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Polymer is a key component of drug-eluting stent (DES) platforms and controls the kinetics of drug release. Because bare-metal scaff olds generally do not have long-term eff ects on the vessel wall, eff orts to improve safety of DES platforms have mainly focused on changes to the polymer coating. Moving from the fi rst-generation polyethylene-co-vinyl acetate and poly n-butyl methacrylate-based permanent polymer DES (eg, Cypher) to the thinner-layer fl uorocopolymer-based everolimus-eluting stent (eg, Xience) substantially improved safety outcomes after DES implantation.1,2 However, the chronic infl ammatory process in the vessel wall, which seems to be related to permanent polymer coatings on the stent strut surface, might promote neoatheroslerosis within the stented segment.3 There fore, another solution to achieve drug release from DES platforms is needed.

The use of a biodegradable polymer to control drug release from the DES surface has been associated with earlier endothelialisation of stent struts and better preserved endothelium-dependent vasomotion of stented arteries than with the use of fi rst-generation

perma nent polymer DES.4,5 In particular, better long-term clinical outcomes were reported with a biodegradable polymer sirolimus-eluting stent (the Yukon Choice stent backbone, Translumina, Hechingen, Germany) and a biodegradable polymer umirolimus (commonly known as biolimus)-eluting stent (BioMatrix Flex stent, Biosensor Inc, New Port Beach, CA, USA) than with the Cypher stent.6

In the eagerly awaited COMPARE II trial, published in The Lancet, Pieter Cornelis Smits and colleagues7 have compared, for the fi rst time, a biodegradable polymer biolimus-eluting stent (Nobori, Terumo, Tokyo, Japan) with a second-generation permanent polymer-based everolimus-eluting stent (Xience V or Prime, Abbott Vascular, Santa Clara, CA, USA, or Promus, Boston Scientifi c, Natick, MA, USA). After 1 year, the combined safety and effi cacy endpoint of cardiac death, non-fatal myocardial infarction, and clinically indicated target vessel revascularisation (primary endpoint) had occurred in 93 (5·2%) of 1795 patients randomly assigned to receive the biolimus-eluting stent and 44 (4·8%) of 912 patients assigned to receive the everolimus-eluting stent. Since

Degradable polymer drug-eluting stents: a durable benefi t?

all the trials of CABG versus PCI. The investigators2 estimate that currently about two-thirds of patients with complex coronary artery disease are best treated with CABG. SYNTAX will continue to shape both clinical practice and guidelines and should, by emphasising that treatment recommendations need to be made by a heart team rather than an individual practitioner, ensure the most appropriate interventional strategy for individual patients.

David P TaggartNuffi eld Department of Surgical Sciences, Oxford University, John Radcliff e Hospital, Oxford OX3 9DU, UKdavid.taggart@ouh.nhs.uk

I act as adviser to Medtronic, VGS, and Novadaq and have received speaker’s fees from each. I received a speaker’s fee for presenting an overview of CABG versus stents at the European Association for Cardio-Thoracic Surgery annual meeting, 2012. I have taken part in many international debates on this topic for which travel and accommodation fees have been sponsored by the relevant societies.

1 Taggart DP. Thomas B Ferguson Lecture. Coronary artery bypass grafting is still the best treatment for multivessel and left main disease, but patients need to know. Ann Thorac Surg 2006; 82: 1966–75.

2 Mohr FW, Morice M-C, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013; 381: 629–38.

3 Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet 2013; 381: 639–50.

4 Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI), et al. Guidelines on myocardial revascularization. Eur J Cardiothorac Surg 2010; 38 (suppl): S1–52.

5 Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011; 58: e123–210.

6 Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012; 367: 2375–84.

7 Weintraub WS, Grau-Sepulveda MV, Weiss JM, et al. Comparative eff ectiveness of revascularization strategies. N Engl J Med 2012; 366: 1467–76.

8 Taggart DP, D’Amico R, Altman DG. Eff ect of arterial revascularisation on survival: a systematic review of studies comparing bilateral and single internal mammary arteries. Lancet 2001; 358: 870–75.

9 Trikalinos TA, Alsheikh-Ali AA, Tatsioni A, Nallamothu BK, Kent DM. Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis. Lancet 2009; 373: 911–18.

10 Pursnani S, Korley F, Gopaul R, et al. Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials. Circ Cardiovasc Interv 2012; 5: 476–90.

11 Farooq V, Vergouwe Y, Räber L, et al. Combined anatomical and clinical factors for the long-term risk stratifi cation of patients undergoing percutaneous coronary intervention: the logistic clinical SYNTAX score. Eur Heart J 2012; 33: 3098–104.

Published OnlineJanuary 30, 2013http://dx.doi.org/10.1016/S0140-6736(12)62193-X

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Comment

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the absolute diff erence in the primary endpoint was below the assumed non-inferiority margin of 4% (delta 0·36%, pnon-inferiority<0·0001), the biodegradable polymer biolimus-eluting stent was proven to be non-inferior to the permanent polymer everolimus-eluting stent.

Although 2707 patients were enrolled as planned, the power of the study was attenuated because not only was the primary endpoint event rate nearly 50% lower than the 9·5% event rate assumed in the sample size calculation, but it was also very similar to the prespecifi ed non-inferiority margin. This lower than expected incidence of the primary endpoint has affl icted many other randomised trials in interventional cardiology.8,9 This result clearly emphasises the increased safety and effi cacy of contemporary percutaneous coronary intervention due to extensive use of improved DES platforms, more potent antiplatelet therapy, and the increasing ability of operators to make decisions and carry out intervention techniques.10–12

The lower than expected incidence of the primary end-point in COMPARE II was arguably largely driven by a low incidence of myocardial infarction—a result that might be partly explained by lesion complexity and the severity of patients’ cardiovascular risk profi les.13,14 Only 26% of eligible patients were randomly assigned to a treatment group in this trial, refl ecting the very selective eligibility criteria. By contrast, in the all-comer TWENTE trial,15 the frequency of myocardial infarction after implantation of a permanent polymer everolimus-eluting stent was 4·6% (compared with 2·5% in COMPARE II). Similarly, more patients in the all-comer LEADERS trial16 who under went implantation of a similar biodegradable polymer biolimus-eluting stent (BioMatrix Flex) to that used in COMPARE II had myocardial infarction than did those in COMPARE II who received the biolimus-eluting stent (4·6% vs 2·8%, respectively). Additionally, during the past decade the defi nition of peri-interventional myocardial infarction has evolved, and now takes into account more sensitive cardiac markers such as troponin.17 Especially in the case of COMPARE II, in which 25% of patients presented with a totally or subtotally occluded target vessel (compared with 16% in TWENTE15 and 20% in LEADERS16), the eff ect of the myocardial infarction defi nition used on the reported frequencies of the event cannot be ruled out.

Severity of coronary artery disease and the extent of routine angiographical follow-up after percutaneous

coronary intervention aff ect the incidence of repeat revascularisations in stent comparison trials. Smits and colleagues reported similar target vessel revascularisation (TVR) and target lesion revascularisation (TLR) rates at 1 year in the biolimus-eluting stent group (TVR, 3·7% and TLR, 2·7%), as have previously published trials.15,18 These rates, compared with previously published registries and randomised studies,19,20 are the lowest reported TVR and TLR rates of all biodegradable polymer-based DES platforms assessed in randomised trials;16,21 the cumulative incidence of TLR was 10·9% in the biodegradable polymer sirolimus-eluting stent group in the ISAR-TEST 4 trial21 and 5·4% in the biodegradable polymer biolimus-eluting stent (BioMatrix Flex) group in the LEADERS trial.16 These fi ndings refl ect the diff erences in routine angiographical follow-up rates of various trials—80% in ISAR-TEST 4, 20% in LEADERS, and 0% in COMPARE II—and the diff erences in angiographic characteristics such as vessel size and lesion length. The unavailability of some sizes of the biolimus-eluting Nobori stent—due to manufacturing reasons—would have defi nitely aff ected whether the COMPARE II investigators treated larger coronary vessels (mean size of all vessels was 2·9 mm) to a greater extent than in other studies (mean vessel size 2·6–2·8 mm) that did not use the Nobori stent.

Are the incidences of late catch-up restenosis and late stent thrombosis decreasing as more bio-degradable polymer DES platforms are used? In two meta-analyses of randomised controlled trials,2,6 at 4 year follow-up the risk for TLR was reduced by nearly 20% with second-generation biodegradable polymer DES and permanent polymer everolimus-eluting stents compared with the fi rst-generation Cypher stent. Additionally, a substantial reduction in very late stent thrombosis with both the second-generation permanent polymer everolimus-eluting stent (50%) and biodegradable polymer DES (80%) compared with the Cypher stent was reported.5,15 2 year follow-up data from the NOBORI 2 registry19 showing a remarkably low 0·1% defi nite stent thrombosis rate 1–2 years after implantation of the Nobori stent is very promising. However, large numbers of patients are needed to assess diff erences in rare events. Data from the ISAR-TEST 6 trial (n=2010; NCT01068106) coming later in 2013 will help to address this issue.

The COMPARE II investigators should be congratu-lated for comparing the biodegradable polymer

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More than 10 years after publication of the fi rst random-ised trial to assess drug-eluting stents (DES) in patients with coronary artery disease,1 many studies have helped to clarify the advantages and limitations of fi rst-generation DES. Despite having high antirestenotic effi cacy in the fi rst year after implantation, fi rst-gener-ation DES are associated with a delayed healing eff ect, leading to increased risk of late stent thrombosis2 and a decrease in antirestenotic effi cacy over time,3 which has aff ected acceptance and stimulated the search for better successors. Polymers have become the main focus of the

drawbacks associated with fi rst-generation DES. For this reason, research eff orts have been directed at improve-ment in biocompatibility of permanent polymers, the use of biodegradable polymer coatings that disappear over time, and the development of DES completely bereft of polymer.

However, direct evidence that implicates polymers in the delayed healing eff ect of DES is scarce. An animal study4 compared biodegradable with permanent polymer-coated stents eluting sirolimus; the biodegradable polymer-based DES showed more durable effi cacy,

SORT OUT V: a new episode in the DES wars

biolimus-eluting Nobori stent with the benchmark second-generation permanent polymer-based evero-limus-eluting stent. They should be encouraged to follow-up COMPARE II patients for up to 5 years, because the hypothesised advantage of biodegradable polymer DES is that non-inferiority at 1 year should transform into long-term clinical superiority over durable polymer DES. Only then can we be certain that a stent with a disappearing polymer provides lasting clinical benefi t for patients treated in routine practice.

Julinda MehilliKlinikum der Universitaet Munich, Medizinische Klinik I, Campus Grosshadern, 81377 Munich, Germanyjulinda.mehilli@med.uni-muenchen.de

JM has received lecture fees from Abbott Vascular, Terumo, Translumina, Lilly/Daiichi Sankyo, and The Medicines Company.

1 Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012; 379: 1393–402.

2 de Waha A, Cassese S, Park DW, et al. Everolimus-eluting versus sirolimus-eluting stents: an updated meta-analysis of randomized trials. Clin Res Cardiol 2012; 101: 461–67.

3 Nakazawa G, Vorpahl M, Finn AV, Narula J, Virmani R. One step forward and two steps back with drug-eluting-stents: from preventing restenosis to causing late thrombosis and nouveau atherosclerosis. JACC Cardiovasc Imaging 2009; 2: 625–28.

4 Hamilos MI, Ostojic M, Beleslin B, et al. Diff erential eff ects of drug-eluting stents on local endothelium-dependent coronary vasomotion. J Am Coll Cardiol 2008; 51: 2123–29.

5 Barlis P, Regar E, Serruys PW, et al. An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: a LEADERS trial sub-study. Eur Heart J 2010; 31: 165–76.

6 Stefanini GG, Byrne RA, Serruys PW, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012; 33: 1214–22.

7 Smits PC, Hofma S, Togni M, et al. Abluminal biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent (COMPARE II): a randomised, controlled, non-inferiority trial. Lancet 2013; published online Jan 30. http://dx.doi.org/10.1016/S0140-6736(12)61852-2.

8 Raber L, Kelbaek H, Ostojic M, et al. Eff ect 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 2012; 308: 777–87.

9 Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305: 1097–105.

10 Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study: old, new, and evolving strategies. Circulation 2010; 121: 1235–43.

11 Tonino PA, De Bruyne B, Pijls NH, et al. Fractional fl ow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009; 360: 213–24.

12 Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15.

13 Kastrati A, Neumann FJ, Schulz S, et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 2011; 365: 1980–89.

14 Mehilli J, Pache J, Abdel-Wahab M, et al. Drug-eluting versus bare-metal stents in saphenous vein graft lesions (ISAR-CABG): a randomised controlled superiority trial. Lancet 2011; 378: 1071–78.

15 von Birgelen C, Basalus MW, Tandjung K, et al. A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: the TWENTE trial. J Am Coll Cardiol 2012; 59: 1350–61.

16 Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008; 372: 1163–73.

17 Thygesen K, Alpert JS, Jaff e AS, et al. Third universal defi nition of myocardial infarction. Circulation 2012; 126: 2020–35.

18 Serruys PW, Silber S, Garg S, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010; 363: 136–46.

19 Danzi GB, Chevalier B, Urban P, et al, for the NOBORI 2 investigators. Clinical performance of a drug-eluting stent with a biodegradable polymer in an unselected patient population: the NOBORI 2 study. EuroIntervention 2012; 8: 109–16.

20 Chevalier B, Silber S, Park SJ, et al, for the NOBORI 1 clinical investigators. Randomized comparison of the Nobori biolimus A9-eluting coronary stent with the Taxus Liberté paclitaxel-eluting coronary stent in patients with stenosis in native coronary arteries: the NOBORI 1 trial—phase 2. Circ Cardiovasc Interv 2009; 2: 188–95.

21 Byrne RA, Kastrati A, Kufner S, et al. Randomized, non-inferiority trial of three limus agent-eluting stents with diff erent polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Effi cacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial. Eur Heart J 2009; 30: 2441–49.

Published OnlineJanuary 30, 2013http://dx.doi.org/10.1016/S0140-6736(13)60055-0

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