 
2. Borlaug, B. A. The pathophysiology of heart failure with preserved ejection fraction. Nat. Rev. 
Cardiol. 11, 507–515 (2014). 
3. Bottle, A. et al. Real-world presentation with heart failure in primary care: do patients selected 
to follow diagnostic and management guidelines have better outcomes? Open Heart 5, 
e000935 (2018). 
4. Alderwick, H. & Dixon, J. The NHS long term plan. (British Medical Journal Publishing Group, 
2019). 
5. Kearney, M. Prevention and treatment of CVD: a new priority for the NHS. Heart 105, 1924–
1924 (2019). 
6. Zheng, Y.-Y., Ma, Y.-T., Zhang, J.-Y. & Xie, X. COVID-19 and the cardiovascular system. Nat. 
Rev. Cardiol. 17, 259–260 (2020). 
7. Puntmann, V. O. et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients 
Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. (2020) 
doi:10.1001/jamacardio.2020.3557. 
8. BTS. British Thoracic Society Guidance on Respiratory Follow Up of Patients with a Clinico-

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and Integrity Team 
 
DUO-EF-19 STUDY PROTOCOL V2.0 04/02/2021 IRAS: 285417    Page 28 of 29 
© Imperial College of Science, Technology and Medicine   
Radiological Diagnosis of COVID-19 Pneumonia. (2020). 
9. Cowie, M. R. The heart failure epidemic: a UK perspective. Echo Res. Pract. 4, R15–R20 
(2017). 
10. Attia, Z. I. et al. Prospective validation of a deep learning electrocardiogram algorithm for the 
detection of left ventricular systolic dysfunction. J. Cardiovasc. Electrophysiol. 30, 668–674 
(2019). 
11. Kapoor, T. & Kapa, S. Prospective Analysis of Utility of Signals from an ECG-enabled 
Stethoscope to Automatically Detect a Low Ejection Fraction using neural networks trained 
from the standard 12-lead ECG. 
https://www.morressier.com/article/5d19cfb257558b317a10dda5 (2019) 
doi:10.26226/morressier.5d19cfb257558b317a10dda5. 
12. Yamani, H., Cai, Q. & Ahmad, M. Three-Dimensional Echocardiography in Evaluation of Left 
Ventricular Indices. Echocardiography 29, 66–75 (2012). 
13. Quinones, M. A. et al. A new, simplified and accurate method for determining ejection fraction 
with two-dimensional echocardiography. Circulation 64, 744–753 (1981). 
 
 
 
 
 
 
Appendix 1. Summary of investigations, treatment and assessments 
 
Exam 
Week of Treatment 
 
Pre-treatment 
Group 1 
Group 2 
Group 3 
Initial/repeat (for GP and 
COVID-19 follow up patients) 
DUO-EF reading at 
echocardiography/cMRI 
Nil 
X 
X 
X  

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Initial DUO-EF reading in 
COVID-19 clinic or with GP 
Nil 
 
X 
X 
24 month follow-up phone call 
for DUO-EF positive but gold 
standard negative 
Nil 
X 
X 
X