Abstract
Background
The Absorb™ BVS is a bioresorbable, everolimus-eluting scaffold approved and marketed for coronary use. Published data on long-term results after treatment are limited to a small number of patients, most of them with elective PCI of simple lesions. The importance of scaffold resorption is variably appreciated among cardiologists, and indications for use from health technology assessment bodies or guidelines are missing. Instruments are needed to collect, share and assess the experience being accumulated with this new device in several centres.
Methods/Design
The BVS-RAI Registry is a spontaneous initiative of a group of Italian interventional cardiologists in cooperation with Centro di Ricerche Farmacologiche e Biomediche “Mario Negri” Institute, and is not recipient of funding or benefits originating from the BVS manufacturer. It is a prospective registry with 5-year follow-up of all consecutive patients who have undergone successful implantation of 1 or more coronary BVS following the indications, techniques and protocols used in each of the participating institutions. Outcome measures are BVS target lesion failure within one year and device-oriented major adverse cardiac events within 5 years. The registry started in October 2012 and will extend enrolment throughout 2015, with the aim to include about 1000 patients. ClinicalTrials.gov identifier is CT02298413.
Conclusions
The BVS-RAI Registry will contribute observational knowledge on the long-term safety and efficacy of the Absorb™ BVS as used in a number of Italian interventional centres in a broad spectrum of settings. Unrewarded and undirected consecutive patient enrolments are key-features of this observation, which is therefore likely to reflect common clinical practice in those centres.
Highlights
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prospective data collection of successful Absorb implantation;
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expert Italian centers;
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no restrictions for enrollment/no exclusion criteria;
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clinical follow up;
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“modern” primary EP: DOCE;
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up to 5 years follow up.
1
Background
The Absorb™ BVS (Abbott Vascular, Temecula, USA) is a bioresorbable poly(L-lactide)(PLLA) scaffold for coronary use, with a drug (everolimus) and a polymer (polyD,L-lactide) (PDLLA) coating. As part of the Abbott Vascular Absorb Clinical Program, the ABSORB Cohort A , ABSORB Cohort B , and ABSORB EXTEND trials have provided preliminary data on the performance of this device. Evidence of complete resorption of the Absorb™ BVS about three years after implantation in human coronary arteries has been provided by imaging with optical coherence tomography (OCT), along with proof of late expansive vessel remodeling, and restoration of vasomotion .
Published data on long-term results after treatment with BVS are, however, still limited to a small number of patients, most of them with elective percutaneous coronary interventions (PCI) of simple lesions . These data are in keeping with a substantial equipoise with new generation drug-eluting stents (DES), namely Abbott Xience™, as to mid-term major adverse cardiovascular events (MACE). BVS performance in patients with diabetes mellitus, chronic kidney disease (CKD) or acute coronary syndromes is poorly known so far.
The results of the ABSORB II trial, the first direct comparison with the Xience platform, have recently been published. In this prospective study 501 patients with de novo lesions were randomized to BVS or EES in a 2:1 fashion. Study co-primary endpoints, vasomotion (the difference in mean lumen diameter at 3 years) and difference between minimum lumen diameter after the index procedure and at 3 years are not yet available. However, 12-month MACE (a composite of cardiac death, myocardial infarction and target vessel failure) were similar (5% in the BVS and 5% in the DES group, p = 0.78) .
The Absorb™ BVS received a CE-mark in December 2010, and has been sold in Italy since 2012. As per instructions for use (IFU), both lesion- and patient-related contraindications to the use of this device, in addition to those which apply to all DES, are very limited, namely: lesions of venous and arterial coronary grafts and of the unprotected left main trunk.
The use of resorbable coronary scaffolds has been addressed by the National Institute for Clinical Excellence (NICE) in the UK . This report, mostly based on studies with the Absorb™ BVS, concludes that current evidence on the short-term safety and efficacy of this technology is adequate, but the quantity of evidence on its safety and efficacy in the long term is not. A recommendation is therefore made by NICE, that details about all patients undergoing implantation of this device should be entered into the UK Central Cardiac Audit Database, and that the clinical outcomes should be locally reviewed. Nothing similar to the above-mentioned UK Central Cardiac Audit Database exists in Italy to date. The only documented attempt to reach an expert consensus about the indications for use of the Absorb™ BVS in Italy was of no avail .
In 2012, a group of 22 Italian interventional centres spontaneously joined into a working group named Italian Absorb Registry (BVS-RAI), to share their experience with the Absorb™ BVS and to assess its performance in the long-term. The importance of scaffold resorption was variably appreciated among interventional cardiologists, who “believed” on their own personal grounds and experience that this device would be especially effective in one or another set of patients or lesions. The need for an instrument to collect, share and assess the experience being accumulated in several centres with this new device became fully apparent.
2
Methods/Design
2.1
Study setting
The BVS-RAI Registry is a spontaneous initiative of a group of Italian interventional cardiologists who wanted to test the long-term outcomes of their patients following successful coronary implantation of BVS.
Participation to the BVS-RAI Registry is offered to all Italian interventional centres using the Absorb™ BVS, without restriction. The steering committee of the BVS-RAI Registry includes one representative of each centre which complies with its rules.
The BVS-RAI Registry was developed in cooperation with the Institute Centro di Ricerche Farmacologiche e Biomediche “Mario Negri” and is not recipient of funding or benefits originating from the BVS manufacturer. BVS devices are regularly purchased by the participating centres.
Each participating centre is willing to prospectively input data of its patients treated with BVS, and is committed to enroll at least 50 consecutive patients — or all of its consecutive patients during 1 year — and to report their outcomes for the entire length of follow-up (5 years) ( Fig. 1 ). Patient recruitment is neither directed per protocol, nor is it rewarded. Inclusion into the BVS-RAI Registry is proposed to patients only after BVS implant has been performed following the indications, techniques and protocols used in each of the participating institutions. Baseline patient clinical data, with special attention to biochemistry and drug treatment in patients with diabetes and CKD, as well as procedural data (and intravascular imaging data when available), are entered into a web-based case report form (CRF). It is a web database application developed on a LAMP (short for Linux, Apache, MySQL and PHP) open-source web development platform. Data are stored in a MySQL database and organized into tables containing related data. Follow-up data from yearly outpatient visits or phone interviews, and from subsequent admissions and coronary angiograms as clinically required or according to the protocols being used in each institution, are prospectively collected and entered into the database. All data within the CRF are always visible to all registered participants, with the exception of patients’ identity remaining visible only for the physician who input data. In the CRF, query tools are available for registered participants to select patient and lesion subsets or events in the common database, whose procedural or follow-up details may be of special interest. Random source verification is performed by the PI, requiring submission of the original documents (cath reports, discharge documents) covering 5% of patients in each centre.
The conduct of the trial has been approved by the ethics committee (EC) of the Promoting Centre (Azienda Ospedaliera Santa Croce e Carle, Cuneo), and accepted by the EC of each participating centre.
2.2
Patient selection
This is an all-comers study, and includes all consecutive patients who have been treated with 1 or more BVS in the study time-lapse in each participating centre.
Inclusion criteria are:
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Successful implantation of 1 or more coronary BVS;
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Age < 75 years;
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Patient’s informed consent.
Although compliance with the BVS IFU was recommended, there were no angiographic exclusion criteria.
2.3
BVS implantation procedure
By consensus among the RAI Registry researchers, balloon dilatation before and after BVS implantation (with a maximum diameter 0.5 mm larger than the BVS diameter) was recommended, as was either the “marker-to-marker”, or the “marker-over-marker” overlap strategy in case of multiple overlapping BVS. These recommendations have been made by the BVS Absorb manufacturer since the device became available in Italy, and have recently been published in an expert consensus paper . Dual antiplatelet treatment length and concomitant medications according to the most recent ESC guidelines were also recommended .
2.4
Patient follow-up
Patient visits were recommended at 6 months after Absorb™ BVS implantation, and yearly thereafter up to 5 years, with collection of biochemistry and drug treatment data, as part of guideline-recommended work-up, especially in patients with diabetes and CKD. Angiographic follow up was not scheduled per protocol, but was performed in case of planned “step” revascularization or if clinically indicated. All available data from angiographic and intravascular imaging follow up were collected in the electronic CRF.
2.5
Outcome measures
Primary outcome measures:
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Target lesion revascularization (TLR) at 1 year.
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Scaffold thrombosis: acute, subacute, late and very late.
Secondary outcome measures:
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Device-oriented cardiac events (DOCE), as assessed yearly through the 5-year follow up: cardiac death, TLR, and target-vessel myocardial infarction.
All clinical events will be recorded and reported during the follow-up. Events are defined according to the Academic Research Consortium recommendations . All participants are asked to keep documentation of clinical events for adjudication. A clinical event committee of clinical and interventional cardiologists not involved in BVS-RAI Registry data collection, is established to adjudicate events.
The BVS-RAI Registry is identified as NCT02298413 at ClinicalTrials.gov.
2.6
Study dimensions and statistical analyses
The BVS-RAI Registry has enrolled its first patients in October 2012, and will include about 1000 patients. Enrolment will extend throughout 2015.
All patients enrolled in the BVS-RAI Registry will be included in the principal analysis. Continuous variables will be analysed and presented as mean, standard deviation, median, minimum and maximum; discrete variables as numbers and percentages with confidence intervals. The Kaplan–Meier method will be used in survival analysis. Subgroup analysis according to baseline clinical, angiographic and procedural characteristics will be performed, with use of the Student-t, Fisher and log-rank tests, and of multivariable logistic regression when appropriate.
Since no direct comparison of our patient population with external benchmark outcome data is available, sample size calculation is not critical to warrant statistical power. Our choice was oriented by the call for appropriate confidence intervals. In fact, if we assume a 5% estimate for MACE rate at 1 year , 95% confidence interval would be a comfortable 3.6–6.4 % for a 1000-patient sample size.
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