Accurate identification of potential critical coronary lesions for the reduction of risk of cardiovascular events: study protocol for a randomized, open-label, active-controlled multi-center trial

Wen-Bin Lu; Jian Zhu; Li-Juan Chen; Yu Wang; Yi Feng; Gen-Shan Ma

doi:10.4103/2542-3975.242958

STUDY PROTOCOL

Year : 2018 | Volume : 3 | Issue : 3 | Page : 106-110

Accurate identification of potential critical coronary lesions for the reduction of risk of cardiovascular events: study protocol for a randomized, open-label, active-controlled multi-center trial

Wen-Bin Lu MD, PhD , Jian Zhu, Li-Juan Chen, Yu Wang, Yi Feng, Gen-Shan Ma MD, PhD
Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, China

Date of Submission	21-May-2018
Date of Decision	02-Aug-2018
Date of Acceptance	04-Aug-2018
Date of Web Publication	23-Oct-2018

Correspondence Address:
Gen-Shan Ma
Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province
China
Wen-Bin Lu
Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province
China

Source of Support: This work was supported by the National Natural Science Foundation of China (No. 81670326); Social Development and Standardized Therapy for Key Diseases of Science and Technology Department of Jiangsu Province (No. BE2016785); Jiangsu Provincial Medical Youth Talent Project (No. QNRC2016814)., Conflict of Interest: None

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DOI: 10.4103/2542-3975.242958

Clinical trial registration NCT 03195621

Abstract

Background and objectives: The allocation of coronary artery disease patients with moderate coronary stenoses to interventional therapy or conservative treatment is a challenge because there is a lack of effective and accurate methods for identifying critical coronary lesions. This study is planned to determine whether therapy guided by identification of high-risk coronary plaque can reduce the risk of major adverse cardiovascular events (MACEs) in patients with critical lesions (50–75% stenoses).
Design: This is a randomized, open-label, active-controlled multi-center trial.
Methods: A total of 246 patients with suspected coronary artery disease will receive treatment guided by multimodality assessment (including risk factor score [RFS], fractional flow reserve [FFR], intravascular ultrasound [IVUS], or intracoronary optical coherence tomography [OCT] of coronary plaque) (RFS + FFR/IVUS/OCT group) versus treatment guided by routine assessment with 2D quantitative coronary angiography (QCA group).
Outcome measures: The primary endpoint will be MACEs from baseline to 24 months. The secondary endpoint will be the overall economic burden on patients from enrollment to the end of the 24 months.
Discussion: This study will assess the noninferiority of the treatment regimen for patients diagnosed with critical coronary lesions. The results may help to guide therapy to reduce the risk of MACEs.
Ethics and dissemination: This study was approved by the Medical Ethics Committee of Southeast University (approval number: 2017ZDSYLL023-p01). Dissemination plans include presentations at scientific conferences and publication in scientific journals.
Trial registration: ClinicalTrials.gov Identifier: NCT03195621, registered on June 22, 2017.

Keywords: coronary artery disease; critical lesions; percutaneous coronary intervention; risk stratification; randomized controlled trial

How to cite this article:
Lu WB, Zhu J, Chen LJ, Wang Y, Feng Y, Ma GS. Accurate identification of potential critical coronary lesions for the reduction of risk of cardiovascular events: study protocol for a randomized, open-label, active-controlled multi-center trial. Clin Trials Degener Dis 2018;3:106-10

How to cite this URL:
Lu WB, Zhu J, Chen LJ, Wang Y, Feng Y, Ma GS. Accurate identification of potential critical coronary lesions for the reduction of risk of cardiovascular events: study protocol for a randomized, open-label, active-controlled multi-center trial. Clin Trials Degener Dis [serial online] 2018 [cited 2023 Sep 23];3:106-10. Available from: https://www.clinicaltdd.com/text.asp?2018/3/3/106/242958

Introduction

Coronary artery disease (CAD) is the most common chronic cardiac disease. It is associated with impaired quality of life, increased risk of myocardial infarction (MI), heart failure, and death. Secondary prevention is necessary in most CAD patients, especially those with intermediate lesions (stenoses of 50–75%, named “critical lesions” here).^[1] It is well known that most myocardial infarctions (MI) occur due to the rupture of vulnerable plaques with < 70% stenosis. Recently, it has been suggested that acute coronary syndromes predominantly occur at the site of coronary stenoses of < 50%.^[2],[3] It is reported that approximately 6% of CAD patients diagnosed with critical lesions on angiography suffer from acute coronary events requiring interventional therapy over the subsequent 1 year. Studies have suggested that > 70% of critical lesions in acute MI (AMI) patients requiring interventional therapy were plaques of intermediate lesions detected in previous coronary angiography.^[4],[5],[6] Therefore, overlooking intermediate lesions may miss the real culprit lesion. Obviously, excessive intervention in mild and moderate stenosis increases patient suffering and medical costs. Most findings indicate that a mild stenosis with a thin fibrous cap is potentially more dangerous than a tighter stenosis without vulnerable plaque.^[7],[8]

To date, there have been rare prospective studies to solve this conundrum. More patients receiving percutaneous coronary intervention (PCI) combined with optimal medical therapy (OMT) exhibited a significant ischemia reduction. Patients experiencing ischemia reduction had lower unadjusted risk for death or MI, particularly when baseline ischemia was moderate and severe.^{[9],[10],[11]} However, the BARI-2D trial evaluated whether PCI or coronary artery bypass grafting combined with OMT would be better than OMT alone in patients with type 2 diabetes and they found that that all-cause mortality at 5-year follow-up did not differ between the two treatment strategies.^[12],[13] It is suggested that there is still controversy regarding treatment strategy for patients with stenoses ≥ 70%. The ESC 2010/2013 guidelines also suggest further assessing obstructive coronary artery stenosis, the amount of related ischemia, and the expected benefits on prognosis and/or symptoms when considering rehabilitation therapy.^[14] All of the above enabled the detailed evaluation of the coronary wall and atherosclerotic plaques in critical lesions.

Objectives

This randomized controlled trial will examine whether therapy under the guidance of quantitative coronary angiography (QCA) plus accurate assessment of coronary plaque using risk factor score (RFS), fractional flow reserve (FFR), intravascular ultrasound (IVUS), or optical coherence tomography (OCT) could reduce the risk of MACEs in patients with critical lesions, but not increase the overall economic burden of patients over the subsequent 2 years compared with therapy under the guidance of QCA only.

Methods/Design

Study design

The study will be a randomized, open-label, active-controlled, multi-center trial. As shown in [Figure 1], patients undergoing coronary angiography for the reason of chest tightness or chest pain with intermediate lesions will be randomly assigned to the QCA-directed treatment group (patients will receive treatments according to assessment from two experienced independent physicians) or RFS + FFR/IVUS/OCT-directed treatment group (patients will receive treatment based on further data detected by examination of the coronary lumen). The study will enroll 246 critical lesions of coronary artery disease (CTCAD) patients. In the research center, allocation will be achieved using sealed envelopes containing a computer-generated sequence.

Figure 1: The CTCAD trial.
Note: CAD: Coronary artery disease; RFS: risk factor score; FFR: fractional flow reserve; IVUS: intravascular ultrasound; OCT: optical coherence tomography; QCA: quantitative coronary angiography; OMT: optimal medical therapy; PCI: percutaneous coronary intervention; D2L2FSBH: Diabetes (2 points), Low density lipoprotein cholesterol (LDL-C ≥ 2.6 mM 2 score, LDL-C ≥ 2.0 mM 1 point), Family history of coronary artery disease (1 point), current/former smoker (1 point), Body mass index (BMI ≥ 28 kg/m² 1 point), treated/untreated hypertension (1 point).

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Inclusion and exclusion criteria

The trial will consist of at least 246 patients with suspected coronary artery disease with symptoms of chest tightness or chest pain; these patients will be scheduled to undergo coronary angiography. The inclusion criteria are as follows: (1) Agreement to participate in this study and provision of written informed consent; (2) men or non-pregnant women ≥ 18 and ≤ 80 years of age; (3) one or more critical lesions. Exclusion criteria include: (1) active liver disease (aspartate aminotransferase or alanine aminotransferase ≥ 3 times the normal value) or renal insufficiency (estimated glomerular filtration rate ≤ 60 mL/min); (2) uncontrolled hypertension (≥ 160/100 mmHg); (3) patients with coagulation disorders; (4) any contraindication against the use of anti-platelet drugs such as aspirin; (5) platelet count < 100 × 10^[9]/L or hemoglobin level < 100 g/L; (6) participation in another investigational drug or device study in the past 30 days before enrollment.

Information such as relevant medical history, smoking history, family history of cardiac diseases, vital signs, physical examination, New York Heart Association classification, weight, and height will be collected. The beginning time of the trial is defined as the time of randomization after quantitative coronary angiography. Actual treatment will begin after randomization. Once QCA or RFS + FFR/ IVUS/OCT-directed treatment is decided, therapy will be initiated. The cut-off values set for further PCI are: FFR ≤ 0.8; IVUS: a minimum lumen area < 4 mm² in LAD, LCX or RCA and a minimum lumen area < 6 mm² in the left main coronary artery; OCT: thickness of fibrous cap ≤ 65 µm. We will make a second random decision to choose further examination of FFR or IVUS or OCT in the RFS + FFR/ IVUS/OCT-directed treatment group. All patients included are required to be treated with secondary prevention of coronary artery disease for a minimum of 1 year including aspirin, angiotensin-converting enzyme inhibitors, beta blockers, the management of blood pressure and cholesterol, cigarettes, diet, diabetes control, education, and exercise.

The RFS used will be D2L2FSBH, in which diabetes adds 2 points, low density lipoprotein cholesterol (LDL-C ≥ 2.6 mM adds 2 points, LDL-C ≥ 2.0 mM adds 1 point, family history of coronary artery disease adds 1 point, current/former smoker adds 1 point, body mass index (BMI) ≥ 28 kg/m² adds 1 point, and treated or untreated hypertension adds 1 point. A D2L2FSB score ≥ 4 is to be considered high-risk.

All patients will be contacted during hospitalization as well as after discharge (at 1, 3, 6, 12, 24 months) (by phone or meeting). Patients will be monitored for compliance with oral drugs, primary and secondary outcome measures, and adverse events (AEs)/MACEs.

Outcome measures

The primary outcome measure will be MACEs (definition: death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina). The secondary outcome measure will be the overall economic burden on patients from enrollment to the end of the 24-month follow-up.

Ethics and informed consent

This study will be performed in accordance with the ethical principles of the Declaration of Helsinki and the International Conference on Harmonization and Good clinical practice. The study protocol, including the final version of the informed consent form (ICF) was approved by the Medical Ethics Committee (IEC) of Southeast University, China (approval number: 2017ZDSYLL023-p01). The investigator will offer written approval to the IEC before the enrollment of patients into the study. We will ensure that all patients are given full and adequate oral and written information about the nature, purpose, risks, and benefits of the study. All patients know that they are free to discontinue the study at any time. The patients’ signed and dated informed consent will be obtained before performing the study.

Sample size

The study is planned to investigate whether therapy based upon RSF plus accurate assessment of coronary plaque using FFR/IVUS/OCT can reduce the risk of MACEs in patients with critical lesions. The study will last for 36 months, and subject accrual (entry) will occur in the first 12 months and the followup visits will occur over the subsequent 24 months. Based on European Society of Cardiology guidelines^[14] on the management of stable coronary artery disease and some retrospective studies,^{[15],[16],[17],[18],[19],[20],[21]} 26% and 12% of MACEs in the QCA-directed treatment group and RFS + FFR/ IVUS/OCT-directed treatment group at 24 months, respectively, are anticipated. Thus the sample size is estimated to be 246 (123 in each group) with a drop-out rate of 5%, with an expected yield of 93 primary endpoint events, which would provide 80% power to test for superiority of RFS + FFR/ IVUS/OCT-directed treatment versus QCA-directed treatment at the 5% 2-sided alpha level (log-rank test) [Figure 2].

Figure 2: Two independence proportions (null case) power analysis.
Note: Group sample sizes of 123 in each group achieve 80% power to detect a difference between the group proportions of 0.14. The proportion in group one (the treatment group) is assumed to be 0.12 under the null hypothesis and 0.26 under the alternative hypothesis. The proportion in group two (the control group) is 0.12. The test statistic used is the two-sided Z test with pooled variance. The significance level of the test was targeted at 0.05. The significance level actually achieved by this design is not applicable.

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Statistical analysis

Data management and statistical analysis were performed using SAS software version 9.1 (SAS Institute, USA). A value of P < 0.05 was considered statistically significant. Data are expressed as the mean ± standard deviation. Categorical variables were compared using the chi-square test. Kaplan-Meier survival curves were used to compare event-free survival (the first occurrence of the clinical events) between groups.

Discussion

Percutaneous coronary angiography has been widely accepted as the gold standard to diagnose coronary artery disease.^[22] However, it is insufficient for the analysis of plaque components, especially in conditions of uncertain therapeutic strategy, and therefore, cannot be used to predict the risk status or vulnerability of atherosclerotic plaque. The recognition of such limitations has impelled the development of intracoronary technologies. Intracoronary assessment of stenosis severity is becoming more and more important. Studies have confirmed that the measurement of FFR during adenosine infusion is particularly helpful in identifying hemodynamically or functionally evident stenosis; it is also demonstrated that medical treatment provides better outcomes than immediate revascularization when FFR is > 0.80.^{[23],[24],[25]} Similar to FFR, the use of IVUS has been broadly used to investigate the stenosis severity in SCAD patients. The conventionally approved or accepted cut-off limit for IVUS is 3.5–4.0 mm² for major coronary artery stenosis and 6.0 mm² for left main stenosis.^{[26],[27],[28],[29],[30]} More recently, OCT has been developed as a new intracoronary imaging tool with superior resolution (less than 10 µm) able to offer detailed assessment of superficial components including measurements of the thickness of the fibrous cap of plaques.^{[29],[30],[31]}

We plan to use FFR/IVUS/OCT as the assessment tools in the experimental group mainly based on the following considerations: First, due to both locations of the lesion and the areas supplied by diseased blood vessels are different in each patient, different types of lesions may need a specific appropriate assessment method for further evaluation.^[32] Second, FFR, IVUS, and OCT are all the most commonly used intravascular assessment methods; the pros and cons of these assessment methods are also expected to be observed in this study.^[33] Third, we expect this study to be more practical for clinical practice and to benefit more patients.

Currently, few prospective randomized studies have been conducted in critical lesions. In the ACCELERATE trial, the primary endpoint occurred in 12.9% and 12.8% of the patients in the evacetrapib and placebo groups, respectively. In the FAME trail, after 5 years, MACEs occurred in 31% of patients (154 of 496) in the angiography-guided group versus 28% (143 of 509 patients) in the FFR-guided group. In the FAME II trial at three years, MACEs occurred was 10.1% versus 22.0%; another prospective study (NCT00180466), a natural-history study of coronary atherosclerosis, showed that the 3-year cumulative rate of MACEs was 20.4%. Considering the above studies, we hypothesize that 26% and 12% of MACEs will occur in the QCA-directed treatment group and RFS + FFR/ IVUS/OCT-directed treatment groups, respectively, at 24 months.

Conclusion

To date, there has been a lack of consensus among guidelines for patients with critical lesions. Excessive neglect of critical lesions may miss the real culprit stenoses. Furthermore, it is obvious that excessive intervention in intermediate lesions not only increases patient suffering but also increases medical costs. Our study is the first prospective, randomized and active-controlled one to assess whether treatment guided by assessment of coronary plaque content can reduce the risk of MACEs and not increase the overall economic burden in patients with critical lesions. This trial will help to explore and determine a new potential therapeutic regimen for patients with moderate coronary stenoses.

Trial Status

We are currently recruiting participants.

Additional file

Additional file 1: SPIRIT checklist.[Additional file 1]

Author contributions

Study conception and design, manuscript writing: WBL; ethics and statistical analysis of study: JZ; protocol registration: LJC; data collection and analysis, manuscript writing: YW and YF; study design and final approval of manuscript: GSM.

Conflicts of interest

The authors have no conflicts of interest to declare.

Financial support

This work was supported by the National Natural Science Foundation of China (No. 81670326); Social Development and Standardized Therapy for Key Diseases of Science and Technology Department of Jiangsu Province (No. BE2016785); Jiangsu Provincial Medical Youth Talent Project (No. QNRC2016814).

Institutional review board statement

This study was approved by the Medical Ethics Committee of Southeast University (approval number: 2017ZDSYLL023-p01). The trial was registered with ClinicalTrials.gov (identifier: NCT03195621)on June 22, 2017.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form, the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study followed the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Southeast University in China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data will not be available. However, the study protocol and informed consent form will be made available beginning 3 months and ending 5 years following article publication. In order to gain access, data requestors will need to sign a data access agreement. Proposals should be directed to [email protected].

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Funding: This work was supported by the National Natural Science Foundation of China (No. 81670326); Social Development and Standardized Therapy for Key Diseases of Science and Technology Department of Jiangsu Province (No. BE2016785); Jiangsu Provincial Medical Youth Talent Project (No. QNRC2016814).

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