Editorial Comment

Creating Biodegradable-PolymerDrug-Eluting Stents: Shorteningthe Duration of Polymer and DualAntiplatelet Therapy WhileLengthening the Follow-Up

Ahmed Abdel-Latif, MD, MSPH andDavid J. Moliterno,* MD

Division of Cardiovascular MedicineGill Heart Institute and University of KentuckyLexington, Kentucky

The field of percutaneous coronary intervention(PCI) has gone through major revolutions over the lasttwo decades, and presently drug-eluting stents (DES)represent the best of what real-world practice has tooffer. DES have reduced major adverse cardiac eventrates (MACE) near exclusively by reducing the ratesof repeat target vessel revascularization (TVR) [1].However, the delayed endothelialization associatedwith DES has lead to increased rates of late stentthrombosis (ST), particularly with first-generation DESand in complex lesion subsets [2]. The etiology behindST is multifactorial with the possibility that the dura-ble polymer used to hold and release the antiprolifera-tive drug results in chronic arterial wall inflammationand neoatherosclerosis. Therefore, there is growing in-terest in designing stents with biodegradable-polymersthat may overcome this potential shortcoming of dura-ble-polymer DES.

The LEADERS (Limus Eluted from A Durable ver-sus Erodable Stent coating) trial was the first large (N5 1,707) randomized study to examine a biodegrad-able-polymer biolimus-eluting stent (BES) versus adurable-polymer sirolimus-eluting stent (SES) amongpatients with coronary artery disease. The studyshowed non-inferiority of the BES stent at 9-month aswell as 4-year follow-up for the composite MACE ofcardiac death, myocardial infarction, or clinically indi-cated TVR [3]. Interestingly, BES use was associatedwith a lower incidence of very late ST but not early orlate ST, supporting a possible role of polymer-inducedarterial inflammation in the pathogenesis of ST–albeitvery late. The rate of late ST (after 1 month of stentimplantation) was suggested to be reduced with

biodegradable-polymer DES when compared to dura-ble-polymer DES in a pooled analysis of roughly7,000 patients [4], but the number of events is strik-ingly low. The ISAR-TEST-4 (Intracoronary Stentingand Angiographic Results—Test Efficacy of 3 Limus-Eluting STent) study that examined a biodegradable-polymer limus-eluting stent versus an everolimus-elut-ing stent (EES) and SES in a broad-inclusion settingalso did not detect differences in the primary endpoint(composite of cardiac death, TVR, and target vesselrelated myocardial infarction) or the rates of definiteand probable stent thrombosis [5]. These trends wereconfirmed by a large meta-analysis comparing durableand biodegradable-polymer DES studies as no differ-ence in the rate of revascularization was observed at1-year follow-up [6]. However, given the somewhatshort follow-up in the included studies, the meta-analy-sis may not have been able to detect differences in therate of ST.In this issue of Catheterization and Cardiovascular

Interventions, Han et al. [7] report the results of thelongest follow-up for the EXCEL Biodegradable Poly-mer Drug Eluting Stent (CREATE) study in a ‘‘realworld’’ setting. The study enrolled 2,077 patients whoreceived the EXCEL stent followed by 6 months ofdual antiplatelet therapy (DAPT), and the primaryendpoint was MACE (composite of cardiac death,non-fatal myocardial infarction, and TLR) while sec-ondary endpoints consisted of TLR and ST. At 36months, the overall MACE rate was relatively low at4.5%, and male gender and multiple stents were inde-pendent predictors of adverse outcome. The overallrate of definite or probable ST was 1%, and the rateof very late ST (occurring beyond 1 year) was low at0.35%, which is in agreement with other biodegrad-

Conflict of interest: Dr. Moliterno has received past honoraria for

serving on data-safety monitoring committees for stent manufac-

turers, including Boston-Scientific and Abbott.

*Correspondence to: David J. Moliterno, MD, Department of Cardi-

ovascular Medicine, University of Kentucky, 900 S. Limestone Ave-

nue, 317 Wethington Building, Lexington, KY 40536-0200; Tel.:

1859-323-5843. Fax: 1859-257-3537. E-mail: moliterno@uky.edu

Received 13 December 2011; Revision accepted 13 December 2011

DOI 10.1002/ccd.24294

Published online 20 January 2012 in Wiley Online Library

(wileyonlinelibrary.com).

' 2012 Wiley Periodicals, Inc.

Catheterization and Cardiovascular Interventions 79:217–218 (2012)

able-polymer DES studies [3–6]. Interestingly, thecontinuation of DAPT beyond 6 months was not ben-eficial in reducing MACE or ST. This is consistentwith the optical coherence tomography (OCT) obser-vations confirming early strut coverage with biode-gradable-polymer DES. Yet conclusions cannot befully certain since only 20% of patients continuedDAPT beyond 6 months, and this was not a random-ized comparison—suggesting the possibility for a biasin continuing clopidogrel in some patients.

The selection of the biodegradable polymer, includ-ing its rate of degradation leaving the bare metal scaf-fold, will be an important factor in designing futurebiodegradable-polymer DES as this may play a pivotalrole in predicting future events and the need for pro-longed DAPT. While the LEADERS trial mandated atleast 12 months of DAPT, the study by Han et al.observed no benefit of extending DAPT beyond 6months. Future studies are needed to examine the opti-mal polymers to achieve the balance between lowerrevascularization rates and risk of ST. The OCT sub-study of the LEADERS trial demonstrated earlier strutcoverage with the BES compared to SES at 9 monthwith similar strut coverage at 24 months [8]. Clearly,polymers vary in their degradation properties, and thestudy by Han et al. should be considered in this con-text. Furthermore, the rare nature of ST makes it chal-lenging for biodegradable-polymer stents to demon-strate superiority compared to durable-polymer DES,and the follow-up should be further extended. Theavailable data suggest that some of the differencesbetween durable and biodegradable-polymer DES maynot be seen until quite long-term follow-up. While theuse of biodegradable-polymer DES is appealing, it isyet to be established whether this platform will provesuperior to durable-polymer DES given the extremelylow rates of events noted with second-generation DESin recent trials [9]. At this stage, it is not certainwhether biodegradable-polymer DES present an evolu-tion to current stents, a revolution that will change ourmanagement of coronary artery disease, or neither.Certainly, any advancement decreasing the occurrenceof late ST or reducing the needed duration of DAPTwill be welcomed. Until then, more studies examiningdifferent biodegradable-polymers in multiple clinical

settings with particularly long-term follow-up areneeded.

REFERENCES

1. Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Scho-

mig A, Pfisterer ME, Stone GW, Leon MB, de Lezo JS, et al.

Outcomes associated with drug-eluting and bare-metal stents: A

collaborative network meta-analysis. Lancet 2007;370:937–948.

2. van Werkum JW, Heestermans AA, de Korte FI, Kelder JC, Sut-

torp MJ, Rensing BJ, Zwart B, Brueren BR, Koolen JJ, Dambrink

JH, et al. Long-term clinical outcome after a first angiographi-

cally confirmed coronary stent thrombosis: An analysis of 431

cases. Circulation 2009;119:828–834.

3. Stefanini GG, Kalesan B, Serruys PW, Heg D, Buszman P, Linke

A, Ischinger T, Klauss V, Eberli F, Wijns W, et al. Long-term

clinical outcomes of biodegradable polymer biolimus-eluting

stents versus durable polymer sirolimus-eluting stents in patients

with coronary artery disease (LEADERS): 4 year follow-up of a

randomised non-inferiority trial. Lancet 2011;378:1940–1948.

4. Salinas P, Moreno R, Jimenez-Valero S, Galeote G, Sanchez-

Recalde A, Plaza I, Lopez-Sendon J. Stent thrombosis did biode-

gradable polymers fail or are we too impatient? J Am Coll Car-

diol 2011;58:885–886; author reply 886–887.

5. Byrne RA, Kastrati A, Massberg S, Wieczorek A, Laugwitz KL,

Hadamitzky M, Schulz S, Pache J, Fusaro M, Hausleiter J, et al.

Biodegradable polymer versus permanent polymer drug-eluting

stents and everolimus- versus sirolimus-eluting stents in patients

with coronary artery disease: 3-year outcomes from a randomized

clinical trial. J Am Coll Cardiol 2011;58:1325–1331.

6. Ahmed TA, Bergheanu SC, Stijnen T, Plevier JW, Quax PH,

Jukema JW. Clinical performance of drug-eluting stents with bio-

degradable polymeric coating: A meta-analysis and systematic

review. EuroIntervention 2011;7:505–516.

7. Han Y, Jing Q, Li Y, Yang L, Liu H, Shang X, Jiang T, Li Z,

Zhang H, Yan G. Sustained clinical safety and efficacy of a

biodegradable-polymer coated sirolimus-eluting stent in ‘‘real-

world’’ practice: Three-year outcomes of the CREATE (multi-

center registry of EXCEL biodegradable polymer drug eluting

stents) study. Catheter Cardiovasc Interv 2012;79:211–216.

8. Gutierrez-Chico JL, Juni P, Garcia-Garcia HM, Regar E, Nuesch

E, Borgia F, van der Giessen WJ, Davies S, van Geuns RJ, Secco

GG, et al. Long-term tissue coverage of a biodegradable polylac-

tide polymer-coated biolimus-eluting stent: Comparative sequen-

tial assessment with optical coherence tomography until complete

resorption of the polymer. Am Heart J 2011;162:922–931.

9. Smits PC, Kedhi E, Royaards KJ, Joesoef KS, Wassing J, Rade-

maker-Havinga TA, McFadden E. 2-year follow-up of a random-

ized controlled trial of everolimus- and paclitaxel-eluting stents

for coronary revascularization in daily practice. COMPARE

(Comparison of the everolimus eluting XIENCE-V stent with the

paclitaxel eluting TAXUS LIBERTE stent in all-comers: A

randomized open label trial). J Am Coll Cardiol 2011;58:11–18.

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

218 Abdel-Latif and Moliterno