Title: Drug-Eluting Stents

SBAR: Situation-Background-Assessment-Recommendation
Initiation and Feedback Phase

Situation:
Trinity Health purchases almost 30,000 Drug Eluting Stents (DES) annually spending over $22M.
During the past 24 months new levels of technology have been released with current vendors, a new
vendor came to market, and an additional vendor is expected in the future. With potentially five
vendors in the market, a review of clinical outcomes data is warranted to direct our acquisition strategy
to bring better value as well as the best technology for our patients.

Background:
Currently there are four vendors with DES products in the US market, Abbott Vascular, Medtronic,
Boston Scientific, and Cardinal Health (Cordis). Biotronik expects to enter the market pending FDA
approval in the next 60 to 90 days. Trinity Health has maintained a dual vendor commitment and
pricing strategy with Abbott Vascular and Medtronic for many years, with the last clinical review in 2016
with the entrance of a biodegradable polymer stent that was determined not to offer clinical superiority.
Compliance to these two suppliers have been extremely high at over 99 percent. Because of this “dual
source” relationship, we have been able to maintain very favorable pricing verses an “all-play” strategy
with the vendors while offering product that continues to demonstrate strong clinical performance in
ongoing research trials.
Assessment:
Drug Eluting Stent Market Summary

Vendor Product lines Drug Elution Method

Abbott Xience Alpine Everolimus Durable Polymer
Abbott Xience Sierra Everolimus Durable Polymer
Medtronic Resolute Integrity Zotarolimus Durable Polymer
Medtronic Resolute Onyx Zotarolimus Durable Polymer
Boston Promus Elite Everolimus Durable Polymer
Boston Promus Premier Everolimus Durable Polymer
Boston Synergy Everolimus Biodegradable Polymer
Cordis EluNir Ridaforolimus Durable Elastomer
Biotronik Orsiro* Limus Drug Hybrid - coated and biocompatible
*Not FDA Approved:
UPDATE: During the review
process, the FDA approved the
Biotronik product – this was taken
into consideration when making the
final recommendation.

As stated above, from time-to-time the question of durable verses biodegradable polymers have
surfaced claiming that a biodegradable polymer causes less inflammation and potentially better
outcomes. In March 2017, a meta-analysis study was published in the Journal of Cardiovascular
Interventions comparing the safety and efficacy of biodegradable polymer stents to second-generation
durable polymer stents. The authors compared 16 randomized controlled studies of 19,886 patients
and concluded that biodegradable polymer stents have similar safety and efficacy profiles to second-
generation durable polymer stents.

In September 2018 a European study comparing Medtronic’s Onyx stent to Biotronik’s Orsiro* stent
was published in The Lancet. This non-inferiority trial concluded that Resolute Onyx was noninferior to
Orsiro.

From April to June, 2018 Trinity Health conducted a voluntary product evaluation of Cardinal’s EluNir
DES. Seven Trinity facilities evaluated 140 stents with varying results. Most concluded that the stent
was “okay” or “somewhat adequate” but no evaluator stated EluNir was superior to our current
contracted products. It should be noted that since Trinity’s evaluation concluded there have been a
few somewhat concerning reports in the FDA’s MAUDE database of stents coming off the balloon in
tortuous vessels and balloons bursting with as little as 2 ATM.

Recommendation:
The CV CEC endorsed the recommendations made by the CV Interventional Expert Panel to continue
the current dual-vendor contracting practices due to no new compelling evidence to change and with
an impact significant financial savings for the organization.

References/ Citations:
El-Hayek, MD, G, et.al. (2017) Meta-Analysis of Randomized Clinical Trials Comparing Biodegradable
Polymer Drug-Eluting Stent to Second Generation Durable Polymer Drug-Eluting Stents. JACC:
Cardiovascular Interventions Vol. 10, No.5 (

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32001-4/fulltext

Submitted by:Kelley Young, Director Supply Chain; Laura Archbold, RN, VP, ICS Operations and
Stephen Rosenblum, MD, Medical Director Cardiovascular
CEC/CLG/CSG: Cardiovascular CEC
Date 1/15/2019
Title: Drug-Eluting Stents
Final Decision and Action Planning Phase
CEC Decision for Implementation:
1. What were final decisions? Would include any changes to the recommendations out for
feedback.
Continue with currently contract two vendors Abbott and Medtronic
2. Who owns the next steps?
Supply Chain will complete new contract for March 1, 2019 and implement in procurement
systems. Cardiovascular Sourcing Advisory Team will communicate outcome of decision
locally.
3. Estimated timeframe: beginning March 1, 2019
Complete all communication and system updates within 30 days.
4. Which functional groups will be involved in the implementation?
Supply Chain and Cath Lab local leadership will be primary for implementation, appreciate
support on compliance to selected vendors by CMO and MGPS as requested.
5. Regional ICLT to communicate to functional leads and areas.
Teams Actions When
CMO Awareness of decision – Ongoing
consult with local cardiologist
as needed to ensure
compliance
CNO Awareness of decision
MG PS Awareness of decision – Ongoing
consult with local cardiologist
as needed to ensure
compliance

Finalized by: Kelley Young, Director Supply Chain; Laura Archbold, RN, VP, ICS Operations and
Stephen Rosenblum, MD, Medical Director Cardiovascular

CEC/CLG/CSG: Cardiovascular CEC

Date 2/26/2019
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017

PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN ISSN 1936-8798/$36.00

COLLEGE OF CARDIOLOGY FOUNDATION http://dx.doi.org/10.1016/j.jcin.2016.12.002

Meta-Analysis of Randomized Clinical

Trials Comparing Biodegradable Polymer
Drug-Eluting Stent to Second-Generation
Durable Polymer Drug-Eluting Stents
Georges El-Hayek, MD,a Sripal Bangalore, MD, MHA,b Abel Casso Dominguez, MD,c Chandan Devireddy, MD,a
Wissam Jaber, MD,a Gautam Kumar, MD,a Kreton Mavromatis, MD,a Jacqueline Tamis-Holland, MD,c
Habib Samady, MDa

ABSTRACT

OBJECTIVES The authors sought to perform a meta-analysis of randomized clinical trials (RCTs) comparing the
safety and efficacy of biodegradable polymer drug-eluting stents (BP-DES) to second-generation durable
polymer drug-eluting stents (DP-DES).

BACKGROUND Prior meta-analyses have established the superiority of BP-DES over bare-metal stents and
first-generation DP-DES; however, their advantage compared with second-generation DP-DES remains controversial.

METHODS The authors searched PubMed and Scopus databases for RCTs comparing BP-DES to the second-generation
DP-DES. Outcomes included target vessel revascularization (TVR) as efficacy outcome and cardiac death, myocardial
infarction (MI), and definite or probable stent thrombosis (ST) as safety outcomes. In addition, we performed landmark
analysis for endpoints beyond 1 year of follow-up and a subgroup analysis based on the stent characteristics.

RESULTS The authors included 16 RCTs comprising 19,886 patients in the meta-analysis. At the longest available
follow-up (mean duration 26 months), we observed no significant differences in TVR (p ¼ 0.62), cardiac death
(p ¼ 0.46), MI (p ¼ 0.98), or ST (risk ratio: 0.83, 95% confidence interval: 0.64 to 1.09; p ¼ 0.19). Our landmark analysis
showed that BP-DES were not associated with a reduction in the risk of very late ST (risk ratio: 0.87, 95% confidence
interval: 0.49 to 1.53; p ¼ 0.62). Similar outcomes were seen regardless of the eluting drug (biolimus vs. sirolimus), the
stent platform (stainless steel vs. alloy), the kinetics of polymer degradation or drug release (<6 months vs. >6 months),
the strut thickness of the BP-DES (thin <100 mm vs. thick >100 mm), or the DAPT duration ($6 months vs. $12 months).

CONCLUSIONS BP-DES have similar safety and efficacy profiles to second-generation DP-DES. (J Am Coll Cardiol Intv
2017;10:462–73) Published by Elsevier on behalf of the American College of Cardiology Foundation.

C ompared with bare-metal stents (BMS), first-

generation durable polymer drug-eluting
stents (DP-DES) result in reduced rates of
restenosis with concerns of higher rates of stent
first-generation devices with reduced rates of ST
(2–4). Recently, however, very late ST and neoathero-
sclerosis, resulting in adverse clinical outcomes, have
been observed with second-generation DP-DES (5–7).
thrombosis (ST) (1). Second-generation DP-DES One mechanism of late stent failure has been attrib-
have maintained the low restenosis rates of uted to the delayed endothelial healing secondary to

From the aDivision of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; bLeon H.
Charney Division of Cardiology, New York University School of Medicine, New York, New York; and the cDepartment of Car-
diovascular Diseases, Mount Sinai St. Luke’s Hospital, New York, New York. Dr. Bangalore has received research grants from
Abbott Vascular; and travel grants from Medtronic and Boston Scientific. Dr. Devireddy is a scientific advisory board member with
Medtronic and Vascular Dynamics. Dr. Kumar is a consultant for Trireme Medical, CSI Medical, and Abiomed. Dr. Samady has
received research funding from Volcano Corporation, St. Jude Medical, Medtronic, Inc., and Abbott Vascular. All other authors
have reported that they have no relationships relevant to the content of this paper to disclose.

Manuscript received September 26, 2016; revised manuscript received November 22, 2016, accepted December 5, 2016.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017
MARCH 13, 2017:462–73
a hypersensitivity reaction to the durable polymer
(8–10). To address this potential limitation of dura-
ble polymer, DES with biodegradable-polymer (BP-
DES) has been developed. After complete release of
the drug within 3 to 9 months, the polymer gradu-
ally degrades into water and carbon dioxide mole-
cules. In this manner, BP-DES are designed to
provide the antiproliferative benefits of a DP-DES
before functionally transforming into a BMS once
drug delivery and polymer biodegradation are com-
plete (11). In doing so, BP-DES would be expected
to reduce the risk of adverse cardiac events related
to ST beyond the first year that may be related to
durable polymer.
SEE PAGE 474
A prior meta-analysis of 3 randomized controlled
trials (RCTs) has shown superiority of BP-DES over
first-generation DP-DES in reducing the risk of ST and
myocardial infarction (MI) at 4-year follow-up (12).
However, compared with second-generation DP-DES,
results of BP-DES meta-analyses have been incon-
sistent and lacked long-term follow up (13–16). Since
then, several more RCTs comparing second-
generation DP-DES to BP-DES have been performed
and longer-term follow-up data are available from
the previous trials. Accordingly, we conducted a
meta-analysis of all existing RCTs comparing the
safety and efficacy of BP-DES to the second-
generation DP-DES, examining the performance of
BP-DES stratified by the type of drug eluted, the
polymer degradation and drug release kinetics, strut
thickness, and duration of dual anti-platelet therapy
(DAPT).
METHODS
STUDY SEARCH AND ELIGIBILITY CRITERIA. Two
authors (G.E. and A.C.D.) independently and in dupli-
cate searched PubMed and Scopus databases until the
end of June 2016 to identify RCTs comparing BP-DES to
second-generation DP-DES. We did the systematic
search using the key words “biodegradable,” “bio-
absorbable,” “polymer,” “everolimus,” “zotarolimus,”
“Endeavor,” “Resolute,” “Xience,” and “drug-eluting
stent.” We also reviewed prior meta-analyses and the
reference lists of the original trials and review articles.
We did not set any search limitations by publication
dates or language.
We included trials that compared BP-DES to
the second-generation DP-DES for cardiac outcomes
of interest. We excluded trials that compared
El-Hayek et al. 463
Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy
BP-DES to BMS, to first-generation DES ABBREVIATIONS
(sirolimus and paclitaxel), and to polymer- AND ACRONYMS
free DES. We also excluded trials of biode-
BMS = bare-metal stent(s)
gradable scaffolds.
BP-DES = biodegradable
polymer drug-eluting stent(s)
DATA EXTRACTION AND QUALITY ASSESSMENT.
We extracted the baseline characteristics and CI = confidence interval
the treatment variables of the study popula- DAPT = dual-antiplatelet
therapy
tion, including the cardiovascular risk factors
DES = drug-eluting stent(s)
of the included patients, the sample size of
the trials, the duration of DAPT following DP-DES = durable polymer
drug-eluting stent(s)
stenting, and the duration of follow-up. We
MI = myocardial infarction
also extracted information regarding the
RCT = randomized controlled
architecture of the BP-DES and DP-DES used
trial
in the trials (eluting agent, scaffold material,
RR = risk ratio
elution and biodegradation kinetics, and strut
ST = stent thrombosis
thickness).
Quality assessment of RCTs was based TVR = target vessel
revascularization
on sequence generation, randomized alloca-
tion, concealment, blinding of participants, personnel
and outcome assessors, incomplete data, selective
outcome reporting, and other sources of bias (17). If
any of the first 3 components presented low quality,
we classified the study as having a high or unclear risk
for bias.
EFFICACY AND SAFETY OUTCOMES. The efficacy
outcome of the analysis was target vessel revascu-
larization (TVR), and the safety outcomes included
separate endpoints of cardiac death, MI, and definite
or probable ST according to the Academic Research
Consortium definition. We extracted these endpoints
at 1 year and at the longest available follow-up of
each trial. In addition, we performed a landmark
analysis after 1 year of follow-up to compare the 2
types of stents for late cardiac outcomes. Only trials
with follow-up duration longer than 1 year were
included in the analysis.
STATISTICAL ANALYSIS. The statistical analysis
was done in line with recommendations from
the Cochrane Collaboration and the Preferred
Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines using Review Manager
(RevMan) version 5.1.7 (Copenhagen, Denmark,
Nordic Cochrane Centre, The Cochrane Collaboration,
2012). Heterogeneity was assessed using the I2
statistic, defined as the proportion of total variation
observed between the trials attributable to differences
between trials rather than sampling error (chance),
with values <25% considered as low and >75% as high
(18). Analysis was performed on an intention-to-treat
basis. We performed fixed effect analysis when the I 2
was up to 25% and the p value at least 0.05 or higher;
464 El-Hayek et al.
Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy
F I G U R E 1 PRISMA Diagram
Algorithm of the literature search for studies included in the meta-analysis.
BMS ¼ bare-metal stent(s); BP-DES ¼ biodegradable polymer drug-eluting stent(s);
PF ¼ polymer-free; PRISMA ¼ Preferred Reporting Items for Systematic Reviews
and Meta-Analyses; RCT ¼ randomized controlled trial.
otherwise, we used random effect.
bias was estimated visually by funnel plots, and/or
using Begg’s test and the weighted regression test of
Egger (19).
We performed subgroup analysis based on the
characteristics of the BP-DES: 1) eluting drugs
(biolimus vs. sirolimus); 2) scaffold material (alloy
vs. stainless steel); 3) kinetics of polymer degradation
(<6 months vs. $6 months); 4) kinetics of drug release
(<6 months vs. $6 months); 5) strut thickness (thin
<100 mm vs. thick >100 m m); and 6) the duration of
DAPT following percutaneous coronary intervention
($6 months vs. $12 months).
RESULTS
As shown in Figure 1, our search strategy yielded
16 RCTs of 792 articles initially screened. We
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017
MARCH 13, 2017:462–73
included 19,886 patients in the meta-analysis, with
10,859 patients receiving BP-DES compared with
9,027 patients treated with second-generation
DP-DES. The mean duration of follow-up was
26 months. Baseline characteristics on the included
trials are outlined in Table 1 (Online Table 1).
INTERMEDIATE AND LONG-TERM OUTCOMES. At
the longest available follow-up, BP-DES were not
associated with any reduction in the risk of TVR
compared with second-generation DP-DES (risk
ratio [RR]: 1.06, 95% confidence interval [CI]: 0.96
to 1.18; p ¼ 0.24) (Figure 2). From safety standpoint,
we did not observe any difference between the 2
groups in the risk of cardiac death (RR: 1.08,
95% CI: 0.89 to 1.31; p ¼ 0.46) (Figure 3) or MI (RR:
1.00, 95% CI: 0.87 to 1.15; p ¼ 0.98) (Figure 4).
Compared with 106 patients (0.98%) in the BP-
DES group, 104 patients (1.15%) in the DP-DES
group had definite or probable ST that did not
correspond to any statistically relevant reduction
in the rate of ST (RR: 0.83, 95% CI: 0.64 to 1.09;
p ¼ 0.19) (Figure 5).
VERY LATE OUTCOMES. Only 6 RCTs studied the
outcomes of 11,866 patients beyond 1 year of follow-
up and were included in the landmark analysis. No
significant differences between BP-DES and DP-DES
were observed in rates of TVR (RR: 1.12, 95% CI:
0.93 to 1.35; p ¼ 0.25), cardiac death (RR: 1.13, 95%
CI: 0.82 to 1.56; p ¼ 0.45), or MI (RR: 0.95, 95% CI:
0.71 to 1.29; p ¼ 0.75). In the BP-DES arm, 25 -
patients (0.37%) had very late definite or
probable ST compared with 23 patients (0.45%) in
the DP-DES arm, which did not correspond to
significant reduction in very late ST between the 2
Publication
stents (RR: 0.87, 95% CI: 0.49 to 1.53; p ¼ 0.62)
(Figure 6).
ANALYSIS BY DURATION OF DAPT AND STENT
CHARACTERISTICS. Table 2 summarizes the cardiac
outcomes in the different subgroups. There were no
significant differences seen between BP-DES and
DP-DES in regard to TVR (p ¼ 0.45), cardiac death
(p ¼ 0.38), MI (p ¼ 0.52), and ST (p ¼ 0.83) in patients
who received biolimus-eluting versus sirolimus-
eluting BP-DES. Our subgroup analysis based on the
BP-DES scaffold material showed no difference in
outcomes (TVR p ¼ 0.15, cardiac death p ¼ 0.52, MI
p ¼ 0.58, and ST p ¼ 0.78) when stainless steel versus
alloy BP-DES were compared with DP-DES. Similar
outcomes were seen whether BP-DES with polymer
degradation time or drug release within <6 months
or >6 months were compared with DP-DES. In
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017 El-Hayek et al. 465
MARCH 13, 2017:462–73 Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy

T A B L E 1 Characteristics of the Included Trials and Stent Used

Number of Patients (N) BP-DES Characteristics

DAPT Duration Follow-Up
Study/First Author (Ref. #) BP-DES DP-DES (Months) (Months) Stent Strut Thickness (m m) Drug

BASKET-PROVE II (20) 765 765 12 24 Nobori 120 Biolimus

BIOFLOW II (21) 298 154 >6 12 Orsiro 60 Sirolimus
BIOSCIENCE (22) 1063 1056 12 24 Orsiro 60 Sirolimus
CENTURY II (23) 551 550 >6 9 Ultimaster 80 Sirolimus
COMPARE II (24) 1,795 912 12 36 Nobori 120 Biolimus
DESSOLVE II (25) 123 61 6 to 12 9 MiStent 64 Sirolimus
EVERBIO II (26) 80 80 >6 9 BioMatrix Flex 112 Biolimus
EVOLVE FHU (27) 193 98 >6 24 Synergy 74 Everolimus
EVOLVE II (28) 846 838 >6 12 Synergy 74 Everolimus
ISAR-TEST 4 (29) 1,299 1,304 >6 60 Yukon choice PC 87 Sirolimus
LONG-DES V (30) 245 255 >12 12 Nobori 120 Biolimus
NEXT (31) 1,617 1,618 >3 36 Nobori 120 Biolimus
Separham et al. (32) 100 100 >12 12 BioMatrix 112 Biolimus
SORT OUT VI (33) 1,497 1,502 >12 12 BioMatrix Flex 112 Biolimus
TARGET I (34) 227 231 >12 12 Firehawk 86 Sirolimus
Xu et al. (35) 168 156 6 24 Tivoli 80 Sirolimus

T A B L E 1 Continued

BP-DES Characteristics DP-DES Characteristics

Scaffold Drug Release Polymer Biodegradation Strut

Study/First Author (Ref. #) Material (Months) (Months) Stent Thickness (m m) Drug Scaffold Material

BASKET-PROVE II (20) SS 6–9 12 Xience Prime 81 Everolimus Co-Cr

BIOFLOW II (21) Co-Cr 12 14 Xience Prime 81 Everolimus Co-Cr
BIOSCIENCE (22) Co-Cr 12 14 Xience Prime 81 Everolimus Co-Cr
CENTURY II (23) Co-Cr 4 4 Xience V 81 Everolimus Co-Cr
COMPARE II (24) SS 6–9 12 Xience V/ Prime 81 Everolimus Co-Cr
DESSOLVE II (25) Co-Cr 9 3 Endeavor 91 Zotarolimus Co-Cr
EVERBIO II (26) SS 6–9 6-9 Promus Element 81 Everolimus Pl-Cr
EVOLVE FHU (27) Pl-Cr 3 4 Promus Element 81 Everolimus Pl-Cr
EVOLVE II (28) Pl-Cr 3 4 Promus Element 81 Everolimus Pl-Cr
ISAR-TEST 4 (29) SS 1 2-3 Xience V 81 Everolimus Co-Cr
LONG-DES V (30) SS 6–9 12 Promus Element 81 Everolimus Pl-Cr
NEXT (31) SS 6–9 12 Xience/Promus 81 Everolimus Co-Cr/Pl-Cr
Separham et al. (32) SS 6–9 12 Xience V 81 Everolimus Co-Cr
SORT OUT VI (33) SS 6–9 6-9 Resolute Integrity 91 Zotarolimus Co-Cr
TARGET I (34) Co-Cr 1 6-9 Xience V 81 Everolimus Co-Cr
Xu et al. (35) Co-Cr 1 6 Endeavor 91 Zotarolimus Co-Cr

BP-DES ¼ biodegradable polymer drug-eluting stent(s); Co-Cr ¼ cobalt-chromium; DAPT ¼ dual-antiplatelet therapy; DP-DES ¼ durable polymer drug-eluting stent(s); Pl-Cr ¼ platinum-
chromium; SS ¼ stainless steel.

addition, we observed no difference in outcomes However, compared with contemporary second-

when we compared thin struts or thick struts BP-DES generation DP-DES, prior studies have been limited
separately to DP-DES (Figure 7). Finally, BP-DES by short follow-up duration and insufficient
and DP-DES showed similar safety and efficacy pro- power to detect significant differences in important
files (Figure 8) regardless of the DAPT duration outcomes such as very late ST. The present
($6 months vs. $12 months). meta-analysis is the largest analysis exclusively
comparing BP-DES to the second-generation DP-DES
DISCUSSION derived from 16 trials including 19,886 patients with
longer follow-up duration (mean 26 months). We
Prior network meta-analyses have established the demonstrate that both DP-DES and BP-DES platforms
superiority of BP-DES over BMS and first generation have similar safety and efficacy profiles, and
DP-DES in terms of safety and efficacy (15,16). importantly, that BP-DES are not associated with
466 El-Hayek et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017

Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy MARCH 13, 2017:462–73

F I G U R E 2 Risk Estimates of TVR

Forest plot reporting the risk ratios (RRs) with 95% confidence interval (CI) of target vessel revascularization in patients treated with BP-DES
compared with DP-DES. The diamond indicates the point estimate, and the left and right end of the line indicate the 95% CI.
BP-DES ¼ biodegradable polymer drug-eluting stents; DP-DES ¼ durable polymer drug-eluting stents; M-H ¼ Mantel-Haenszel test;
TVR ¼ target vessel revascularization.

F I G U R E 3 Risk Estimates of Cardiac Death

Forest plot reporting the RR with 95% CI of the outcome of cardiac death in patients treated with BP-DES compared with DP-DES.
The diamond indicates the point estimate, and the left and right end of the line indicate the 95% CI. Abbreviations as in Figure 2.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017 El-Hayek et al. 467
MARCH 13, 2017:462–73 Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy

F I G U R E 4 Risk Estimates of MI

Forest plot reporting the RR with 95% CI of the outcome of myocardial infarction in patients treated with BP-DES compared with DP-DES.
The diamond indicates the point estimate, and the left and right end of the line indicate the 95% CI. MI ¼ myocardial infarction; other
abbreviations as in Figure 2.

F I G U R E 5 Risk Estimates of ST

Forest plot reporting the RR with 95% CI of definite or probable stent thrombosis in patients treated with BP-DES compared with DP-DES.
The diamond indicates the point estimate, and the left and right end of the line indicate the 95% CI. ST ¼ stent thrombosis; other
abbreviations as in Figure 2.
468 El-Hayek et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017

Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy MARCH 13, 2017:462–73

F I G U R E 6 Risk Estimates of Very Late ST

Forest plot reporting the RR with 95% CI of very late definite or probable ST beyond 1 year of follow-up in patients treated with BP-DES
compared with DP-DES. The diamond indicates the point estimate, and the left and right end of the line indicate the 95% CI. Abbreviations
as in Figures 2 and 5.

significantly reduced risk of ST beyond 1 year inflammatory reaction induced by the durable poly-
compared with DP-DES (RR: 0.87, 95% CI: 0.49 to mer. However, several studies have shown that
1.53; p ¼ 0.62). polymers requiring active bioresorption are associ-
BP-DES were initially developed to overcome the ated with higher rates of inflammation than DP
risk of delayed healing process attributed to the (36,37). This inflammatory process seen with

T A B L E 2 Cardiac Outcomes

Analysis (No. of Trials Included) TVR RR (95% CI) Cardiac Death RR (95% CI) MI RR (95% CI) Definite/Probable ST RR (95% CI)

Outcomes at 1 yr (12) 1.08 (0.94–1.23) 1.05 (0.82–1.36) 1.02 (0.87–1.20) 0.82 (0.59–1.12)
Outcomes at the longest follow-up (16) 1.06 (0.96–1.18) 1.08 (0.89–1.31) 1.00 (0.87–1.15) 0.83 (0.64–1.09)
Landmark analysis beyond 1 yr (6) 1.12 (0.93–1.35) 1.13 (0.82–1.56) 0.95 (0.71–1.29) 0.87 (0.49–1.53)
Subgroup analysis
BP eluting drug
Biolimus (7) 1.11 (0.97–1.28) 1.18 (0.90–1.54) 1.02 (0.84–1.23) 0.88 (0.56–1.39)
Sirolimus (7) 1.02 (0.86–1.22) 0.99 (0.74–1.32) 0.92 (0.73–1.16) 0.83 (0.59–1.17)
BP-DES strut thickness
Thin struts (9) 1.00 (0.85–1.17) 0.97 (0.73–1.28) 0.98 (0.81–1.20) 0.81 (0.58–1.13)
Thick struts (7) 1.11 (0.97–1.28) 1.18 (0.90–1.54) 1.02 (0.84–1.23) 0.88 (0.56–1.39)
BP-DES scaffold
Alloy (8) 0.94 (0.76–1.15) 0.96 (0.65–1.42) 0.95 (0.76–1.20) 0.81 (0.56–1.16)
Stainless steel (8) 1.11 (0.99–1.26) 1.12 (0.89–1.40) 1.03 (0.87–1.22) 0.87 (0.58–1.30)
BP-DES drug release
<6 months 0.99 (0.81–1.21) 0.96 (0.67–1.38) 1.08 (0.83–1.40) 0.86 (0.47–1.57)
>6 months 1.09 (0.97–1.24) 1.13 (0.89–1.42) 0.97 (0.83–1.14) 0.83 (0.61–1.12)
Polymer degradation
<6 months 0.99 (0.81–1.21) 0.93 (0.65–1.34) 1.09 (0.84–1.42) 0.84 (0.47–1.51)
>6 months 1.09 (0.97–1.24) 1.14 (0.90–1.43) 0.97 (0.83–1.14) 0.83 (0.61–1.13)
DP eluting drug
Everolimus (13) 1.09 (0.97–1.21) 1.06 (0.86–1.31) 1.00 (0.87–1.15) 0.86 (0.65–1.14)
Zotarolimus (3) 0.92 (0.68–1.24) 1.18 (0.69–2.03) 1.01 (0.64–1.59) 0.66 (0.29–1.52)
DAPT duration
$6 months (8) 0.95 (0.79–1.15) 0.94 (0.66–1.33) 1.09 (0.84–1.42) 0.84 (0.47–1.51)
$12 months (7) 1.13 (0.99–1.28) 1.14 (0.87–1.50) 0.94 (0.77–1.14) 0.81 (0.59–1.11)

MI ¼ myocardial infarction; RR ¼ risk ratio; ST ¼ stent thrombosis; TVR ¼ target vessel revascularization; other abbreviations as in Table 1.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017 El-Hayek et al. 469
MARCH 13, 2017:462–73 Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy

F I G U R E 7 Risk Estimates of ST in the Thin- and Thick-Strut BP-DES Subgroups

Subgroup analysis based on the strut thickness of the BP-DES comparing BP-DES to DP-DES for definite or probable ST. The p value in the test
for subgroup differences represents the interaction between the subgroups. Abbreviations as in Figures 2 and 5.

biodegradation could possibly explain the attenuated
benefit of BP-DES. In fact, several prior meta-
analyses have demonstrated worse outcomes with
BP-DES compared with DP-DES. Indeed, Palmerini
et al. (15) demonstrated that BP-DES were associ-
ated with a higher rate of 1-year definite ST (odds
ratio: 2.44, 95% CI: 1.30 to 4.76) compared with
cobalt chromium everolimus-eluting stents. Simi-
larly, Bangalore et al. (16) found that BP-DES were
associated with higher mortality compared with
cobalt chromium everolimus-eluting stents beyond
1 year of follow-up (RR: 1.52, 95% CI: 1.02 to 2.22).
In the present analysis, we included a greater
number of trials and longer-term clinical follow-up
(ranging from 1 to 5 years). We observed no sig-
nificant difference in mortality (RR: 1.08, 95% CI:
0.89 to 1.31; p ¼ 0.46) or in ST (RR: 0.83, 95% CI:
0.64 to 1.09; p ¼ 0.46). In fact, we observed
numerically lower rates of ST events with BP-DES
(0.98%) compared with DP-DES (1.15%). Taken
together, these data indicate that BP-DES share
similar safety and efficacy profiles with DP-DES and
do not seem to be associated with worse outcomes
at the long term.
COMPARISON OF BP-DES TO DP-DES BASED ON
STENT CHARACTERISTICS. The clinical success
of the second-generation DES has been attributed,
not only to improvements in durable polymer
biocompatibility, but also to the thinner struts in the
refined platforms (38). Indeed, compared with the
thicker struts, thinner strut platforms have been
shown to reduce platelet aggregation and inflam-
matory cell adhesion (39,40). To specifically address
whether BP-DES strut thickness influences outcomes
relative to second-generation DP-DES, we performed
470 El-Hayek et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017

Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy MARCH 13, 2017:462–73

F I G U R E 8 Risk Estimates of ST in the Subgroups Treated With at Least 6 vs. 12 Months of DAPT

Subgroup analysis based on the duration of dual-antiplatelet therapy (DAPT) comparing BP-DES to DP-DES for definite or probable ST.
The p value in the test for subgroup differences represents the interaction between the subgroups. Abbreviations as in Figures 2 and 5.

a subgroup analysis based on strut thickness. We Biodegradable Polymer Sirolimus-eluting Stent in

found no differences in safety or efficacy endpoints “Real-World” Practice) trial addressed the question
between thin- or thick-strut BP-DES and DP-DES whether the rate of drug elution and polymer ab-
(Table 2). Our clinical results corroborate the imag- sorption would affect the clinical outcomes of BP-DES
ing results of the BIOFLOW-II (Biotronik-Safety and (41). The poly-lactide polymer-based Excel
Clinical Performance of the Drug Eluting Orsiro (with sirolimus elution for 3 months and polymer
Stent in the Treatment of Subjects With Single De bioresorption within 9 months) (JW Medical Systems,
Novo Coronary Artery Lesions-II) trial (21), which Beijing, China) was compared with the poly-
demonstrated similar optimal coherence tomogra- lactide-co-glycolide polymer-based BuMA stent
phy–defined neointimal thickness between the (with sirolimus elution for 1 month and polymer ab-
biodegradable polymer Orsiro stent (60 m m) (Bio- sorption within 3 months) (SINOMED, Tianjin, China).
tronik, Bülach, Switzerland) and in the Xience Prime At 1 year of follow-up, there was no difference in the
(Abbott Vascular, Santa Clara, California) DP-DES composite outcomes of cardiac death, target vessel
(81 m m). MI, or ischemia-driven target lesion revasculariza-
Furthermore, our subgroup analysis of stent ma- tion. However, there was a trend toward less definite
terial comparing stainless steel or alloy scaffold or probable ST with the BuMA stent, which elutes
material of BP-DES to second-generation DP-DES and resorbs polymer more rapidly (0.5% vs 1.3%;
demonstrated no significant differences and overall p ¼ 0.048). In the present meta-analysis, we found no
comparable clinical outcomes (Table 2). difference in outcomes between BP-DES with poly-
The PANDA III (Comparison of BuMAeG Based mer degradation or drug release within <6 months
BioDegradable Polymer Stent versus EXCEL or $6 months and DP-DES (Table 2).
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 5, 2017
MARCH 13, 2017:462–73
DAPT DURATION, STENT PLATFORM, AND CLINICAL
IMPLICATIONS. The proposed rationale for devel-
opment of BP-DES is improved vascular healing in
the stented segment that would result in shorter
duration of DAPT. Based on the various polymer
and drug elution kinetics of the BP-DES, DAPT is
mandatory for a minimum duration that corre-
sponds to the time of complete drug release. This
period varies among BP-DES between 1 month
(Firehawk, MicroPort Scientific, Shanghai, China)
and 12 months (Orsiro). For instance, SYNERGY
(Boston Scientific, Natick, Massachusetts) is a BP-
DES that elutes everolimus over 3 months and
polymer degradation within 4 months. Accordingly,
patients enrolled in the EVOLVE II trial
compared SYNERGY to PROMUS were treated for
a minimum of 6 months of DAPT and shared
similar outcomes. This particular interest in addi-
tional shortening of DAPT will be studied in the
EVOLVE DAPT trial (NCT02605447) that is currently
enrolling patients at high risk of bleeding and will
be studying the safety of 3 months of DAPT
following SYNERGY. In the present meta-analysis,
different DAPT durations were used
the included studies and varied between a mini-
mum of 3 months and 12 months, but both patients
assigned to BP-DES and DP-DES were treated for a
similar DAPT period. Our data demonstrate that
whether treated for at least 6 months or 12 months
of DAPT, both stents exhibit similar rates of ST
(Figure 8).
Although the latest American College of Cardiol-
ogy/American Heart Association guidelines have
shortened the recommended DAPT in patients
with stable ischemic heart disease from 12 months
to 6 months following DES (Class I) (42), even
shorter DAPT duration might be safe following
specific BP-DES. Hence, BP-DES might be of value
in patients at high risk of bleeding who present
with complex lesions. These patients might not
tolerate DAPT as long as 6 months and can still
benefit from the superior profile of BP-DES over
BMS. In aggregate, the results on the present meta-
analysis demonstrating comparable performance
of BP-DES and DP-DES allow us to tailor our
therapy with the stent of choice for the appro-
priate patient taking into consideration bleeding
risk, patient compliance, and underlying lesion
complexity.
STUDY LIMITATIONS. As in any meta-analysis, our
study is limited by the design and the quality of the
selected trials. Different BP-DES platforms were used
in this analysis. Nevertheless, we attempted to
El-Hayek et al. 471
Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy
overcome these differences by performing subgroup
analysis based on BP-DES drug elution characteris-
tics, strut thickness, and scaffold material. Another
potential limitation of the present analysis is that
data on very late ST was only available from 6 RCTs
(11,866 patients), and the mean follow-up duration
was only 26 months, which might not be sufficient to
detect differences in rare outcomes such as late ST.
Larger populations and longer duration of follow-up
are required for this studied outcome to reach sta-
tistical significance. Finally, this is a study-level and
not a patient-level meta-analysis, and therefore,
differences in the impact of clinical presentations,
risk factors, and pharmacotherapy could not be
that assessed.
CONCLUSIONS
In this large meta-analysis comparing BP-DES to the
second-generation DP-DES to date, we found no sig-
nificant differences in TVR, ST, MI, or cardiac death
between the 2 platforms, suggesting similar safety and
efficacy.
in
ADDRESS FOR CORRESPONDENCE: Dr. Habib
Samady, Emory University School of Medicine, 1364
Clifton Road F622, Atlanta, Georgia 30322. E-mail:
hsamady@emory.edu.
PERSPECTIVES
WHAT IS KNOWN? Delayed endothelial healing secondary
to durable polymer is one of the mechanisms of late stent
failure. DES with biodegradable-polymer were developed
and showed superior profiles compared with BMS and
first-generation DP-DES.
WHAT IS NEW? Compared with second-generation DP-DES,
BP-DES share a similar safety and efficacy profile. We found no
significant differences in TVR late ST between second-generation
DP-DES and BP-DES, even after accounting for stent character-
istics such as strut thickness, antiproliferative drug, drug elution
kinetics, and DAPT.
WHAT IS NEXT? More clinical trials comparing BP-DES
to second-generation DP-DES focused on short-term DAPT
and powered by a long duration of follow-up and a large
population, are needed to tailor therapy with the stent of
choice for the appropriate patient taking into consideration
bleeding risk, patient compliance, and underlying lesion
complexity.
472 El-Hayek et al.
Biodegradable Polymer Drug-Eluting Stent Safety and Efficacy
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KEY WORDS biodegradable polymer,
drug-eluting stent(s), durable polymer,
meta-analysis
A PP END IX For a supplemental table, please
see the online version of this article.