JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 64, NO. 23, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2014.09.041

REVIEW TOPIC OF THE WEEK

Current Status of Bioresorbable Scaffolds in the Treatment of Coronary Artery Disease Jens Wiebe, MD, Holger M. Nef, MD, Christian W. Hamm, MD

ABSTRACT State-of-the-art drug-eluting metal stents are the gold standard for interventional treatment of coronary artery disease. Although they overcome some disadvantages and limitations of plain balloon angioplasty and bare-metal stents, some limitations apply, most notably a chronic local inflammatory reaction due to permanent implantation of a foreign body, restriction of vascular vasomotion due to a metal cage, and the risk of late and very late stent thrombosis. The development of biodegradable scaffolds is a new approach that attempts to circumvent these drawbacks. These devices provide short-term scaffolding of the vessel and then dissolve, which should theoretically circumvent the side effects of metal drug-eluting stents. Various types of these bioresorbable scaffolds are currently under clinical evaluation. This review discusses different concepts of bioresorbable scaffolds with respect to material, design, and drug elution and presents the most recent evidence. (J Am Coll Cardiol 2014;64:2541–51) © 2014 by the American College of Cardiology Foundation.

N

ew techniques for interventional treatment

of late and very late stent thrombosis; continued

of coronary artery disease are continuously

neointimal tissue growth and neoatherosclerosis;

being developed. Important milestones in-

malapposition; potential stent fracture; incomplete

clude the launch of balloon angioplasty in 1977, the

endothelialization;

introduction of bare-metal stents in the 1980s, and

abnormal vasomotion.

and

vessel

caging

causing

the application of drug-eluting stents (DES) since

An anticipated major cause of late and very late DES

2000. DES were widely investigated in different set-

thrombosis is impaired arterial healing, possibly due

tings, demonstrated clinical success, and entered

to the durable coating, which results in a chronic in-

into clinical guidelines as the treatment of choice

flammatory reaction with incomplete stent endothe-

for interventional revascularization of coronary ar-

lialization and persistent fibrinogenesis and platelet

tery stenosis (1,2). DES overcame disadvantages,

aggregation, affecting blood flow and vessel remod-

such as acute vessel recoil and dissection risk after

eling (4–7). Next-generation metal stents with biode-

plain balloon angioplasty and decreased myocardial

gradable polymer coatings are designed to overcome

infarction and target lesion revascularization (TLR)

these shortcomings. A trial that randomly assigned

rates compared with bare-metal stents due to

patients to percutaneous coronary intervention (PCI)

reduced neointimal tissue growth (3). Despite these

with DES with either a bioresorbable polymer coating

and other benefits, some concerns remain: the risk

or a durable coating demonstrated a significantly

From the Department of Cardiology, Kerckhoff Heart Center, University of Giessen, Giessen, Germany. Dr. Nef has received research grant and honoraria for lectures from Abbott Vascular; and honoraria for lectures from Elixir Medical. Dr. Hamm has received honoraria for lectures from Abbott Vascular. Dr. Wiebe has reported that he has no relationships relevant to the contents of this paper to disclose. Manuscript received December 30, 2013; revised manuscript received September 23, 2014, accepted September 26, 2014.

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Current Status of Bioresorbable Scaffolds

DECEMBER 16, 2014:2541–51

ABBREVIATIONS

lower rate of definite very late stent throm-

toward broader use of drug elution, with mTOR

AND ACRONYMS

bosis with the bioresorbable polymer coating

(mammalian

during a 4-year follow-up (8). Additionally,

the most frequently used antiproliferative drugs in

improved vasomotion and endothelialization

DES.

BRS = bioresorbable scaffold(s)

BVS = bioresorbable vascular scaffold

CE = Conformité Européenne DES = drug-eluting stent(s)

target

of

rapamycin)

inhibitors

as

was seen (9,10), although hard endpoints

The Central Illustration provides an overview of

(e.g., myocardial infarction, TLR, cardiac

different designs and characteristics of existing BRS,

death) did not differ significantly (8,11). In

with representative images in Figures 1 and 2.

another randomized, controlled trial, no sig-

POLY- L -LACTIC ACID. Different materials are used

nificant differences were observed in out-

for manufacturing BRS, with poly-L -lactic acid (PLLA)

ultrasound

comes between DES types during a 3-year

being the most commonly used. For most existing PLLA-based devices, strut thickness is 150 m m. A BRS

IVUS = intravascular

MACE = major adverse

follow-up (12). Furthermore, a recent meta-

cardiac event(s)

analysis revealed nonsuperiority, even infe-

OCT = optical

riority, of DES coated with bioresorbable

coherence tomography

polymer compared with cobalt–chromium

cording to the manufacturer, a PLLA-based scaffold

everolimus-eluting stents (13). In addition to

has radial strength comparable to that of current

the need for more long-term data, further

drug-eluting metal stents. Directly after implanta-

PCI = percutaneous coronary intervention

PLLA = poly-L-lactic acid TLR = target lesion revascularization

currently being developed has the thinnest struts (100 m m) of all BRS, irrespective of composition. Ac-

challenges must be addressed to improve

tion, radial strength is w1,200 mm Hg, and the

preliminary results. Nevertheless, this stent

observed radial force can still be as great as 800

type cannot resolve long-term vessel caging

mm Hg after 1 year. Degradation by hydrolysis of

and the side effects associated with permanent

interlactic bonds of the long PLLA chains results in

implants.

particles that macrophages can phagocytose. The

The next interventional cardiology advance may be

end product is lactic acid, metabolized via pyruvate

the introduction of bioresorbable scaffolds (BRS). The

into carbon dioxide and water through the Krebs cy-

term scaffold highlights the temporary nature of a

cle (15), with complete degradation achieved in 1 to 3

BRS, distinct from a stent associated with a perma-

years (Central Illustration). Figure 3 shows degrada-

nent implant. All resorbable scaffolds are commonly

tion over time of the BRS compared with the Xience

referred to as bioresorbable, even though some are

DES (Abbott Vascular, Santa Clara, California). PLLA-

not made of biomaterials.

based devices ensure radial support for w6 months.

The idea of dissolvable scaffolds is not new, dating to the description of Tamai et al. (14) of the first successful use of a fully degradable stent in the early 1990s. However, this concept was nearly forgotten due to the success of bare-metal stents and, later, DES. With long-term data and the revelation of the risks of metal stents, BRS development was reinitiated, resulting in a variety of devices.

MAGNESIUM. Magnesium,

complemented by rare

earth metals to improve radial strength, is another currently used BRS production base. The first magnesium-based scaffolds were uncoated and lacked antiproliferative drug elution. The underlying idea is that the electronegative charge that emerges during the degradation of metal BRS is antithrombotic (16,17). A further potential benefit is its high mechan-

MATERIAL COMPOSITION AND PROPERTIES The optimal BRS should ensure adequate short- to mid-term scaffolding of the previously stenosed vessel to avoid recoil and completely dissolve afterward to prevent side effects. Thus, temporarily sufficient radial support is needed, with struts as thin as possible. The design should warrant deliverability

ical strength, making it a stent with thinner struts, but radial strength similar to that of other bioresorbable scaffolds, possible. Depending on composition, degradation takes between 2 and 12 months. The products of stent dissolution by corrosion are inorganic salts (17). The latest generation device offers 9 to 12 months of radial support (18).

OTHER MATERIALS

and straightforward handling, flexibility in different during

A tyrosine polycarbonate–based BRS providing up to

resorption. The optimal duration until full resorption

6 months of radial support is also under investigation.

is not yet defined. To achieve these goals, a consid-

Resorption takes between 24 and 36 months. Final

erable variety of materials and designs are under

products of degradation, which starts with hydrolysis

investigation.

and ends with the Krebs cycle, are ethanol, water, and

anatomic

circumstances,

and

integrity

Furthermore, the use of drug elution is inconsis-

carbon dioxide (19).

tent. Several different substances have been applied,

A BRS made of polylactic anhydride containing

and some BRS are noneluting. The current trend is

2 salicylic acid molecules linked to 1 sebacic acid

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Wiebe et al.

DECEMBER 16, 2014:2541–51

Current Status of Bioresorbable Scaffolds

molecule was developed to provide mechanical sup-

computed

port. Degradation into salicylate, water, and carbon

imaging, because they do not cause artifacts, and

tomography

and

magnetic

resonance

dioxide is complete within w15 months (19).

follow-up is possible with these modalities. Moreover, BRS implantation might allow surgeons to

POTENTIAL BENEFITS

carry out anastomosis of coronary artery bypass grafts at distal segments, and in patients who might

BRS achieve successful acute revascularization of

require multiple interventions, there will be no

coronary artery lesions and show reasonably low

interference with previously implanted DES because

rates of TLR and major adverse cardiac events (MACE)

side branches can sometimes be especially difficult

during early follow-up (Central Illustration). Multiple

to recross.

imaging analyses reveal beneficial plaque stabilization and sealing caused by BRS-induced remodeling

THE FIRST BIORESORBABLE SCAFFOLD

(20), although the clinical impact needs further assessment. Due to BRS degradation, no foreign body

The Igaki-Tamai stent (Kyoto Medical Planning Co.,

remains in the vessel long term. Thus, late and very

Ltd., Kyoto, Japan) was the first BRS used in humans.

late stent thrombosis risks are potentially reduced

This PLLA-based BRS is self-expandable when heated;

or eliminated, depending on resorption duration.

consequently, contrast dye at 80
C is used for balloon

Total stent length is a well-known stent thrombosis

inflation. Expansion continues at body temperature

risk factor. Because BRS dissolve, this risk may be

until dilation and vessel wall resistance reach

reduced, especially in long or complex lesions and

equilibrium. In 2000, Tamai et al. (14) reported initial

diffuse disease, when several would be implanted

results from 15 patients in whom 25 stents were suc-

simultaneously. Additionally, the permanent com-

cessfully implanted. Long-term data with >10 years of

plete

decrease.

follow-up for 50 patients treated with 84 Igaki-Tamai

Because struts degrade, long-term uncovered stent

biodegradable stents are available (32). Interestingly,

struts are unlikely to factor in stent thrombosis.

during the first 6 months, minimal lumen diameter

Incomplete endothelialization was observed for DES

decreased and then constantly increased to 2.22 

as long as 40 months after implantation (7). There are

0.56 mm at the 3-year follow-up. IVUS analysis

also reduced neointimal tissue growth and neo-

showed almost constant stent cross-sectional area

atherosclerosis and chronic inflammation risks as re-

after 1, 2, and 3 years, whereas minimal lumen cross-

side-branch

occlusion

risk

may

actions to a permanent metal implant, all well-known

sectional area decreased from 5.44 mm2 immediately

late and very late stent thrombosis triggers in DES.

after the procedure to 3.64 mm 2 after 6 months, then

Because the BRS coating is degradable, not durable,

increased to 5.18 mm 2 after 3 years. During the

another stent thrombosis stimulus is absent. Intra-

follow-up period, a total of 14 TLRs, 1 acute scaffold

vascular ultrasound (IVUS) and optical coherence to-

thrombosis and 1 very late scaffold thrombosis, 1

mography (OCT) examinations display late lumen

lesion-related myocardial infarction, and 1 cardiac

enlargement in numerous patients with the Absorb

death were noted. Accordingly, cumulative TLR rates

bioresorbable vascular scaffold (BVS) and DESolve

per patient were 16% after 1 and 3 years, 18% after

BRS (Elixir Medical Corporation, Sunnyvale, Califor-

5 years, and 28% after 10 years (32).

nia) (15,21–29).

Despite these promising results, development

The initial mechanical flexibility of some BRS may

of the Igaki-Tamai biodegradable stent was dis-

maintain original vessel geometry better than rigid

continued due to 2 limitations: first, implantation

metal stents; this would reduce their influence on

requires an 8-French guiding catheter, and second,

biomechanical properties and blood flow. Further-

the heated contrast dye may cause vessel wall injury.

more, minor malapposition can be resolved by BRS

A new version of the device is currently undergoing

self-correction, and its degradation avoids long-term

pre-clinical evaluation.

malapposition (29). Incomplete stent apposition, as observed with DES after thrombus resolution, is

BIORESORBABLE SCAFFOLDS CURRENTLY

also unlikely. Because there is no long-term vessel

AVAILABLE IN CLINICAL PRACTICE

caging, abnormal shear stress may be reduced, as revealed by restored vasomotion (30). In contrast,

Several BRS types are currently in development, but

paradoxical vasoconstriction was observed after

only 2 have the Conformité Européenne (CE) mark

DES implantation, most likely due to impaired endo-

for use in coronary artery disease: the Absorb bio-

thelial function (31). BRS are better suited than metal

resorbable vascular scaffold (BVS) (Abbott Vascular)

stents for noninvasive imaging, such as coronary

and the DESolve scaffold (Elixir Medical Corporation).

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Current Status of Bioresorbable Scaffolds

DECEMBER 16, 2014:2541–51

CENTR AL I LLU ST RAT ION

Results for Current Existing Bioresorbable Scaffolds

POLY-LACTIC ACID

Basic material Igaki-Tamai Stent

Absorb BVS 1.0

Absorb BVS 1.1

DESolve 1st generation

DESolve 2nd generation

Amaranth

Manufacturer

Elixir Medical Kyoto Medical Abbott Vascular, Abbott Vascular, Elixir Medical Amaranth Planning Co, Ltd, Santa Monica, Santa Monica, Corp., Sunnyvale, Corp., Sunnyvale, Medical Inc., Kyoto, Japan CA, USA CA, USA CA, USA CA, USA CA, USA

Composition

PLLA

PLLA

PLLA

PLLA

PLLA

PLLA

Acute BRS

ART18Z BRS

Xinsorb BRS

Arterial Remodeling Tech., France

OrbusNeich, Shandong HuaAn Biotech., Fort Lauderdale Co. Ltd., China FL, USA

PLLA,

Poly-lactic acid, PLLA,

PDLA

L-latic-co-εpoly ε-caprolactone, caprolactone, poly-glycolic acid

PDLA

Design of the latest generation

Zigzag helical coil

Out-of-phase sinusoidal hoops with links

In-phase zigzag hoops, cross-linked by bridges

Tubularly arranged hoops, linked by bridges

Tubularly arranged hoops, linked by bridges

Zigzag hoops, linked by bridges

Creepresistant hinge

--

Helically linked double ring

Thickness of strut, μm

170

150

150

150

150

--

--

150−170

150

Visualization

Gold radiopaque markers at both ends

Radiopaque metal markers at both ends

Radiopaque metal markers at both ends

2 platinum radiopaque markers

2 platinum radiopaque markers

--

--

2 radiopaque markers

Radiopaque markers

Special feature

Selfexpandable when heated

--

--

Minor Consists of Minor malapposition is malapposition is multiple layers self-corrected self-corrected

--

Radial strength Dual elution is comparable to that of DES

Antiproliferative drug elution

No

Everolimus

Everolimus

Myolimus

Novolimus

No

No

Sirolimus

Abluminal side: sirolimus Luminal: CD34+ antibodies

Resorption time

3 yrs

Up to 3 yrs

Up to 3 yrs

1 yr

1 yr

1−2 yrs

1.5−2 yrs

--

--

Status

CE mark (for peripheral use)

Clinical evaluation, new version under dev.

Clinical evaluation

30 patients enrolled in FiM study

Pre-clinical evaluation

Trials (no. in cohort and duration)

IgakiTamai-FiM 50 patients 127±17 mos

Cohort A 30 patients 5 yrs

Amaranth FiM 13 patients 6 mos

Pre-clinical results

Pre-clinical results

--

Acute recoil 22 ± 7%

Acute recoil 0.20 ± 0.21 mm Min. lumen area: 5.45 ± 1.08 mm2 MLD: post-procedural; 2.32 mm 2 post-procedural; 5.12 ± 1.01 mm at 6-mos; 1.89 mm 5.13 ± 1.25 mm2 at 6 mos; at 2-yrs = 1.76 mm

Acute recoil: 2.9%

Acute recoil: 2.9%

Acute recoil: 0.66 ± 4.32%

LLL: 10 years) clinical outcomes of first-inhuman biodegradable poly-l-lactic acid coronary stents: Igaki-Tamai stents. Circulation 2012; 125:2343–53.

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35. Leon M. The DESolve Nx Novolimus-Eluting Bioresorbable Coronary Scaffold: first report of one-year clinical and CT imaging results. Paper presented at: Transcatheter Cardiovascular Therapeutics; October 29, 2013; San Francisco, CA. 36. Gori T, Schulz E, Hink U, et al. Early outcome after implantation of Absorb bioresorbable drugeluting scaffolds in patients with acute coronary syndromes. EuroIntervention 2014;9:1036–41. 37. Wiebe J, Möllmann H, Most A, et al. Shortterm outcome of patients with ST-segment elevation myocardial infarction (STEMI) treated with an everolimus-eluting bioresorbable vascular scaffold. Clin Res Cardiol 2014;103:141–8. 38. Muramatsu T, Onuma Y, van Geuns RJ, et al., for the ABSORB Cohort B Investigators, ABSORB EXTEND Investigators, SPIRIT FIRST Investigators, SPIRIT II Investigators, SPIRIT III Investigators, SPIRIT IV Investigators. 1-year clinical outcomes of diabetic patients treated with everolimus-eluting bioresorbable vascular

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KEY WORDS bioresorbable scaffold, coronary artery disease

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