“I do not know what I may appear to the world, but to myself I seem to have been only like a boy playing on the sea-shore, diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me.” Sir Isaac Newton
Advances in Percutaneous Coronary Intervention – An Overview
Over the last 10 years, the interventional cardiology field has evolved tremendously.1 From the ground-breaking work of Frossmann in the 1960s to Andreas Gruentzig’s successful procedure with a percutaneous transluminal coronary angioplasty (PTCA) balloon catheter in 1977, the application of devices used to open up clogged coronary arteries has expanded manifold.1 As soon as PTCA balloon angioplasty became popular, problems surrounding the use of the plain old balloon angioplasty (POBA) technique emerged in the form of dissections and abrupt vessel closures.2
These issues were soon tackled using metal scaffolding designed by Palmaz-Schatz and others and soon the concerns surrounding the POBA technique were virtually eliminated by stenting.3,4 However, while stenting emerged as a sound technique to hold dissected vessel flaps and thus the expanded vessel, it caused injury and thus gave rise to a ubiquitous problem known as restenosis, the exuberance of neointimal proliferation, which again in-turn threatened to narrow or close down the vessel in the mid-term period. While restenosis remained the Achilles’ heel of interventional cardiology for a while, stent thrombosis also emerged as an important safety parameter that threatened the success of the procedure.5
On a parallel front, this development saw the rise of antiplatelet therapy in the form of aspirin, ticlopidine and then clopidogrel, which arrested the thrombosis issue.6–10 Two novel forms of treatment for curbing restenosis came into existence. The first treatment was brachytherapy, but this was quickly abandoned due to its technological problems, and the second treatment was releasing an antiproliferative agent at the site of stent implantation that would work in situ and have control over restenosis. This came to be known as drug-eluting stent (DES) therapy. Soon, DES therapy caught on to the fast developmental pace and, today, more than 5 million PTCAs and stenting procedures are performed worldwide. More than 70% of stents are DES.
The efficacy of DES brought a high degree of treatment satisfaction and, worldwide, interventional cardiologists observed that perhaps an era of complete control over neointimal proliferation had arrived.11–13 Event-free survival similar/superior to that achieved by coronary artery bypass graft surgery14 (CABG) was also observed.
Drug-eluting Stents in the Eye of the Storm
The well charted time-course of evolution of novel technologies (see Figure 1) flows as follows. Unbridled enthusiasm follows innovations that find high acceptance since they promise new ways of tackling existing problems. After a period of time with expanding usage, issues surface and usage dips. Shaken confidence prompts developers to bring about thoughtful adaptations. Once again, de-bugged technology is re-launched, giving rise to its ultimate applicability.
Prompted by excellent first-in-man results with first-generation DES,11–13 larger randomised clinical trials were conducted and showed a small increment in late loss, restenosis and major adverse cardiac events (MACE),15–19 but this was still significantly lower than its bare-metal counterpart, truly cementing DES therapy as the gold standard. This enthused operators worldwide to expand DES usage to so-called ‘off-label’ indications. Interestingly, the real-world usage of DES failed to replicate the results of randomised controlled trials, and the results showed a late stent thrombosis of 0.53% per year with a continued increase to 3% over four years.20,21 In patients with complex multivessel disease in the Arterial Revascularisation Therapies Study Part II (ARTS II) trial, the rate of combined definite, probable and possible stent thrombosis was as high as 9.4% at five years, accounting for 32% of MACE events.22
While these late ST episodes continued to flummox operators, one of the initial suspects was non-compliance to thienopyridine therapy.23 Thus, the research turned around to investigate antiplatelet therapy compliance-related benefits. However, analysis of the timing of late stent thrombosis events in the Basel Stent Cost-effectiveness trial-Late Thrombotic Events (BASKET-LATE) study showed that events continued to occur over six to 18 months after stopping clopidogrel, an observation that would not be expected if the withdrawal of clopidogrel were the single trigger of thrombosis.24
Interestingly, the two-year follow-up of patients with diabetes included in the RESEARCH registry (three-year clinical follow-up of the unrestricted use of the Sirolimus eluting stents as part of the Rapamycin Eluting Stent Evaluated At Rotterdam Cardiology Hospital) showed that very late DES thrombosis may still occur in patients with diabetes with antiplatelet treatment and the analysis of multiple registries has shown a lack of noticeable increase in the rate of thrombosis and thrombosis-related events immediately after stopping clopidogrel.25,26
These findings suggest that ‘dual antiplatelet’ treatment is not the only factor associated with late stent thrombosis. Multiple factors related to the procedure, the patient, lesion morphology and even the entire device – stent, drug and polymer – are thought to be responsible in isolation or in conjunction for late ST.
From the above observations, the criteria for DES safety have emerged as: reducing vessel injury, ensuring complete stent apposition; use of thrombo-resistant polymers, ensuring optimal antiplatelet treatment for reduction of acute events and encouraging re-endothelialisation; resolving local inflammation; and, finally, facilitating the generation of functional endothelium for the reduction of late events.
Considering the above safety parameters, criteria for sound DES construction are:
- a thin strut stent platform design that minimises injury, ensures complete apposition and endothelialises well due to conformability against the vessel wall;
- a drug that ensures antiproliferative/anti-inflammatory effect, is not cytotoxic, has a broad therapeutic window and has been tested in similar clinical situations; and
- a polymeric coating that is non-thrombogenic, has elastic properties to allow for thin coating and withstands mechanical trauma while being biodegradable.
The Penrose Triangle of Drug-eluting Stent Development
Having identified the classical triad of an ‘ideal DES’ construction, the challenge of creating one is like the creation of Penrose’s impossible triangle. The Penrose triangle (see Figure 2) is a typical combination of properties that cannot be realised by any 3D object in ordinary Euclidean space and is a demonstration of the current challenges during the design and development of an ideal DES. All the classic parameters of a DES construction are polarised and offer little homogeneity when combined. Any compromise in the stent architecture and the drug formulation would cause incomplete healing; likewise, inappropriate polymer usage would cause inflammation and sub-optimal drug-release kinetics.
Moving Towards Biomimicry and the Development of the BioMime™ Sirolimus-eluting Coronary Stent System
Derived from the clinical and the technological need gaps in the existing coronary stents and DES, the BioMime™ sirolimus-eluting stent (SES) has been developed on simple yet fundamentally sound principles. The resultant DES has the ability to be arterially biocompatible, leading to its predictably safe and efficacious profile.
BioMime Sirolimus-eluting Stent – Primary Device Description
The BioMime SES is made of the following components:
- stent – NexGen™ Cobalt Chromium Coronary Stent System;
- drug – sirolimus (Rapamycin) 1.25μg/mm2; and
- polymer – BioPoly™, the biodegradable co-polymer combination of poly-L-lactic acid (PLLA) and poly-L-glycolic acid (PLGA).
The Right Stent Architecture
The BioMime SES (see Figure 3) employs the CE-marked NexGen Cobalt Chromium Coronary Stent System – a novel concept conceived to minimise intra-arterial injury.
The design stretches the boundaries of structural engineering with an ultra-low strut thickness (65μm) stent maintained across all 54 dimensions without any loss in radial strength. On bench testing, NexGen demonstrates a high radial strength of 1.1 bar with a mean recoil of <3% and a foreshortening of 0.29%.27
The novel stent design ensures a morphology-mediated expansion27 (see Figure 4) due to a hybrid cell design structure (open-cell configurations in the centre and closed at the edges). This unique method of expansion eliminates the classic dog-boning seen in conventional designs and also ensures minimal edge injury.27 Furthermore, the struts have unique strut width variability (see Figure 5), which ensures flexibility while retaining high radial strength. Evidently, due to these features, the stent demonstrates superior acute gain (see Figure 6) and complete wall apposition. Thus, it appears to endothelialise quickly (see Figure 7) in porcine coronary artery models at 28 days.27
The stent delivery system also ensures minimal arterial injury. The semi-compliant rapid exchange balloon catheter shoulders are carefully constructed short tapers and abrupt with a marginal overhang (see Figure 8). This allows for high trackability and deliverability at the same time, minimising any chance of balloon-related edge injury.27
The resultant stent system has a predictably low injury profile. Simons et al. have proved through their experimental work that topography of the stent as measured by its strut thickness has a direct impact on endothelialisation,28 and Kastrati et al. have proved through the Intracoronary Stenting and Angiographic Results: Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO)29 and ISAR STEREO 230 trials that low strut thickness stents, irrespective of the stent design, are associated with a significant reduction of angiographic and clinical restenosis after coronary stenting. In an interesting pre-clinical evaluation undertaken in a porcine coronary artery model, low strut thickness (65μm) NexGen™ stents were compared with high strut thickness (91μm) Driver stent (Medtronic, US). Piglets were sacrificed at 28 and 90 days to appraise the biocompatibility. The primary end-point was mid in-stent neointimal thickness. Histomorphometric analysis at 28 days showed significant differences in mid-stent neointimal thickness: 0.18±0.08mm for NexGen segments versus 0.30±0.41mm for Driver segments; p=0.03 favouring thinner strut cobalt chromium stents (see Figure 9). This beneficial result was maintained at 90 days: 0.09±0.04mm for NexGen segments versus 0.25±0.03mm for Driver segments.27 This study corroborates earlier stated results obtained in humans by Kastrati et al., which allowed for predictability in lowering restenosis and target vessel revascularisation (TVR) incidence versus high strut thickness.
The Right Antiproliferative Drug – Sirolimus
The BioMime stent releases the tried and tested sirolimus. In this context, sirolimus is the right candidate for DES application since it targets the ‘final common pathway’ to prevent vascular smooth-muscle-cell proliferation.
The efficacy of SES in animals has long been established and a large volume of published data in human coronaries is available. In a pre-clinical model involving porcine coronary arteries, piglets were randomised to receive either BioMime or NexGen with polymer (control stent) or Cypher (Cordis, US), and arteries were explanted at 28 or 90 days.27
At 28 and 90 days, BioMime-stented segments were as safe as corresponding control stents or Cypher and demonstrated a superiority in reducing neointimal thickness over the control stent or Cypher.27 The control stent, which was NexGen coated with biodegradable polymer, was found to be equivalent in terms of biocompatibility to the NexGen bare stent, itself suggesting a non-inflammatory nature of the polymer.27 In terms of drug release kinetics, BioMime demonstrated release kinetics similar to Cypher (see Figure 10).27
The Right Polymer – BioPoly
BioPoly is a biodegradable polymeric base in BioMime comprising a proprietary co-polymer formulation mix consisting of PLLA and PLGA. The principal mode of degradation of BioPoly is via hydrolysis. Degradation precedes diffusion of water into the material, followed by random hydrolysis, fragmentation of the material and, finally, a more extensive hydrolysis accompanied by phagocytosis, diffusion and metabolism. Once hydrolysed, the products are either metabolised or excreted. The lactic acid generated becomes incorporated into the tricarboxylic acid cycle (Kreb’s cycle) and is excreted as carbon dioxide and water. BioPoly has been found to have a short degradation time and has been found to be non-inflammatory in the pre-clinical model. The composition offers a uniform stent coating and does not crack, web, lump or stick to the balloon surface.27 On BioMime the drug plus BioPoly coating thickness is maintained at 2μm, which is the thinnest among the available DES on the market (see Figure 11).
Achieving Biomimicry Behaviour – Endothelialisation
BioMime in a Pre-clinical Model
In a pre-clinical model, BioMime demonstrated almost 100% endothelialisation at the end of one month, as can be seen in Figure 12. A uniform endothelial coating over and between the struts on edges (close cell configuration) and in mid-segment (open-cell configuration) were observed (see Figure 12).
BioMime Clinical Update
Based on the encouraging pre-clinical results and predictable design configuration, BioMime was studied in a phase IV prospective, single-arm, primary efficacy and safety study involving 30 patients. All patients presented with a single, discrete de novo lesion and were stented with BioMime ranging from 2.5 to 3.5mm and lengths from 13 to 24mm. The primary end-point was MACE, defined as death, myocardial infarction (MI) or any ischaemia-driven target lesion revascularisation (TLR). Zero per cent MACE was noted at six-month clinical follow-up. No cases of death (cardiac or non-cardiac), MI (Q-wave or non-Q-wave) or ischaemia-driven TLR were reported.31 All of the patients will now be entering eight-month angiographic and intravascular ultrasound (IVUS) follow-up to understand the stent’s qualitative coronary angiography (QCA) parameters of late lumen loss and volumetric obstruction. The RAndomized study with the sirolimus coated Bx VELocity balloon (RAVEL) study reported a MACE rate of 5.8% in the Cypher arm at one-year follow-up11 and, so far, with 0% MACE in BioMime-stented patients, the results are encouraging.
In a larger multicentre, non-randomised all-comers study known as the MeriT-1 trial, BioMime is being studied in 250 patients in a real-world scenario; the only exclusion criteria are saphenous vein grafts (SVGs), acute MIs, left main disease and a left ventricular ejection fraction (LVEF) <30%. The follow-up schedule is to be maintained at 30 days, six months, one year, three years and five years. All patients will undergo angiographic follow-up at eight months.
Primary safety and efficacy end-points are defined as MACE, which is a composite of death, MI (Q-wave and non-Q-wave), emergent CABG and clinically driven TLR. In-stent and in-segment late loss will be calculated via QCA. Secondary end-points will be MACE at one year and device-related serious adverse events until 12 months, and angiographic stent thrombosis (acute, sub-acute and late). Angiographic and device success and procedural success will be additional parameters in the secondary point. The trial is now under way and no adverse events related to device usage have been reported.32
Insights and Conclusions
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. Hence, all of the ingredients that allow for optimal endothelialisation have been incorporated in BioMime development. The stent (CE-marked) 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, which 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 cell division cycle without an exceptional risk of necrosis induction. The BioPoly is a co-polymer combination of the well-known biodegradable polymers 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 pre-clinical models and in the primary safety and efficacy study. Notable is the 0% rate of MACE at six months. Data from a large multicentric trial involving 250 real-world patients will further establish its credibility in routine clinical practice. Hence, based on the available pre-clinical and initial clinical reports, it can be predicted that this third-generation DES has adapted from the learning curve of the past DES and will set a path for the biomimicry concept in DES design for future.