Benefits of and Safety Concerns Associated with Drug-eluting Coronary Stents

Scot Garg; Patrick Serruys

Expert Rev Cardiovasc Ther. 2010;8(3):449-470.

Abstract and Introduction

Abstract

Drug-eluting coronary stents are being used with increasing frequency in patients undergoing percutaneous coronary intervention. Although these stents have shown remarkably low rates of restenosis compared with their predecessors, there have been increasing concerns lately regarding their safety. Extensive data have been published that demonstrate a higher risk of very late stent thrombosis with drug-eluting stents; however, this has not had any impact on long-term mortality or the risk of myocardial infarction when compared with bare-metal stents. Their overall net clinical benefit therefore still favors their use. Recent research has led to a greater understanding of the multifactorial cause of stent thrombosis, which has enabled measures to be taken to reduce an individual patient's risk. In the future, new stent designs and new antiplatelet agents may help to reduce this risk further.

Introduction

Stent thrombosis (ST) is fortunately rare, but in recent years it has emerged as a major safety concern with the use of coronary stents.^[1–7] The increasing use of percutaneous coronary intervention (PCI) to treat coronary artery disease, and high overall drug-eluting stent (DES) usage in PCI procedures,^[8] ensures that these safety concerns have important far-reaching implications, and warrant careful evaluation and critical review. This article will review the safety concerns and the benefits of DES, the causes of ST and the clinical impact of this condition.

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Table 1. Rates of death, myocardial infarction and target lesion revascularization from recent meta-analyses of drug-eluting stents compared with bare-metal stents.
Stent type	Patients (n)	Longest follow-up (years)	Death (DES vs BMS)	MI (DES vs BMS)	TLR (DES vs BMS)	Ref.
SES vs BMS	8646 (4643 SES; 4003 BMS)	4	HR 1.0 (p = 0.89)	HR 0.81 (p = 0.03)	HR: 0.3 (p < 0.0001)	^[35]
	1748 (878 SES; 870 BMS)	4	6.7 vs 5.3% (p = 0.23)	6.4 vs 6.2% (p = 0.86)	7.8 vs 23.6% (p < 0.001)	^[36]
	4958 (2486 SES; 2472 BMS)	5	6.0 vs 5.9% (p = 0.80)	9.7 vs 10.2%^† (p = 0.76)	HR: 0.43^‡ (p < 0.001)	^[37]
PES vs BMS	8330 (4327 PES; 4003 BMS)	4	HR 1.03 (p = 0.75)	HR 1.0 (p = 0.99)	HR: 0.42 (p < 0.0001)	^[35]
PES vs BMS	3513 (1755 PES; 1758 BMS)	4	6.1 vs 6.6% (p = 0.68)	7.0 vs 6.3% (p = 0.66)	10.1 vs 20.0% (p < 0.001)	^[36]
Other	8970 (4643 SES; 4327 PES)	4	HR 0.96 (p = 0.80)	HR 0.83 (p = 0.045)	HR: 0.70 (p = 0.002)	^[35]
	10,727 (5534 DES; 5193 BMS)	5	5.9 vs 5.7% (p = 0.79)	1.6 vs 1.2% (p = 0.32)	4.0 vs 3.3% (p = 0.16)	^[52]
	9470 (4867 DES; 4603 BMS)	4	HR 0.97 (p = 0.72)	HR 0.95 (p = 0.54)	HR: 0.45 (p < 0.001)	^[43]

^†Combined death or MI.
^‡Combined death, MI or TVR.
BMS: Bare-metal stent; DES: Drug-eluting stent; HR: Hazard ratio; MI: Myocardial infarction; PES: Paclitaxel-eluting stent; SES: Sirolimus-eluting stent; TLR: Target lesion revascularization; TVR: Target vessel revascularization.

Table 2. Rates of overall, early, late and very late stent thrombosis from recent meta-analyses comparing drug-eluting stents with bare-metal stents.
DES	Study	Patients (n)	Longest follow-up (years)	Overall ST (DES vs BMS)	Early ST (DES vs BMS)	Late ST (DES vs BMS)	Very late ST (DES vs BMS)	Ref.
Sirolimus-eluting stent versus bare-metal stent	Spaudling et al. ^†	1748 (878 SES; 870 BMS)	4	3.6 vs 3.3% (p = 0.80)	0.5 vs 0.5% (p = 0.70)	0.3 vs 1.3% (p = 0.03)	2.8 vs 1.7% (p = 0.14)	^[32]
	Stettler et al. ^†	8646 (4643 SES; 4003 BMS)	4	HR 1.00 (p = 1.0)	HR 1.02 (p = 0.96)	HR 1.14 (p = 0.78)	HR 1.43 (p = 0.64)	^[35]
	Stone et al. ^‡	1748 (878 SES; 870 BMS)	4	1.2% vs 0.6% (p = 0.20)	0.5 vs 0.1% (p = 0.23)	0.1% vs 0.5% (p = 0.18)	0.6 vs 0.0% (p = 0.03)	^[36]
	Kastrati et al. ^‡	4958 (2486 SES; 2472 BMS)	5	HR 1.09 (p = 0.75)			0.6 vs 0.05% (p = 0.02)	^[37]
PES vs BMS	Stettler et al. ^†	8330 (4327 PES; 4003 BMS)	4	HR 1.38 (p = 0.14)	HR 0.95 (p = 0.90)	HR 1.61 (p = 0.23)	HR 3.57 (p = 0.71)	^[35]
PES vs BMS	Stone et al. ^‡	3513 (1755 PES; 1758 BMS)	4	1.3 vs 0.9% (p = 0.3)	0.5 vs 0.6% (p = 0.79)	0.2 vs 0.1% (p = 0.28)	0.7 vs 0.2% (p = 0.028)	^[36]
Other	Stettler et al. ^†	8970 (4643 SES; 4327 PES)	4	HR 0.71^§ (p = 0.21)	HR 1.05^§ (p = 0.90)	HR 0.68^§ (p = 0.43)	HR 0.39^§ (p = 0.10)	^[35]
Other	Roukoz et al. ^‡	10,727 (5534 DES; 5193 BMS)	5	1.4 vs 1.3% (p = 0.48)	0.8 vs 0.9% (p = 0.79)	0.3 vs 0.4% (p = 0.82)	0.7 vs 0.1% (p = 0.006)	^[52]

Stent thrombosis defined by ^†Academic Research Council definitions or ^‡Study protocols.
^§SES vs PES.
BMS: Bare metal stent; DES: Drug-eluting stent; HR: Hazard ratio; PES: Paclitaxel-eluting stent; SES: Sirolimus eluting stent; ST: Stent thrombosis.

Table 3. New metallic and bioabsorbable stents.
Stent platform	Stent name	Company	Drug	Stent platform	Status
Metallic stent bioabsorbable polymer	Biomatrix™	Biosensors (Morges, Switzerland)	Biolimus A9	SS	CE
	AXXESS	Devax (CA, USA)	Biolimus A9	Nitinol	CE
	Nobori®	Terumo (NJ, USA)	Biolimus A9	SS	CE
	Xtent	Menlo Pk (CA, USA)	Biolimus A9	CoCr	CE
	JacPro/Evolution	Boston Scientific (MA, USA)	Everolimus	PtCr	Trial
	Infinnium®	Sahajanand (Gujarat, India)	Paclitaxel	SS	CE
	JacTAX Liberté	Boston Scientific	Paclitaxel	SS	Trial
	Labcoat Element	Boston Scientific	Paclitaxel	Platinum chromium	Trial
	NEVO™	Cordis (CA, USA)	Sirolimus	CoCr	Trial
	Supralimus®	Sahajanand	Sirolimus	SS	Trial
Metallic stent polymer free	BioFreedom™	Biosensors	Biolimus A9	SS	Trial
	Catania™	CeloNova BioSciences (GA, USA)		CoCr	CE
	OPTIMA	Sorin (Milan, Italy)	Tacrolimus	SS	CE
	Titan-2®	Hexacath (Rueil-Malmaison, France)	Titanium nitride oxide	SS	CE
	VESTAsync™	MIV Therapeutics (BC, Canada)	Sirolimus	SS	Trial
	Yukon®	Translumina (Hechingen,Germany)	Sirolimus	SS	CE
Bioabsorbable stents	AMS-1	Biotronik (Berlin, Germany)		Magnesium alloy	Trial
	IDEAL™	Bioabsorbable Therapeutics Inc (CA, USA)	Sirolimus salicylate	Polymer salicylate	Trial
	BVS stent	ABBOTT Vascular (IL, USA)	Everolimus	Poly-L-lactide	Trial
	Igaki-Tamai®	Kyoto Medical Planning Co., Ltd. (Kyoto, Japan)		Poly-L-lactic acid	Trial
	REVA Stent	Boston Scientific		Polymer tyrosine-derived polycarbonate	Trial

AMS: Absorbable metallic stent; BVS: Bioabsorbable Vascular Solutions; CE: Conformité Européene; CoCr: Cobalt chromium; SS: Stainless steel.

Box 1. Summary of the definition of stent thrombosis according to the Academic Research Council.
Definite stent thrombosis: The highest level of certainty Either angiographic or post-mortem evidence of thrombotic stent occlusion Probable stent thrombosis: Any unexplained death within 30 days of stent implantation Any myocardial infarction in the territory of the implanted stent without angiographic confirmation of stent thrombosis, and in the absence of any other obvious cause Possible stent thrombosis: Any unexplained death beyond 30 days until the end of follow-up

Data from ^[44].

Box 2. Definition of early, late and very late stent thrombosis.
Early stent thrombosis: stent thrombosis occurring within the first 30 days of stent implantation Late stent thrombosis: stent thrombosis occurring between 1 month and 1 year of stent implantation Very late stent thrombosis: stent thrombosis occurring after 1 year of stent implantation

Box 3. Potential predictors of stent thrombosis.
Device factors Hypersensitivity to drug coating or polymer Incomplete endothelialization Stent design
Procedural factors Inadequate stent expansion Incomplete stent apposition Stent deployment in necrotic core
Lesion characteristics Lesion/stent length Vessel/stent diameter Complex lesions (bifurcation lesions or chronic total occlusions)
Patient factors Percutaneous coronary intervention for acute coronary syndrome/ST-elevation myocardial infarction Diabetes mellitus Renal failure Impaired left ventricular function Premature cessation of dual antiplatelet therapy Clopidogrel nonresponsiveness Prior brachytherapy

Box 4. Mechanisms underlying clopidogrel resistance.
Cellular factors Accelerated platelet turnover Reduced CYP3A metabolic activity Increased ADP exposure Upregulation of the P2Y₁/P2Y₁₂pathway Upregulation of the P2Y-independent pathways
Genetic basis Polymorphisms of CYP Polymorphisms of GPIa Polymorphisms of P2Y₁₂ Polymorphisms of GPIIIa
Clinical factors Poor patient compliance Poor absorption Acute coronary syndrome Comorbidities (e.g., diabetes mellitus) Elevated BMI Elevated platelet count
Drug interactions Statins Proton pump inhibitors (omeprazole)

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