Title:

Combined Optical Coherence Tomography Morphologic and Fractional Flow Reserve Hemodynamic Assessment of Non-Culprit Lesions to Better Predict Adverse Event Outcomes in Diabetes Mellitus Patients COMBINE (OCT-FFR) Prospective Register

To study the natural evolution of patients with at least one intermediate angiographic but non-hemodynamic significant stenotic lesion, in two subgroups of patients, with TCFA vs. no TCFA as detected by OCT imaging and to compare these two groups of patients with each other as well as to a subset of patients with FFR-positive and PCI-treated intermediate lesions on future MACE.

Hypothesis Diabetes Mellitus (DM) patients with angiographically intermediate coronary lesions remain at risk for future MACE events, including those patients with fractional flow reserve (FFR) negative lesions. Use of FFR measurements combined with Optimal Coherence Tomography (OCT) detection of thin-cap fibroatheroma (TCFA) in will help predict future MACE rates.

Objective To study the natural evolution of patients with at least one intermediate angiographic but non-hemodynamic significant stenotic lesion, in two subgroups of patients, with TCFA vs. no TCFA as detected by OCT imaging and to compare these two groups of patients with each other as well as to a subset of patients with FFR-positive and PCI-treated intermediate lesions on future MACE.

Design Prospective, open label natural history registry. DM patients bearing target lesions {Any de novo lesion with an angiographic visual estimation of ≥ 40%- ≤ 80% Diameter Stenosis (DS) that is located in a non-grafted coronary segment. In patients with an MI at presentation the target lesion should be different from the culprit lesion} and have undergone FFR and OCT imaging as for clinical routine will be prospectively enrolled and followed. Patients with negative FFR (> 0.80) will be divided in two categories depending on corelab OCT imaging findings: No-TCFA (cap thickness >65µ) (Group A) or TCFA (cap thickness ≤ 65µ) (group B). All patients that had a positive FFR and therefore have been treated with PCI as per standard care in all target lesions will also be followed (group C), however if after the PCI there is at least one remaining target lesion where FFR was negative these patients should be followed in group A or B depending on the OCT findings. Clinical endpoints at 1.5 year will be recorded.

The investigators strongly recommend that all major epicardial coronary vessels of stentable size that show any form of atherosclerosis to be interrogated with FFR and OCT.

The investigators strongly recommend to not perform cap thickness measurements in the cathlab. The plaque cap thickness as measured in the corelab will not be disclosed to operators and patients.

Population Patients aged ≥18 years Diabetes mellitus (DM) patients with any presentation. Coronary angiography, FFR and OCT imaging in at least one coronary de novo stenosis in a native vessel with a visually estimated diameter of stenosis (DS) of ≥ 40%-≤ 80% (target lesion).

Angiographic criteria target lesion:

(i) ≥ 40%-≤ 80% diameter stenosis (DS) (ii) de novo lesion located in native non-grafted vessel (iii) target lesion reference diameter of ≥ 2.0 mm (iv) TIMI 3 flow

Primary Endpoint The per patient incidence of the target lesion(s) related composite MACE defined as Cardiac Death, MI, clinically-driven target lesion revascularisation or hospitalization due to unstable or progressive angina at 18 months in the FFR-negative No-TCFA (Group A) and FFR-negative TCFA (Group B).

Statistics This is an observational study (prospective natural history register) where no randomization takes place, therefore a power calculation is strictly not necessary.

However, in order to observe meaningful differences between groups (as described in the design) and deduct founded conclusions, the minimal number of patients required was calculated as follows. The target lesion related primary endpoint at 18 months in the A and B group respectively are assumed to be 5 % and 20% respectively. Taking into account an expected loss in FU of 7%, a total of 500 patients enrolled in the study will provide 80% power to reject the null hypothesis with 5% type I error (alpha). The enrolment in group C will stop after the first 166 patients have been enrolled in this group. The rest of the rest of 334 patients will be distributed in groups A and B depending on the OCT corelab findings. Nul hypothesis: the MACE rate in group B is not different from group A.

Inclusion Criteria:

1. Age ≥ 18 years
2. History of DM with any indication for angiography (Stable Angina (SA) or any type of Acute Coronary Syndrome (ACS) including ST-Elevation MI).
3. Coronary angiography, including FFR and OCT imaging of at least one coronary de novo stenosis in a native not-grafted vessel with a visually estimated diameter stenosis (DS) of ≥ 40 - ≤ 80% (target lesion) . Target lesion should be other than the culprit lesion(s) in patients presenting with MI (STEMI or non-STEMI).

Exclusion Criteria:

1. TIMI flow < 3 in the target lesion(s)
2. Target lesion reference diameter (on visual estimation) < 2.0 mm
3. Known left ventricular ejection fraction <30%
4. Known malignancy
5. Life expectancy < 2 years
6. Unwilling or unable to provide inform consent

The COMBINE (OCT-FFR) Trial is an investigator driven study: a prospective natural history registry. Patients aged ≥ 18 years bearing target lesions (see definition section) that fulfil the inclusion criteria and have undergone FFR and OCT imaging as per clinical practice will be enrolled in the study.