A randomized controlled trial of a physiology-guided percutaneous coronary intervention optimization strategy: Rationale and design of the TARGET FFR study.

Post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) ≥0.90 confers an improved cardiac prognosis. There are currently limited data available to determine how often it is possible to improve an angiographically acceptable but physiologically suboptimal result. A physiology-guided optimization strategy can achieve a clinically meaningful increase in the proportion of patients achieving a final post-PCI FFR ≥0.90 compared to standard care. Following angiographically successful PCI procedures, 260 patients will be randomized (1:1) to receive either a physiology-guided incremental optimization strategy (intervention group) or blinded post-PCI coronary physiology measurements (control group). Patients undergoing successful, standard-of-care PCI for either stable angina or non-ST-segment-elevation myocardial infarction who meet the study's inclusion and exclusion criteria will be eligible for randomization. The primary endpoint is defined as the proportion of patients with a final post-PCI FFR result ≥0.90. Secondary endpoints include change from baseline in Seattle Angina Questionnaire and EQ-5D-5L scores at 3 months and the rate of target vessel failure and its components (cardiac death, myocardial infarction, stent thrombosis, unplanned rehospitalization with target vessel revascularization) at 3 months and 1 year. 260 individual patients were successfully randomized between March 2018 and November 2019. Key baseline demographics of the study population are reported within. TARGET FFR is an investigator-initiated, prospective, single-center, randomized controlled trial of an FFR-guided PCI optimization strategy. The study has completed recruitment and is now in clinical follow-up. It is anticipated that primary results will be presented in Autumn 2020.


| INTRODUCTION
The utility of fractional flow reserve (FFR) for assessing the physiological significance of coronary stenoses and the benefits of FFRguided decision making prior to percutaneous coronary intervention (PCI) have been well-established in randomized clinical trials. 1,2 However, FFR is rarely used to assess the final PCI result where standard practice continues to be angiographic assessment alone.  13 Published values for overall mean or median final post-PCI FFR results range from 0.84 to 0.95. 3,[5][6][7]9,12, The proportion of patients actually achieving a final FFR ≥0.90 varies widely between studies and ranges from 37% to 93%. [3][4][5][6][7][8]16,18,29,38,39 Of perhaps greater concern however, is the incidence of suboptimal FFR results after stenting. Where reported, the proportion of patients with post-PCI FFR values ≤0.80 ranges from 4% to 20%. 9,11,24,28,34,37,40 This indicates that, despite angiographically satisfactory results, as many as one in five patients may have a post-PCI FFR result that remains below the threshold for performing revascularization in the first place.
With up to 38% of patients still reporting angina 1 year after PCI procedures, 41 it seems plausible that persistently abnormal post-PCI FFR results may be associated with symptom recurrence.
It has been suggested that non-hyperemic pressure ratios (NHPRs), such as the instantaneous wave-free ratio (iFR), also have potential to be used as objective measures of improvement in physiology following PCI. 25 A recent study employing blinded post-PCI iFR assessments reported residual ischemia (iFR <0.90) in nearly one in four patients despite angiographically successful stenting results. The authors concluded that 81.6% of these cases were due to inapparent focal lesions potentially amenable to treatment with additional PCI. 42 While an NHPR-guided PCI optimization strategy might be more appealing to clinicians as it could facilitate multiple physiological assessments without the need to repeatedly induce hyperemia, data on the prognostic value of post-PCI NHPR values are currently lacking. The original NHPR, the ratio of distal coronary to aortic pressure (Pd/Pa) is routinely available with all diagnostic guidewires.
Recently, two new resting physiology indices have been developed which have diagnostic equivalence to iFR: the diastolic pressure ratio (dPR) and the resting full-cycle ratio (RFR). 43,44 One of the reasons clinicians do not routinely measure post-PCI FFR is that there are currently limited data available to determine how often it is possible to improve an angiographically acceptable but physiologically suboptimal result.
Given the potential prognostic significance of post-PCI FFR, but general lack of adoption, there is a clear need for randomized controlled trials to: 1. establish the prevalence of suboptimal post-PCI FFR results in clinical practice; 2. systematically categorize the remediable mechanisms where this occurs; 3. establish which PCI optimization strategies can effectively increase the proportion of patients with functionally optimal revascularization.

| METHODS
TARGET FFR is an investigator-initiated, prospective, single-center, randomized controlled trial of an FFR-guided PCI optimization strategy.
The primary hypothesis is that this strategy will result in a clinically meaningful increase in the proportion of patients achieving a final post-PCI FFR ≥0.90 compared to standard care. Following angiographically successful PCI procedures, 260 patients will be randomized (1:1) to receive either a physiology-guided incremental optimization strategy (PIOS intervention group) or blinded post-PCI coronary physiology measurements (control group). Patients undergoing successful, standard-of-care PCI for either stable angina or Non-ST segment elevation myocardial infarction (NSTEMI) who meet the study's inclusion and exclusion criteria (Table 1) will be eligible for randomization. All patients will complete the Seattle Angina Questionnaire (SAQ-7) and EQ-5D-5L questionnaire both prior to, and 3 months after, their procedure. Longer term outcomes will be assessed using record linkage. The study flowchart is depicted in Figure 1.

| Study endpoints
The primary endpoint is defined as the proportion of patients with a

| Study procedures
PCI procedures will be performed according to standard clinical practice. Treatment decisions (including the use of adjunctive intracoronary imaging such as OCT or IVUS) and the definition of an angiographically acceptable PCI result will be left entirely to the operator's judgment. The study protocol mandates that all enrolled patients should have pre-PCI coronary physiology assessments performed, however, the decision whether to then use the pressure wire for PCI or employ an alternative angioplasty wire is at the operator's discretion. Decisions on choice and duration of antiplatelet medications and/or combination with anticoagulant therapy will also be left to the operator's clinical judgment. Patients will only be randomized and post-PCI study measurements/interventions performed after the operator has declared the standard care procedure to be complete.

| PIOS intervention group (group A)
If post-PCI FFR is <0.90, the coronary physiology results and hyperemic pullback assessment will be disclosed to the operator. Based on the interpretation of the pullback recording, the operator will attempt to obtain the target optimal post-PCI FFR result by following the steps of the PIOS algorithm outlined below: • Patients >18 years of age with coronary artery disease including stable angina and NSTEMI • Participants must be able to provide informed consent Exclusion criteria • PCI in a coronary artery bypass graft • PCI to an ISR lesion • PCI to a target artery providing Rentrop grade 2 or 3 collateral blood supply to another vessel • Inability to receive adenosine (eg, severe reactive airway disease, marked hypotension, or advanced atrioventricular block without pacemaker). • Recent (within 1 week prior to cardiac catheterisation) STEMI in any arterial distribution (not specifically target lesion). • Severe cardiomyopathy (LVEF <30%). 3. If there is a step-up of ≥0.05 across a relatively focal (<20 mm) unstented segment that is technically suitable for further stenting, then a further stent should be deployed followed by repeat FFR.
4. If the FFR remains <0.90 after steps B ± C, a further FFR pullback will be performed. If the criteria for further stent optimization or implantation are again met, additional postdilation should be undertaken and/or one additional stent may be deployed followed by a final FFR pullback.

| Control group (group B)
In keeping with standard care, the operator will determine procedural completeness and success based on the angiographic and/or intracoronary imaging appearances. Post-PCI coronary physiology measurements will be performed but not disclosed to the operator.
No further intervention or optimization measures will be undertaken.

| Follow-up
Follow-up will be performed by clinical research nurses blinded to both the assigned treatment arm and the final FFR result. All patients will be contacted by letter and/or telephone 3 months after their PCI procedure to repeat the SAQ-7 and EQ-5D-5L questionnaires. In cases where an adverse event or clinical endpoint has occurred, additional information will be retrieved from the patient's electronic health record or general practitioner. Clinical outcomes will be reviewed again at 1 year using electronic health record linkage. have 90% power to detect a 20% difference between groups at the 5% significance level; therefore, 260 patients will be randomized.
Patients presenting with stable angina or NSTEMI who attend our institution for diagnostic coronary angiography proceed to PCI during the same procedure in approximately 40% of cases. It is therefore estimated that approximately 650 patients will be enrolled in the study in order to randomize 260 patients following their standard-ofcare PCI.

| Statistical analysis
The study data will be summarized for the randomized population overall, and by randomized group. The number of observations and number of missing values will be reported. Continuous variables will have normality tests applied and be summarized using the mean ± SD or median and interquartile range according to their distribution. Differences in continuous variables between randomized groups will be assessed using Student's t tests or Mann-Whitney U tests as appropriate. The Pearson correlation coefficient will be applied to parametric variables while correlation between nonparametric variables will be assessed using Spearman's rank correlation. Categorical variables will be summarized with frequencies and percentages. Differences in categorical variables between randomized groups will be evaluated using Chisquare tests or Fisher's exact tests.
Where relevant, changes from baseline will be summarized. Multivariate logistic regression analyses will be employed to assess for clinical predictors of post-PCI FFR values ≥0.90 and ≤0.80. The primary outcome will be summarized in the full analysis set as a whole and by treatment group. A test and 95% CI for two proportions (adjusted Wald method) will be employed, together with Fisher's exact test. Additional secondary analyses on this outcome will use logistic regression to investigate whether any of the baseline characteristics affect the outcome. This will be performed by first investigating each characteristic on its own (together with the treatment group). Any variables that are significant here will be added to build a larger model, bearing in mind sample size limitations. For the binary categorical secondary outcomes, the same analysis approach will be used as with the primary outcome. For quantitative secondary outcomes, two sample t tests or Mann Whitney U tests will be used as appropriate, as well as further analyses using regression to investigate whether any of the baseline characteristics affect the outcome. All tests will be two sided and a P-value of <.05 will be considered significant. Efficacy analyses will be carried out according to the intention to treat principle, that is, in relation to randomized treatment allocation, rather than treatment received. Safety analyses will be carried out in relation to treatment received. Details of subgroup and additional analyses are provided in the Supplementary Appendix.

| Study organization
The study received ethical approval from the West of Scotland  Table 3. The trial is now in clinical follow-up and it is anticipated the primary results will be presented in Autumn 2020. according to the target vessels involved. 46 Consequently, the PIOS intervention may not be effective at increasing the FFR value to such an extent, or at least, not in the proportions desired.

| Limitations
There are potential concerns regarding both performance and confirmation bias with this trial design and as such the following steps were taken to minimize their effects.
By its very nature, the PIOS group potentially receives more focused attention from the interventionalist than the control group.
Despite the operator's best efforts, this does not necessarily translate into higher final FFR values (the primary endpoint), however, and that is the question the trial seeks to answer-does routinely applying a post-PCI physiology-guided optimization strategy actually achieve a clinically meaningful difference in the proportion of patients with optimal final FFR results?
Following PCI procedures, the treating interventionalists reassured all patients that they received the highest standard of care, regardless of their randomization group. Specific results of the final physiology measurements were not disclosed to patients in either group.
In an effort to mitigate the potential Hawthorne ("observer") effect, the study could have on local PCI practices, other than cases Furthermore, we posit that rather than being subject to confirmation bias, the primary results of the trial will actually challenge such bias regarding the functional results of PCI procedures.

| SUMMARY
TARGET FFR is an investigator-initiated, prospective, single-center, randomized controlled trial to determine the feasibility and efficacy of using a coronary physiology-guided optimization strategy to achieve final post-PCI FFR results ≥0.90.