Drug-eluting Stents: The Next Generation

James A Shand; Ian BA Menown

Interv Cardiol. 2010;2(3):341-350.

Abstract and Introduction

Abstract

The small but absolute increase in late and very late stent thrombosis associated with drug-eluting stent technology may in part be related to the permanent, durable polymers currently employed with these stent platforms. Research has recently focused on two strategies to combat this problem; bioabsorbable polymers and polymer-free stents. This article critically reviews the key clinical trials and recent conference updates surrounding these two approaches and future directions for technology development.

Introduction

Since their introduction, drug-eluting stents (DES) have revolutionized percutaneous treatment of coronary artery disease with rates of in-stent restenosis of between 2 and 10%^[1] and significant reductions in target lesion revascularization.^[2] However, there has been a small but important absolute increase in rates of late and very late stent thrombosis (VLST) when compared with bare-metal stents (BMS).^[3–5] This increased risk is, in part, due to delayed intimal healing secondary to the antiproliferative drugs employed in current generation stent technology as observed in preclinical,^[6] human autopsy, angioscopic and more recently optical coherence tomography (OCT) studies.^[7–9] However, the phenomenon is likely to be multifactorial in origin. Clinical and procedural risk factors include overlapping stent zones, stent malapposition, premature discontinuation of antiplatelet therapy, cytochrome P450 2C19*2 loss-of-function allelic variation, diabetes and acute coronary syndrome.^[10–13] Increasing concern also surrounds the polymers currently used to bind and control release of drug from stents. Nonerodable permanent (or 'durable') polymers, for example polyethylene-co-vinyl acetate and poly n-butyl methacrylate as used in Cypher® and poly(styrene-b-isobutylene-b-styrene) as used in Taxus™, have been shown to illicit vascular hypersensitivity responses in animal models.^[14] Expanded characteristics of contemporary permanent polymer DES are listed in Table 1. In addition, damage to the surface integrity of drug-polymer coating has been described during delivery of durable polymer DES, which may represent a nidus for late thrombus formation (Figure 1).^[15]

(Enlarge Image)

Figure 1.

Damage to drug-eluting stent surface integrity after failed deployment. (A) Cypher select®, (B) Cypher select, (C) TAXUS Liberté®, (D) TAXUS Liberté, (E) CoStar™ drug-eluting stent (note absence of drug in microwell), (F) Endeavor RX®, (G) Endeavor RX, (H) Xience V™. Reproduced with permission from ^[15].

These observations have led to several distinct approaches to combat the problems associated with durable polymers. This article examines the clinical trial evidence and recent conference updates accumulated for (i) bioabsorbable polymers that control the release of drug over the short term, but are designed such that after a variable time they have completely degraded leaving only a BMS, and (ii) polymer-free technology that utilizes unique stent design to control drug release.

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Table 1. Permanent polymer drug-eluting stent characteristics.
DES name	Stent platform	Strut thickness (µm)	Polymer	Antiproliferative drug
Cypher Select®	Stainless steel	140	Polyethylene-co-vinyl acetate and poly (n-butyl methacrylate)	Sirolimus
Endeavor®	Cobalt–chromium	91	Phosphorylcholine	Zotarolimus
Endeavor Resolute®	Cobalt–chromium	91	C19 polymer, polyvinylpyrrolidinone and C10 polymer	Zotarolimus
TAXUS Liberte®	Stainless steel	97	Poly (styrene-b-isobutylene-b-styrene)	Paclitaxel
Xience V™	Cobalt–chromium	81	Poly vinylidene fluoride and hexafluoropropylene copolymer	Everolimus

DES: Drug-eluting stent.

Table 2. Key trials investigating bioabsorbable polymer drug-eluting stents.
Stent	Key trials	Patients (n)	Primary end point	Result	Significance
CoStar™ DES	CoStar II	1700	Composite: death, non-Q or Q MI, TVR	CoStar inferior to TAXUS® Express	–
BioMatrix™ Flex	Leaders	1707	Composite: cardiac death, MI, clinically indicated TVR at 9 months	BioMatrix Flex 9.2% vs Cypher® Select 10.5%	p (noninferiority) = 0.003
Nobori™	Nobori 1 Phase II	243	In-stent late loss	TAXUS® Liberté 0.32 ± 0.50 mm vs Nobori 0.11 ± 0.30 mm	p (noninferiority) < 0.001
	Nobori 2	3074^†	Composite: death, MI and TLR	First 1000 patients <5%	–
Yukon® (bioabsorbable)	ISAR Test 4	2603	Composite: death, target vessel MI, TLR	RR: 0.96 (Yukon vs Cypher/Xience)	p = 0.66
Supralimus	Paint Study	274	In-stent late loss 9/12	0.54 ± 0.44 mm (Cypher), 0.32 ± 0.43 mm (Supralimus) vs 0.90 ± 0.45 mm (BMS – Infinium)	p < 0.01
	eSeris Registry	1181^†	Composite: death, MI, TLR/TVR	4.5%	–
JACTAX	OCTDESI	60	% uncovered stent struts by OCT 6 months	5.3 (Liberté) vs 4.6 vs 7.0% (LD and HD Jactax)	p = 0.81
NEVO	NEVO RES-Elution 1	364	Late lumen loss	0.13 mm (NEVO) vs 0.36 mm (TAXUS Liberté)	p < 0.001
Elixir Novolimus	FIM	9	In-stent late loss	0.16 ± 0.23 mm	–
Elixir Myolimus	FIM	Group 1: 15 Group 2: 15	In-stent late loss 6/12 In-stent late loss 12/12	0.08 ± 0.16 mm Awaited	–
Biomime™	Preclinical only	NA	NA	NA	–
CardioMind Sparrow™	CARE II	220^†	In-stent late lumen loss	Awaited	–

^†Patient recruitment and enrollment not completed.
BMS: Bare-metal stent; CARE: CardioMind Sparrow DES system; DES: Drug-eluting stent; FIM: First-in-man; HD: High-dose; ISAR: Intracoronary stenting and angiographic results; Leaders: Limus Eluted From A Durable Versus Erodable Stent Coating; LD: Low-dose; MI: Myocardial infarction; NA: Not applicable; OCTDESI: Optical Coherence Tomography Drug Eluting Stent Investigation; TLR: Target lesion revascularizaton; TVR: Target vessel revascularization.

Table 3. Key trials investigating polymer-free drug-eluting stents.
Stent	Key trials	Patients (n)	Primary end point	Result	Significance level
CID Optima®	Matrix 1 registry	572	Acute, subacute and late stent thrombosis	Overall 0.17% stent thrombosis with no late thrombosis seen (12/12 fu)	NA
BioFreedom™	BioFreedom™ FIM	75	In-stent late loss	SD 0.08 mm; LD 0.12 mm vs TAXUS® Liberté 0.37 mm	p = 0.0001; p = 0.002
Amazonia Pax®	Pax A	30^†	Percentage of neointimal hyperplasia obstruction	NA	NA
	Pax B	100^†	In-stent late lumen loss	NA	NA
Nile Pax®	BiPax	100^†	Angiographic binary restenosis	NA	NA
Yukon® (polymer-free)	ISAR Test 2	1007	Angiographic restenosis	12% (Yukon®) and 11% (Cypher®) vs 19.3% (Endeavor®)	p = 0.002