Introduction
Percutaneous coronary intervention (PCI), especially stent implantation, is recognised as the most important treatment for symptomatic myocardial ischaemia and acute coronary syndrome (ACS). However, following coronary stent implantation, 5–10% of patients experience in-stent restenosis (ISR) even with the advent of new-generation drug-eluting stents (DES),1–3 which is an important cause of PCI failure. Obviously, management of patients with ISR represents an international difficulty and research hotspot. Current clinical practice guidelines recommend drug-eluting balloons (DEB) or DES as main treatment for ISR.4 5 However, there are still 10–30% of the ISR requiring repeated revascularisation after DES/DEB treatment,6 which significantly increases the incidence of the major adverse cardiovascular and cerebrovascular events (MACCEs) and brings serious psychological stress and economic burden to patients. Therefore, effective management is urgently needed to be established to mitigate the risk of repeated ISR and MACCEs in patients with recurrent ISR (RISR) after interventional therapy.
Inflammatory response is widely considered as a pivotal mechanism of RISR. Previous studies have suggested that anti-inflammatory (AI) drugs (colchicine and prednisone) can reduce the incidence of ISR after bare metal stent (BMS) implantation, in parallel with the decrease of revascularisation and MACCEs.7–9 Nevertheless, there has been no prospective study on the efficacy of these AI drugs in patients with RISR after DES implantation.
A preliminary small-sample study of our team showed that a couple of RISR patients, who were given oral prednisone after PCI (DEB), nine of them did not develop ISR, and the rest unfortunately recrudesced due to the discontinuation of prednisone for lung cancer combined with systemic vasculitis requiring surgery. This small-sample clinical observational study showed a significant effect of oral prednisone in the prevention and treatment of RISR. Therefore, the current AI-ISR study is aimed at testing the hypothesis that low-dose colchicine or prednisone treatment for 12 months after PCI can prevent the re-occurrence of ISR in RISR patients.
Methods
Study identification
The AI-ISR trial is a prospective, randomised, open-label, multicentre clinical study in China. Its objective is to determine whether low-dose colchicine or prednisone can provide additional benefits in reducing the incidence of ISR and MACCEs, apart from standard medications and interventional therapy (figure 1).
ISR trial flowchart. AI, anti-inflammatory; DEB, drug eluting balloon; DES, drug eluting stent; ISR, in-stent restenosis; PCI, percutaneous coronary intervention.
A total of 15 centres (including the principal site, listed in table 1) are expected to participate. The study was registered on the ClinicalTrials.gov, with the registration number of NCT06090890 and was initially released on 15 October 2023. The study officially commenced on 30 October 2023, with a planned primary completion date of 29 October 2026, and an anticipated overall study completion date of 29 October 2027.
List of participating centres, arranged by number
Eligibility
Patients presenting with RISR will undergo preliminary screening to determine their qualification based on the inclusion and exclusion criteria listed in boxes 1 and 2. Notably, intravascular imaging (IVI) (either intravascular ultrasound (IVUS) or Optical Coherence Tomography (OCT)) will be used to rigorously exclude procedural or mechanical causes of ISR, such as stent under-expansion, malapposition or stent fracture. In addition, neoatherosclerosis as a cause of restenosis will also be ruled out through imaging assessment. To further ensure that the enrolled population reflects a non-mechanical, inflammation-driven RISR phenotype, we will exclude patients with systemic vasculitis, autoimmune diseases or metal/polymer hypersensitivity. This will be achieved by reviewing relevant laboratory and immunological parameters, including C reactive protein (CRP), erythrocyte sedimentation rate (ESR), Antinuclear Antibody (ANA)/Antineutrophil Cytoplasmic Antibody (ANCA), and results from metal allergen testing.
Inclusion criteria
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CAD patients over 18 years old
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At least one coronary artery lesion meets the RISR criteria: target lesion ≥2 ISRs, defined as a binary restenosis ≥50% at the stent segment or its edges (5 mm mm segments adjacent to the stent)
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Intended intervention treatment for RISR lesions
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Acceptable for standard secondary prevention drug for CAD, including DAPT and statins
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Willing to participate in the trial and complete follow-up and is able to sign an informed consent approved by the ethics committee
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CAD, coronary artery disease; DAPT, dual antiplatelet therapy; RISR, recurrent in-stent restenosis.
Exclusion criteria
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The previous interventional treatment situation is unknown.
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The mechanism of intracavitary imaging to clarify ISR is operator-related (poor stent adhesion, incomplete dilation and stent fracture).
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Clearly diagnose vascular inflammatory diseases or connective tissue diseases (including arteritis, Behçet’s disease, systemic lupus erythematosus, etc) involving the coronary artery
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Immunosuppressive drugs, including glucocorticoids, have been used in the past 30 days.
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There are contraindications to the use of prednisone or colchicine, including: serious infectious diseases, including active infection, hepatitis B, hepatitis C or AIDS patients; haematological diseases, such as thrombocytopenia, severe anaemia, leukaemia, etc, uncontrolled diabetes; severe liver and kidney function damage; active peptic ulcer or gastrointestinal bleeding; severe osteoporosis (with previous pathological fractures); inflammatory bowel disease or chronic diarrhoea.
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A history of malignant tumours within 3 years.
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Cognitive disorder
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Not willing to participate or follow-up
A total of 252 eligible patients will be enrolled into the trial after signing the informed consent.
Intervention measures
Eligible RISR patients (n=252) are randomly allocated (1:1:1) to three groups: standard medications (control group); standard medications with low-dose colchicine (colchicine group); standard medications with prednisone (prednisone group). Standard medications include routine dual antiplatelet therapy (DAPT) after PCI, lipid-lowering drugs and active pharmacological treatment to manage blood pressure and blood glucose if there are indications. DAPT (aspirin 100 mg once per day combined with either clopidogrel 75 mg once per day or ticagrelor 90 mg two times per day) should be used after PCI for at least 1 year in patients treated with re-implanting DES and for at least 3 months in patients treated with DEB dilation. Lipid-lowering therapy will consist of at least moderate-intensity statin treatment, with Low-Density Lipoprotein Cholesterol (LDL-C) goals set at <1.4 mmol/L. If LDL-C targets are not achieved, ezetimibe or PCSK9 inhibitors will be added as appropriate. In addition, blood pressure and blood glucose levels will be actively managed to meet recommended targets using appropriate pharmacological therapies. These strategies apply equally across all treatment arms to ensure consistency and allow the effects of colchicine and prednisone to be evaluated on top of standardised background therapy.
Colchicine (0.5 mg/day orally) should be used within 48 hours after PCI and the dose of prednisone was 0.5 mg/kg/day orally for 1 month following with reduced dose at a rate of 5 mg/day per month to 5–10 mg/day, maintained for 1 year after PCI.
Randomisation
A computer-based central randomisation system is applied in the trial. The Statistics Center of Fuwai Hospital Chinese Academy of Medical Sciences (Beijing, China) is responsible for the operation and maintenance of the randomisation system. After screening, the information of eligible patients will be entered into an Interactive Web Respond System and the system will immediately generate and release the random codes and grouping information.
Baseline evaluation
Baseline evaluation is performed within 2 days after randomisation. The items for baseline evaluation are listed in detail in box 3.
Baseline
Epidemiological background
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Age (year)
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Male
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BMI
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Smoking
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Hypertension
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Diabetes; insulin-treated
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LVEF, %
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Family history of CAD
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History of gout
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History of renal dysfunction
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Clinical presentation; Stable CAD; ACS
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CRP
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ESR
Discharge medications
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Aspirin+clopidogrel
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Aspirin+ticagrelor
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Statin
Procedure-related parameters
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ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; CRP, C reactive protein; CTO, chronic total occlusion; ESR, erythrocyte sedimentation rate; ISR, in-stent restenosis; LAD, left anterior descending coronary; LCX, left circumflex artery; LVEF, left ventricular ejection fraction; RCA, right coronary artery.
Follow-up and endpoints
Follow-up will consist of monthly telephone interviews, quarterly outpatient clinic visits and a detailed inpatient assessment at the 12-month endpoint (box 4). The primary endpoint of the AI-ISR trial is target lesion ISR confirmed by coronary angiography at 12 months. The secondary endpoints are about the clinical outcomes, such as MACCE, TLR and other coronary artery disease revascularisation at 12 months.
Endpoints (12 months after intervention)
Primary endpoint
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Target lesion ISR confirmed by coronary angiography
Secondary endpoints
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MACCEs, the composite of cardiovascular death, myocardial infarction, stroke and target vessel revascularisation
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Target lesion revascularisation
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Revascularisation of other coronary artery lesions
ISR is defined as ≥50% luminal narrowing at the stented segment or its 5 mm proximal/distal edges, confirmed by quantitative coronary angiography. To minimise assessment bias, all coronary angiograms will be evaluated centrally by a Core Lab composed of three experienced interventional cardiologists from the coordinating centre. These experts will assess the angiograms independently and in a blinded manner.
In addition, all endpoint events will be adjudicated by an independent, blinded Clinical Events Committee (CEC). The CEC consists of three experienced clinical experts who are not involved in patient follow-up or data management. For each suspected endpoint event, relevant medical records and diagnostic results will be uploaded to a secure, blinded adjudication system. All identifiable patient information and treatment group assignments will be removed prior to review. Each CEC member will evaluate the event independently based on prespecified criteria. If discrepancies arise among reviewers, the case will be discussed collectively until a consensus is reached. The adjudication outcome determined by the CEC will serve as the final determination of the endpoint event.
Adverse events and safety analysis
Adverse events (AEs) are defined as any unfavourable medical occurrences during the study period, regardless of their relationship to the study drug. A serious AE (SAE) is defined as any AE that meets one or more of the following criteria: (1) death; (2) life-threatening condition; (3) congenital malformation or birth defect; (4) significant impairment of working ability; (5) temporary or permanent disability; (6) hospitalisation or prolongation of existing hospitalisation.
All AEs will be evaluated for their potential association with the study drug, documented in the case report form and followed until resolution or stabilisation. SAEs will be reported within 24 hours to the sponsor, lead study site, clinical research organisation, ethics committee, China Food and Drug Administration and relevant health authorities.
Known adverse drug reactions (ADRs) will be actively monitored. For prednisone, potential side effects include hyperglycaemia, hypertension, fluid retention, infection, osteoporosis and adrenal suppression. For colchicine, known risks include gastrointestinal intolerance, leucopenia and myotoxicity. Although both agents are administered at low doses in this trial, we have implemented several risk mitigation strategies. For example, high-risk individuals for osteoporosis (such as elderly women) will receive prophylactic supplementation with vitamin D and calcium, and patients with diabetes or hypertension will undergo enhanced monitoring and timely adjustment of concurrent medications.
The incidence of AEs, ADRs and SAEs will be documented, monitored throughout the trial and compared between the control, colchicine and prednisone groups as part of the final safety analysis.
Statistical analysis plan
The AI-ISR study is designed as a randomised controlled trial (RCT). The safety and efficacy of colchicine and prednisone in recurrent restenosis are evaluated by comparing the main outcome indicators of subjects who received colchicine (n=84) or prednisone (n=84) combined with standard drugs and those who only received standard drugs (n=84). Furthermore, the differences in the incidence of ISR, MACE and drug safety between the two regimens (combined low-dose colchicine vs combined low-dose prednisone) can be compared (detailed in the Statistical Analysis Plan (SAP)).
The sample size for this trial was calculated based on prior studies evaluating the impact of AI therapy on the incidence of ISR. Deftereos et al demonstrated that colchicine (0.5 mg two times per day) significantly reduced ISR from 33% to 16% in diabetic patients receiving bare-metal stents.7 The IMPRESS study reported a reduction in 6-month ISR from 33% to 7% with oral prednisone in patients with elevated CRP.9 The CEREA-DES trial showed that prednisone therapy was effective in reducing restenosis in both BMS and DES recipients over long-term follow-up.8 While these studies were conducted in the BMS era and did not specifically focus on patients with RISR, they provide a conservative estimate of the expected effect size of AI interventions. Given the lack of large-scale epidemiological data on RISR in the DES era, we referenced the 2023 Society for Cardiovascular Angiography and Interventions (SCAI) Expert Consensus Statement10, which reported a greater than 50% 2-year revascularisation rate in RISR patients. Based on these findings and our prior exploratory data, we conservatively assumed that, for RISR lesions, the incidence of target lesion ISR 1 year after PCI is 30% in the control group and is expected to be reduced to 10% in prednisone or colchicine treatment groups within 1 year after PCI. Under these assumptions, we aim to test the efficacy of two treatment groups—colchicine and prednisone—compared with the control group. Two primary null hypotheses are defined as follows: H01: there is no difference in the incidence of ISR between the colchicine group and the control group. H02: there is no difference in the incidence of ISR between the prednisone group and the control group. To control for type I error arising from multiple comparisons, we applied a Bonferroni correction and set the two-sided alpha level for each hypothesis at 0.025. A total sample size of 252 patients (84 per group) will provide 80% power to detect this 20% absolute risk reduction. This calculation accounts for a 10% dropout rate and assumes a 1:1:1 allocation ratio among the three groups.
Efficacy comparison was performed according to the principle of intention-to-treat analysis. The log-rank test was used to compare the differences of the primary and secondary endpoints between the control and treatment groups, and the HR and 95% CI were calculated according to the Cox proportional-hazards model. Continuous variables are presented as mean±SD. Categorical data are presented as frequencies and percentages. Comparisons of continuous variables at baseline with those at follow-up are done with the paired analysis of variance (ANOVA) . Comparison of non-parametric data between groups is undertaken using the Wilcoxon rank sum test and the Mann-Whitney test. Stratified analysis was performed according to the interventional treatment strategy (DES vs DEB). Statistical analysis was performed at a bilateral 0.05 significance level. EPI DATA V.3.0 and SPSS V.20.0 were used for data management and statistical analysis respectively. The National Cardiovascular Center Medical Research and Biostatistics Center is responsible for data management and statistical analysis.
Data management and quality control
This study follows local regulations on the storage of patient medical records and the relevant provisions of clinical research in Fuwai Hospital. After the completion or termination of the study, documents will be retained for at least 5 years. If a longer study period is required, applicable regulatory requirements should be considered.
In order to ensure the accuracy and authenticity of data collection quality, each participating site has its own study group and a senior investigator with experience in clinical trials, who has conducted unified data quality control training. Standard operating procedures for the measurements and analysis of important tests, such as ECG, echocardiography and coronary angiography and intervention, are established by the core laboratories of Fuwai Hospital in Beijing, China. And each participating site adheres closely to standard operating protocols to evaluate and analyse trial-related examination outcomes.
The complete data of this study is stored in the information medical record management system of Fuwai Hospital, and the data export process follows the principle of confidentiality, ensuring the database is not leaked. During the follow-up survey, the designated researchers are responsible for data collection and input. The data will be entered by two people to identify missing values, outliers and logical errors, effectively avoiding mistakes. After the database is established, non-researchers are unable to access the database, and researchers must obtain the permission of the project leader before accessing the database. No one is allowed to modify or copy database information.
The steering committee is chaired by Haiyan Qian, MD, Fellow of the American College of Cardiology (FACC), professor of cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences (CAMS), National Center for Cardiovascular Diseases (NCCD), which is responsible for formulating the scientific protocol, supervising the trial implementation and the publication of research results. In addition, an academic committee, a clinical endpoint committee, a data and safety monitoring board and a third-party data statistical unit are also involved in and responsible for the AI-ISR trial.
Patient and public involvement
Patients and the public were not involved in the design, conduct, reporting or dissemination of this research.
Discussion
The incidence of coronary artery disease (CAD) worldwide is still on the rise nowadays. As the core treatment, the annual operation volume of PCI has reached more than one million. However, ISR, defined as a binary restenosis ≥50% at the stent segment or its edges (5 mm segments adjacent to the stent),11 has still been an international challenge hindering the progress of PCI. In the prestent era, the rates of restenosis of coronary segments treated by plain old balloon angioplasty alone ranged between 32% and 55% of all revascularisations,12 but fell to 17–41% in the BMS era.13 14 With the advent of DES, the incidence of clinical and angiographic ISR has drastically decreased based on the advancement of interventional techniques and CAD drugs, especially IVI,15 16 with the ISR rates ranging from 5% to 10%.1–3 However, the demand for repeated revascularisation caused by DES-ISR continues to grow at a rate of 1–2% per year.17 And according to the National Cardiovascular Data Registry database, PCI caused by ISR accounts for about 10% of the total,18 thus leading to a significant increase in MACCE and even mortality rates. For ISR, the current guidelines recommend the use of either DES or DEBs for revascularisation based on robust clinical evidence (both Class IA recommendation).4 5 However, 10–20% of patients will still experience RISR (defined as failure of at least two revascularisation procedures) after DES or DEB treatment.6 19 Due to the large number of PCI bases, the number of RISR patients will be steadily increasing, thus posing a therapeutic challenge.
In current clinical practice, the treatment strategies for RISR include the additional DES implantation, the use of DEB, excimer laser coronary angioplasty and intravascular brachytherapy. The use of IVI (IVUS and OCT) can help differentiate the causes of RISR and determine the treatment strategy.20 However, previous studies have shown that 10–30% of RISR patients still require repeated revascularisation within 1 year, and the incidence of MACE is as high as 10–33%.19 21 A prospective non-randomised control study involving 171 multimetal-layered ISR lesions showed that the target lesion revascularisation (TLR) after treatment with second-generation DES or DEB was 12.5% and 10.9% within 1 year, 27.7% and 38.3% within 2 years.19 Furthermore, compared with PCI recipients for de novo lesions, patients treated for ISR had a higher cardiovascular risk due to their more complex coronary anatomy, with approximately 1/4 experiencing acute myocardial infarction (Non–ST-Elevation Myocardial Infarction (NSTEMI) or ST-Elevation Myocardial Infarction (STEMI)).22 Since most RISR patients require repeated PCI or even coronary artery bypass grafting (CABG), it burdens both family and society with additional risks and economic expenses.23
The mechanism of RISR is multifactorial,24 in addition to mechanical factors such as stent underexpansion or fracture, biological factors including neointimal hyperplasia (NIH), neoatherosclerosis and systemic diseases, which also play important roles. Inflammatory response has been an international research hotspot in recent years25: the operation of PCI damages the endothelium and walls of blood vessels by mechanical force, the non-degradable metal stent wires and polymer exist in the local artery, and patients with clear or suspicious systemic or coronary local vasculitis may experience inflammatory response in the early postoperative stage, promoting the migration, proliferation and phenotype transformation of vascular smooth muscle cells, secreting excessive collagen and finally deposited in the stent. Undoubtedly, it led to the occurrence of ISR.23 25 In the past 20 years, under the guidance of IVI, we have managed mechanical-related ISR by optimising PCI again; neoatherosclerosis-related ISR by improving lifestyle and more aggressive secondary prevention drugs; other ISRs, especially inflammation-related, tend to relapse if simply treated with PCI or CABG, without corresponding AI medications. In view of this, in recent years, several clinical trials have been conducted to explore the feasibility of AI intervention to prevent ISR.
Colchicine is an ancient AI drug that has been used for the prevention and treatment of gout attacks. Recent studies have shown that it can suppress the production and release of Interleukin (IL)-1β and IL-18 by inhibiting neutrophil recruitment, activation and degranulation, which in turn improves endothelial function and stabilises26 plaques.27 A RCT involving 196 CAD patients with diabetes showed that colchicine (0.5 mg two times per day) could prevent the NIH and ISR after BMS implantation.7 Compared with the control group, the ISR rate assessed by IVUS decreased by 58% (OR 0.42, 95% CI 0.22 to 0.81, p=0.006) after 6 months in the colchicine group. Several RCTs also confirmed that low-dose colchicine (0.5 mg once per day/two times per day) can reduce the risk of stable CAD and ACS patients undergoing revascularisation and MACE.28–31 A meta-analysis involving 11 816 patients showed that colchicine significantly reduced the risk for MACCE by 25%, myocardial infarction by 22%, stroke by 46% and coronary revascularisation by 23% and did not increase other AEs.32 Based on the above studies, 2021 European Society of Cardiology (ESC) guidelines on cardiovascular disease (CVD) prevention (Class IIb recommendation, level A evidence)33 and 2023 American Heart Association (AHA) guidelines for the management of chronic coronary disease (Class IIb recommendation, level B evidence)34 both recommend colchicine as secondary prevention of CVD, particularly if recurrent CVD events occur under optimal therapy. Subsequently, in June 2023, the U.S. Food and Drug Administration has approved the use of low-dose colchicine as the first AI drug for CVD to reduce the risk of myocardial infarction, stroke, coronary revascularisation and cardiovascular death in adult patients diagnosed with atherosclerotic disease or with multiple cardiovascular risk factors.
Prednisone is another classic AI drug, which acts on the glucocorticoid receptors in cytoplasm to promote the expression of AI proteins and inhibit pro-inflammatory proteins.35 Early RCTs indicated that oral prednisone can significantly reduce the ISR rates in patients with high inflammatory response (elevated CRP) after BMS implantation.9 However, for non-selective CAD patients, the results of perioperative or postoperative application of prednisone in BMS-PCI were different.8 36 A meta-analysis of three RCTs included showed that postoperative oral prednisone (1 mg/kg/day, 40–45 days of withdrawal) did not reduce the risk of death in CAD patients implanted with BMS, but significantly reduced ISR (RR 0.60, 95 % CI 0.37 to 0.97, p=0.04) and target vessel revascularisation rates (RR 0.56, 95 % CI 0.34 to 0.92, p=0.02) at 6 months after PCI.37
The above-mentioned studies on colchicine and glucocorticoids mostly enrolled patients with BMS, and most lesions were de novo. While in the DES era, there is no prospective study to evaluate the role of AI drugs in RISR lesions. Therefore, we intend to test the efficacy and safety of colchicine and glucocorticoids in patients undergoing RISR. The colchicine intervention dosage of AI-ISR was informed by the LoDoCo trial38 as well as the 2023 AHA guideline for the management of chronic coronary disease, where colchicine is given a Class IIb recommendation with level B evidence.34 And the prednisone dosing strategy was based on the glucocorticoids treatment protocol for large-vessel vasculitis used at Fuwai Hospital, as well as the initial dose and tapering recommendations jointly published by the American College of Rheumatology and the Vasculitis Foundation.39 Additionally, it aligns with the Glucocorticoid (GC) dosing regimen used in the IMPRESS study.9 Our study includes proactive safety monitoring, consisting of regular blood tests, scheduled follow-up visits and detailed documentation of any adverse effects. All drug-related AEs are rigorously recorded and assessed, with close surveillance of participants’ overall health status throughout the trial.
Our AI-ISR trial is innovative and of significant clinical value.
Ethics and dissemination section
This study has been reviewed and approved by the Ethics Committee of Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, approval No.2023–2076, which is serving as the central institutional review board for the entire multicentre trial. All 15 participating sites are located in China. Written informed consent will be obtained from all participants prior to enrolment (available in the online supplemental material). The study will be conducted in accordance with the Declaration of Helsinki and the relevant national regulations on biomedical research involving human subjects.
Patient safety will be closely monitored throughout the trial. AEs and serious AEs will be documented, reported and evaluated by the trial’s Data and Safety Monitoring Board. Any protocol amendments affecting patient safety will be submitted to the Ethics Committee for re-approval.
The results of this trial will be disseminated through peer-reviewed journal publications and academic conference presentations. Deidentified individual participant data will be securely stored and will be available only on reasonable request and with approval from the study investigators, in accordance with BMJ Open’s data-sharing policy. The trial will also be updated on ClinicalTrials.gov (ID: NCT06090890) as required.
