Healtth Policy Ad
dvisorry Com
mmitteee on Tecchnolo
ogy Tech
hnology Brief Biodeggradable
e stents Feb
bruary 2
2013 © State of Queenslaand (Queensland Departm
ment of Health) 2013 This worrk is licensed
d under a Cre
eative Comm
mons Attributtion Non‐Commercial Noo Derivativess 2.5 Australiaa licence. In essence, you are free too copy and co
ommunicate
e the work inn its current fform for non‐com
mmercial purrposes, as long as you atttribute the aauthors and a
abide by the licence term
ms. You may nott alter or adaapt the work in any way.
To view a copy of this licence, visit http://creeativecommons.org/licen
nses/by‐nc‐nnd/2.5/au/. her informattion, contact the HealthPPACT Secretaariat at: For furth
HealthPA
ACT Secretariat c/o Cliniical Access and Redesign Unit, Healthh Service & C
Clinical Innovvation Divisioon Queenslland Departm
ment of Health Lobby 2,, Level 2, Citilink Business Centre 153 Cam
mpbell Streett, Bowen Hills QLD 4006
Postal A
Address: GPO
O Box 48, Brissbane Qld 40001 Email: HealthPACT@
@health.qld.gov.au
Telepho
one: +61 7 3
3131 6969 For perm
missions beyond the scop
pe of this liceence contactt: Intellectua
al Property O
Officer, Queensland Health, G
GPO Box 48,, Brisbane Qld 4001, emaail ip_officer@
@health.qld.gov.au, phoone (07) 3234
4 1479. Electron
nic copies ccan be obtaiined from: hhttp://www.health.qld.ggov.au/healthhpact DISCLAIM
MER: This brrief is publish
hed with the intention off providing in
nformation oof interest. Itt is based on informatio
on available a
at the time oof research and cannot be expected tto cover any developments arisin
ng from subsequent imprrovements to
o health tech
hnologies. Thhis brief is ba
ased on a limited
d literature ssearch and iss not a definiitive stateme
ent on the sa
afety, effectivveness or co
ost‐
effectiveeness of the health techn
nology coverred. The Statte of Queenssland acting tthrough Queeensland Dep
partment of Health doess not guaranttee the accuracyy, currency o
or completen
ness of the innformation in this brief. Information may contain
n or summarrise the view
ws of others, a
and not neceessarily refle
ect the views of Queenslaand Departm
ment of Health. nded to be u
used as mediical advice an
nd it is not in
ntended to bbe used to diagnose, This brieef is not inten
treat, cu
ure or preven
nt any diseasse, nor shoulld it be used for therapeu
utic purposees or as a sub
bstitute for a heaalth professional's advice
e. It must noot be relied u
upon withoutt verificationn from autho
oritative sources.. Queensland
d Departmen
nt of Health ddoes not acccept any liability, includinng for any injjury, loss or damaage, incurred
d by use of orr reliance onn the informaation. This brieef was comm
missioned by Queenslandd Department of Health, in its role as the Secretarriat of the Health Policy Ad
dvisory Comm
mittee on Te chnology (He
ealthPACT). The producttion of this brief was overseen by HealthP
PACT. Health
hPACT comprrises represe
entatives from health deppartments in
n all States and Territoriees, the Australian and Neew Zealand ggovernmentss and MSAC. It is a sub‐
committtee of the Au
ustralian Hea
alth Ministerrs’ Advisory C
Council (AHM
MAC), reportting to AHMA
AC’s Hospitall Principal Co
ommittee (HPC). AHMACC supports He
ealthPACT th
hrough fundiing. This brieef was prepared by Dr. Vicki Foersterr, Dr. Merrîccc Edgar‐Hugh
hes, Deanne Forel and Sttefanie Gurgaczz from the Au
ustralian Safe
ety and Effic acy Registerr of New Inte
erventional PProcedures –
– Surgical (ASERNIP‐S).
Technology, Company and Licensing Register ID WP139 Technology name Biodegradable polymer drug eluting stents Patient indication Treatment of coronary artery disease Description of the technology Coronary vascular stents are metallic ‘scaffolds’ that hold a blocked vessel open to restore blood flow (Figure 1) to the cardiac muscle.1 Stents for management of coronary artery disease (CAD) are generally inserted via percutaneous coronary intervention (PCI) procedures2. The earliest types of stents developed were bare metal stents (BMS). Drug‐
eluting stents (DES) which are comprised of a BMS coated in a durable polymer impregnated with anti‐proliferative agents such as everolimus, biolimus or sirolimus. DES have radically reduced restenosis of the coronary arteries; however, mortality rates are equivalent to rates achieved with BMS. Hypersensitivity reactions to the durable polymer component of the first generation DES can produce chronic inflammation which is thought to delay endothelial healing and favour stent thrombosis (ST).3 As a result, further developments in DES stents involved improving the polymer coating containing the anti‐proliferative agents, using biodegradable instead of durable formulations.4 Figure 1
1
Position of a stent in a vessel
Two recent innovations to stent technology are biodegradable and bioabsorbable stents. With biodegradable stents, a biodegradable polymer impregnated with anti‐proliferative agents is designed to elute the anti‐proliferative drug from the metallic stent scaffold in a Biodegradable stents: February 2013 1 controlled fashion. The biocompatible polymer coating, slowly degrades over time into inert organic monomers leaving behind the bare metal stent. This minimises the risks associated with the long‐term presence of durable polymer in the coronary vessel wall. With bioabsorbable stents the metal scaffold is replaced with a biodegradable vascular scaffold, which over time is absorbed. The primary focus of this Technology Brief is biodegradable polymer drug‐eluting stents. Company or developer Table 1 is adapted from information sourced from manufacturer’s websites and an online article.5 Table 1 Company or developer of biodegradable stents
Technology name
Marketed
Nobori®, biolimus-eluting biodegradable polymer,
stainless steel scaffold stent
®
BioMatrix Flex , the biolimus A9™ biodegradable
polymer DES, stainless steel scaffold
Company
Country/Continent
Terumo
Excel sirolimus-eluting biodegradable polymer
metal scaffold stent
Supralimus sirolimus-eluting biodegradable
polymer stainless steel scaffold
Orsiro limus-eluting biodegradable polymer cobalt
chromium alloy
JW Medical Systems
Europe, Latin America,
Asia and Japan
Europe, Middle East,
Africa and selected
Asian markets
None reported
Close to launch
Drug Eluting Absorbable Metal Scaffold
(DREAMS), magnesium alloy scaffold*
SYNERGY™ Everolimus-Eluting Platinum
Chromium Coronary Stent System
BioSensors International
Sahajanand Medical
Technologies
Biotronik AG
India
Europe
Biotronik AG
Boston Scientific
Corporation™
Europe (select centres)
TIVOLI® rapamycin†-eluting cobalt chromium
scaffold stent
Essen Technologies™
China**
ISAR® rapamycin†-eluting stainless steel scaffold
stent
Deutsches Herzzentrum
Muenchen
Germany‡
* currently under investigational use as part of the BIOSOLVE studies.** currently under investigational use and development
in China under the ‘Evaluate Safety And Effectiveness Of The Tivoli® DES and The Firebird2® DES For Treatment Coronary
Revascularization’ study. † rapamycin is also known as sirolimus. ‡ the ISAR stent was tested in the ISAR-test three, ISARtest four and ISAR-test five clinical trials.
Reason for assessment An innovative device for coronary artery disease with the advantage of a biodegradable polymer which breaks down overtime leaving only a BMS, theoretically reducing the risk of late stent thrombosis thought be associated with traditional DES using durable polymers. Biodegradable stents: February 2013 2 Stage of development in Australia ☐ ☐ Yet to emerge Experimental ☒ ☐ Investigational Nearly established ☐ ☐ ☐ Established Established but changed indication or modification of technique Should be taken out of use Licensing, reimbursement and other approval Five metallic scaffold stents with a biodegradable polymer impregnated with anti‐
proliferative agents are currently licensed for marketing: 
The Nobori® stent (Terumo Europe, Belgium) has received a CE mark and is marketed in Europe, Latin America, Asia and Japan.6 
The BioMatrix Flex® stent (BioSensors International, Switzerland) has received a CE mark in January 2010.7 
The Supralimus® stent developed by Sahajanand Medical Technologies™ (India) has received a CE mark in June 2011.8 
The SYNERGY™ Everolimus‐Eluting Platinum Chromium Coronary Stent System, Boston Scientific Corporation has received a CE mark on 31 October 2012.9 
The Orsiro hybrid DES (Biotronik AG, Germany) has received a CE mark of approval in early 2011.10 No reporting of market approval was identified in any jurisdiction for the TIVOLI® stent (Essen Technology, China), though one trial is underway in China. On 15 June 2011 the Cordis Corporation (United States) indicated it would no longer pursue the development of the NEVO™ Sirolimus‐Eluting Coronary Stent which was a sirolimus‐eluting stent with a cobalt scaffold. Further Cordis Corporation will also discontinue the manufacture of the CYPHER® and CYPHER SELECT® Plus Sirolimus‐Eluting Coronary Stents by the end of 2011.11 Australian Therapeutic Goods Administration approval ☐ ☒ ☐ ARTG number (s) Yes No Not applicable Technology type Device Technology use Therapeutic Biodegradable stents: February 2013 3 Patientt Indication and Settingg Diseasee descriptio
on and associated morttality and m
morbidity CAD is tthe most co
ommon form
m of cardiovvascular dissease; major coronary events occu
urred in close to
o 50,000 Australian adu
ults (62% m
male) in the 2007‐08 financial year,, or about 1
135 per day; nearly 40 per cent were ffatal. Preva lence is higgher among males thann females in
n all age groups over 35 yeaars and incrreases markkedly with aage, i.e., sevven per centt of Australians aged 555 to 64 yearrs were estimated to h ave CAD, in
ncreasing to
o 24 per cennt for those aged 85 yearrs and over. For Indigen
nous Austraalians, prevaalence is tw
wice that of non‐Indigenous Australiians when aadjusted forr age differeences. In a ttrend seen clearly for m
males (less so for femaless), overall C
CAD prevalence is higheest in the lo
owest socioe
economic ggroup and lo
owest in 12
the high
hest socioecconomic group. Numbeer of patientts In 20077‐08 there w
were about 160,000 hoospitalisations (episode
es of care) w
with a principal diagnossis of CAD, ccomprising two per cennt of all hosspitalisation
ns; of these,, angina acccounted for 44 p
per cent and
d acute MI ffor 35 per ccent. A declining trend has been seeen over th
he past two deccades, i.e., ffrom 867 ho
ospitalisatioons per 100
0,000 popula
ation in 19993‐94 to 709 per 6
100,0000 in 2007‐08
8. PCI is a common procedure to
o treat CAD and the vast majority of PCIs incl ude use of stents (94% off the 35,000
0 procedure
es in 2007‐008). The age
e‐standardissed rate forr PCIs for maales is much higher than tthat for fem
males (241 vvs 74 per 10
00,000 peop
ple in 2007‐‐08). The rate climbs w
with age up
p to 85 years. Between 2000‐01 an
nd 2007‐08,, the numbeer of PCIs increaseed by 57 peer cent (117
7 per 100,0000 populatio
on vs 155 per 100,000,, respective
ely), with a h
higher rate for males th
han femaless ( Figure 2).12 Similar data for Neew Zealand were not reeadily availaable. Figure 2
PCI intervention rates, by s
sex, in Austtralian adultts, 2000-01 tto 2007-0812
Biodegraadable stents: February 201
13 4 Speciality Cardiovascular disease and vascular surgery Technology setting Specialist hospital Impact Alternative and/or complementary technology Biodegradable DES are likely to be used instead of BMS or DES with a durable polymer coating, depending on safety and efficacy outcomes and cost. An alternative intervention for CAD is conventional or percutaneous coronary artery bypass surgery. Another generation of coronary stent exists; these are bioresorbable stents, which consist of polylactide, which is a fully absorbable material, in place of the traditional metal scaffold. As a result, bioresorbable stents degrade completely over a period of two to three years, leaving behind a treated vessel which is free from a permanent BMS. The advantage of the use of bioresorbable stents is the absence of a metal stent after treatment which decreases the risk of stent thrombosis. However, issues surrounding the rate of stent reabsorption and the challenges associated with implantation of such a stent, given its inability to be visualised on X‐ray and its greater risk of fracture, must also be considered. Current technology BMS or DES with a durable polymer Diffusion of technology in Australia There are no biodegradable polymer DES stents included on the Australian Register of Therapeutic Goods. There is one clinical trial underway in multiple sites throughout Australia (Table 2). Table 2
Clinical trial sites in Australia
EVOLVE (NCT01135225)
New South Wales
Queensland
Victoria
Fremantle Hospital
The Prince Charles Hospital
St. Vincent’s Hospital
Monash Medical Centre
EVOLVE, Non-inferiority Trial to Assess the Safety and Performance of the Evolution Coronary Stent
Biodegradable stents: February 2013 5 International utilisation Country
Level of Use
Trials underway or
completed
Austria

Australia

Belgium

Brazil

Canada

China

Czech Republic

Denmark

France

Germany

India

Ireland

Japan

Jordan

Korea

Latvia

Lithuania

Morocco

Netherlands

New Zealand

Poland

Portugal

Russia

Spain

Sweden

Switzerland

United Kingdom

United States

Limited use
Widely diffused
Cost infrastructure and economic consequences Biodegradable polymer DES can be implanted using the same system of catheter‐based techniques used for the implantation of both BMS and DES with a durable polymer. The effect on healthcare resources, such as equipment and training of staff, is unlikely to be significant; however, the financial impact is unclear, as the costs of the devices are unknown. Given that the infrastructure is in place to use biodegradable polymer DES, rapid diffusion of this technology is possible. Details of Commonwealth Government funding via the Medical Benefits Schedule are listed in Table 3 for relevant CAD / PCI procedures involving stents. Biodegradable stents: February 2013 6 Table 3
Medical Benefits Schedule of procedures related to the treatment for CAD and
stenting
Category
Item
Number
Benefit
(A$)
Number of Claims
(July 2011 to June
2012)
Transluminal insertion of stent or stents into one
occlusional site including associated balloon
dilatation for coronary artery, percutaneous or by
open exposure.
38306
762.35
32,047
Percutaneous transluminal rotational atherectomy of
1 coronary artery, including balloon angioplasty with
insertion of 1 or more stents.
38312
1132.35
258
Percutaneous transluminal rotational atherectomy of
more than 1 coronary artery, including balloon
angioplasty, with insertion of 1 or more stents.
38318
1586.35
38
A$, Australian dollars
Review of the Australian Prosthesis list13 identified 23 BMS available from multiple manufacturers, with a rebate of A$1,800. A further 51 self‐expanding stents were documented with a rebate of A$1,800 to A$2,970. One DES with a durable polymer, namely, the Zilver PTX paclitaxel‐eluting stent (Cook Medical Australia Pty. Ltd., Sydney, Australia), was available with a rebate of A$2,400. A manufacturer of biodegradable polymer drug eluting stents was contacted for cost data however no response was received. HealthPACT advice indicates that the cost of a biodegradable polymer drug eluding stent may be approximately 10 per cent higher than that of conventional DES with a durable polymer. Ethical, cultural or religious considerations No specific considerations were identified. Evidence and Policy Safety and effectiveness Three studies provided evidence of the safety and efficacy of biodegradable stents for the treatment of CAD: a meta‐analysis comparing biodegradable DES to non‐biodegradable DES (level I intervention evidence),14 a randomised controlled trial (RCT) comparing biodegradable DES to BMS (level II intervention evidence),15 and a large, single‐arm registry study reporting five‐year safety and effectiveness data for biodegradable DES (level IV intervention evidence).16 Lupi et al14 The meta‐analysis included 10 RCTs that enrolled a total of 5834 patients with a median follow‐up of one year. Studies were published between 2007 and 2011. Only studies considering biodegradable DES ‘with limus agents as cytostatic drugs and a film of polylactic co‐glycolic acid covering the stent struts without interruptions’ were included. Four Biodegradable stents: February 2013 7 different stents were assessed, namely the Nobori® (Terumo Europe™, Belgium), BioMatrix Flex® (BioSensors International™, Switzerland), TIVOLI® (Essen Technology, China) and ISAR® (Deutsches Herzzentrum Muenchen, Germany) stents. The Nobori® and BioMatrix Flex® stents elute biolimus, whilst the TIVOLI and ISAR stents sirolimus (also known as rapamycin). Patients were randomised to treatment with biodegradable or non‐biodegradable DES. Outcomes of interest included overall death, acute myocardial infarction (MI), late stent thrombosis (LST), target lesion revascularisation (TLR) and late lumen loss (LLL). The meta‐
analysis was performed according to the Guidelines for Randomized Controlled Trials of the Cochrane Collaboration, with included studies appraised for quality. Risk of publication bias was appraised by geographical inspection of funnel plots for each outcome, and heterogeneity was assessed by the Cochran’s Q test. Safety and Effectiveness Results Among the 10 included studies, mean patient age ranged from 57 to 67 years; the proportion of males ranged from 68 to 80 per cent; proportion with diabetes ranged from 22 to 48 per cent and with acute coronary syndrome from 14 to 55 per cent; and mean follow‐up ranged from 6 to 12 months. Types of included stents varied: (a) for biodegradable DES, eight studies focussed on biolimus A9 and two on sirolimus eluting stents; (b) for DES, four types were included across studies. A sub‐analysis was carried out for the studies of biolimus A9 biodegradable DES. Overall, heterogeneity among studies (assessed by Cochran’s Q test with 2‐tailed p=0.1 plus a statistical inconsistency test [I2]) was deemed to be low. Quality assessment showed that studies had fairly low risk of bias. With respect to heterogeneity among outcome measures, little was found for overall death, acute MI and LST; however, more heterogeneity was found for TLR and LLL. Results showed no significant differences for biodegradable DES versus non‐biodegradable DES for outcomes of overall death (OR 0.97, 95% CI [0.73, 1.29], p<0.83), acute MI (OR 1.13, 95% CI [0.87, 1.46], p<0.36) and LST (OR 0.64, 95% CI [0.36, 1.16], p<0.14). However, significantly lower rates of TLR (OR 0.68, 95% CI [0.0.47, 0.98], p<0.04), in‐stent LLL (weighted mean difference ‐0.10 mm, 95% CI [‐0.17, ‐0.03], p=0.004) and in‐segment LLL (weighted mean difference ‐0.06 mm, 95% CI [‐0.10, ‐0.01], p=0.01) were observed in patients treated with biodegradable DES. In other words, although biodegradable stents did not improve rates of overall death, acute MI and LST there was some benefit in TLR and LLL. Räber et al15 An assessor‐blinded RCT (COMFORTABLE, NCT00962416) with one year of follow‐up compared biodegradable DES (BioMatrix Flex®, Biosensors International) to BMS (Gazelle®, Biosensors International) in 1161 patients with ST‐segment elevation MI (STEMI) undergoing primary PCI at 11 sites in Europe and Israel. The mean age of patients was 61 (standard deviation 12) years and 79 per cent were men. Patients were randomly allocated 1:1 to treatment with biodegradable DES (specifically, stents eluting biolimus from a Biodegradable stents: February 2013 8 biodegradable polylactic acid polymer) or BMS of an otherwise identical design. All patients received dual antiplatelet therapy (DAPT) for at least one year. The primary end point was the rate of major adverse cardiac events (MACE), a composite of cardiac death, target vessel‐related reinfarction (TVR), and ischemia‐driven TLR at one year. Primary analysis included data for 1126 patients (97%) at one year. Baseline medications and clinical, angiographic (including lesion complexity), and procedural characteristics were similar between groups although statistical analysis of differences was not provided. Safety and Effectiveness Results Rates of cardiac death at one year were similar between the biodegradable DES and BMS groups (16 [2.9%] vs 20 [3.5%] patients, p=0.53). Definite stent thrombosis (ST) occurred in fewer patients in the biodegradable stents group but the difference was not significant: five (0.9%) versus 12 patients (2.1%); hazard ratio [HR] of 0.42 (95% CI [0.15, 1.19], p=0.10). However, rates of MACE were significantly different, occurring in 24 patients (4.3%) receiving biodegradable stents versus 49 patients (8.7%) with BMS; HR of 0.49 (95% CI [0.30, 0.80], p=0.004). The absolute reduction in MACE at one year was 4.4 per cent and the relative reduction was 51 per cent; the authors calculated that this extrapolated to prevention of 42 events per 1000 patients treated with the biodegradable stents versus BMS. The MACE difference was driven by a lower risk of TVR‐related reinfarction and ischemia‐driven TLR in the drug‐
eluting biodegradable stents versus BMS groups: 
TVR‐related reinfarction: three (0.5%) vs 15 (2.7%); HR 0.20 (95% CI [0.06, 0.69], p=0.01) 
Ischemia‐driven TLR: nine (1.6%) vs 32 (5.7%); HR 0.28 (95% CI [0.13‐0.59], p=0.001); the authors noted that the 4.1 per cent absolute risk reduction means that 24 patients need to be treated with the biodegradable stents to prevent one MACE. Han et al16 CREATE is a multi‐centre (59 centres in 4 countries), post‐marketing, surveillance registry of patients receiving EXCEL® biodegradable polymer DES (JW Medical System, China) and six months of DAPT (aspirin and clopidogrel). This article reported on five years of experience, apparently the longest available follow‐up of biodegradable polymer stent technology. Initially 2,077 patients were enrolled (mean age 60.6±11.1 years, 74% men); 90 per cent were admitted with acute coronary syndromes, including 19 per cent with acute MI. A total of 3748 stents were implanted at the index procedure (1.8 stents per patient). Excluded were patients with device or procedural failure, at least one stent in addition to the protocol stent, DAPT contraindications, heart function worse than New York Heart Association Class III, or a planned upcoming surgery. Patients had clinical evaluations at 30 days, every six Biodegradable stents: February 2013 9 months for two years, and every 12 months. Outcomes were MACE (composite of cardiac death, non‐fatal MI and TLR), cumulative TLR and thrombotic event rates. Safety and Effectiveness Results Registry enrolment dropped slightly to 1982 patients (95%) at five‐year follow‐up. The rates of cardiac death, non‐fatal MI, TLR and overall MACE were 3.0, 1.5, 3.7 and 7.4 per cent, respectively. The rates of ‘definite or probable’ ST and ‘definite’ ST from one to five years were 1.1 and 0.6 per cent, respectively; independent predictors of ST were heart failure and prior MI. The authors concluded that their study demonstrated satisfactory and sustained five‐year clinical safety and efficacy profiles, as evidenced by the low rates of MACE and ST. Given that the included studies used different biodegradable polymer DES it is difficult to make accurate conclusions about their safety and effectiveness as it is unknown if the results seen were as a result of the stent itself or an individual component of it, i.e. the scaffold material, the polymer that carries the drug or the anti‐proliferative drug specifically. Economic evaluation No economic information was identified. Ongoing research The Australian New Zealand Clinical Trials Register and ClinicalTrials.gov list 11 trials of biodegradable stents for CAD. One of these the EVOLVE trial, is being conducted in four centres throughout New South Wales, Queensland and Victoria (Table 4). Recently, Terumo Europe™ has commenced a second prospective RCT in order to validate, in a real‐life setting, the safety and effectiveness of the Nobori® stent in 3,067 consecutive patients undergoing PCI. Preliminary results of this trial were published in May 2012 and the trial is ongoing. Biodegradable stents: February 2013 10 Table 4
A selection of clinical trials currently underway involving biodegradable stents
Study
Location
Number of
patients
Expected end date
BESS (Biolimus-eluting Biodegradable
®
Polymer Stents [Nobori ] versus
Everolimus-eluting Stents [Promus
Element®])
Korea, multiple
sites
1462
July 2015
NCT01268371
BIO-RESORT (Comparison of
BIOdegradable Polymer [Orsiro®] and
DuRablE Polymer Drug-eluting Stents
[Synergy® and Resolute Integrity®] in
an All COmeRs PopulaTion)
The
Netherlands
3640
November 2016
6 European
locations
NR
December 2011
Switzerland
1161
December 2015**
Korea
2880
July 2016
69 international
sites
4000
September 2016
29 international
sites
291
May 2016
29 international
sites (United
States, Canada
and Japan)
1684
June 2018
Germany
2010
September 2013
10 European
sites
1700
June 2012*
NCT01674803
BIOSOLVE - I (BIOTRONIKS-Safety
and Clinical Performance Of the First
Drug-Eluting Generation Absorbable
Metal Stent In Patients With de Novo
Lesions in NatiVE Coronary Arteries)
NCT01168830
COMFORTABLE (Comparison of
Biomatrix Versus Gazelle in STElevation Myocardial Infarction
[STEMI]).
NCT00962416
CHOICE (Comparison of DES with biodegradable polymer [BioMatrix or
Nobori] and durable polymer [Xience V
or Endeavor Resolute])
NCT01397175
eBMX-PMR (e-BioMatrix PostMarket
Registry)
NCT01289002
EVOLVE (A prospective randomised
multi-centre single-blind non-inferiority
trial to assess the safety and
performance of the Evolution Coronary
Stent System for the treatment of de
novo atherosclerotic lesion)
Australia (4
sites), New
Zealand (3
sites)
NCT01135225
The EVOLVE II Clinical Trial To Assess
the SYNERGY Stent System for the
Treatment of Atherosclerotic Lesion(s)
NCT01665053
ISAR-TEST6 (Test Efficacy of
Biodegradable [Nobori® biodegradable
polymer limus-eluting stents] and
Permanent Limus-Eluting Stents
[Xience-V®])
NCT01068106
LEADERS (Limus-eluted from a durable
versus erodible stent coating)
NCT00389220
Biodegradable stents: February 2013 11 Study
Location
Number of
patients
Expected end date
NEXT (Nobori® biolimus-eluting versus
XIENCE/PROMUS everolimus-eluting
stent trial
Japan
3200
August 2015
China
300
Late 2014
China
2790
September 2018
Switzerland
2100
April 2017
NCT01303640
NOYA CoCr biodegradable coating
sirolimus-eluting coronary stent system
NCT01226355
Evaluate Safety And Effectiveness Of
The Tivoli® DES and The Firebird2®
DES For Treatment Coronary
Revascularization
NCT01681381
Sirolimus-eluting stents with
®
biodegradable polymer [Orsiro ] vs
everolimus-eluting stents
NCT01443104
* results of this trial are available from multiple publications. ** one-year follow-up results of this ongoing trial are published and
reported in this brief in Räber et al 2012.
Other issues Potential issues with biodegradable stents include local inflammation and a slow rate of resorption which may lead to restenosis. With respect to funding and conflicts‐of‐interest for the included studies, the meta‐
analysis14 received no specific funding (public, commercial or not‐for‐profit). The included RCT15 was supported by the Swiss National Science Foundation and an unrestricted research grant from the biodegradable stent manufacturer, Biosensors Europe SA, although the sponsors had no role in the design and conduct of the study, data analysis or manuscript preparation; many of the RCT’s 22 authors reported potential conflicts‐of‐interest. The registry report16 was supported by the ‘National Key Technology R&D Program in the 12th Five‐Year Plan of China, Major High‐Tech Clinical Army Projects’ with the authors declaring no potential conflicts‐of‐interest. There were two trials published which assessed the use of biodegradable stents; they were: 
Sort‐Out V: this was a multicentre (3 sites across western Denmark), randomised, all‐
comer, non‐inferiority trial which aimed to compare the effects of biodegradable polymer biolimus‐eluting stents (n=1229) with first‐generation durable polymer‐
coated sirolimus‐eluting stents (n=1239). At 9 months follow‐up, composite safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularisation) was met in 4.1% of patients in the biolimus‐eluting stent group and 3.1% of patients in the sirolimus‐eluting stent group (pone‐sided non‐
inferiority=0.06). 
Compare II: this was a multicentre (12 European sites), open‐label, prospective, randomised, controlled, non‐inferiority trial which aimed to compare the safety and Biodegradable stents: February 2013 12 efficacy of a biodegradable polymer‐coated biolimus‐eluting stent (n=1795) with a thin‐strut everolimus‐eluting stent coated with a durable biocompatible polymer (n=912). The findings of this trial were as follows, composite safety (cardiac death and non‐fatal myocardial infarction) and efficacy (clinically indicated target revascularisation) was met in 5.2% of patients in the biolimus‐eluting stent group at 12 months after discharge compared with 4.8% of patients in the everolimus‐eluting stent group (p<0.0001). Summary of findings This assessment of biodegradable polymer stents for CAD was based on a meta‐analysis of 10 RCTs, a large RCT and a single‐arm registry with five years of data. The most rigorous evidence, a recent meta‐analysis, found no significant benefit of biodegradable stents for CAD with respect to death, MI or LST, although benefits were found in rates of TLR and LLL. The authors postulated that the lack of demonstrated benefit could have been due to heterogeneity among studies for the TLR and LLL outcomes, and variation in types of non‐
biodegradable DES employed (with most being first versus second generation DES). As such, the findings of this meta‐analysis cannot be highly weighted. Ideally, future studies should compare stents that utilise the same metal scaffold and anti‐proliferative drug, with the only difference being the presence of a durable versus biodegradable polymer, so that the true safety and effectiveness of biodegradable polymer DES can be determined. The RCT also found no significant differences in rates of death and ST, although outcomes for biodegradable stents were superior with respect to MACE (driven by lower risks of TVR‐
related reinfarction and ischemia‐driven TLR). Finally, the single‐arm, five‐year registry report (lowest level of evidence among included studies) revealed fairly low rates of cardiac death, non‐fatal MI, TLR and overall MACE, interpreted by the authors as satisfactory and sustained safety and efficacy profiles for biodegradable stents. A number of other studies have been completed or are underway, with expected dates of completion out to 2017. Results of these studies will provide additional information about the safety and effectiveness of the technology. Cost data and economic analyses were not located; therefore, the financial impact of the technology is unknown at present. HealthPACT assessment As the only difference in specification between biodegradable DES and durable polymer (conventional) DES is the dissolution of the biodegradable polymer, and a scaffold is retained within the lumen of the vessel for both types of stents, biodegradable DES may have little benefit over durable polymer stents in current practice. Preliminary data presented in this brief identifies no clinical benefit in using a drug‐eluting stent with a biodegradable polymer compared to a conventional DES. Clinical trials investigating a new type of bioresorbable stent, which completely dissolves leaving no stent Biodegradable stents: February 2013 13 in situ are underway and will be of future interest. In order to review further long‐term clinical trial data and any further iterations of the drug‐eluting biodegradable stents this technology will be monitored for a period of 12 months. Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies 3 Total number of Level I intervention studies 1 Total number of Level II intervention studies 1 Total number of Level IV intervention studies 1 References 1. National Institutes of Health (2006). Diagram of coronary angioplasty and stent placement. Available from: http://en.wikipedia.org/wiki/File:PTCA_stent_NIH.gif [Accessed 15 Jan 2013]. 2.
Levine, G. N., Bates, E. R. et al (2011). '2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions', Circulation,124(23), e574‐
651. 3.
Garg, S. & Serruys, P. W. (2010). 'Coronary stents: current status', J Am Coll Cardiol,56(10 Suppl), S1‐42. 4. Garg, S. & Serruys, P. W. (2010). 'Coronary stents: looking forward', J Am Coll Cardiol,56(10 Suppl), S43‐78. 5. Kunz, J.S., Turco, M.A. (2011). The DES landscape in 2011 [internet]. Cardiac Interventions Today. Available from: http://bmctoday.net/citoday/2011/02/article.asp?f=the‐des‐landscape‐in‐2011 [Acessed 17 January 2013]. 6. Terumo (2008). Press release: Terumo announces forst CE Certified Nobori™ DES om use. Terumo. Avalable from: http://www.terumo‐
europe.com/cardiology/nobori/product‐information.php [Acessed January 2013]. 7. PR Newswire (2013). Biosensors receives CE mark approval for BioFreedom™. PR Newswire. Available from: http://www.prnewswire.com/news‐releases/biosensors‐
receives‐ce‐mark‐approval‐for‐biofreedom‐188766941.html[Acessed January 2013]. 8. MedtechInsider India (2011). Sahajanand medical technologies receives CE mark for sirolimus‐eluting coronary stents. MedtechInsider. Available from: http://india.medtechinsider.com/archives/685 [Accessed 17 January]. 9. Boston Scientific (2012). Boston scientific receives CE mark approval for the SYNERGY™ everolimus‐eluting platinum chromium coronary stent system, featuring a novel bioabsorbable polymer coating. Boston Scientific. Available from: http://bostonscientific.mediaroom.com/2012‐10‐31‐Boston‐Scientific‐Receives‐CE‐
Biodegradable stents: February 2013 14 Mark‐Approval‐for‐the‐SYNERGY‐Everolimus‐Eluting‐Platinum‐Chromium‐Coronary‐
Stent‐System‐Featuring‐A‐Novel‐Bioabsorbable‐Polymer‐Coating [ Accessed 17 January]. 10. Biotronik (2011). Press release: Biotronic announces first patients treated in BIOFLOWW‐II clinical study comparing ORSIRO hybrid drug‐eluting stent to abbotts XIENCE PRIME™. Biotronik. Available from : http://www.biotronik.com/files/95F5AC507236018CC12578CC00523A72/$FILE/PR_
BIOFLOW‐II_EN_final.pdf [Acessed 17 January 2013]. 11. Johnson and Johnson (2011). Press release: Cordis announces discontinuation of Nevo™ sirolumus‐eluting coronary stent. Johnson and Johnson. Available from: http://www.jnj.com/connect/news/all/cordis‐announces‐discontinuation‐of‐nevo‐
sirolimus‐eluting‐coronary‐stent [Accessed 17 January 2013]. 12. Australian Institute of Health and Welfare (2011). Cardiovascular disease: Australian facts 2011. AIHW, Canberra. 13. Australian Government Department of Health and Ageing (2012). Australian Prosthesis List, Australian Government Department of Health and Aging, Canberra, Available from: http://www.health.gov.au/internet/main/publishing.nsf/content/C1E6D9026742A90
2CA2576C70076D667/$File/Part%20A%20‐%20Prostheses%20List.pdf. 14. Lupi, A. Rognoni, A. et al (2012). 'Biodegradable versus durable polymer drug eluting stents in coronary artery disease: Insights from a meta‐analysis of 5834 patients', Eur J Prev Cardiol,Epub ahead of print 14 November 2012. 15. Raber, L. Kelbaek, H. et al (2012). 'Effect of biolimus‐eluting stents with biodegradable polymer vs bare‐metal stents on cardiovascular events among patients with acute myocardial infarction: the COMFORTABLE AMI randomized trial', JAMA, 308(8), 777‐87. 16. Han, Y. L. Zhang, L. et al (2012). 'A new generation of biodegradable polymer‐coated sirolimus‐eluting stents for the treatment of coronary artery disease: final 5‐year clinical outcomes from the CREATE study', EuroIntervention, 8(7), 815‐22. Search criteria to be used (MeSH terms) MeSH: Absorbable Implants; stents Keywords: Biodegradable; bioresorbable; stents Biodegradable stents: February 2013 15