The Development of the Novel BioMime™ Sirolimus-eluting Coronary Stent System
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
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
larger randomised clinical trials were conducted and showed a small increment in late loss, restenosis and major adverse cardiac events (MACE),15–19
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:
EUROPEAN CARDIOLOGY Polymer Release kinetics • • •
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.
79 Drug Figure 1: Time-course of Drug-eluting Stent Evolution
Unbridled enthusiasm Efficacy
Harsh realities ST Innovation
Thoughtful adaptations Safety
Time BioMime entry point
Figure 2: Penrose’s Triangle of Drug-eluting Stent Development
Stent architecture Safety + efficacy Ultimate applicability
Incomplete healing
Inflammatory reaction
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