Predictors and Long-term Incidence of In-stent Restenosis After Chronic Total Occlusion Percutaneous Coronary Intervention

Predictors and Long-term Incidence of In-stent Restenosis After Chronic Total Occlusion Percutaneous Coronary Intervention: a Cohort Study

The goal of this clinical trial is to describe the long-term (≥ 3 years) patency of coronary artery stents following chronic total occlusion percutaneous coronary intervention (CTO PCI). The main questions it aims to answer are:

• What is the incidence of in-stent restenosis after CTO PCI?
• What are patient-, lesion-, and procedure-related factors associated with an increased risk of in-stent restenosis after CTO PCI?

Study Overview

• Status: Completed
• Conditions: Chronic Total Occlusion of Coronary Artery; Coronary Artery Disease (CAD); Chronic Total Occlusion (CTO)
• Intervention / Treatment: Procedure: chronic total occlusion percutaneous coronary intervention (CTO PCI); Diagnostic test: coronary computed tomography angiography; Diagnostic test: invasive coronary angiography

Detailed Description

This study was approved by the ethics committee of Helsinki University Central Hospital (approval number HUS/12527/2022) and complied with the Declaration of Helsinki.

Patient selection Study participants were selected from a registry that included stable coronary artery disease patients with a chronic total occlusion (CTO) treated with percutaneous coronary intervention (CTO PCI) in Helsinki University Central Hospital 2014-2021. Optimal medical therapy was prescribed to all patients at the time of CTO PCI. All patients, who received surveillance imaging, gave written, informed consent prior to the beginning of the study.

Definition Segments extending 5 mm proximal and 5 mm distal to the stent were included as part of the stent for the evaluation of in-stent restenosis (ISR). CTO stents consisted of one or more coronary artery stents, potentially involving different stent types. Stent overlap was taken into consideration in cases of multiple stents. In coronary computed tomography angiography (CCTA) radiological ISR was defined as luminal narrowing of ≥ 50 % within the CTO stent. In native coronary arteries, stenosis was classified as minimal (<25 %), mild (25-49 %), moderate (50-69 %), severe (70-99 %), and total occlusion (100 %).

In CCTA, a non-contrast calcium score was obtained initially. This was followed by third-generation dual-source CCTA (Somatom Force, Siemens) using contrast medium (Omnipaque 350, GE Healthcare). Sublingual nitroglycerin was administered prior to scanning. The imaging protocol was optimised according to the patient's heart rate and in cases where the heart rate exceeded > 70/min, intravenous metoprolol was administered.

Patients' symptomatic status at the time of surveillance imaging was assessed using the Canadian Cardiovascular Society (CCS) classification via a telephone interview. For patients without study-driven surveillance imaging, the CCS classification at clinical imaging follow-up was determined based on electronic medical records.

CCTA results and clinical data were reviewed by the interventional cardiologists of the study, and invasive coronary angiography (ICA) was offered to patients with:

1. ISR or inconclusive finding in the long CTO stent.
2. Anginal symptoms with ≥ 50 % stenosis or inconclusive finding in any native coronary artery or non-CTO stent.

In ICA, ISR was defined as ≥ 50 % luminal narrowing in the stent. Physiological assessment (fractional flow reserve) and intravascular imaging (intravascular ultrasound, optical coherence tomography) were performed during ICA at the discretion of the interventional cardiologist. Any incidental findings were evaluated separately.

Patient-, lesion-, and procedure-related factors examined in the study:

age (years), body mass index (kg/m2), sex, smoking history, medical conditions at CTO PCI (diabetes, insulin required diabetes, heart failure, peripheral artery disease, dyslipidemia, hypertension, pulmonary disease, chronic kidney disease, atrial fibrillation, cardiac pacemaker, prior myocardial infarction, prior stroke, prior PCI, prior coronary artery bypass surgery (CABG)), double-CTO (two treated CTO:s in one procedure), primary procedure in-stent CTO, a non-CTO stent implanted in the CTO PCI procedure, clinical presentation (stable angina pectoris or acute coronary syndrome), stented vessel (right coronary artery, right coronary artery vein graft, left anterior descending coronary artery, left circumflex coronary artery), Japanese-CTO score (objective index of CTO procedure difficulty), access site (femoral or radial approach), procedural characteristis (antegrade or retrograde procedure, utilisation of a re-entry device), stent parameters (number of consecutive stents, stent length (mm), stent diameter (mm)), symptomatic status at stent imaging (assessed with CCS classification grade 0-IV)

To provide clinical context for the study's main research questions, other prespecified endpoints were: complications (access site complication, coronary perforation, pericardial centisis, left ventricle assist device, acute kidney injury, procedural death), all-cause death, time to all-cause death (years), cardiovascular death, myocardial infarction, stroke, target lesion revascularisation, stent thrombosis, any coronary artery revascularisation and combined clinical outcome (including all-cause death, MI, stroke and any revascularisation)

Statistical analysis Descriptive statistics were presented as median and interquartile range (IQR) or range (minimum-maximum) for continuous variables, and as frequency (%) for categorical variables. The temporal distribution of all-cause death and ISR was analysed using Kaplan-Meier curves, with two-sided 95% pointwise confidence intervals. For ISR analysis, patients were censored at the time of death, end of follow-up, or TLR in the absence of prior ISR. Fatal clinical outcomes were presented as Kaplan-Meier estimates. Non-fatal clinical outcomes were presented as Kaplan-Meier estimates, with censoring at death or end of follow-up; for stent thrombosis, patients were censored at death, end of follow-up, or TLR. Predictors of ISR were assessed using logistic regression models that included baseline patient and procedural variables. A p-value <0.05 was considered statistically significant. All variables were first analysed in univariate models and subsequently entered into multivariate analysis if statistical significance was reached. There were no missing data for the variables used in any analyses and no imputation was performed. Statistical analyses were performed with JMP version 18.2.0 (JMP Statistical Discovery LLC).

Descriptive statistics were presented as median and interquartile range (IQR) or range (minimum-maximum) for continuous variables, and as frequency (%) for categorical variables. The temporal distribution of all-cause death and ISR was analysed with Kaplan-Meier curves. Predictors of ISR were assessed using logistic regression models, that included baseline patient and procedural variables. A p-value <0.05 was considered statistically significant. All variables were first analysed in univariate models and subsequently entered into multivariate analysis if statistical significance was reached. Statistical analyses were performed with JMP version 18.2.0 (JMP Statistical Discovery LLC, Cary, NC, USA).

• Study Type: Interventional
• Enrollment (Actual): 294
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00290
      • Helsinki University Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Study inclusion criteria were the following:

• Successful CTO PCI with a drug-eluting stent
• Primary procedure minimum of 3 years prior to study date

Of the included patients, CTO stent patency surveillance imaging with CCTA was conducted according to the following criteria. Patients were consecutive and prospectively recruited.

Surveillance imaging inclusion criteria

• Surviving patients ≤ 80 years old at the time of surveillance imaging
• Communication in Finnish, Swedish or English

Exclusion Criteria:

• Target lesion revascularisation or angiographically verified ISR after CTO PCI
• Malignancy with ongoing diagnostics or poor prognosis
• Considerable functional impairment in activities of daily living
• Presence of a clinically significant psychiatric disorder
• Ongoing alcohol or drug abuse
• Presence of a memory disorder or other clinically significant cognitive impairment
• Coronary artery bypass surgery (CABG) after CTO PCI
• Estimated glomerular filtration rate ≤40 ml/min
• invasive coronary angiography performed less than 6 months prior to the surveillance imaging date

CCTA results were reviewed by the interventional cardiologists of the study and ICA was offered to patients with:

1. ISR or an inconclusive finding within the CTO stent.
2. Anginal symptoms with either ≥ 50 % stenosis or an inconclusive finding in any native coronary artery or within a non-CTO stent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Study population; All patients included in the study

Procedure: chronic total occlusion percutaneous coronary intervention (CTO PCI); All patients in the study have received CTO PCI with a drug-eluting stent.; Diagnostic test: coronary computed tomography angiography; Patients meeting the surveillance imaging criteria received computed tomography angiography.; Diagnostic test: invasive coronary angiography; According to the study criteria, some of the patients received confirmation imaging with invasive coronary angiography after coronary computed tomography angiography.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of long-term ISR after CTO PCI	ISR was defined as a ≥ 50 % luminal diameter narrowing within the coronary artery stent.	Through study completion, up to 10.9 years, with an average follow-up of 7.1 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of procedural complications	Incidence of procedural complications (access site complication, coronary artery perforation, pericardiocentesis, left ventricular assist device use, acute kidney injury, procedural death).	Perioperative/Periprocedural
Incidence of clinical endpoints	Incidence of clinical endpoints during follow-up (all-cause death, cardiovascular death, myocardial infarction, stroke, target lesion revascularisation, any coronary artery revascularisation, stent thrombosis, combined clinical outcome (including all-cause death, MI, stroke and any revascularisation))	Through study completion, up to 10.9 years, with an average follow-up of 7.1 years.

Collaborators and Investigators

• Sponsor: Lauri Mansikkaniemi
• Investigators: Principal Investigator: Petri Laine, Ph.D., Department of Cardiology, Heart and Lung Center, Helsinki University Central Hospital and University of Helsinki

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2023
• Primary Completion (Actual): February 6, 2025
• Study Completion (Actual): February 24, 2025

Study Registration Dates

• First Submitted: November 25, 2025
• First Submitted That Met QC Criteria: March 12, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: percutaneous coronary intervention; coronary artery disease; chronic total occlusion; drug-eluting stent; in-stent restenosis
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Ischemia; Coronary Artery Disease
• Other Study ID Numbers: HUS/12527/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No