Investigational device
The POBA platform is coated with crystalline sirolimus (Fig. 1) with a dose of 4µg per mm2 balloon surface using a butylated hydroxyl toluene as an excipient. The exact composition is proprietary.
Trial Design
This is a single-armed, prospective, international, multi-center, post-market study in patients with coronary artery disease and indication for percutaneous coronary intervention (PCI) either due to documented ischemia by non-invasive or invasive functional testing or due to angina symptoms and a relevant stenotic coronary lesion during angiography (Fig. 2). The aim of the study is to assess continued safety and efficacy of the cSCB. The product under investigation will be used in routine clinical practice according to the latest ESC guidelines and according to the instructions for use. Those data that are obtained in routine clinical use will be documented in the Case Report Form (CRF). All patients who undergo a target intervention with the SCB will be followed for 12 and 24 months after initial PCI.
Objectives
The objective of the study is to assess the safety and efficacy of crystalline sirolimus-coated balloon (cSCB, SeQuent® SCB, B.Braun Melsungen AG) within its approved indications to treat "real world" de-novo and restenotic lesions in native coronary arteries and coronary bypass grafts.
Aim
The aim of the study is to assess the safety and efficacy of the cSCB to treat coronary artery disease with reference vessel diameters between ≥ 2 mm and ≤ 4 mm with suitable lesion lengths. There is no limitation of lesion lengths. In case the lesion is longer than 36 mm, more than one device needs to be used.
Statistics
Primary outcome variable
The primary outcome variable is the target lesion failure (TLF) rate at 12 months, defined as the composite rate of target vessel myocardial infarction (TV-MI), cardiac death or ischemia-driven target lesion revascularization (TLR).
Secondary Outcome Variable
The secondary outcome variables are listed as follows:
- TLF at 24 months
- Ischemia driven TLR at 12 and 24 months
- All-cause death, cardiac death at 12 and 24 months
- All myocardial infarction and TV-MI at 12 and 24 months
- Major adverse coronary event (MACE), defined as composite of cardiovascular death, myocardial infarction or ischemia-driven TLR at 12 and 24 months
- Duration of DAPT in real-life with (telephone) follow-up at 4 weeks, 3 and 12 months
- Probable or definite stent-thrombosis of In-stent treated lesions accumulated at 12 and 24 months
-Procedural success (final diameter stenosis < 30% without flow-limiting dissections)
-Major and minor bleeding complications according to BARC classification, during hospital stay and accumulated at 3, 12 and 24 months follow-up. Severe bleeding is defined as categorized with BARC 3–5.
Sample Size
Despite the fact that this is a single-armed, observational study within clinical routine (post-market surveillance), a pro-forma sample size calculation was highly recommended by the Notified Body of the manufacturer. In particular, the predecessor device iopromide-paclitaxel coated DCB is suited as a comparator.
The target lesion failure rate (TLF) is chosen as the primary variable. The study is designed to detect a difference in TLF in this patient population as compared to comparable patient groups described in the literature, i.e. the test hypotheses are:
H0: TLFcSCB ≥ TLFPCB
Ha: H0 is false or TLFcSCB < TLFPCB
The target lesion failure rate in cSCB is not higher than or equal to the historic and published TLF rate of the predecessor device PCB.
Based on the above mentioned hypothesis we assume the following:
Alpha = 5%
TLFPCB= 6.8% (historic group from the literature, [15])
TLFcSCB= 6.8% (test group)
Follow-up rate = 85%
Non-inferiority margin = 3.0%
Based on the above assumptions 1106 patients must be followed up to compare their TLF rate to the TLF rate of the predecessor device. To account for patients lost to follow-up, a follow-up rate of 85% from previous studies will be assumed so that a total of 1302 patients will have to be recruited.
Pre-specified Of Analyses
Additionally, the following definitions are made:
- Patients who withdrew from this study are not replaced by additionally recruited patients to meet the minimum target of 1302 patients.
- nQuery Advisor® 7.0 software was used for sample size calculations.
- If a study site is recruiting less than 10 patients with less than 50% of follow-up, the patient data will be excluded from the analysis unless there are AE reported in this particular site.
- If the target number of patients are reached prior to the expected end of the recruitment period, patient enrolment will continue to the specified last day of recruitment.
- In case the necessary number of patients are not reached within the defined recruitment time, an extension for patient enrolment is possible.
All data will be analyzed by means of tables, figures, listings and statistical tests if appropriate. The final programming will be performed after closure of the database by use of an appropriate statistical software package (e.g. SPSS, SAS or R).
Since there is a wealth of clinical data for PCB angioplasty based on the all-comers approach, a propensity-score matched analysis is planned to compare SCB and PCB treatment of de novo and different types of ISR.
Prespecified Subgroups
Dedicated subgroup analyses include all patients who were treated for chronic total inclusions (CTO), the Asian study population and other groups with a higher than expected clinical outcome rate such as diabetics and patients of older age (≥ 75 years).
Interventions
Patients with indication for PCI according to current guidelines (ESC guidelines myocardial revasc, ESC NSTEMI und STEMI guidelines) are suitable for study participation. Estimation of %vessel stenosis, vessel diameter, stenosis length, lesion morphology, and if needed functional assessment using FFR or related indices (iFR, RFR) or intravascular imaging are done by operators’ discretion. Adequate lesion preparation with pre-dilation using semi- and/or non-compliant balloons with a balloon-to-vessel ration of 1:1 or debulking devices is performed on operator’s discretion. It is encouraged to achieve a residual diameter stenosis of ≤ 30% before dilating the lesion with the cSCB balloon (SeQuent SCB, B Braun Melsungen GmbH, Germany) according to the manufacturer IFU. Short delivery time of the SCB, slow balloon inflation, sufficient inflation time (30–60 s) and a balloon/vessel ratio of 1:1 or slightly higher should be attempted. In case of suboptimal angiographic results after lesion preparation (flow-limiting dissections, residual stenosis > 30%, FFR ≤ 0.80, TIMI-flow grade ≤ 2) bail-out stenting using a modern drug-eluting stent is advised [22]. The lesion and at least 2 mm proximally and distally should be covered with the DCB. For long lesions > 36 mm two DCBs have to be used. For bifurcation lesions, both, lesions of the main branch (MB) and the side branch (SB), are feasible for treatment with the study device. In bifurcation lesions 2 DCB strategies can be used by the operator: (1) DES in MB and DCB in SB, or (2) DCBs in both, MB and SB.
Evaluation Of Adverse Events
An independent critical event committee consisting of three members from Denmark (Prof. Jens Lassen, Odense Universitetshospital & University of Southern Denmark), Germany (Dr. Florian Krackhardt, Charité Universitätsmedizin, Berlin) and France (Dr. Georgios Sideris, Georges Pompidou APHP Paris) evaluated all device-event relationships for serious adverse events.
Adverse events (AE), including non-serious and serious AEs, are continously monitored before patient discharge of index PCI and during 4-weeks, 3-, 12- and 24 months follow-up.
Stopping and Discontinuation Criteria
The study will be stopped if the in-hospital TLR rate in the first 50 patients is higher than 10% and/or the in-hospital MACE rate is higher than 15%. At any rate, all included patients will be followed-up according to the protocol.
Recruitment
Patient inclusion criteria
- All common significant coronary lesions with clinical indication for PCI of a de novo or in-stent coronary stenosis according to the latest ESC guideline [8] recommendations
- Any target lesion length > 36 mm needs to be covered with at least 2 devices
- Patients eligible for this study must be at least 18 years of age.
- The patient must fulfil the standard recommendations for PCI, based on the last ESC recommendations within his/ her regular treatment or that the use of the product has already been decided within the regular planning of the patient’s treatment.
- In patients with multi-vessel coronary artery disease all vessels other than the target-vessel will be treated according to the operator’s discretion.
- In case more than one vessel is treated with the investigational device (cSCB) all vessels will be separately documented and analyzed.
- Only one lesion per vessel shall be included.
- In case more than one lesion need to be treated in the target-vessel, all lesions treated in a different way than the investigational procedure must be separated from the target-lesion by ≥ 20 mm or shall be seen as one lesion treated according to this study protocol.
- Written informed consent
General patient exclusion criteria
- Known intolerance to sirolimus
- Allergy to any component of the coating
- Severe allergy to contrast media
- Pregnancy and lactation
- Hemorrhagic diathesis or another disorder such as gastro-intestinal ulceration or cerebral circulatory disorders, which restrict the use of platelet aggregation inhibitor therapy and anti-coagulation therapy
- Cardiogenic shock
- Patients with an ejection fraction of < 30%
- Comorbidity with a life expectancy < 1 year
- Contraindication for whichever accompanying medication is necessary
- Treatment shortly after myocardial infarction with indications of thrombus or TIMI flow ≤ 2
- Indication for surgical revascularization
Angiographic exclusion criteria
- Complete occlusion of the target vessel. Complete occlusions present an exclusion criterion for the majority of the participating study sites. However, in preselected centers with expertise in CTO interventions and a proven track record (> 10% of all DCB interventions) of DCB application in CTO cases, complete occlusions may still be treated if there is a sufficiently high benefit-risk-ratio due to operators discretion.
- Lesions which are untreatable with PCI or other interventional techniques and coronary artery spasm in the absence of a significant stenosis
- Vascular reference diameter < 2.00 mm or > 4 mm
- Treatment of the left main coronary artery as study lesion
- Target lesion not suitable for a drug-coated balloon-only PCI based on the discretion of the operator (e.g. severe calcification, subtotal occlusion)