How Often Can Optimal Post Percutaneous Coronary Intervention (PCI) Fractional Flow Reserve (FFR) Results be Achieved? - a Randomised Controlled Trial of FFR Targeted PCI (the Target FFR Study)
Phase: NA
Conditions: Coronary Artery Disease, Coronary Stenosis
Sponsor: NHS National Waiting Times Centre Board

An Evaluation of a Physiology-guided  
PCI Optimisation Strategy (Target-FFR) 
 
 
Clinical Investigation Plan / Study Protocol 
 
Study Title: 
How often can optimal post percutaneous coronary intervention (PCI) fractional 
flow reserve (FFR) results be achieved? - A randomised controlled trial of a 
coronary physiology-guided optimisation strategy (The Target FFR Study) 
 
Short Title: 
 
Target-FFR 
 
REC Ref: 
 
17/WS/0153 
IRAS ID: 
 
223780 
Sponsor Ref: 
 
17/CARD/10 
 
ClinicalTrials.gov  
Identifier:  
 
NCT03259815 
 
Sponsor: 
 
Golden Jubilee Research Institute (NHS National Waiting Times Centre Board) 
 
Protocol Version: 
v1.0 
Date: 08 June 2017 

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How often can optimal post percutaneous coronary intervention 
(PCI) fractional flow reserve (FFR) results be achieved?  
– a randomised controlled trial of FFR targeted PCI  
(The Target FFR Study) 
 
Dr Damien Collison, Fellow in Interventional Cardiology1 
Dr John D McClure, Lecturer in Statistics2 
Professor Colin Berry, Consultant Physician & Cardiologist1,2 
Professor Keith G Oldroyd, Consultant Interventional Cardiologist1 
 
 
 
 
1 West of Scotland Regional Heart & Lung Centre, Golden Jubilee National Hospital, Glasgow, United Kingdom 
2 Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abstract 
 
There has recently been renewed interest in the measurement of post percutaneous 
coronary intervention (PCI) Fractional Flow Reserve (FFR). Previous studies have suggested 
that post PCI FFR values ≥ 0.90 are associated with better clinical outcomes for patients but 
the available data suggest that despite angiographically satisfactory results, this is actually 
achieved in less than 40% of cases.  
The main mechanisms for sub-optimal post PCI FFR measurements have been proposed to 
be stent underexpansion, unmasking of a second lesion in the target vessel post PCI, 
residual diffuse disease in the untreated segments and pressure drift (a technical artifact of 
pressure wire technology).  
Using post PCI FFR to guide stent optimisation and/or further intervention in the target 
vessel has been shown to increase the frequency of achieving optimal post PCI FFR results 
(and therefore presumably better clinical outcomes). However, there are additional costs 
involved in the routine use of post PCI FFR and it is not clear just how often it is even 
possible to increase the initial post PCI FFR to ≥ 0.90. This uncertainty means that it is 
currently difficult to either recommend the routine use of post PCI FFR or justify its cost.  
We propose a prospective study to assess the feasibility of achieving post PCI FFR ≥ 0.90 
during standard PCI procedures in consecutive patients. We would also attempt to elucidate 
the mechanisms for sub-optimal FFR results when they occur. We would anticipate using 
the data from this developmental study to support a subsequent funding application to 
BHF/MRC/NIHR for a definitive phase 3 study of the impact of FFR targeted PCI on clinical 
outcomes. 
 
Background 
 
The utility of FFR for assessing the physiological significance of coronary stenoses and the 
benefits of FFR-guided decision making prior to PCI have been well established in several 
landmark trials.1,2 There is also a growing body of evidence that post PCI FFR can predict 
clinical outcomes. Much of this data is from the era of bare-metal stents, when a post-stent 
FFR ≥ 0.95 was recommended as the cut-off value for optimum (physiologically guided) 
stent implantation. This value was validated in a series of intravascular ultrasound (IVUS) 
studies although it should be noted that most studies of IVUS guided stenting have shown 
little or no benefit in terms of longer term clinical outcomes.3-6  
More recent studies on the prognostic value of FFR post drug-eluting stent (DES) 
implantation have suggested that a post PCI FFR of ≤ 0.90 correlated with greater adverse 
cardiac event rates.7-12 However, these series have generally recruited small numbers of 
patients and have yielded conflicting results. For example, Leesar et al investigated a group 
of 66 patients undergoing PCI with primarily DES. They found that an FFR ≥ 0.96 was 
achieved in only 35 patients (53%) after PCI but adverse event rates were significantly lower 
in this group.7 Conversely, Matsuo et al reported that a post-stent FFR of ≥ 0.90 was 
achieved in only 39% of their cohort of 69 patients and were unable to demonstrate that 
post-stent FFR predicted target lesion revascularisation (TLR) in patients who received DES.8   
A larger, retrospective study of 664 lesions (in 574 patients) by Agarwal et al found that 
approximately 1 in 5 lesions (21%) demonstrated persistent ischaemia (post PCI FFR ≤ 0.81) 
after intervention despite angiographically satisfactory PCI results.13 The authors report that 
a post PCI FFR of > 0.91 was achieved in 34% of their patients which increased to 43% 

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following subsequent interventions to achieve “functional optimization”. After excluding 
patients with diabetes, CKD and/or diffuse coronary disease, achieving a final FFR > 0.91 was 
associated with lower adverse event rates compared to the final FFR ≤ 0.91 group (7.1% vs. 
18.9%; p = 0.04). 
Data from a small series of patients at our own institute would also appear to corroborate 
the previous findings that an initial post PCI FFR ≥ 0.90 is only achieved in less than 40% of 
patients. Of the 21 patients in this group, only 8 (38%) had an initial post PCI FFR ≥ 0.90. 
Following further stent optimisation and/or additional stenting, this increased to 12 patients 
(57%) with a final FFR ≥ 0.90. 
Pijls et al measured post PCI FFR in 750 patients and reported a final FFR result > 0.90 in 68% 
of their cohort. They found that FFR after stenting is a strong independent predictor of 
outcome at 6 months and that the event rate was over three times higher in patients with 
post PCI FFR < 0.90 compared to those with an FFR between 0.90 and 0.95 (20.3% vs. 
6.2%).14 
In a meta-analysis from Johnson et al, almost 2/3 of 966 patients who had post PCI FFR 
measured had values below 0.90. The rate of MACE (death, MI, repeat revascularisation) 
was 40% at 3 years in patients within the lowest tertile of post PCI FFR [median IQR 0.83 
(0.79-0.86)], almost twice as high as that in patients in the highest tertile of post PCI FFR 
[0.98 (0.96-1.00)]; p< 0.001].15 This may of course reflect the effects of diffuse 
atherosclerosis but it may also indicate physiologically suboptimal revascularisation and 
thereby represents a target for improved treatment. 
Rimac et al recently published one of the largest meta-analyses to date on the clinical value 
of post PCI FFR. They included a total of 105 studies from 1995 - 2015 (7470 patients) and 
found that higher post PCI FFR values (≥ 0.90) were associated with reduced rates of 
repeat intervention and MACE. They concluded that FFR measurement after PCI was 
associated with prognostic significance and recommended further investigation to assess 
the role of post PCI FFR and validate cut off values in contemporary clinical practice.16 
 
 
Original hypothesis 
 
A simple Physiologically-guided Incremental Optimisation Strategy (PIOS) can increase the 
proportion of patients undergoing PCI in whom a post PCI FFR ≥ 0.90 can be achieved from 
40% to 60%. 
 
 
 
Experimental details and design of proposed investigation 
 
Overall aim:  
 
A randomised control trial of a physiologically-guided optimisation strategy to determine 
the feasibility of increasing the proportion of post PCI FFR measurements ≥ 0.90 in a 
consecutive series of patients undergoing standard PCI procedures. 
 
Study Population:  
 

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260 consecutive patients with stable angina referred for invasive management to the 
cardiac catheterisation lab who have been selected to undergo PCI based on either 
angiographic appearances or prior FFR assessment. Patients will be caffeine free for >12 
hours pre-procedure. 
 
Inclusion criteria:  
 
Patients >18 years of age with coronary artery disease including stable angina and stabilised 
non-ST-elevation myocardial infarction (NSTEMI) able to provide informed consent. 
 
Exclusion Criteria:  
 
• 
PCI in a coronary artery bypass graft 
• 
Inability to receive adenosine (for example, severe reactive airway disease, 
marked hypotension, or advanced atrioventricular block without pacemaker). 
• 
Recent (within 1 week prior to cardiac catheterization) ST-segment elevation 
myocardial infarction (STEMI) in any arterial distribution (not specifically target 
lesion). 
• 
Severe cardiomyopathy (ejection fraction <30%). 
• 
Renal insufficiency such that an additional 20 to 30 mL of contrast would, in the 
opinion of the operator, pose unwarranted risk to the patient. 
 
Methods/Design:  
 
Informed consent will be obtained prior to cardiac catheterisation in all potential subjects 
conforming to the inclusion and exclusion criteria.  
Patients will then be randomised to one of two groups (described below) and PCI will be 
performed, using a pressure guidewire, according to standard practice at the Golden Jubilee 
National Hospital (including lesion pre-dilation and post-dilation of the stented segment). 
 
Group 1 (PIOS Group):  
 
Operator-blinded FFR will be measured post PCI.  
If FFR is ≥ 0.90, no further intervention will be performed and the procedure is considered 
complete.  
If FFR is < 0.90, the result will be disclosed to the operator and a hyperaemic pressure wire 
pullback during either a standard peripheral intravenous adenosine infusion 
(140mcg/kg/min) or an intracoronary adenosine infusion (360mcg/min) via a microcatheter 
will be performed. Depending on the result the operator would then have the following 
options: 
A. If there is a step-up of ≥ 0.05 across the stented segment(s) further post-dilatation 
with a 0.25 - 0.50mm larger non-compliant balloon to at least 18 atmospheres 
should be performed followed by repeat FFR. Alternatively, the operator may choose 
to employ intracoronary imaging (IVUS or OCT) to guide post-dilation/optimisation 
of the stented segment. 

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B. If there is a step-up of ≥ 0.05 across a relatively focal (<20mm) unstented segment 
which is technically suitable for further stenting then a further stent should be 
implanted followed by repeat FFR. 
C. If the FFR remains < 0.90 after steps A +/- B, a further FFR pullback will be 
performed. If the criteria for Step B are again met, one additional stent may be 
deployed and a final FFR pullback performed. Following this, the FFR result will be 
accepted. 
D. If the residual pressure gradient is interpreted to reflect diffuse atherosclerosis with 
no focal step-ups, the result is accepted. 
E. At the end of the procedure the pressure wire sensor will be withdrawn to the tip of 
the guiding catheter and compared with the aortic pressure. A pressure drift of ≤ 
0.03 will be accepted and the final FFR result adjusted accordingly.  
F. If there is a drift of ≥ 0.04, the wire should be re-equalised and the final FFR 
measurement be repeated. 
G. The patients will have their demographics and procedure details recorded. All 
patients will receive 3-month telephone follow-up. 
 
Group 2 (Control Group):  
 
Post PCI FFR will be recorded but not disclosed to the operator. The angiographically 
defined result will be accepted. The patients will have their demographics and procedure 
details recorded. All patients will receive 3-month telephone follow-up. 
 
 
 
Primary Outcome 
 
The primary end-point in this study will be the proportion of patients with a physiologically 
optimal result post PCI (FFR ≥ 0.90). We hypothesise that our PIOS intervention can 
increase the proportion of patients achieving this target from 40% to 60% and believe that 
an increment of at least this magnitude would be necessary to make a future larger study 
with both patient-oriented clinical (target vessel failure) and health care system (resource 
utilisation) outcomes acceptable to the interventional cardiology community and potential 
funders. 
 
Secondary Outcomes 
 
The main secondary outcome measure will centre on assessing change from baseline in self-
reported health outcomes at 3 months using both generic and disease-specific quality of life 
measurement tools.  
The EQ5D is a generic quality of life measurement tool which expresses preference for 
health status using a single index score and is the recommended tool by the National 
Institute for Health and Clinical Excellence (NICE) for calculation of Quality-Adjusted Life 
Years. It covers 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  
The SAQ is a self-administered, disease-specific measure for patients with coronary artery 
disease that has previously been demonstrated to be valid, reproducible, and sensitive to 

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clinical change. The SAQ quantifies patients’ physical limitations caused by angina, the 
frequency of and recent changes in their symptoms, their satisfaction with treatment, and 
the degree to which they perceive their disease to affect their quality of life. 
 
The rate of target vessel failure and its component features (cardiac death, myocardial 
infarction, stent thrombosis, unplanned rehospitalisation with target vessel 
revascularisation) will be analysed at 3 months. 
 
Additional secondary outcomes including procedural/patient safety factors will also be 
measured. These would include: procedure time, fluoroscopy dose, contrast dose, 
complications and cost of additional equipment employed (balloons/stents/intra-coronary 
imaging). 
 
 
Power calculations 
 
Assuming (as per data from previous studies) that 40% of patients in the control arm have a 
post PCI FFR ≥ 0.90 and that it is considered clinically relevant if the equivalent percentage 
in the PIOS treatment arm is at least 60%, we will require a sample size of 130 per group to 
have 90% power to be able to detect a difference in the population in these proportions at 
the 5% significance level. 
 
 
Expected value of results 
 
1. 
Confirmation that the proposed PIOS protocol significantly increases the 
proportion of patients obtaining a physiologically optimal post PCI result will 
demonstrate the feasibility of this strategy and should lead to an increase in post 
PCI pressure wire usage to achieve physiologically optimal results for patients. 
 
2. 
The secondary outcome measures, albeit underpowered for clinical outcomes in 
this study, will hopefully still give a signal that achieving a target post PCI FFR ≥ 
0.90 does yield objective benefits for patients. This could then form the basis for 
a larger phase 3 trial to confirm improved clinical outcomes and cost-
effectiveness of FFR targeted PCI 
 
 
References 
 
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2. Tonino PA, De Bruyne B, Pijls NH, et al. FAME Study Investigators. Fractional flow 
reserve versus angiography for guiding percutaneous coronary intervention. N Engl J 
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