Defining a Gold Standard for Ischaemia: Effects of Interventional Revascularisation Versus Optimum Medical Therapy on Exercise Capacity in Patients With Stable Coronary Artery Disease
Phase: NA
Conditions: Stable Angina
Sponsor: Imperial College London

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Defining a gold standard for ischaemia:  
Effects of interventional revascularization vs. optimal 
medical therapy on exercise capacity in patients with stable 
coronary artery disease 
 
 
 
 
 
 
 
 
STUDY PROTOCOL V3.0 
 
 
 
 
 
 
 
 
 
 
 
Steering committee 
 
Justin Davies, Roland Wensel, Darrel Francis, Rasha Al-Lamee and Dan Keene  
 
 
 
 
 
 
 
 
 
Imperial College London 
August 2014 
 
 
 
 
 
 
 
 

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Background 
Previous studies have suggested that there is no added benefit to performing 
percutaneous coronary intervention (PCI) above treatment with medical therapy alone 
in patients with stable angina.1, 2 However these data were based on subjective 
measures of angina symptoms and there was no attempt to blind investigators or 
patients to the treatment they had received which may have biased the results.1, 2 As yet 
no study has investigated the effect of PCI on symptoms as measured by objective 
measures of exercise capacity and non-invasive and invasive measures of coronary 
ischaemia under blinded conditions.  
 
Fractional flow reserve (FFR) has been used to measure the physiological significance of 
coronary stenosis3 for many years. PCI was shown to be superior to medical therapy in 
patients with functionally significant FFR values; however, while the study was halted 
prematurely due to a significantly higher rate of urgent revascularization in the medical 
therapy arm,4 a significant limitation was the lack of blinding between the 2 study arms. 
A novel invasive approach for assessing coronary stenosis severity, the instantaneous 
wave free ratio (iFR), has been developed5 and has been shown to correlate well with 
FFR.6 It is likely that a positive physiological assessment using these techniques will be 
associated with a larger improvement in exercise capacity following PCI. Exercise 
capacity in patients on optimal medical therapy (OMT) will be most limited in those 
with positive functional tests.   
 
Hypotheses 
Hypothesis 1: 
Under bias-resistant blinded conditions, PCI increases objective exercise capacity more 
than OMT alone, with OMT given to both groups.  
a.    Principal endpoint: Exercise time on treadmill 
b. Secondary endpoints: 
i. 
Peak VO2 
ii. 
Exercise time to development of angina 
iii. 
Exercise time to ST depression of 1 mm  
 
Hypothesis 2: 
The stenting induced increment in exercise capacity is related to the severity at 
baseline. We define the stenting induced increment in the physiological variable as the 
increment seen in the PCI+OMT group minus the increment seen in the Placebo+OMT 
group. 
 
a. Physiological severity defined as baseline FFR 
 
b. Physiological severity defined as baseline iFR 
 
c. Anatomic severity assessed by quantitative coronary angiography 
 
Hypothesis 3: 
Under bias-resistant blinded conditions, these techniques can identify the changes pre- 
and post-PCI: 
a. Duke treadmill score 
b. Dobutamine stress echocardiography (DSE) analysed, blinded to order and 
patient, by 2 independent observers 
c. iFR (measured twice 10min apart) 
d. FFR (measured twice 10min apart) 

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e. Exercise increment in high sensitivity-Troponin I (hsTNI) 
 
Value of results 
1. If these are confirmed, this would confirm that PCI+OMT leads to an improvement in 
exercise capacity over blinded Placebo+OMT alone.  
2. The improvement is greatest in patients with physiologically significant lesions.  
 
Sample size calculation  
Hypothesis 1 will be tested by comparing the endpoint variables between the groups. 
This will be done by an unpaired t-test (Mann-Whitney if skewed distribution). The 
expected difference in exercise duration would be 30s or greater. The expected 
standard deviation is based on observational studies using the treadmill Bruce protocol 
in patients with coronary artery disease.7  
 
Table 1: Numbers of power to detect significant changes 
 
Effect size 
 
Standard Deviation  
1-Beta  
Alpha  
n 
 
30s 
 
 
90s 
 
 
 
0.8 
 
0.05 
 
143 
45s 
 
 
90s 
 
 
 
0.98 
 
0.05 
 
143 
 
To test hypothesis 2 we will plot the regression relationship between the increment in 
treadmill time pre/post and the baseline measure of severity. Separate regression 
relationships will be plotted for the PCI+OMT and Placebo+OMT groups. The difference 
between the 2 regression relationships will indicate the stenting induced increment. 
With a sample size of 143, the power to detect a significant relationship between the 
pre/post PCI increment and the baseline physiological variable, of the order of r=0.3, is 
95% at the 5% significance level.  
 
Hypothesis 3 is a simple test of the efficacy of each of the markers in detecting the 
change that occurs with stenting. For the continuous variables, iFR and FFR, our pilot 
experience is that these are extremely highly powered (>99.9%) because they undergo 
a relatively large positive change compared to their own reproducibility.8 For Duke 
treadmill score, based on a conservatively assumed increment of 30s, i.e. 0.5 points, and 
a standard deviation of difference of 1.5 points, then 143 patients would give us 80% 
power at the 5% significance level. 
 
 
 
 
 
 
 
 
 
 
 
 

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Study protocol 
 
Recruitment group: 
Patients with stable angina and appropriate use criteria for revascularization; who have 
had diagnostic angiography showing at least 1 lesion with angiographic stenosis ≥70% 
in a single vessel. 
 
Exclusion criteria: 
a. Acute coronary syndrome 
b. Previous coronary artery bypass graft surgery 
c. Left main stem disease 
d. Contraindications to PCI or drug-eluting stent (DES) implantation 
e. Heavily calcified or tortuous vessels 
f. Chronic total occlusion in target vessel 
g. Life expectancy <2yr 
h. Pregnancy 
i. Age <18yr or >85yr 
j. Angiographic stenosis ≥ 50% in non-target vessel  
k. Inability to consent 
 

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Protocol: 
Once enrolled in the study the patients will have the following: 
1. Aggressive optimization of medical therapy 
Weekly clinic visits to introduce and uptitrate medications with the aim for 
treatment regimen to be as follows by 6 weeks with heart rate ≤60bpm and systolic 
blood pressure >100mmHg: 
i. 
Aspirin 75mg OD 
ii. 
Bisoprolol ≥5mg OD (or alternative β blocker) 
iii. 
Atorvastatin ≥40mg OD (or alternative statin) 
iv. 
Isosorbide Mononitrate S/R 
v. 
Amlodipine ≥5mg OD 
vi. 
Perindopril ≥4mg OD (or alternative ACEI) 
vii. 
Alternative anti-anginals at physician’s discretion: verapamil, 
diltiazem, nicorandil, ivabradine, ranolazine  
viii. 
Dual antiplatelet therapy loading for 5-7 days prior to angiography 
 
2. Baseline functional assessment 
To be performed on one visit 1 week after optimal medical treatment regimen is 
achieved. At this stage they will have the following: 
a. Clinical assessment: 
Quality of life questionnaire (European EQ-5D), Rose angina questionnaire, 
Seattle Angina Questionnaire, Short IPAQ 
CCS angina class 
Need for medical consultations or admissions 
Resting ECG, heart rate variability 
b. Blood and urine investigations: Fasting lipid profile, baseline hsTNI 
c. Cardiopulmonary exercise test (CPET): 
Using exercise tolerance test to measure: 
i. 
Exercise time on treadmill 
ii. 
Peak VO2 
iii. 
Exercise time to development of angina 
iv. 
Exercise time to ST depression of 1 mm  
d. Blood investigations 3hr after completion of CPET: Metabolomics and hsTNI 
e. DSE with contrast enhancement: 
β blocker will be stopped for 3 days, prior to DSE. β blocker will be restarted 
immediately afterwards. Quantitative analysis with segment scoring reported in 
corelab each on 2 separate occasions by 2 operators.  
 
3. Invasive functional assessment 
Coronary angiogram with iFR and FFR assessment (using IV adenosine 
140mcg/kg/min) to each ≥70% coronary stenosis with pressure wire placed in 
distal vessel at least 3 vessel diameters beyond the last stenosis. Each measurement 
will be repeated twice with 10min interval between measurements. Normalisation 
will be documented prior to making each measurement.  Operators will be blinded 
to the results of these functional tests.  After each measurement the wire will be 
checked for drift and, if evident, measurements repeated. 
 
4. Sedation, randomization and blinding 

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Patient will be sedated and randomized 1:1 to PCI+OMT or Placebo+OMT alone 
using computerized randomization. Patients will be given headphones during the 
course of the procedure. The nursing staff and physicians performing the PCI will 
have no further contact with the patient until after they are unblinded at the final 
follow-up point. Any other nursing staff or physicians involved in patient care and 
the research team will be blinded to the treatment strategy.  
 
5. PCI 
PCI group will have angioplasty and stent implantation with second generation DES 
as per operator’s discretion to all lesions within the vessel that are deemed to be 
angiographically significant. Stent optimization with post-dilatation will be standard 
and intravascular ultrasound will be used as necessary. 
 
6. Repeat invasive assessment 
iFR and FFR assessment will be repeated in all coronary lesions post PCI in those 
who have had PCI. 
 
7. Study protocol cross-over 
Patients will not be eligible for randomization if: 
a. They have complication necessitating PCI during invasive functional 
assessment procedure.  
 
Patients will cross-over from Placebo+OMT to PCI+OMT arm in the following 
circumstances: 
a. They have intractable angina necessitating PCI. 
b. Positive ETT or DSE at follow-up functional assessment. 
c. They develop acute coronary syndrome. 
 
If patients cross-over, they will have repeat iFR/FFR measurement at angiography. 
 
8. Follow-up functional assessment 
To be performed 4-6wk after coronary angiogram +/- angioplasty. 
At this stage they will have the following: 
a.    Clinical assessment: 
       Quality of life questionnaire (European EQ-5D), Rose angina questionnaire,    
       Seattle Angina Questionnaire, Short IPAQ 
       CCS angina class 
       Need for medical consultations or admissions 
       Resting ECG, heart rate variability 
b. Blood and urine investigations: Fasting lipid profile, baseline hsTNI 
c. CPET: 
Using ETT to measure: 
i. 
Exercise time on treadmill 
ii. 
Peak VO2 
iii. 
Exercise time to development of angina 
iv. 
Exercise time to ST depression of 1 mm  
d. Blood investigations 3hr after completion of CPET: Metabolomics, hsTNI 
e. DSE with contrast enhancement: 

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β blocker will be stopped for 3 days, prior to DSE. β blocker will be restarted 
immediately afterwards. Quantitative analysis with segment scoring reported in 
corelab each on 2 separate occasions by 2 operators.  
f.   Wear a physical activity tracker 
 
9. Un-blinding and study end 
Following the 4-6wk follow-up investigations, patients will be un-blinded to 
treatment group and routine medical care will be continued. Dual antiplatelet 
therapy will be stopped in blinded OMT group. At this stage, patients in the blinded 
OMT will be given the opportunity to undergo PCI at the discretion of the physician.  
 
Statistical analysis 
Data will be summarised as mean (SD) or median (interquartile range) for skewed data. 
Statistical comparisons will be undertaken using a paired Student’s t-test (after log 
transformation if necessary) or nonparametric alternative if data are not normalised by 
log transformation. 
 
Study reporting 
We anticipate that it will take 6 months to complete patient recruitment with study end 
6 months later therefore total study time of 12 months. We will aim to begin 
recruitment after Ethics approval in October 2013 with first results available for 
presentation in autumn 2014. 
 
Study sites and enrolment  
We anticipate the study enrolling with 3-4 large high volume PCI centres with 
experience in all of the physiological techniques proposed in this study.  We envisage 
enrolment would take place within 6 months. 
 
Documentation 
All documentation will be collected electronically using the Imperial College Clinical 
Trials Unit (ICTU).  The ICTU has a track record for running large multi-centre 
international (eg. ASCOT study).  Clinical, and physiological records will be saved to 
DVD and then to a central server within ICTU in accordance with GCP guidelines.   
 
Regulatory Issues 
1. Ethics 
Ethical approval has been obtained from our Local Research Ethics Committee. The 
study will be conducted in accordance with the recommendations for physicians 
involved in research on human subjects by the 18th World Medical Assembly, 
Helsinki 1964 and later revisions. 
 
2. Consent 
Signed participant consent to be involved in the study will be sought from each 
participant only after a full explanation has been given, an information leaflet 
offered and a minimum of 48 hours allowed for consideration. The right of the 
participant to refuse to participate without giving reasons will be respected.  
 

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All participants are free to withdraw at any time without giving reasons and without 
prejudicing further treatment. On withdrawal from the study, identifiable data will 
be destroyed securely. Non-identifiable data will be deleted from the database. 
 
3. Confidentiality 
The Chief Investigator will preserve the confidentiality of participants taking part in 
the study and registered under the Data Protection Act. 
4. Indemnity 
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study. 
 
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. 
 
6. Funding 
The study will be funded internally through a charitable fund. 
 
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 NHS Research Governance Framework for Health and Social Care (2nd edition). 
 
8. Documentation 
All documentation will be collected electronically using the Imperial College Clinical 
Trials Unit (ICTU).  The ICTU has a track record for running large multi-centre 
international (eg. ASCOT study).  Clinical, and physiological records will be saved to 
DVD and then to a central server within ICTU in accordance with GCP guidelines.   

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