A Chronic Total Occlusion or CTO of a coronary artery is a an artery that has been blocked for >/= 3 months. More than a decade ago, patients with such coronary artery blockage would have been sent for Coronary Artery Bypass Graft (CABG) surgery. Newer tools and techniques have facilitated the opening (angioplasty or percutaneous coronary intervention (PCI)) of such occluded arteries- however success is not 100% unlike in simple coronary blockages.

Computed Tomography Coronary Angiography (CTCA) identifies the artery path and characteristics of the CTO including calcification - the latter many times is the reason for failure to cross the CTO.

The investigators aim to conduct a feasibility study to assess the effectiveness of CTCA prior to CTO PCI by randomizing suitable CTO patients to CTCA or direct CTO PCI.

20 patients will be randomized 1:1 using the sealed envelope technique and compared for:

Primary endpoint:

CTO PCI success rate in CTCA arm versus no CTCA arm

Secondary endpoints:

i. Angina by the Seattle Angina Questionnaire (SAQ) at 6 months (range 0-100, lower score worse, higher scores better, based on 5 characteristics - severity, frequency, treatment satisfaction and quality of life scores).

ii. Compare the number of patients who required a second CTO PCI procedure in the CTCA arm versus no CTCA arm iii. Procedural differences between the intervention CTCA arm versus no CTCA arm including: Health Economics: Cost saved per patient due to improved success and reduction in readmission or further procedure CTO PCI efficiency: Wire crossing time, Procedure time CTO PCI safety outcomes: Procedural complications (Ellis perforation, tamponade, acute kidney injury/contrast induced nephropathy, access site bleeding, donor vessel injury), Radiation: CTCA dose, CTO PCI dose, and combined CTCA and CTO PCI dose. Contrast: CTCA volume, CTO PCI volume, and combined CTCA and CTO PCI volume Change in CTO PCI strategy hierarchy as a result of the CTCA review

Patients will have a telephonic follow up at 6 months to assess angina ( by the Seattle Angina Questionnaire)

Computed Tomography Coronary Angiography (CTCA) prior to Chronic Total Occlusion (CTO) Percutaneous Coronary Intervention (PCI) - a feasibility study

Summary of Trial design:

Randomised, prospective, single centre feasibility study of CTCA prior to CTO PCI

Site and Chief Investigator:

Sandwell and West Birmingham NHS Trust, Birmingham, United Kingdom Vinoda Sharma

Participant population Patients undergoing CTO PCI Planned sample size 20 Number of sites 1 Intervention duration Prior to index CTO PCI procedure Follow up duration 6 months Planned trial duration 1 year Primary objective: To determine if CTCA prior to CTO PCI results in improved procedural success rate? Secondary objectives: i) To determine if CTCA prior to CTO PCI results in improved angina as determined by Seattle Angina Questionnaire (SAQ)? ii) To determine if CTCA prior to CTO PCI reduces the need for a second procedure due to improved procedural success rate? iii) Are there procedural differences between the intervention arm (CTCA) and usual care Intervention Randomised to CTCA versus no CTCA prior to CTO PCI

ABBREVIATIONS:

AUC: Area Under the Curve

CABG: Coronary Artery Bypass Graft

CAD: Coronary Artery Disease

CTCA: Computed Tomography Coronary Angiogram

CTO: Chronic Total Occlusion

J-CTO: Japanese Chronic Total Occlusion NHS: National Health Service

PCI: Percutaneous Coronary Intervention

QALYS: Quality Adjusted Life Years

QoL: Quality of Life

SAQ: Seattle Angina Questionnaire

UK: United Kingdom

Trial Protocol Synopsis Item Description

Title Computed Tomography Coronary Angiography (CTCA) prior to Chronic Total Occlusion (CTO) Percutaneous Coronary Intervention (PCI)

Introduction

Description of research question Null Hypothesis:

CTCA performed prior to CTO PCI will not improve procedural success

Existing knowledge:

A chronic total occlusion (CTO) is present in 15-20% of patients with angina who are referred for coronary angiography. Due to the complexity of occlusive coronary artery disease (CAD), including a high prevalence of calcium and tortuosity within long segments of disease, CTO PCI is associated with higher procedural complication rates. Inability to detect the intraluminal path in the CTO artery, combined with calcification and tortuosity can result in unsuccessful guidewire crossing and procedural failure.

Successful CTO PCI has been shown to improve Quality of Life (QoL) at 12 months. These patients are more likely to be angina free at 12 months as assessed by the Seattle Angina Questionnaire (SAQ) (7, 8). CTO PCI in symptomatic patients is cost effective and results in greater quality-adjusted-life-years (QALYS).

CTO percutaneous coronary intervention (PCI) procedure success rates increased from 68% to 79% between 2000 and 2011, and are as high as 90% when performed by high-volume CTO operators (2, 3). Complexity of the CTO is determined by several factors and several CTO complexity scores, derived from (invasive) angiographic lesion and clinical characteristics, have been shown to correlate with procedural success and complication rates (JCTO, PROGRESS, RECHARGE, Euro-CASTLE).

The most commonly utilized score is the J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) which assigns a score of 1 each to the angiographic CTO proximal cap (tapered or blunt), calcification, tortuosity (>45degrees), lesion length (≥20mm) and previous failure, with a maximum score =5. Scores ≥2 are considered CTOs that are difficult to perform and require advanced techniques for successful revascularization.

In a proportion of these patients, the first procedure either fails completely or partially succeeds in forming a tract within the occluded artery but this is inadequate for stent delivery and the patient requires a second procedure, occasionally a third for complete success and reconstruction of the fully occluded artery.

Angiographically, the CTO artery usually shows a short proximal portion of dye filled artery prior to the occlusion. In most patients there are some collaterals from the contralateral coronary artery which try to fill part of the occluded CTO artery. However the actual body of the CTO is not visible angiographically.

Computed Tomography Coronary Angiography (CTCA) can delineate the coronary anatomy in 3-dimensions, determining atherosclerotic plaque and occlusion location, severity and morphology. This makes it an attractive modality to assess the coronary CTO. Development of a CTCA based complexity score for stratifying CTOs by difficulty resulted in the CT-RECTOR score (Computed Tomography Registry of Chronic Total Occlusion Revascularization, table 1). Variables included in this score are multiple occlusions, blunt stump, severe calcification, bending, duration of CTO ≥12 months and previously failed PCI (all scored 1). The CT-RECTOR score correlates with the J-CTO score and has a better area under ROC curve (ROC AUC 0.83 for CT-RECTOR score and 0.71 for J-CTO, p < 0.001) and predicts CTO PCI success.

The role of routine CTCA pre-CTO PCI is as yet undefined as current practice involves the use of CTCA in patients who have had an unsuccessful CTO PCI attempt or previous coronary artery bypass grafting (CABG).

Need for a feasibility study:

Current practice at our center involves the use of CTCA in patients who have had an unsuccessful CTO PCI attempt or previous coronary artery bypass grafting (CABG) but the role of routine CTCA pre-CTO PCI is as yet undefined.

The small additional investment of a CTCA could help plan/improve a complex procedure and may reduce the need for additional procedures and readmissions.

The mean acute treatment cost of a CTO PCI is approximately (combined day-case -ordinary elective spell) £6933 whereas the approximate cost of a CTCA is £360 (as per local billing). Elective readmission for a failed CTO PCI procedure would entail an additional financial (to the provider) and emotional cost (to the patient).

The cost of an additional CTO PCI procedure aside, readmission and bed charges themselves can reach £1000/day (readmission =£255/day) and bed cost=£600/day). Including the cost of a second CTO PCI procedure (combined day-case -ordinary elective spell) £6933 - the overall cost can total to £10,000. In contrast, the cost of a CTCA is £360 (as per local billing).

Financial costs are one part of the issue, but a second CTO PCI procedure can also heighten patient anxiety and discomfort which are well known in patients prior to any PCI.

A feasibility study will help establish the role of a CTCA prior to CTO PCI to positively influence strategy and/or outcomes.

Methods:

Study setting: Sandwell and West Birmingham NHS Trust, Birmingham, United Kingdom.

Trial design: This is a randomized (1:1), prospective, single center study. Patients with suitable eligibility criteria will be included and randomized to CTCA or no CTCA prior to CTO PCI and the primary and secondary outcomes compared between the two groups

Sample size: This is a feasibility study- to ensure completion within a year, the investigators have estimated 20 patients, randomized 1:1 to each arm (10 patients per arm) as a sample size in a moderate size hospital which performs approximately 100 CTO PCIs annually.

Intervention assignment: Block randomization with sealed envelope technique.

Participant/project timeline: To complete: 1 year

Data collection, management and analysis

• eCRF (electronic Case Report Form) and online database to collect demographic, procedural and SAQ information
• SAQ at 6 months post PCI
• Blood samples pre and post PCI
• Comparison of demographics, procedural details, procedural success and complications, bloods, SAQ, and financial cost between the CTCA and non-CTCA groups
• Categorical variables will be presented as percentage and compared with the chi square or Fisher's test
• Continuous variables will be presented as median (range) and compared with student's t-test or Mann Whitney test.
• In addition, modelling will be performed by binary logistic regression analysis to predictors of CTO PCI success.

Monitoring: CTO PCI procedural adverse events will be reported as usual on the national database and this data will be collected in the eCRF.

Ethics: Ethical approval for this prospective study has been obtained All patients will be consented prior to inclusion in this study.

Blood: Routine blood tests will be performed immediately before the CTO PCI and after the procedure prior to discharge-this is standard of care.

Inclusion Criteria:

• ≥18 years
• CTO with J-CTO score≥2
• Appropriate indication for CTO PCI
• Adequate CTCA images for analysis

Exclusion Criteria:

• <18 years of age
• CTO with J-CTO score<2
• Inadequate/degraded CTCA images
• Pregnant/lactating women
• Patients with severe contrast allergy
• Patients unable to provide written informed consent