The first-generation drug-eluting stents (DES) initially demonstrated good promise in terms of reducing the degree of restenosis. They succeeded in arresting the neo-intimal proliferation, which was the bane of coronary stents.1 Over a period of time, however, the polymeric degradation by-products failed to bring about an essential component of the healing process: endothelialisation. Failure of endothelialisation gave rise to an important safety issue, primarily led by stent thrombosis-related myocardial infarction (MI) and even death.2
Subsequent DES technology has aimed to minimise vascular injury during angioplasty and stenting procedures by using ultra-low strut thickness stents. The use of biodegradable and biocompatible polymeric materials to encourage endothelialisation of the stents is now gaining popularity. Such materials are used to eliminate stent thrombosis and major adverse cardiac events, while preserving primary efficacy requirements of the DES. Sirolimus-eluting coronary stents have been in use since their approval by the US Food and Drug Administration in 2003. Since then, millions of patients worldwide have been treated with the Cypher stent (Cordis), which consists of a 140μm thick strut stainless steel stent coated with 1.4μg/mm2 sirolimus bound to permanent polymers – polyethylene-co-vinyl acetate and poly-n-butyl methacrylate.3
The meriT-1 study is being conducted to determine the safety and efficacy of the new-generation sirolimus-eluting stent (SES), BioMime™. It uses non-inflammatory, biodegradable, biocompatible polymers eluted from a very low strut thickness. The SES has a novel stent platform design primarily aimed at early endothelialisation, thus reducing/eliminating early or late complications, such as major adverse cardiovascular events (MACE) and stent thrombosis.
The meriT-1 study has a prospective, single-arm, single-centre, non-randomised, open-label format.
Patients were considered to be eligible if they were above 18 years of age and presented with stable or unstable angina and/or had a positive functional test for coronary ischaemia through standard test methods. The essential inclusion criterion was the presence of a single, discrete, de novo target lesion located in the native coronary artery that was suitable and amenable to conventional angioplasty and stenting techniques.
Patients also had to be acceptable candidates for an emergency coronary artery bypass graft (CABG) surgery. They had to be willing to sign a pre-approved informed consent form and appear for all stipulated follow ups.
The main exclusion criteria were:
- known hypersensitivity/contraindication to sirolimus or any other mTOR inhibitor;
- hypersensitivity/contraindication to aspirin, clopidogrel or other thienopyridines; and
- hypersensitivity/contraindication to cobalt, chromium, heparin or contrast media that are routinely present during stent procedures.
Other exclusion criteria included:
- pretreatment of target lesions by stenting methods;
- previous brachytherapy;
- presence of significant nontarget lesions requiring treatment within 30 days of the index procedure;
- prior CABG to the target vessel;
- acute MI within 72 hours.
The main angiographic inclusion criterion was a target lesion present in the native epicardial coronary artery 2.5–3.5mm in diameter that can be covered by a single BioMime stent with a maximum length of 24mm. Lesions having severe calcification, tortuosity, presence of intraluminal thrombus, bifurcation sites, involving left main coronary artery stems, saphenous vein grafts and those with left ventricular ejection fraction <30% were excluded from this trial.
BioMime Sirolimus-eluting Coronary Stent System
All study patients received a single BioMime SES.
The base stent is made of cobalt chromium (L605) and has an ultra-low (65μm/0.0026 inch) strut thickness. The novel design incorporates an intelligent mix of open and closed cells, allowing for morphology-mediated expansion of the stent. This hybrid stent has a high radial strength and comes premounted on a flexible delivery system that maintains short-abrupt balloon shoulders to minimise balloon-related edge injuries.
The entire stent surface is coated with a thin 2μm mix of the biodegradable polymers poly-L-lactic acid (PLLA) and poly-L-glycolic acid (PLGA), along with the active antiproliferative drug sirolimus (1.25μg/mm2). The drug is timed to elute over a period of 30 days, while the polymeric mixture degrades via hydrolysis then phagocytosis and is eventually eliminated via the Kreb’s cycle as carbon dioxide and water.
The stent has been sufficiently studied in porcine coronary artery and rabbit iliac models for its preclinical safety and efficacy to have been established. The BioMime stent has been used in clinical practice since the beginning of 2009.
Each patient was treated by routine angioplasty procedure and predilatation was done in each case with a suitable rapid-exchange percutaneous transluminal coronary angioplasty (PTCA) balloon dilatation catheter. A BioMime SES was deployed once visual estimation of the vessel diameter and lesion characterisation had been undertaken, always keeping in mind the angiographic inclusion and exclusion criteria. At the end of the stent implantation, it was left to the interventional cardiologist’s discretion whether or not to further treat the patient with a postdilatation balloon catheter.
An intravenous bolus of standard unfractionated heparin was administered to maintain an activated clotting time of 250 s or more. This drug was discontinued after 12 hours. Each patient was pretreated with a loading dose of 300mg aspirin and a bolus of 300mg clopidogrel prior to the treatment. Dual antiplatelet therapy (aspirin plus clopidogrel) was continued for up to one year post-procedure.
Procedural success was defined as a successful device implantation with a residual stenosis of <20% of the vessel diameter, event-free sheath removal and subsequent discharge from the hospital. Tables 1 and 2 provide baseline demographics and treatment details.
The follow-up time-points were 30 days, six months, eight months, one year and two years. With the exception of the eight-month time-point, which involved an angiographic study to assess the late luminal loss by quantitative coronary angiographic (QCA) method, the rest are clinical end-points. A hospital visit was required for the 30- day time-point and the rest of the follow-up sessions were carried out via telephone interview.
Quantitative Coronary Angiographic Evaluation
A diagnostic angiogram was obtained for each patient at eight-month follow-up, with target vessel cine views captured in at least two orthogonal views or the one in which maximum stented length was easily discernable. At least two cardiac cycles were recorded and the arteries were filmed while having maximum contrast passage to maximise understanding of the QCA study.
All such recordings were obtained at three distinct time-points – pre-stenting, post-stenting (also known as baseline) and at eight-month follow-up. Each CD was labelled and sent to an independent core laboratory, in this case the Cardiovascular Research Centre in Sao Paulo, Brazil. QCA was performed using leading software and edge-detection techniques. The advanced understanding of the experts was used to characterise the lesions. In-stent and in-segment morphologies were measured. The target lesion was defined as the stented segment that could clearly be seen on the software. The 5mm segments immediately pre- and post-stented length were considered to be the in-segment portion.
The primary safety end-point was MACE at 30 days. MACE comprised hard end-points, such as: death (cardiac or non-cardiac); MI (Q-wave or non-Q-wave); and ischaemia-driven revascularisation, either via repeat PCI or CABG. The primary efficacy end-point was in-stent late luminal loss, as calculated by QCA method at eight months angiographic follow-up.
The secondary safety end-points included the occurrence of ARC-defined definite stent thrombosis at acute, subacute, late and very late time-points, and MACE at six months, eight months, one year and two years. Secondary efficacy end-points included percentage of angiographic stenosis and binary restenosis as understood from the eight-month angiographic follow-up.
Characteristics of the Patients
Between March 2009 and February 2010, 30 patients who met the eligibility criteria were treated with a single BioMime stent. All patients were Indian in origin and belonged to the Asian race. Overall, 83% patients were male, with a mean age of 50.5 ± 8.0 years. A high prevalence of diabetes (30%), hypertension (57%) and high blood pressure (67%) was noted in these patients. Most of the patients had a high body mass index of 24.3 (considered overweight in Indians). Seventy per cent of patients presented with acute coronary syndrome, which was a mixture of stable and unstable angina along with a past MI episode.
The target lesion site was the left anterior descending coronary artery in 40% of cases and the right coronary artery in 37% of cases. Left circumflex artery disease was seen in 10% of patients. Lesions in the remaining patients involved the right posterior descending artery and the obtuse marginal artery, which accounted for 3 and 10% of cases, respectively. Seventy-three per cent of patients presented with thrombolysis in MI flows I and II and 73% of patients had lesion classification of type B1 and B2 (with type B1 lesion dominating in 70% of the treatment settings). As severe calcification was an angiographic exclusion criterion, 33% of mild to moderate calcification patients were treated. Two patients had undergone a previous PCI and a CABG procedure.
All patients were treated with standard arterial puncture methods and routine prescription of in-process anticoagulants. An antiplatelet regimen was administered, along with other cardiac drugs, as deemed necessary. While the maximum stent diameters used were 3mm (47%), in 43% of the cases the stented lengths were 24mm, which is representative of clinical practice.
Intra- and Post-procedural Details
All patients successfully received a single BioMime stent. Physician experience of stent acute performance, such as stent trackability, deliverability and radio-opacity, was found to be satisfactory. All patients were desheathed and subsequently discharged without any procedural event. Table 3 provides post-procedure baseline demographics.
Quantitative Coronary Angiography
Data on angiographic follow-up data at eight months are available for 20 (68%) out of the 30 patients treated so far. The interim analysis provided by the core laboratory demonstrates an excellent in-stent late lumen loss of 0.15mm and an in-segment late lumen loss of 0.22mm. These results compare favourably with those of currently available DES studies.
As can be seen in Table 4, the median lesion length was 13.67mm. The numbers mentioned in the parenthesis are the lower 25th percentile and upper 75th percentile values – in this case ranging from 12mm to 17.15mm. Median reference vessel diameter was found to be 3.02mm and minimum luminal diameter (MLD) was 0.36mm. Median diameter stenosis was 88.8% in these patients.
Post-procedure QCA details are given in Table 5. Post-procedure in-stent MLD was 3.02mm and residual diameter stenosis was maintained at a median of 6.3%, well below the 20% mark that is indicative of a technically sound procedure and acute product performance. In-stent acute gain was measured to be 2.37mm. In-segment analysis revealed a MLD of 2.77mm and a residual diameter stenosis of 13.3%, with an acute gain of 2.22mm.
The eight-month angiographic follow-up data from 20 patients were studied and an interesting set of values is available in Table 6. Median in-stent MLD was found to be 2.7mm, with a diameter stenosis of 11.2% and a late lumen loss of 0.15mm. Interestingly, binary restenosis was not found in any patients and this remained 0% at the end of eight months, thereby indicating high efficacy. Likewise median in-segment MLD was 2.4mm and thus the late loss was calculated as 0.18mm, with no binary restenosis.
Major Adverse Cardiac Events and Stent Thrombosis
All patients completed the 30-day primary end-point and were followed up to eight months and one year with 0% MACE.
Zero per cent stent thrombosis from acute to late phase follow-up was observed, demonstrating a high standard of safety. One of the major concerns of first-generation DES has been stent thrombosis at various time-points after implantation. Most of the time, malapposition, polymer-related inflammation, lack of optimal endothelialisation and inadequate healing are the reasons for stent thrombosis. No other complications occurred during this time frame, demonstrating the high safety profile of this new generation of SES.
First-generation DES were linked with late stent thrombosis and were created on bulky stent platforms with questionable deliverability and polymer biocompatibility. BioMime SES is a fresh approach to the design of DES, keeping in mind that the DES should endothelialise in a few months. For this reason, all of the ingredients that allow for optimal endothelialisation have been incorporated in BioMime development. The base NexGen™ stent platform is cobalt–chromium, with ultra-low strut thickness (65μm), variable strut width and a novel geometry involving an intelligent hybrid of open and closed cells. This allows for morphology-mediated expansion of the stent while retaining high radial strength and conformability. The drug employed is sirolimus, which is an ideal choice considering that it acts on the common final pathway of the cell division cycle without an exceptional risk of necrosis induction. The BioPoly™ is a copolymer combination of PLLA and PLGA, which are non-inflammatory and allow for a 2μm stable coating. The resultant SES has drug elution kinetics of 30 days and a polymer degradation that is short and well documented. BioMime has been found to be safe and efficacious in preclinical models and in the primary safety and efficacy study.
Thus far, the meriT-1 study has demonstrated no major adverse cardiac event (MACE), which is death (both cardiac and non-cardiac), MI (a composite of Q-wave and non-Q-wave) and ischaemia-driven revascularisation (either repeat PCI or a CABG procedure). No cases of stent thrombosis or any other complications have been observed.
In terms of its efficacy parameters, at eight-month angiographic follow-up, 0.15mm of in-stent medial late luminal loss has been observed, which can be favourably compared with some of the new-generation stents. More importantly, 0% binary restenosis has been recorded thus far.
BioMime has been granted the Conformite Europeene mark and is supported by routine successful clinical experience, wherein BioMime stents are being used to treat patients. This study corroborates sound product science and can be included in regular clinical practice.