CYPHER_INVESTIGATOR BKT-1 - Activeweb Medical Solutions

IntroductionDrug-eluting Stents:A New Era in Interventional CardiologyNot since the groundbreaking early days of balloonangioplasty in the late 1970s has there been a moreexciting time to be involved in interventional cardiology.The potential of drug-eluting stents is immense and bringscardiologists another important step closer to the idealin patient care.Until recently, arterial restenosis has been the Achilles’heel of interventional cardiology. The introduction ofcoronary stents in the early 1990s was seen as abreakthrough in interventional medicine. These deviceseffectively abolished early elastic recoil and late constrictiveremodelling, two of the primary mechanisms of restenosisfollowing angioplasty, and provided significantimprovements in angiographic and clinical outcomes.However, restenosis continued to be the major limitationof stent implantation due to neointimal hyperplasia. Thiscomplex biological process, in response to vessel injuryincurred during stent deployment, causes in-stentrestenosis in as many as 30% of patients who receive abare metal stent.Various approaches have been proposed for the treatmentof in-stent restenosis including repeat balloon angioplasty,directional and rotational atherectomy, cutting balloonand brachytherapy. But none of these have provided anoptimal solution. Prevention is better than cure, and soattention turned to pharmacological agents that mightprevent neointimal hyperplasia following delivery via thestent. A drug-eluting stent was seen as an attractiveoption because it provides an efficient method to addressrecoil, remodelling and neointimal hyperplasia in onedevice. Local drug delivery maximises the effect whenand where it is needed, with minimal potential for systemictoxicity.Sirolimus: a Novel Approach to the Treatment ofNeointimal HyperplasiaThe Cordis programme to identify drugs with the potentialto prevent restenosis when mounted on a stent screenedseveral hundred compounds. Sirolimus was selectedbecause it is ideally suited to block the key steps in theprocess of neointimal hyperplasia, while not affecting cellviability or natural healing.Vascular injury following stent implantation triggers acomplex wound healing process. The release of growthfactors and cytokines from endothelial cells, platelets andinflammatory leukocytes initiates the proliferation of smoothmuscle cells (SMCs).In preventing neointimal hyperplasia, sirolimus exhibits adual mechanism of action. Not only does it act directlyon SMCs to stop them from proliferating, but it alsoexhibits anti-inflammatory effects by blocking T-cellactivation and proliferation in the vessel wall. Thissubsequently reduces tissue injury and further amplificationof SMC proliferation.Sirolimus blocks the proliferation of both SMCs andT-cells through its action on a key signal transductionenzyme called TOR (target of rapamycin). This stopsgrowth factor signals and safely arrests the cell cycle inthe early G1 phase. This cytostatic effect allows SMCsto remain viable and return to a resting state or G0.Through this action on TOR, sirolimus selectively targetsSMCs and inflammatory cells, leaving the natural healingprocess of re-endothelialisation to progress unhindered,as demonstrated in animal models.In pre-clinical animal trials, sirolimus-eluting stentsdemonstrated a broad therapeutic window. Biologicalactivity was exhibited with doses ranging from18-1200 µg/stent without displaying toxicity to the vesselwall. In the clinical setting, a broad therapeutic profilemay mean that long, overlapping or adjoining stents canbe deployed without the risk of toxicity.CYPHER Sirolimus-eluting Stent: The First Anti-Proliferative InterventionThe development of a sirolimus-eluting stent involved theapplication of sirolimus in a proprietary biocompatiblepolymer to the Bx Stent platform. The closed cell designof the Bx Stent offers optimal drug delivery by providinguniform coverage of the vessel wall for even drugdistribution. The polymer coating was developed to releasethe majority of the sirolimus dose over the first 30 daysafter implantation – the critical time for the inhibition ofneointimal hyperplasia. Furthermore, tests confirmed thatthe polymer is non-thrombogenic, does not induceinflammation of the vessel wall, and maintains its integrityeven when overexpanded. The resulting CYPHERSirolimus-eluting Stent was the first anti-proliferativeintervention specifically designed to prevent in-stentrestenosis due to neointimal hyperplasia.The CYPHER Stent was the first drug-eluting stent toreceive CE mark and FDA approval, being the first tocomplete a first-in-man pilot study, and subsequentrandomised, controlled clinical trials. The CYPHERStent clinical trial programme has been instrumental inheralding a new era in interventional cardiology, not leastfor bringing the first drug-eluting stent to market. Scientificrigour applied to an exhaustive study programme hasprovided meaningful and dependable results. Essentially,physicians can expect to achieve the same excellentresults in practice as demonstrated in the following clinicaltrials.3