Abstract
Background
Intravascular ultrasound (IVUS) guidance for percutaneous coronary intervention (PCI) has been associated with a reduction in clinical events. Whereas most evidence is generated in Asian-Pacific populations, its global adoption remains low.
Methods
The IVUS complex high-risk indicated procedures (CHIP) trial is a multicenter, international, event-driven, randomized superiority trial comparing IVUS-guided PCI with angio-guided PCI during complex high-risk indicated procedures. The primary endpoint is target vessel failure, defined as a composite of cardiac death, target vessel myocardial infarction, or clinically indicated target vessel revascularization. The IVUS CHIP trial utilizes an event-driven approach. The outcomes for the primary endpoint are first reported when at least 169 patients with a primary endpoint have been confirmed. A total of 2020 patients will be enrolled in 37 European sites.
Conclusions
The aim of the IVUS CHIP trial is to assess the superiority of an IVUS-guided approach vs an angio-guided approach in patients undergoing complex high-risk indicated procedures in terms of the study primary endpoint of target vessel failure.
Trial Registration
The IVUS CHIP trial is registered at ClinicalTrial.gov and assigned the identifier NCT04854070.
Background
Intravascular ultrasound (IVUS) guidance has been reported to improve clinical outcomes after percutaneous coronary intervention (PCI). ,,,,, Most of the evidence has been obtained in Asian-Pacific populations, where IVUS-guided PCI is more commonly used. Conversely, its adoption in Western countries remains low. Data suggest that IVUS-guidance plays a critical role both before stenting, allowing lesion assessment and plaque preparation, as well as poststenting for optimization of results. ,, The latter proved to be of particular relevance in patients with complex coronary lesions. ,, In August 2024, updated European guidelines for the management of chronic coronary syndromes upgraded the use of intracoronary imaging guidance when performing PCI in anatomically complex lesions, in particular left main (LM) lesions, true bifurcations and long lesions to a class I, level of evidence A recommendation. Of note, specific guideline recommendations for the use of intracoronary imaging in moderate to heavily calcified coronary lesions are lacking.
American guidelines for coronary artery revascularization recommend considering the use of IVUS in LM disease and in in-stent restenosis (ISR). However, these guidelines do not support the use of intracoronary imaging during routine PCI. More recently, the updated American guidelines for the management of patients with acute coronary syndromes (ACSs) have promoted the use of imaging-guided PCI in LM disease and in complex lesions.
The intravascular ultrasound guidance for complex high-risk indicated procedures (IVUS CHIP) randomized trial was designed to investigate whether IVUS-guided PCI is associated with a reduction in clinical events compared to an angio-guided PCI, in patients undergoing CHIP.
Methods
Study design
The IVUS CHIP trial is a multicenter, international, event-driven, randomized trial designed to investigate the superiority of IVUS-guided PCI compared with angiography-guided PCI ( Figure 1 ) in terms of target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, and clinically-driven target vessel revascularization.
Study flow-chart.
The study is currently undertaken at 37 high-volume interventional centers in seven European countries, including Belgium, France, Germany, Italy, Spain, the Netherlands, and the United Kingdom. All centers were selected on the basis of established IVUS-guidance experience within their routine care. The authors take responsibility for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Study population
This study enrolls patients presenting with silent ischemia, stable angina, unstable angina, or non-ST-elevation ACS, planned to undergo percutaneous revascularization of complex coronary lesions, or in patients with an indication for elective mechanical circulatory support-assisted PCI. Complex lesions include angiographic heavy calcification, ostial lesions, true bifurcation lesions involving side-branches >2.5 mm, LM lesions, chronic total occlusion (CTO), ISR, and long lesions (estimated stent length >28 mm). Full eligibility criteria are available in Table 1 .
Table 1
Inclusion and exclusion criteria
| Inclusion criteria |
|---|
| The patient must be ≥18 years of age |
| Patients with an indication for PCI of at least one lesion satisfying any of the following criteria: |
| Angiographic heavy calcification |
| Ostial lesions |
| True bifurcation lesions involving side-branches >2.5 mm |
| Left main lesions |
| Chronic total occlusion |
| In-stent restenosis |
| Long lesions (estimated stent length >28 mm) |
| Patient with an indication for PCI for any lesion and in need for elective mechanical circulatory support assisted PCI |
| Presenting with silent ischemia, stable angina, unstable angina, or non-ST-elevation acute coronary syndrome (NSTE-ACS) |
| All lesions must be suitable for treatment with the Synergy stent system, Synergy Megatron system, or other Synergy platform iteration |
| The patient is willing and able to cooperate with study procedures and follow-up until study completion |
| Subject is able to confirm understanding of risks, benefits, and treatment alternatives, and he/she provides informed consent prior to any protocol-related procedure, as approved by the appropriate Ethics Committee |
| Exclusion criteria |
| ST-elevation myocardial infarction |
| Cardiogenic shock |
| Known untreated severe valvular heart disease |
| IVUS is strictly required for pre-PCI lesion severity assessment |
| Requiring PCI in a diseased aorto-coronary bypass |
| Known contraindication or hypersensitivity to everolimus, platinum-chromium, or to anticoagulants |
| Absolute contraindications or allergy that cannot be premedicated to iodinated contrast or to antiplatelet drugs, including both aspirin and P2Y12 inhibitors |
Exclusion criteria include PCI for ST-elevation myocardial infarction, cardiogenic shock, IVUS strictly required for pre-PCI lesion assessment, complex lesion located in a diseased aorto-coronary bypass, absolute contraindications, or allergy that cannot be premedicated to iodinated contrast or to antiplatelet drugs, including both aspirin and P2Y12 inhibitors. The IVUS CHIP trial is not an all-comers trial, but enrolls a selected high-risk study population, at a recommended rate of 2 to 3 patients per site per month.
Informed consent
After the investigator or a designee has screened the routinely available items and determines the patient eligible, the patient is informed about the study and asked to participate.
In patients undergoing ad-hoc revascularization, a staged informed consent process is implemented. In this scenario, patients are orally informed about the nature of the study by one of the investigators, in the presence of an independent witness. Consenting patients provide oral informed consent, which is then signed by both the investigator and an independent witness. After the procedure, and within a maximum of 24 hours, the patient is fully informed of the study details through the complete written informed consent. Both the investigator and the patient, or designee, sign the complete informed consent.
Enrolment and randomization
After informed consent and final eligibility are established, the study participant is randomized in a 1:1 ratio to IVUS-guided PCI or angio-guided PCI using the randomization module of the electronic data capture system. The types of qualifying lesions are captured at randomization. For patients with CTO lesions, randomization occurs after initial successful crossing of the lesion(s). Stratification by site and by presentation (ACS vs non-ACS) is performed to ensure balance across potential local differences in treatment practices. It is strongly recommended that the PCI procedure is scheduled within 24 hours after informed consent for ACS patients, or within 72 hours for stable patients. Relevant baseline characteristics are collected to ensure adequate clinical characterization, including standard modifiable risk factors, cardiovascular medical history, angina status, left ventricular ejection fraction, and valve pathologies .
Study device
The OptiCross High Definition (60 MHz) IVUS catheter (Boston Scientific Corporation, Marlborough, MA) is CE-marked and will be used in this trial. No support by artificial intelligence is anticipated. All study lesions must be treated with the Synergy everolimus-eluting stent or any next generation of the Synergy stent family (Boston Scientific Corporation). The Synergy stent family has received CE-mark and is not under investigation in this study.
Treatment
For patients randomized to IVUS-guided PCI, the protocol highly recommends performing a baseline pre-PCI IVUS for lesion assessment and preparation. IVUS after PCI and post-PCI optimization are mandatory. Only motorized pullbacks are allowed, and the use of the complete pullback length is recommended ( Figure 2 ).
IVUS imaging protocol. Recommended use of IVUS in patients randomized to the IVUS-guided PCI.
Criteria for optimal stenting comprise: (1) A final minimal stent area (MSA) >5 mm 2 or MSA >90% of distal reference lumen; (2) a plaque burden <50% within 5 mm from the proximal or distal stent edge; (3) no edge dissection involving the media and >3 mm in length.
During the study, a stent sizing algorithm was implemented. Stent landing zones are defined as: (1) 3 mm distal and proximal to plaque with <30% area stenosis. (2) No large lipid pools. (3) Plaque burden <50%. (4) Proximal landing zone at least 5 mm proximal to bifurcation of side branches >2.5 mm in order to allow proximal optimization technique. In addition, the study protocol recommends avoiding stent overlap at the site of bifurcations with side-branches >2.5 mm and selecting the stent diameter based on distal reference lumen area or external elastic membrane, and upsize proximally with a postdilatation balloon in case of significant tapering.
In the angiography-guided arm, treatment is performed according to standard clinical practice without IVUS-guidance unless strictly medically indicated, such as in the presence of luminal haziness or doubtful dissection.
In case of multivessel disease, all lesions are to be treated according to the allocated strategy. For intermediate lesions (50%-70% diameter stenosis by angiographic visual estimate), coronary physiology testing (FFR or iFR) is recommended. Lesion preparation is per operator’s discretion. Complete revascularization was strongly encouraged. If the treatment of multivessel disease requires a staged procedure, planned staged procedures are to be completed within 45 days, as defined in previous clinical trials. ,, The intent to stage has to be documented at the end of the first procedure. Staging of multiple lesions in a single vessel is not allowed.
Follow-up
The enrolment period was anticipated to be approximately 24 months. Follow-up of all participants has been planned to continue up to 2 years after randomization or until 169 primary endpoints have occurred, whichever comes last.
Telephone follow-up contacts may be discontinued at the participant’s explicit request. Gathering of clinical follow-up via treating cardiologists, general practitioners, or the civic registries is continued unless the participant objects. In that case, the participant is considered lost to follow-up as of the date of the last clinical contact. Participants are followed for at least 2 years after randomization, with a yearly telephone call starting at 1-year postrandomization, for all listed clinical endpoints, including the occurrence of death, myocardial infarction, repeat revascularization, stent thrombosis, and stroke.
Study endpoints
The primary endpoint of IVUS CHIP is TVF, defined as a composite of cardiac death, target vessel myocardial infarction, or clinically indicated target vessel revascularization.
Additional secondary endpoints are listed in Table 2 . All deaths and major cardiovascular events, including the individual components of primary and secondary endpoints are adjudicated by an independent CEC using standardized definitions. , Furthermore, the Fourth Universal MI definition is adopted to define all spontaneous MI events occurring beyond 48 hours of the procedure, while the Academic Research Consortium-2 MI definition is used for peri-procedural MI. Source documents, including discharge letters, laboratory values, electrocardiograms, and angiographic materials, were available during event adjudication.
Table 2
Primary and secondary endpoints
| Primary endpoint |
|---|
| Target vessel failure defined as a composite of cardiac death, target vessel myocardial infarction * , or clinically indicated target vessel revascularization † |
| Ranked key secondary endpoints |
| Composite of target vessel myocardial infarction * and clinically indicated target vessel revascularization † |
| Clinically-indicated target vessel revascularization † |
| Composite of cardiac death and target vessel myocardial infarction * |
| Target-Lesion Failure (TLF) defined as a composite of cardiac death, target vessel myocardial infarction * , or clinically indicated target-lesion revascularization † |
| Target-lesion revascularization † |
| Cardiac death |
| Other clinical endpoints |
| Patient-oriented Composite Endpoint (POCE) defined as a composite of all-cause death, any stroke, any myocardial infarction * , and any revascularization † |
| Device-oriented Composite Endpoint (DOCE) defined as the composite of cardiovascular death, target vessel MI * , clinically indicated repeat revascularization † of the target lesion |
| Target vessel revascularization † |
| Study vessel revascularization † |
| Any stroke |
| Definite and probable stent thrombosis |
| Procedural endpoints |
| Procedural time |
| Total contrast volume |
| Device usage |
| Additional clinical/procedural endpoints |
| Acute kidney injury |
| Vascular access site complications |
| Bleeding |
| Major intraprocedural complications, including Type C-F dissection, any perforation, persistent slow- or persistent no-reflow, abrupt closure, distal embolization, thrombus, and major (≥2 mm vessel diameter) side branch occlusion |
| Perforations by Ellis criteria |
| Core lab reported endpoints |
| Achievement of optimal IVUS criteria |
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