A Tubular Success

6 April 2008 (Last Updated April 6th, 2008 18:30)

Stent materials have evolved dramatically over recent years, now offering almost limitless possibilities. Where is the technology now and where will it be in the not-too-distant future? Dr Nick West investigates the practical benefits such developments are offering.

A Tubular Success
Stent technology is being continually developed to obtain the best flexibility and biocompatibility possible.

Coronary heart disease continues to be the leading cause of death in the industrialised world, despite ever-increasing measures designed to combat its growth. The development of narrowings (stenoses) within coronary arteries limits bloodflow to the heart muscle itself, resulting in patients experiencing angina or myocardial infarction. Predisposing factors for the development of these stenoses include smoking, elevated blood pressure and cholesterol, and the interlinked issues of increasing obesity and diabetes.

Although public health initiatives have sought to target such risk factors, the number of patients diagnosed with established coronary disease continues to grow.

Relief of the obstruction caused by these stenoses improves patient symptoms and may modulate their future prognosis. In certain patient groups, coronary artery bypass graft surgery (CABG) remains the mode of treatment of choice, but numbers of the less-invasive technique of percutaneous coronary intervention (PCI) now surpass CABG in most European countries.

"The invention and development of intracoronary stents has been central to the growth of PCI worldwide."

The invention and subsequent development of intracoronary stents has been central to the growth of PCI worldwide. While balloon dilatation alone of coronary artery stenoses was found to be effective in reducing vessel obstruction and consequent symptoms, it sometimes resulted in immediate vessel closure during the procedure due to the combination of elastic recoil and dissection (localised vascular damage caused by barotrauma), necessitating emergency CABG.

Furthermore, later renarrowing (restenosis) at the site of balloon inflation occurred in around 30% of cases, primarily due to activation and proliferation of smooth muscle cells stimulated by vessel injury and inflammation. Stents, essentially tiny cylindrical metallic tubes, were designed to combat both immediate vessel recoil and localised dissection by scaffolding the vessel, effectively propping the artery open, to obviate the requirement for emergency CABG. Stents proved successful in this regard, as studies subsequently demonstrated, and additionally provided favourable improvements in the frequency of later restenosis.

With worldwide PCI procedures now approaching a total of around two million a year and PCI rates now outstripping those of CABG (Figure 1), complex cases requiring multiple stents are becoming increasingly common, and industry has responded accordingly.

Stent technology has blossomed since early designs were made commercially available, with subsequent iteration offering potential advantages ranging from improved device handling to reduced restenosis rates. Such benefits are integrally linked to structural design, choice of construction material and most recently to the development of coatings that may be impregnated with drugs or chemicals to modulate vessel biology. Coated stents have resulted in drastic reductions in restenosis rates, but have caused some safety concerns in terms of possible increases in stent thrombosis, leading to heart attack or death

STENT DESIGN

The ideal stent embodies a variety of physical attributes including flexibility, trackability (around bends/arcs), a high radial strength for adequate vessel scaffolding and a low profile for crossing tight narrowings. Such characteristics need to be combined with aspects of biocompatibility and resistance to thrombosis, reducing localised inflammation and blood clot formation respectively. The combination of such attributes should therefore result in ease of stent delivery for the clinician and reduced restenosis and thrombosis rates for the patient, thereby improving outcomes in terms of clinical events.

The first stent used in human coronary arteries, the self-expanding Wallstent (Boston Scientific, Natick, MA), was limited by high restenosis and thrombosis rates in clinical trials, likely due to the high metal:artery ratio. Subsequent designs aimed to reduce the volume of metal deployed in the vessel and stents based on a simple wire coil. These offered excellent stent flexibility and trackability, but radial strength was poor, resulting in worse vessel scaffolding and relatively high early complication rates, predominantly due to stent thrombosis and target vessel occlusion.

The 'godfather' of almost all currently available stent designs is the Palmaz-Schatz stent (Cordis, Johnson & Johnson, Warren, NJ), based on a tubular stainless steel design. Palmaz's work focused on the concept that a suitably engineered slotted tube resulted in a cellular mesh when expanded from the inside by a balloon. Although initially used only as 'bail-out' devices when balloon angioplasty resulted in acute vessel closure, the Palmaz-Schatz stent was subsequently proven in randomised controlled trials to be superior in terms of acute and long-term patient outcomes, and has been central to almost all stent designs since.

Many stent designs currently in use are based on a cellular pattern typified by the Palmaz-Schatz stent, where metal strutwork surrounds cells of varying size and geometry, sometimes referred to as 'closed-cell' designs. Another similar highly successful design type is the modular stent, sometimes referred to as 'open-cell', whereby repeating modules are linked by struts, producing alternating areas of stent coverage and spaces between corresponding to the links between modules. Modular stents are frequently more flexible and conformable than their closed-cell counterparts, but may offer less radial strength and vessel scaffolding given their reduced metal:artery ratio.

"The ideal stent material should be resistant to corrosion, biologically non-reactive and possess high radial strength."

The metal:artery ratio of any stent is governed primarily by the thickness of the struts within the design. Immediate results after stenting are improved by thicker struts, which offer higher radial strength, vessel scaffolding and ease of stent positioning due to better radio-opacity; conversely, stents with thinner struts result in less local vessel trauma and inflammation after deployment and have been proven in clinical trials to have a lower incidence of restenosis. The stent with the thinnest strut currently available is the Driver stent (Medtronic Vascular, Santa Rosa, CA) with strut diameter of only 0.0036in.

One further but seemingly minor aspect of stent manufacture that has immeasurably improved the lot of interventional cardiologists is the change to factory mounting of stents on balloon catheters. Previously, stents had to be hand crimped onto balloons, resulting in frequent stent loss or dislodgement whilst positioning. Furthermore, improvements in balloon catheter technology have reduced the crossing profile of stent catheters and reduced any potential 'overhang', lessening trauma to non-diseased vessel wall when the stent is deployed.

STENT MATERIALS

The ideal material for intracoronary stent construction should be resistant to corrosion, biologically non-reactive and possess high radial strength. The material most commonly used is surgical-grade (316L) stainless steel, which adequately fulfils the first and last requirements, and is additionally nonferromagnetic. Early issues of poor stent flexibility with 316L stainless steel seem to have been largely overcome by newer design patterns, although radio-opacity, needed to facilitate optimal positioning under X-ray guidance, remains limited.

Radio-opacity can be enhanced by coating 316L stents with a thin layer of gold, but this approach unfortunately compromised outcomes by increasing frequency of restenosis and has since been abandoned. Other metals and alloys have been used in stent manufacture, including tantalum and nitinol. More recently, cobalt-based alloys have been developed (Table 1 overleaf), offering increased density to aid radio-opacity and maintain stent radial strength despite reduced strut thickness.

Biocompatibility of stents remains a theoretical concern; 316L stainless steel's biocompatibility is potentially limited by elution of metallic salts including molybdenum and chromium from the stent surface over time. Whether the inflammation and consequent immune response resulting from these ions results in clinical problems is controversial, but both may be implicated in stent thrombosis and restenosis.

Ultimate stent biocompatibility may not be too distant, in the form of biodegradable stents that will provide early support against recoil, but subsequently dissolve without leaving metallic residue within the coronary arteries. Initial bioabsorbable/biodegradable stent designs based on synthetic polymers were largely unsuccessful, but recent studies examining absorbable magnesium-based metallic stent designs and stents manufactured from the polymer poly-l-lactic acid (PLLA) have shown promise.

DRUG-ELUTING STENTS

Although improvements in stent construction and design have reduced the frequency of symptomatic restenosis, given the increase in number of PCI performed contemporaneously, even restenosis rates of around 10–20% have resulted in large numbers of patients requiring repeat PCI procedures or even CABG. Coating stents with additional compounds offers the opportunity to deliver an agent directly to the vessel wall that may modify the vascular response to injury, thereby limiting restenosis, or otherwise improve the stent's biocompatibility and resistance to thrombosis.

Researchers have investigated various coatings, including gold to improve radio-opacity, silicon carbide to reduce inflammation and heparin, an anticoagulant designed to reduce stent thrombosis. However, the most successful coatings use immunosuppressive/antiproliferative drugs aimed at limiting the inflammatory response to vessel injury that ultimately leads to restenosis.

The Cypher stent (Cordis) was the first commercially available drug-eluting stent (DES); this device and its subsequent iterations are coated with sirolimus, an agent inducing cell-cycle arrest and thereby limiting vascular smooth muscle cell proliferation. Clinical studies with this stent have confirmed its safety and efficacy in reducing restenosis when compared with bare metal stents (BMS). Its major competitor, the Taxus stent (Boston Scientific), is coated with the anti-cancer agent paclitaxel, and has likewise demonstrated impressive reductions in restenosis and need for further revacularisation compared with BMS.

Analogues of these agents have also been used successfully in emerging DES, including ABT-578 on the Endeavor stent (Medtronic) and everolimus on the Xience stent (Abbott Vascular). All of these stent platforms utilise a polymer coating to carry and then release the antiproliferative agent to the vascular wall tissues in a controlled fashion. Whether or not such polymers affect long-term stent biocompatibility after drug elution is complete remains controversial; a meta-analysis presented at the European Society of Cardiology meeting seemed to indicate increased rates of late stent thrombosis, possibly linked to persistence of exposed stent and or degraded/damaged polymer coatings. Patient-level analysis of the same data has since largely eradicated such fears, but not before this news had been spread in national newspapers the world over.

This issue has highlighted a potential area of concern with DES: the antiproliferative agents used to prevent restenosis also delays endothelialisation compared with BMS, necessitating prolonged treatment with specific drugs aimed at preventing the occlusion of such stents by thrombosis. A solution to this potential problem is the concept of a drug-eluting stent with a biodegradable polymer, embodied by the early encouraging results obtained with the Nobori biolimus A9-eluting stent (Terumo Corporation, Japan).

Interestingly, the stent platform with high restenosis rates as a BMS has proved successful as a DES; the Cypher stent's thick struts and a high metal:artery ratio are advantageous for DES, given the larger surface area of metal (and therefore drug coating) apposed to the vessel wall. Furthermore, the Endeavor stent, which has thin struts and a modular design, seems to have an increased risk of renarrowing. These findings suggest that the factors influencing optimum design for DES might not necessarily be the same as for BMS.

"The most successful stent coatings use immunosuppressive/antiproliferative drugs aiming at limiting the inflammatory response to vessel injury."

Further developments in this field are ongoing, with new drugs aiming to modify vessel biology and the response to injury being trialled, alongside novel polymers and stent coatings aimed at improving drug delivery and biocompatibility. Other drug delivery mechanisms, such as non-polymer-based drug delivery, either via direct stent coating or carriage within reservoirs within the stent structure are being explored, as well as stent platforms that offer the capability for custom drug coating depending on lesion/patient characteristics.

FUTURE DIRECTIONS

Since their initial conception, intracoronary stents have undergone near-unrecognisable evolution from early designs to today's computer-modelled, catheter-mounted, potentially coated devices. While stent handling and delivery have improved substantially with developments in design and construction, ease of use for interventional cardiologists should always remain secondary to improved patient safety and outcomes.

Concerns over the safety of DES still remain; such issues have occupied column inches in the worldwide press, are well known to informed patients and have engendered wariness in the interventional cardiology community. However, with the 'holy grail' of a biodegradable stent capable of drug delivery seemingly not too distant, and the development of novel lesion-specific stents and stents with customisable drug delivery underway, perhaps patients, interventional cardiologists and the device industry can look forward to a bright future.