Stenting Versus Drug Eluting Balloons Only in Treatment of Coronary Bifurcation Lesion (ROBUST Study)

Overview

The goal of this clinical trial is to learn immediate and follow up results of percutaneous treatment of coronary bifurcation lesion using drug eluting balloons (DEB) only in patients with chronic coronary syndrome (CCS). Researchers will compare endovascular treatment using solely DEB to stenting of coronary bifurcation lesion. The main questions it aims to answer are: * What is immediate and follow up clinical and angiographic results of endovascular treatment of coronary bifurcation lesion using DEB in patients with CCS? * Is efficacy and safety of endovascular treatment of coronary bifurcation lesion using DEB only in patients with CCS non inferior to compare stenting of aforementioned lesion which is contemporary recommended standard of care? Participants will: * Take prescribed medication before and after initial procedure during whole observation period (12 months) * Visit the clinic at 1, 6 and 12 months after the initial procedure for checkup, noninvasive tests and control angiography at 12 months follow up * Inform researchers about all adverse events that might be occur during follow up observation period

Currently, the recommended technique for bifurcation lesion treatment is provisional stenting of the main branch, with optional two-stent strategy, if necessary. However, all the challenges in treating of bifurcation lesions, as well as the impact of main-branch stenting on the geometry and patency of the side branch, have renewed interest in the "leave nothing behind" concept, in particular, the use of drug-eluting balloons (DEBs). However, It should be emphasized, that data on the use of DEBs in the pecutaneous endovascular treatment of bifurcation lesions are scarce. A recently published systematic review with a focused meta-analysis included only 12 (!) completed studies over a 30-year period from 1990 to 2020, including randomized, observational, registry, and retrospective studies. To date, there are no comparative studies between treatment with DEBs alone and second- or later-generation drug-eluting stents. Given the significant knowledge gaps and the lack of meaningful studies on the use of DEBs in bifurcation lesions, the aim of this study was to compare the acute and long-term outcomes of endovascular treatment of coronary bifurcation lesions in patients with CCS using second- and later-generation drug-eluting stents versus second-generation DEBs alone. To address this objective, a multicenter, randomized controlled study with a non-inferiority design based on the primary clinical endpoint is planned. A non-inferiority design assumes that the primary endpoint rate in the experimental group is no less than the non-inferiority margin. The non-inferiority margin for the primary endpoint was calculated based on literature data and set at 4.7% for the comparison group undergoing bifurcation stenting. Researchers generate following hypothesis: 1. PCI of coronary bifurcation stenosis using only drug-eluting balloons is reliably non-inferior ("not worse") in terms of acute and long-term outcomes, in comparison with stenting techniques using 2nd and 3rd generation drug-eluting stents. 2. PCI of coronary bifurcation stenosis with drug-eluting balloons may be associated with a lower complication rate (bleeding, late thrombosis) compared to stenting using drug-eluting stents. The null hypothesis states that the risk difference (R1-R0) is greater than or equal to the non-inferiority margin of 4.7%. The alternative hypothesis is that the difference in adverse events between the groups will be less than 4.7%. The null hypothesis of no less efficacy of drug-eluting balloons compared with drug-eluting stents will be rejected if the upper limit of the 95% confidence interval for the risk difference (R1-R0) is less than 4.7%. This study is a open label, multicenter, prospective, randomized, non-inferiority study including patients with chronic coronary syndrome and bifurcation lesions of epicardial coronary arteries, or their large branches (excluding the left main coronary artery) who are referred for PCI and stenting in routine clinical practice. Patients aged over 18 years who have signed informed consent and have a "true" bifurcation lesion of an epicardial artery or its large branch (diameter ≥ 2.5 mm and ≤ 4.5 mm with stenosis \>50%) requiring PCI and/or implantation of a second- or later-generation drug-eluting stent will be included in the study. Patients were included without restrictions on number of stents implanted, the number of target bifurcation lesions per patient (if meet the inclusion criteria), or the number of drug-eluting balloons used. One of the restrictions is that only patients with chronic coronary syndrome should enrolled in the study. The study must be approved by local ethics committees at each participating center. All patients must sign an informed consent with detailed steps of the PCI procedure, the characteristics of the devices used, potential risks, and expected outcomes. Patients will undergo PCI using one of the recommended bifurcation stenting techniques with 2nd and 3rd gen drug-eluting stents and angioplasty without stents using only drug-eluting balloons. Randomization will be 1:1 by random number generation using a web-based computer model. Randomization will be performed using an electronic interactive system BEFORE BALLOON PREDILATATION OR LESION PREPARATION. During the intervention, one of the intravascular imaging techniques (intravascular ultrasound - IVUS, optical coherence tomography - OCT) is recommended to optimize stenting and/or angioplasty. Follow-up coronary angiography will be done at 12 months after the primary coronary intervention to perform a qualitative analysis of the follow-up coronary angiography. The overall observation period is 12 months, although further follow-up of patients beyond this study is possible. A patient may withdraw from the study at any time for any reason. However, their data may be used for statistical analysis. Furthermore, patient data may be excluded from the study if inappropriate inclusion is detected. The study may also be terminated if the Coordinating Study Site (CSS), the Department of Interventional Cardioangiology at I.M. Sechenov Moscow State Medical University (Sechenov University), receives corresponding recommendations from the independent ethics committee. Patient selection and inclusion in the study will occur during hospitalization (possibly within the first 24 hours, but not exceeding 7 days). Study endpoints are - The primary endpoint is a composite of all-cause death, myocardial infarction (MI), and clinically-driven target lesion revascularization at 12 months after initial procedure Secondary endpoints - 1. restenosis of the target lesion (main, lateral branch) 2. Target lesion thrombosis (definite, probable, possible according to the ARC classification). 3. Any repeat revascularization of target arteries 4. Components of the primary endpoint are cardiogenic death, any AMI 5. Bleeding defined according to the BARC 2-5 classification 6. PCI parameters - procedure duration, radiation dose, and amount of contrast media Investigational product is a sirolimus-coated coronary dilatation balloon catheter with the micreservoir technology. It is planned to use a uniform drug-coated balloons to avoid the influence of the technological factor on study outcomes, because there are no evidence about class effect of DEB. All patients participating in the study should start receiving acetylsalicylic acid (aspirin) at a dose of 100 mg per day in combination with P2Y12 platelet receptor inhibitors (clopidogrel) 75 mg per day at least three days before the scheduled procedure. Since the study includes patients with chronic coronary syndrome (CCS), the use of other more potent drugs (ticagrelor, prasugrel) should be justified. Triple therapy (anticoagulants + DAPT) is determined based on indications for the treatment of the patient's concomitant diseases (e.g., atrial fibrillation). Use of IIb/IIIa receptor inhibitors are at the discretion of the operator. After discharge all patients will be prescribed DAPT, including aspirin at a dose 100 mg and clopidogrel at a dose of at least 75 mg or ticagrelor 90 mg twice daily after discharge for at least 6 months for stenting group and 1 months for DCB group of patients. Concomitant therapy is at the discretion of the physician. Predilation or preparation of the lesion is a mandatory (!) step in performing the procedure when using drug-eluting balloons. It is performed using balloons of a 1:1 diameter, matching the reference diameter of the arteries (main and lateral) involved in the target lesion. The reference diameter of balloons for predilation is determined distal to the lesion, both in the main (parent) and in the side branch, using quantitative computed tomography (QCA) and/or intravascular imaging after intracoronary administration of 200 mcg nitroglycerin. Predilation using balloons of the appropriate diameter is performed sequentially in the main and lateral branches. The use of the "kissing balloon" technique for predilation is NOT ALLOWED. The length of the drug-eluting balloon is selected taking into account the recommendation for complete coverage of the prepared segment (using atheroablation or balloon predilation), including 2-3 mm proximally and distally (the length of the drug-coated balloon should be 5-10 mm longer than the length of the predilation balloon). The balloon inflation time required to ensure optimal and complete drug delivery to the vascular wall varies and is typically 30-60 seconds, depending on the manufacturer's recommendations. However, balloon inflation time may depend on specific PCI parameters (the degree of ischemia during balloon inflation, cardiac arrhythmia, and deterioration of central hemodynamics). Anyway, the recommended inflation time (30-60 seconds) should be followed, but hemodynamic and ECG parameters should be taken into account first and foremost during balloon inflation. After predilation, the result of lesion preparation should assessed for the presence of residual stenosis, dissection (type A-F according to the NHLBI classification) and blood flow (according to the TIMI classification). If intravascular imaging is used, the minimum cross-sectional area, the degree of residual stenosis, the presence and type of dissection, and the residual plaque mass (volume) are also assessed. Since no radiopaque markers are used to define treated segment during angioplasty by drug-eluting balloon (unlike stenting), the proximal and distal positions of the inflated DCB (and, consequently, the drug delivery segment) SHOULD BE DOCUMENTED by cine angiography. This is important for evaluation of the long-term angiographic outcome in the balloon dilation segment. As the final stage of stentless PCI of the target bifurcation lesion using drug-eluting balloons, the "mini-kissing" technique should be used with minimal protrusion of side branch balloon into main vessel at the carina level. The final kissing balloon (FKB) with drug-eluting balloons, is aimed to minimize mechanical trauma of the main artery and reduce the risk of flow-limiting dissection of the vessel wall. The drug-eluting balloon covers the superior junction of the side branch with the main artery (opposite the carina). Therefore, drug is interacted with whole circumference of the side branch ustium. Stenting can be used both in case of suboptimal outcome after balloon predilation (antegrade blood flow-limiting dissection) and as an emergency procedure ("bailout") after the use of a drug-eluting balloon. In the stenting arm The choice of stenting technique is at the operator's discretion, depending on the baseline anatomy of the bifurcation lesion and the results of predilation. Provisional stenting is the preferred technique; however, if necessary, a two-stent technique is permitted (the type of two-stent strategy is at the operator's discretion). Both provisional and two-stent strategies should be completed with the FKB technique and proximal optimization (POT), as adopted by the consensus documents of the European Bifurcation Club. In case of provisional stenting using the kissing balloon technique, a drug-eluting balloon of appropriate diameter (1:1 to reference diameter) should be used in the side branch, since previous studies have shown the benefit of inflating a drug-eluting balloon in the side branch to reduce the rate of MACE and restenosis at the side branch ostium in the follow-up period. The immediate success (outcome) of PCI using DCB is assessed at patient discharge and includes the following: 1. Successful use of the instrument (uncomplicated delivery of the balloon without significant resistance to the target lesion in \<2 min, full balloon deployment under nominal pressure in 30-60 sec, easy uncomplicated removal without damage of the delivery system, residual stenosis in the dilation segment \<30% with verification in the central (core) laboratory using quantitative coronary angiography (QCA)). 2. Absence of antegrade flow-limiting dissection (type C-F) and emergency stenting. 3. Absence of MACEs (cardiac death, periprocedural MI, repeat target lesion revascularization during index hospitalization, stroke, BARC bleeding 3 or 5 regardless of which PCI strategy was used). The immediate success (outcome) of PCI using a drug-eluting stent is assessed at patient discharge and includes the following criteria: 1. Successful use of the instrument (uncomplicated delivery of the stent the target lesion in \<2 min, full balloon/stent deployment under nominal pressure and, if necessary, additional successful post-dilation using a non-compliant balloon, without rupture of the balloon catheter and its unhindered removal (without damage of the delivery system). Final residual stenosis in the stented segment \<10%, verified in a central (core) laboratory using quantitative coronary angiography (QCA)). 2. Absence of MACEs (cardiac death, periprocedural MI, repeat target lesion revascularization during index hospitalization, stroke, BARC bleeding 3 or 5 regardless of which PCI strategy was used). In case of intravascular imaging or physiology used widely accepted IVUS or OCT criteria known from the literature are used to assess the immediate results after stent implantation. By 12 months of follow-up (±1 week), all patients in both groups should undergo control coronary angiography and, if possible, intravascular imaging. On control coronary angiography, binary restenosis is assessed as \>50% of the reference arterial diameter either within the stent (or in a segment dilated with a drug-eluting balloon) or at a distance of 5 mm from the stent edges. Restenosis at the side branch ostium is assessed similarly - i.e. \> 50% diameter stenosis inside the distance of 10 mm from the side branch ostium. Thrombosis of the treated segment (intra-stent or intra-balloon dilation segment) is assessed according to ARC Consortium on stent thrombosis and breaks up into three categories: definite, probable and possible. Thereof, according to the timing of the thrombosis occurrence, acute (0-24 hours), subacute (within 30 days after discharge) and late (\> 30 days after discharge) thrombosis is distinguished. Target lesion thrombosis in the case of DEB PCI is defined as angiographically confirmed thrombus localized in the target segment, including 1 mm proximally and distally to the site of application (inflation) of the drug-eluting balloon or without angiographic confirmation, in the event of the development of the following symptoms within 48 hours after completion of PCI. On the follow up coronary angiography other parameters to be evaluated using quantitative coronary angiography (QCA): 1. Acute lumen gain is the difference between the baseline and post-procedural values of the minimum lumen diameter (MLD) 2. Net lumen gain is the difference between the MLD value in the remote period (12 months) and its baseline value (pre-procedural) 3. Late lumen loss is the difference between the MLD value immediately after the procedure and in the long-term period (after 12 months) 4. Change in the degree of stenosis is the difference between the degree of stenosis in the treated segment immediately after the procedure and in the long-term period (after 12 months) If there is no data on the occurrence of a clinical event at the time of the final visit, the date of the last contact will be considered the final visit.