Clinical trial NCT04403048: Drug Coated Balloon for Side Branch Treatment vs. Conventional Approach in True Bifurcation Coronary Disease: PRO-DAVID
Official title: Rationale and Design of a Prospective, Open Label, Randomized, Multicentric Clinical Trial: Drug Coated Balloon for Side Branch Treatment vs. Conventional Approach in True Bifurcation Coronary Disease: PRO-DAVID
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Stable Angina
Ischemic Heart Disease
Coronary Artery Disease
Unstable Angina
NSTEMI - Non-ST Segment Elevation MI
Keywords: Drug Coated Ballon
Bifurcation coronary disease
SYNTAX score
Medina classification
Coronary angiography
Lead sponsor: Clinical Hospital Center Rijeka
Sponsor class: OTHER
First posted: 2020-05-27
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Bifurcation lesions (BL) on coronary arteries account for 15-20 % of all performed percutaneous coronary interventions (PCI). Preferred approach for treatment of most bifurcation lesions is the stepwise provisional stent strategy with main branch-only stenting followed by provisional balloon angioplasty with or without stenting of the side branch (SB). Stenting of the side branch is indicated when the angiographic result in SB is clearly suboptimal and when flow remains reduced. Upfront use of two stent techniques may be indicated in very complex lesions with large calcified side branches ( most likely to supply at least 10% of fractional myocardial mass), with a long ostial side branch lesion (\>5mm) or anticipated difficulty in accessing an important side branch after main branch stenting, and true distal LM bifurcations.

From a technical point of view, we propose a "Provisional DCB approach" that differs from the standard provisional approach with obligatory SB predilation and good lesion preparation. In case of an adequate result of predilation, the procedure on the SB ends with the DCB deployment. This is followed by main branch stenting with DES, finished with POT. Final 'kissing' balloon dilation is generally not recommended because there is no advantage from final kissing with the one-stent technique. With this approach, there is no need for re-wiring, re-ballooning, side branching and wire jailing and final kissing. This technique is close to a contemporary approach to bifurcation lesions based on the fundamental philosophy of the European Bifurcation Club (EBC): keep it simple, systematic, and safe, with a limited number of stents that should be well apposed and expanded with limited overlap, with respect of the original bifurcation anatomy.

Detailed description: Bifurcation lesions (BL) on coronary arteries account for 15-20 % of all performed percutaneous coronary interventions (PCI). Preferred approach for treatment of most bifurcation lesions is the stepwise provisional stent strategy with main branch-only stenting followed by provisional balloon angioplasty with or without stenting of the side branch (SB). Stenting of the side branch is indicated when the angiographic result in SB is clearly suboptimal and when flow remains reduced. Upfront use of two stent techniques may be indicated in very complex lesions with large calcified side branches ( most likely to supply at least 10% of fractional myocardial mass), with a long ostial side branch lesion (\>5mm) or anticipated difficulty in accessing an important side branch after main branch stenting, and true distal LM bifurcations.

For non-left main bifurcation lesions consensus is that there is no systematic advantage to a more complex dual-stent implantation technique. For true left main lesions EAPCI/EACTS revascularization guidelines gave a IIb recommendation for double-kissing crush two-stent strategy compared to the provisional approach, based on the results of DKCRUSH-V Trial. EBC perspectives, even for the stenting on left main coronary true bifurcation lesions, is that they are best treated with a planned single-stent strategy rather than a planned dual-stent strategy. When a two-stent strategy is used, this will become apparent during a provisional stepwise approach, and finalizing the procedure using a culotte technique or occasionally TAP is recommended.

PCI strategies for complex coronary bifurcation lesions should be individualized, taking into account the anatomical differentiation of coronary bifurcation lesion differences, disease burden and complexity, but also the technical skills and experience of the operator. In daily clinical practice where less experienced operators with limited number of true bifurcations annually are faced with the challenge of treating complex bifurcation lesions, it is imperative to find a standardized and universal approach which would be simple, quick and safe, with a high percentage of procedural success, with a small number of complications, good long term results, with small expenditure of material and contrast volumes, and shorter procedure and fluoroscopy times.

Drug-coated balloon (DCB) technology allows to bring high concentration of an antiproliferative drug with immediate and rapid local delivery even with short contact times between the balloon surface and the vessel wall, sufficient for effective drug delivery without a durable polymer and further permanent metal prosthesis. The application of DCB in SB is an attractive and intriguing solution in treating complex BL. Rationality of such an approach lies in the many theoretical advantages of DCB. The application of DCB in SB respects the original anatomy of bifurcation, which is especially important in the carina area, and allows for the homogeneous application of a high dose of antiproliferative drug on the entire blood vessel surface and avoids the risk of incomplete coverage of the bifurcation area. In the case of a successful DCB application in the SB, unnecessary use of the stent is avoided, obviating long-term problems such as stent malposition and fracturing, scaffolding of the SB ostium, overlapping and crushing of multiple metal layers and polymers with uncontrolled drug release, and therefore re-stenosis and thrombosis and reactions to a foreign body. Even for the simplest provisional technique, the application of DCB has a theoretical advantage over the application of a regular balloon, with the expected positive remodelling of the vessel and plaque stabilization, and better late angiographic results, as well as neoatherosclerosis.

From a technical point of view, we propose a "Provisional DCB approach" that differs from the standard provisional approach with obligatory SB predilation and good lesion preparation. In case of an adequate result of predilation, the procedure on the SB ends with the DCB deployment. This is followed by main branch stenting with DES, finished with POT. Final 'kissing' balloon dilation is generally not recommended because there is no advantage from final kissing with the one-stent technique. With this approach, there is no need for re-wiring, re-ballooning, side branching and wire jailing and final kissing. This technique is close to a contemporary approach to bifurcation lesions based on the fundamental philosophy of the European Bifurcation Club (EBC): keep it simple, systematic, and safe, with a limited number of stents that should be well apposed and expanded with limited overlap, with respect of the original bifurcation anatomy.

The study hypothesis is that in patients with true complex bifurcation lesions (Medina 1,1,1; 1,0,1; 0,1,1) with significant SB, intervention using DCB first in SB and DES in the main vessel will not be inferior then planned single-stent strategy treating with superiority in the simplicity of procedure.

The registry will include patients requiring percutaneous coronary interventions with true bifurcation lesions (Medina 1,1,1; 1,0,1; 0,1,1) of unprotected left main coronary bifurcation disease, and non left main bifurcational lesion with affected important side branches most likely to supply at least 10% of fractional myocardial mass. The SYNTAX score for the lesions that are to be treated should be \<32.

Patients who fulfill inclusion and exclusion criteria and consent to the study will be randomized according to a standard random number generation method. Patient randomisation will be stratified by participating centre.

A diagnostic coronary angiography will be performed on all patients who have the clinical criteria for inclusion into the trial. All of the procedures will be carried out by classical radial or femoral approach depending on the operator choice, and the intervention will be carried out ad hoc or electively, at the operator discretion. Before the PCI procedure the patients will receive 300 mg of acetylsalicylic acid (100 mg if they were saturated earlier) 600 mg clopidogrel (75 mg if they were saturated earlier), or 2 x 90 mg ticagrelor and unfractionated heparin 70 - 100 UI/kg of body weight. The administration of intergrilin is upon operator decision. After intracoronary application of 100-200 µg of nitroglycerin a diagnostic angiogram will be carried out to record several views from various angles to obtain an optimal angiographic view that allows the visualization of branch division as well as the measurement of angles and assessment of the degree of ostial SB stenosis , "the working view". Planned single- and dual-stent techniques will be performed according to the recommendation of the EBC consensus.

The patients will be randomized in one of two groups including standard provisional approach or provisional DBC approach.

Standard provisional approach technique:

Coronary guidewires should be passed to the both main branch ( MB ) and side branch ( SB ) vessels. MB preparation should be considered routine practice in stable patients, but initial SB predilatation is only recommended when access is difficult, in cases of severe diffuse and/or calcified SB lesion or compromised SB flow after wiring. Stenting of the main vessel should be undertaken with a wire jailed in the side vessel to preserve side vessel flow and access. Second-generation DES should be used and stent diameter should be chosen according to the size of the MB beyond the bifurcation, and according to the expansion ability of the stent in proximal MB with proximal optimisation technique ( POT ). Following stenting of the MB, POT should be performed routinely with a short appropriately sized non-compliant balloon. Following POT, rewiring of the SB should aim to recross a distal stent cell. KBI should be performed using two NC balloons, sized according to the actual reference size of the vessels or 0.5 mm below, with individual high-pressure inflation followed by a final lower-pressure kiss dilatation. The procedure should be finalised by POT after kissing to correct the proximal MB stent distortion. SB should not be treated further unless there is one of the following: TIMI flow \<3 in the SB, severe ostial pinching of SB(\>90%), threatened SB closure, SB vessel dissection \>type A, or FFR \> 0,80. Bail-out SB stenting after MB stenting is performed with T-stenting, T and protrusion ( TAP ) or culotte. Implantation technique is selected according to angulations, reference size differences and operator capabilities. If SB stenting is necessary, it should be followed by KBI, and the procedure should be finalised with a second POT

Provisional DCB approach:

Wiring of MB and SB and MB preparation is the same as in standard provisional approach. Initial SB predilatation is obligatory. Predilatation of SB is done with semicompliant or noncompliant balloon, with balloon to vessel ratio of 0.8-1:1 at nominal inflation pressures. Liberal use of scoring or cutting balloons sized 0.5 mm smaller than the vessel size and inflated to high pressure is also recommended. Angio check is repeated after 10 minutes and intracoronary nitroglycerin application to rule out acute recoil. DCB is inflated in SB only after successful predilatation defined as residual stenosis ≤ 30% and no C,D,E,F dissection. Manipulation of the DCB should be done in the way to avoid drug loss during transit : no manipulation during flushing, lesion site should be reached rapidly, care should be taken when crossing the Y-connector and navigating through the proximal coronary artery up to the lesion. Inflation time when applying a DCB is 60 s, using DCB to vessel ratio of 0.8-1:1 at low inflation pressures that should not exceed nominal pressure, to reduce the risk of dissection. DCB inflation in SB is followed by a DES deployment in the main branch. POT is mandatory, and a final kissing balloon or POT/side/POT is not done.

Bail out stenting of SB could be done at two points of the procedure. First decision on the need for bail out SB stenting is after predilatation of SB and angio check. Bail out stenting is indicated in case of unsuccessful SB predilatation ( dissection C,D,E,F, or residual stenosis \>30% ) or in case of decreased flow-TIMI \<3, acute recoil, ischemia or FFR \> 0,80. Bail-out SB stenting can be performed with any two stent technique. Implantation technique is selected according to angulations, reference size differences and operator capabilities, followed by KBI, and the procedure should be finalised with a second POT. After deployment of DCB and POT, there is second decision to perform bail out SB stenting. Here it is indicated in SB pinching ≥ 90% stenosis or FFR \> 0,80 , dissection \>type A, threatened SB closure, decreased flow - TIMI \<3 or ischemia. Bail-out SB stenting after MB stenting is performed with T-stenting, T and protrusion ( TAP ) or culotte. Implantation technique is selected according to angulations, reference size differences and operator capabilities. If SB stenting is necessary, it should be followed by KBI, and the procedure should be finalised with a second POT.

Patients will be followed up by telephone or in person 1, 6, 12 and 36 months, and optional angiographical control after 9 months.

Significant symptoms will trigger further investigation as required.

Eligibility criteria: Inclusion Criteria:

Patients must meet ALL of the inclusion criteria:

Clinical:

1. stable angina Canadian Cardiovascular Society (CCS) 2 to 4, unstable angina, NSTEMI
2. clinical and anatomic eligibility for PCI as agreed to by the local Heart Team
3. in stable angina: a. ischaemic symptoms, or b. proof of ischemia on nonvasive testing, or c. positive FFR or iFR or d. ( for LMS ) IVUS minimal lumen area \<6 mm²
4. patients with mental and logistical conditions for further monitoring
5. patients need to accept clinical monitoring during 3 years and sign a written consent form
6. patients need to be older than 18 years

Angiographical:

1. de novo bifurcational lesion with affected side branch (Medina 1,1,1; 1,0,1; 0,1,1)
2. side branch diameter ≥ 2,5 mm
3. LM SB-DS ≥70% and SB lesion length \> 5 mm
4. non LM: SB-DS ≥ 90% and SB lesion length \> 5 mm
5. side branch length ≥ 73mm
6. for patients with LAD/diagonal BL - Scoring system for diagonal branches (Modified SNuHscore) ≥ 2

Exclusion Criteria:

Clinical:

1. STEMI \<72 hours preceding
2. Chronic total occlusion of either vessel
3. SYNTAX score for planned lesions to be treated \>32
4. cerebrovascular accident within 6 months, surgical procedure within one week
5. pregnant/nursing women
6. ejection fraction LV\< 30%, congestive heart failure, cardiogenic shock or sever valvular disease
7. unfavourable long-term prognosis - patient life expectancy less than 12 months
8. creatinine \> 2,0 mg/dl ( 177 mmol/L)
9. hypersensibility, allergies or contraindication to: aspirin, heparin, clopidogrel, prasugel, steel, sirolimus, everolimus, zotarolimus, biolimus or contrast agents
10. treatment of hyperthyroidism, administration of immunosuppressives or anticoagulant therapy, addiction to alcohol or drugs
11. patients included in other clinical trials

Angiographical:

1. thrombotic lesions
2. severe calcification
3. patients who have had a stent implanted previously ≤ 15 mm from the current lesions which is included in the study
4. lesions on the aorto-coronary venous or arterial grafts or on chronic total occlusions
5. In-stent restenosis or restenosis in a segment closer than 4 mm from the target lesion

Primary outcomes:
measure: Number of participants who develop major adverse cardiac events
timeFrame: 12 months after the procedure
Secondary outcomes:
measure: Number of patients who develop an individual component of the primary endpoint
timeFrame: 12 months and 36 months after the procedure
measure: Rate of angiographic success
timeFrame: immediately after the procedure
measure: Rate of procedural success
timeFrame: immediately after the procedure
measure: Rate of possible, probable or definitive stent thrombosis
timeFrame: 12 months after the procedure
measure: Rate of in segment late lumen loss in any of the treated branches
timeFrame: 9 months after the procedure
measure: Rate of "bailout" stenting and inadequate predilatation
timeFrame: immediately after the procedure
measure: Fluoroscopy time
timeFrame: immediately after the procedure
measure: Fluoroscopy dose
timeFrame: immediately after the procedure
measure: Contrast volume
timeFrame: immediately after the procedure
measure: Assessing a composite of the number of guidewires, balloons and stents opened or used
timeFrame: immediately after the procedure
measure: Rate lumen gain difference of 20%
timeFrame: 6-9 months after the procedure
Other outcomes:
Locations:
Study officials:
affiliation: Clinical Hospital Center Rijeka
name: Deiti Prvulovic, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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