The Role of Stent Design and Polymers in Safety Outcomes - A Review

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Abstract

Each component of a drug-eluting stent (DES) contributes to the safety of the device. Continuous efforts are being dedicated to the search of the optimal compromise between facility of use, safety and long-term efficacy. Shorter balloons reduce the vascular trauma beyond the stent struts; the metallic composition of the stent platform and the platform itself interact with the vascular wall in a long-lasting equilibrium between radial force, vessel patency and reparative cellular regrowth. The modality of drug elution is largely regulated by the chosen drug carrier, rather than by the chemical properties of the drug itself. Drug elution can be accomplished by permanent polymers that remain in the vessel wall forever, by biodegradable polymers that leave the naked metallic structure behind after their complete absorption, or even by direct release of the drug from stent reservoirs. The clinical performance of DESs has been exhaustively assessed in a large number of studies that have showed rapid and continuous improvements, from the first-generation DESs to the latest devices, based on substantial changes in stent design and polymer composition.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Flavio Ribichini, Director, Cardiovascular Interventions Unit, Department of Medicine, University of Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy. E: flavio.ribichini@univr.it
Received date
09 January 2012
Accepted date
27 January 2012
Citation
European Cardiology 2012;8(1):63-6
DOI
https://doi.org/10.15420/ecr.2012.8.1.63

Drug-eluting stents (DESs) have significantly improved the effectiveness of percutaneous revascularisation procedures. Since the initial experiences with the first devices, now called ‘first-generation’, DESs have proved very effective in reducing restenosis.1–3 The ‘second-generation’ DESs were conceived to have at least the same standards of efficacy than their predecessors, but with improved safety margins, as the first-generation devices appeared to be questionable in terms of the risk of late thrombosis – a clinically relevant cardiac event probably related to permanent vascular damage caused by the toxic effects of the antiproliferative drug or drug–stent polymer constituents.4–6

The principal aim of stent technology development is to optimise the efficacy and safety of the devices. Efficacy relates to the stent’s ease of implantation, even in challenging anatomies, and its capacity to reduce the need for reinterventions. Safety relates to the avoidance of serious clinical events, such as myocardial infarction or death, attributable to the stent implantation procedure. Usually, these rare events are the result of acute thrombotic occlusion of the prosthesis, an eventuality strongly determined by the state of ‘recovery’ of the vessel after the procedure, understood as re-endothelialisation and preservation of vascular function.

The platform design and the polymer composition both play a fundamental role in determining the balance between the efficacy and safety of stent devices. Today, different technologies are applied to the manufacture of commercially available DESs. The most relevant aspects of these technologies, influencing stent safety, are discussed in this article.

The Stent Platform
The metal structure – or platform – of the stent is the stent body itself, without other added components. It is commonly referred to as the ‘bare’ or ‘naked’ stent (bare-metal stent [BMS]) to differentiate it from a drug-covered or medicated stent. The stent platform determines its physical properties, which affect the ease of implantation, suitability to the vessel anatomy, and ability to overcome the increased mechanical resistance of the vascular wall due to atherosclerotic calcification (radial force). To a large extent, the stent platform also modulates the long-term reparative response following the vascular damage inflicted by barotrauma and implantation of a foreign body.

To analyse possible differences between stents, one has to distinguish three different constituent variables of their platforms: the material (or alloy), the structure of the mesh, and the thickness of the struts. The first decisively affects the vascular biological response to the foreign body that will reside forever in the vessel wall; the second affects the immediate result of the procedure in terms of success or complications; and the third is a well-known factor playing a role in the long-term effectiveness of the procedure, as thicker struts negatively affect vascular reactivity and cause a more pronounced neointimal growth, which is the main cause of BMS restenosis.7,8

Past changes in the chemical components of the alloys used for the production of stents platforms have proven decisive. Stainless steel (L316) was the reference material of the first stents in the 1990s – and it is still widely used. Subsequently, the cobalt–chromium alloy became the new standard, because it allows better processing of the structure, more flexibility, and finer struts capable of maintaining ufficient radial strength. The new alloy iron–chromium–platinum (Element™), which has attractive properties, is a promising alternative to the cobalt–chromium alloy.9

The design of the stent is crucial for its ease of implantation, the immediate success of the procedure and potential peri-procedural complications. Examples of such peri-operative complications include those related to the behaviour of the stent against the lateral bifurcation branches, the microembolisation of atherosclerotic debris, and the creation of intimal dissections – all of which usually manifest with the rise of cardiac enzymes that indicate myocardial necrosis, defined as post-procedural myocardial infarction.10

In the long term, the structure of the stent, along with the composition of the alloy, can influence the occurrence of stent fractures, which may cause in-stent restenosis or even occlusion.11

The thickness of the stent struts is a well-known variable that influences the long-term restenosis of BMSs;7,8 this is partly why cobalt–chromium alloy platforms, which allow the processing of finer mesh, have been developed and are widely available on the market today. The new iron–chromium–platinum alloy also allows the processing of thin-strut stents. The influence of stent strut thickness on the vascular wall reaction that follows DES implantation is less clear and remains a matter of discussion, since the effectiveness of strong antiproliferative drugs may counteract the stimulation of cell growth caused by thick stent struts. However, the advantages of thin stent struts over thick stent struts have been clearly demonstrated in paclitaxel-eluting stents.12,13

The Drug-eluting System
Initially, the polymer was considered a minor element in the complex interface between the stent and the vascular wall. However, the evidence demonstrating the importance of this component of DESs is now plain. The polymer can regulate the efficacy and safety of a DES, with negative effects ranging from a benign attenuation of the antirestenotic effect (transforming the DES into a simple metal stent with minimal antiproliferative efficacy) to a toxic triggering of serious vasculitic reactions. An attenuation of the antirestenotic effect was seen with the Endeavor® stent; the rapid release of the drug did not allow it to act for the time required to prevent cell regrowth. The stent platform, drug type and drug dose were kept the same, but the chemical composition of the polymer was modified, transforming the Endeavor stent into a highly effective second-generation DES, Endeavor Resolute®.14 Vasculitic reactions with severe necrosis of the vascular wall have been reported in autopsy analyses of patients implanted with the rapamycin-eluting Cypher® stent.15

Other second-generation stents, such as Xience V® and Promus®, contain a permanent fluorinated copolymer known for its ability to maintain elastic elongation despite the expansion of the prosthesis and the trauma in the vascular circuit. At the same time, it allows controlled dilution of the drug in the vascular wall throughout the duration of the healing process post-implantation (about six months). Very recent investigations have shown that this fluorinated copolymer coating does not induce pro-inflammatory reactions and can even be beneficial in terms of reduced thrombogenicity and endothelial integrity, with animal studies showing even better biological results compared with the single metal structure (not covered with polymer) of the same stent.16

Other DESs are covered with a bioabsorbable polymer that is totally absorbed, leaving behind the naked metallic stent structure, six to eight months after implantation. This is the case of the BioMatrix® and Terumo® biolimus-eluting stents; the former has shown superior clinical results compared with the first-generation rapamycin-eluting Cypher stent in an all-comers randomised clinical trial.17

Alternatively, some DESs do not have a carrier of the drug at all and deliver the drug directly from reservoirs engraved within the metallic struts.18Figures 1, 2 and 3 show different types of stents.

Differences in the Chemical Composition and Structural Design of Stent Platforms
The chemical composition of the new iron–chromium–platinum alloy allows the manufacture of very fine mesh (0.0032 inches for stents measuring up to 3.5 mm in diameter and 0.0038 inches for 4 mm stents), an order of magnitude comparable with that obtained with the cobalt–chromium alloy used in the manufacture of the Xience V stent (0.0032 inches). Stent struts that are still manufactured using the older stainless steel alloy are substantially thicker (0.0048 inches, for example, for the BioMatrix stent). Given the broad clinical experience gained over the years in the implantation of stainless steel and cobalt–chromium platforms, and the recent introduction of the iron–chromium–platinum alloy, it seems reasonable to investigate any benefits that may derive from the chemical composition of the new alloy (37 % iron, 18 % chromium and 33 % platinum), and how it affects vascular metabolism.

As for the structural design of the stent, it is known that it can significantly affect the clinical outcomes of stent insertion. The most obvious example comes from the TAXUS ATLAS study, which compared the Taxus Express® and Taxus Liberté® stents.12,13 Both stents feature identical polymers, drugs and alloys (stainless steel), the only change being the structure of the stent and the thickness of its mesh (0.0038 inches for Taxus Liberté versus 0.0052 inches for Taxus Express). The study results significantly favoured the Taxus Liberté stent in terms of efficacy (reduction of restenosis) in the specific context of the most difficult settings, longer lesions and smaller vessel diameter. In addition, the results also showed a marked statistical significance in favour of the Taxus Liberté platform for the most important safety index – i.e., a fourfold reduction in the incidence of myocardial infarction. Such observations confirm the fundamental importance of the stent platform.

The platform (or structure) of a stent is a key element in determining safety, and this can be instantly demonstrated by the post-procedural occurrence of myocardial damage. The rates of in-hospital cardiac events observed in clinical studies comparing different DESs head-to-head provide clear evidence. The SPIRIT studies compared the Xience V and Taxus Express stents, the COMPARE study compared the Xience V and Taxus Liberté stents, and the RESOLUTE AC study compared the Xience V and the Endeavor Resolute stents. The Xience V stent platform was constantly associated with significantly lower rates of peri-procedural cardiac events.14,19–22 These repeated results show the physical and geometrical structure of the Xience V stent platform as very reliable in terms of peri-procedural events.

Comparison tests between iron–chromium–platinum platforms and cobalt–chromium platforms are currently limited to a single trial – i.e., the PLATINUM study – but others are in progress. In that respect, the PLATINUM study confirms, in a selected population of patients, the non-inferiority at one year of the Promus Element® platform versus the Xience V platform.9,23

Although short-term safety is an important aspect of stent design, the most frequent procedure-related clinical events observed so far are generally mild and have a relatively low impact on patient survival. On the contrary, long-term safety is a fundamental issue, because clinical cardiac events, such as myocardial infarction, occurring long after stent implantation due to very late thrombosis usually have considerable clinical consequences for the patient and a dramatic impact on the physician’s perception of the safety of a given device.

Regarding stent platforms, a new analysis variable referred to as ‘longitudinal compression’ – i.e., the shortening of stents implanted in some complex lesions – has been described very recently for the first time by Hanratty and Walsh.24 The authors noted, in particular, cases of marked shortening not only with the Promus Element stent, but also with two other stents (BioMatrix and Resolute). They suggested that this may be a consequence of the fact that these stents have less fixed connections between cells compared to others,24 which allows more flexibility but may also affect other stent characteristics. This emphasises that any structural changes made to stent platforms require comprehensive assessment in order to compare the first performance of new platforms with that of platforms already used in millions of cases, covering the entire spectrum of interventional possibilities. This new variable has fuelled the discussion regarding platform differences and certainly deserves further assessment.

The importance of these observations was highlighted by the authoritative opinion expressed in an editorial accompanying the publication of the article, which stressed that longitudinal compression should not be considered a phenomenon common to all second-generation DESs, but that it is now important to investigate its causes – whether related to design or to thickness of the alloy or mesh – in order to determine differences between the various available devices.25 A detailed description of the different propensities of stents to shorten observed in the most commonly used stent platforms has also been published (see Figure 4).26

Differences in Drug Carriers
One of the lessons to be learned from the experience gained with first-generation DESs is that the polymer used for drug transportation and elution, which remains at the vessel wall in the long term, can induce permanent inflammation, facilitating fibrin deposition and thrombus formation and impairing the regeneration of the endothelial layer.5,6 These changes in the vessel wall have been clearly emonstrated to play a determinant role in the occurrence of major clinical cardiac events in the medium to long term after stenting. Second-generation DESs using new, more biocompatible polymers have shown a significant reduction in late and unexpected clinical events – in particular very late stent thrombosis – as well as a reduced need for further interventions due to late restenosis. According to a recent histological analysis,15 many of these advantages may be due to the enhanced safety profile of the new polymers compared with those used in first-generation DESs.

Conclusions
Clinical data show clear advantages of second- over first-generation DESs in terms of long-term safety.

Medium-term clinical data obtained with second-generation DESs show that it seems possible to obtain comparable safety results with DESs covered with a permanent fluorinated copolymer (for example, Xience V), DESs covered with a modified phosphorylcholine Biolinx™ polymer (for example, Endeavor Resolute) and DESs covered with a bioabsorbable polylactic acid polymer (for example, BioMatrix) – irrespective of the antiproliferative drug eluted by the stents (everolimus, zotarolimus or biolimus A9, respectively). Long-term results are needed to identify possible differences between these DESs.

The promising polymer-free technology has yielded interesting initial results,18 but these are so far less robust compared with those of the polymer-coated DESs.18

Regarding stent platforms, thin struts made of cobalt–chromium (Xience V and Endeavor Resolute) have the strongest clinical evidence, supported by large clinical trials with wide inclusion criteria, and so far have been shown to offer the best clinical results.27 The stainless steel platform of the BioMatrix stent associated with a bioabsorbable polymer and the release of bioloimus has also shown excellent clinical results, and promising data regarding patients with acute myocardial infarction implanted with this type of stent support the interesting concept of bioabsorbable polymer technology.

The new iron–chromium–platinum alloy emerges as a promising alternative to cobalt–chromium, with the advantage of enhanced visibility due to a higher radio-opacity. However, long-term clinical trials are required, in particular to assess the potential clinical consequences of longitudinal compression ocurring with new stent designs which, being highly flexible, may also prove more fragile in some complex and adverse anatomies.

Initial experiences with completely absorbable platforms are encouraging.28 This new class of DESs will soon become available and will certainly add further elements to the discussion regarding the safety issues related to stent designs and polymers.

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