Canadian Journal of Cardiology 31 (2015) 957e959
Editorial
Biodegradable Stent Platforms: Are We Heading in the Right Direction? Shahar Lavi, MD,a and Vladimír Dzavík, MDb a b
London Health Sciences Centre and Western University, London, Ontario, Canada
Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
See article by Konishi et al., pages 980-988 of this issue. Since their inception, stents platforms have undergone continuous modifications.1 With earlier-generation stent platforms, coatings with biocompatible materials such as gold were used in an effort to reduce the inflammatory reaction induced by ion release from metallic stents, often without much success.2 With the introduction of the drug-eluting stent (DES), there was a need to use a thicker coating composed of a polymer to store and elute the drug over time. In first-generation and second-generation DESs that were available in North America, this polymer was nonbiodegradable. The persistent presence of the polymer, which is not useful after completion of the controlled release of the drug, delays healing, induces chronic inflammation, and results in incomplete re-endothelialization, all of which may lead to late cardiovascular events, in particular late stent thrombosis.3 The transition from first- to second-generation DESs included not only the use of thinner struts but also the development of durable polymers with greater biocompatibility, which may have played an important role in the improved results observed with these newer stents.4 Other alternatives in the development of stent platforms trying to mitigate the risks related to the polymer include a polymerfree surface or a polymer that is biodegradable. After the complete degradation of a biodegradable polymer, the remaining material is similar to a bare metal stent (BMS). Although there are theoretical advantages to a biodegradable polymer, there are also potential concerns. The design of the polymer should be such that its degradation will not have a negative effect on drug elution. In other words, the completeness of drug release should match or precede polymer degradation. Furthermore, there is little information regarding the healing process and inflammatory reaction after degradation of the polymer. Received for publication April 8, 2015. Accepted April 9, 2015. Corresponding author: Dr Shahar Lavi, Division of Cardiology, The University of Western Ontario, 339 Windermere Rd, PO Box 5339, London, Ontario N6A 5A5, Canada. Tel.: þ1-519-663-3611; fax: þ1-5190663-3117. E-mail: [email protected] See page 958 for disclosure information.
The Nobori biolimus A9-eluting stent (Terumo Europe, Leuven, Belgium) is a stainless steel alloy with a unique design that includes the biolimus A9 drug and a biodegradable polylactic acidebased polymer that coats only the abluminal side of the stent and that fully degrades into carbon dioxide and water 6-9 months after implantation.5 Theoretically, this design maximizes drug release into the vessel wall, and the absence of coating on the luminal surface allows for rapid endothelialization of the stent, thus decreasing the risk of stent thrombosis.6 Recently, Nakagawa et al.7 reported on the long-term healing of different types of first-generation DESs. Using optical coherence tomography (OCT), they found that the healing and stent coverage were variable among patients, and in particular that there was loss of stent coverage and less endothelialization in some of the paclitaxel-eluting stents. Their results alluded to the potential persistent risk that exists with earlier-generation DESs and the potential need for longer duration and perhaps lifelong dual-antiplatelet therapy.8 Results from the Dual Antiplatelet Therapy Study (DAPT), and in particular results from the subset of patients who received the TAXUS Liberte stent in The TAXUS Liberte Post Approval Study (TL-PAS), reconfirmed the ongoing risk in this group of patients.9,10 Ultimately, randomized trials are essential, but they are very resource intensive and take a long time to complete. When mechanistic and imaging study findings shed light on findings of clinical trials, they can later be used during the initial assessment of newer related technologies. Insights from OCT regarding vascular healing after stenting are invaluable. Furthermore, with improvement in stent platforms and resulting reduction of events, it becomes increasingly more difficult to demonstrate further reduction of events with newer technologies. Indeed, the large randomized trials with the Nobori stent were designed as noninferiority trials,5 and therefore it is important to shed light on the healing process of this stent. In this issue of the Canadian Journal of Cardiology, Konishi et al.11 report on vessel healing after stenting with the Nobori biolimus A9-eluting stent. Their findings regarding this newer-generation stent platform complement the previous report on healing after deployment of first-generation DESs.7
http://dx.doi.org/10.1016/j.cjca.2015.04.005 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
958
The authors describe serial OCT assessment in 17 patients receiving 22 biolimus-eluting stents (BESs) at 6, 12, and 24 months after stenting. They analyzed 500 OCT cross sections at each of these time points, matched according to anatomic landmarks. They describe imaging parameters such as stent strut coverage, ratio of covered stents, degree of unevenness of neointimal thickness, and degree of stent malapposition. Patients who discontinued dual-antiplatelet therapy during the first 6 months were excluded, unfortunately losing the opportunity to study the healing process without dualantiplatelet therapy (DAPT). They found a continuous increase in neointimal thickness without much effect on lumen loss. More important in terms of the potential risk for stent thrombosis, the percentage of stent struts that were uncovered continued to decrease over time. Only 1 stent (5%) was completely covered at 6 months, and this figure increased to 23% at 12 months and 82% at 24 months. Although these authors had previously reported short-term favorable healing after BES implantation, the long-term healing is more relevant, because improved long-term healing is the reason for this stent design. Indeed, at 24 months, on average, less than 1% of struts were uncovered. The biodegradable polymer DESs have been shown to be noninferior to the durable thin-strut second-generation DESs regarding clinical events within the first year after implantation when compared with the second-generation everolimuseluting DES, although interestingly not when compared with the first-generation sirolimus-eluting stent (SES).5,12,13 Stents with biodegradable polymer were developed with the hope of a reduction in stent thrombosis beyond 1 year. The randomized trials were not powered to show a difference in stent thrombosis within the first 12 months. Results from Limus Eluted From a Durable Versus Erodable Stent Coating (LEADERS), another study comparing a biodegradable to a durable polymer, suggest that if differences in the occurrence of stent thrombosis exist, they become apparent only later.14 OCT findings from LEADERS showed that stent coverage was more complete at 9 months with the BES compared with the SES.15 Although the use of biodegradable material appears intriguing, clinical trials provide inconsistent results, and a meta-analysis suggests that stents using newer durable polymers are at least as good as the biodegradable ones.16 Recently, the third-generation Resolute Integrity (Medtronic, Minneapolis, MN), composed of a durable polymer-coated zotarolimus-eluting stent, was found to be noninferior to the biodegradable polymer-based Biomatrix Flex (BIOSENSORS, Singapore) biolimus-eluting stent up to 12 months in The Scandinavian Organization for Randomized Trials with Clinical Outcome 6 (SORT OUT VI) trial.17 The potential advantage of an abluminally coated biodegradable polymer is better anatomic healing that includes more stent coverage and functional healing with a higher likelihood of normal vasomotion once the polymer has dissolved. Local endothelial-dependent vasomotion after implantation of coronary stents depends on the stent platform design, polymer, and drug. Three months after implantation, coronary vasodilator response remains abnormal in a large proportion of patients after implantation of either a biodegradable or durable DES.18 After 9-12 months, newergeneration DESs such as the biolimus A9-eluting and
Canadian Journal of Cardiology Volume 31 2015
zotarolimus-eluting stents demonstrate normal vasodilation, as opposed to the first-generation SES and paclitaxel-eluting stents.19 It is likely that the imaging OCT findings up to 24 months in the study by Konishi et al.11 represent nearly final healing of the Nobori stent regarding stent coverage. A recent study demonstrated full stent coverage of the Nobori stent in 91.6% of cases at 5 years compared with 63.6% after implantation of the first-generation SES. In contrast, coverage of BMSs was complete. The difference between BMSs and BESs may be related to patient selection or to differences in stent design, particularly strut thickness.20 With superior healing of the BES compared with previous-generation DESs, it is possible that shorter duration of DAPT may be a reasonable approach with this type of stent. However, this is yet to be proved. OCT follow-up adds important mechanistic dimension to the overall assessment of new-generation DESs, and therefore Konishi et al. should be commended for performing this meticulous study. They demonstrate continuous arterial healing after implantation of the Nobori BES at different time points after stent implantation, with excellent strut coverage at 2 years. The implications of this study include the need to verify arterial healing before the widespread use of new stent platforms. Serial imaging studies should be performed until acceptable and maintained healing is observed. Furthermore, OCT mechanistic substudies should be incorporated routinely into randomized clinical trials evaluating new stent platforms. Disclosures The authors have no conflicts of interest to disclose. References 1. Simard T, Hibbert B, Ramirez FD, et al. The evolution of coronary stents: a brief review. Can J Cardiol 2014;30:35-45. 2. Kastrati A, Schomig A, Dirschinger J, et al. Increased risk of restenosis after placement of gold-coated stents: results of a randomized trial comparing gold-coated with uncoated steel stents in patients with coronary artery disease. Circulation 2000;101:2478-83. 3. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202. 4. Stone GW, Midei M, Newman W, et al. Comparison of an everolimuseluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA 2008;299:1903-13. 5. 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;381:651-60. 6. Pendyala LK, Matsumoto D, Shinke T, et al. Nobori stent shows less vascular inflammation and early recovery of endothelial function compared with Cypher stent. JACC Cardiovasc Interv 2012;5:436-44. 7. Nakagawa M, Otake H, Shinke T, et al. Analysis by optical coherence tomography of long-term arterial healing after implantation of different types of stents. Can J Cardiol 2014;30:904-11. 8. Lavi S, Camuglia AC. Illuminating and alarming insights into vascular healing. Can J Cardiol 2014;30:855-7.
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9. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371: 2155-66.
15. 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.
10. Garratt KN, Weaver WD, Jenkins RG, et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel-eluting coronary stent placement. Circulation 2015;131:62-73.
16. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes with bioabsorbable polymer- versus durable polymer-based drug-eluting and bare-metal stents: evidence from a comprehensive network metaanalysis. J Am Coll Cardiol 2014;63:299-307.
11. Konishi A, Shinke T, Otake H, et al. Serial optical coherence tomography evaluation at 6, 12, and 24 months after biolimus A9-eluting biodegradable polymer-coated stent implantation. Can J Cardiol 2015;31:980-8
17. Raungaard B, Jensen LO, Tilsted HH, et al. Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradablepolymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial. Lancet 2015;385:1527-35.
12. Natsuaki M, Kozuma K, Morimoto T, et al. Biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent: a randomized, controlled, noninferiority trial. J Am Coll Cardiol 2013;62: 181-90. 13. Christiansen EH, Jensen LO, Thayssen P, et al. Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial. Lancet 2013;381:661-9. 14. Stefanini GG, Kalesan B, Serruys PW, 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;378:1940-8.
18. Karjalainen PP, Varho V, Nammas W, et al. Early neointimal coverage and vasodilator response following biodegradable polymer sirolimuseluting vs. durable polymer zotarolimus-eluting stents in patients with acute coronary syndrome. Circulation 2015;79:360-7. 19. Hamilos M, Sarma J, Ostojic M, et al. Interference of drug-eluting stents with endothelium-dependent coronary vasomotion: evidence for devicespecific responses. Circulation 2008;1:193-200. 20. Kuramitsu S, Sonoda S, Yokoi H, et al. Long-term coronary arterial response to biodegradable polymer biolimus-eluting stents in comparison with durable polymer sirolimus-eluting stents and bare-metal stents: fiveyear follow-up optical coherence tomography study. Atherosclerosis 2014;237:23-9.
Editorial
Biodegradable Stent Platforms: Are We Heading in the Right Direction? Shahar Lavi, MD,a and Vladimír Dzavík, MDb a b
London Health Sciences Centre and Western University, London, Ontario, Canada
Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
See article by Konishi et al., pages 980-988 of this issue. Since their inception, stents platforms have undergone continuous modifications.1 With earlier-generation stent platforms, coatings with biocompatible materials such as gold were used in an effort to reduce the inflammatory reaction induced by ion release from metallic stents, often without much success.2 With the introduction of the drug-eluting stent (DES), there was a need to use a thicker coating composed of a polymer to store and elute the drug over time. In first-generation and second-generation DESs that were available in North America, this polymer was nonbiodegradable. The persistent presence of the polymer, which is not useful after completion of the controlled release of the drug, delays healing, induces chronic inflammation, and results in incomplete re-endothelialization, all of which may lead to late cardiovascular events, in particular late stent thrombosis.3 The transition from first- to second-generation DESs included not only the use of thinner struts but also the development of durable polymers with greater biocompatibility, which may have played an important role in the improved results observed with these newer stents.4 Other alternatives in the development of stent platforms trying to mitigate the risks related to the polymer include a polymerfree surface or a polymer that is biodegradable. After the complete degradation of a biodegradable polymer, the remaining material is similar to a bare metal stent (BMS). Although there are theoretical advantages to a biodegradable polymer, there are also potential concerns. The design of the polymer should be such that its degradation will not have a negative effect on drug elution. In other words, the completeness of drug release should match or precede polymer degradation. Furthermore, there is little information regarding the healing process and inflammatory reaction after degradation of the polymer. Received for publication April 8, 2015. Accepted April 9, 2015. Corresponding author: Dr Shahar Lavi, Division of Cardiology, The University of Western Ontario, 339 Windermere Rd, PO Box 5339, London, Ontario N6A 5A5, Canada. Tel.: þ1-519-663-3611; fax: þ1-5190663-3117. E-mail: [email protected] See page 958 for disclosure information.
The Nobori biolimus A9-eluting stent (Terumo Europe, Leuven, Belgium) is a stainless steel alloy with a unique design that includes the biolimus A9 drug and a biodegradable polylactic acidebased polymer that coats only the abluminal side of the stent and that fully degrades into carbon dioxide and water 6-9 months after implantation.5 Theoretically, this design maximizes drug release into the vessel wall, and the absence of coating on the luminal surface allows for rapid endothelialization of the stent, thus decreasing the risk of stent thrombosis.6 Recently, Nakagawa et al.7 reported on the long-term healing of different types of first-generation DESs. Using optical coherence tomography (OCT), they found that the healing and stent coverage were variable among patients, and in particular that there was loss of stent coverage and less endothelialization in some of the paclitaxel-eluting stents. Their results alluded to the potential persistent risk that exists with earlier-generation DESs and the potential need for longer duration and perhaps lifelong dual-antiplatelet therapy.8 Results from the Dual Antiplatelet Therapy Study (DAPT), and in particular results from the subset of patients who received the TAXUS Liberte stent in The TAXUS Liberte Post Approval Study (TL-PAS), reconfirmed the ongoing risk in this group of patients.9,10 Ultimately, randomized trials are essential, but they are very resource intensive and take a long time to complete. When mechanistic and imaging study findings shed light on findings of clinical trials, they can later be used during the initial assessment of newer related technologies. Insights from OCT regarding vascular healing after stenting are invaluable. Furthermore, with improvement in stent platforms and resulting reduction of events, it becomes increasingly more difficult to demonstrate further reduction of events with newer technologies. Indeed, the large randomized trials with the Nobori stent were designed as noninferiority trials,5 and therefore it is important to shed light on the healing process of this stent. In this issue of the Canadian Journal of Cardiology, Konishi et al.11 report on vessel healing after stenting with the Nobori biolimus A9-eluting stent. Their findings regarding this newer-generation stent platform complement the previous report on healing after deployment of first-generation DESs.7
http://dx.doi.org/10.1016/j.cjca.2015.04.005 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
958
The authors describe serial OCT assessment in 17 patients receiving 22 biolimus-eluting stents (BESs) at 6, 12, and 24 months after stenting. They analyzed 500 OCT cross sections at each of these time points, matched according to anatomic landmarks. They describe imaging parameters such as stent strut coverage, ratio of covered stents, degree of unevenness of neointimal thickness, and degree of stent malapposition. Patients who discontinued dual-antiplatelet therapy during the first 6 months were excluded, unfortunately losing the opportunity to study the healing process without dualantiplatelet therapy (DAPT). They found a continuous increase in neointimal thickness without much effect on lumen loss. More important in terms of the potential risk for stent thrombosis, the percentage of stent struts that were uncovered continued to decrease over time. Only 1 stent (5%) was completely covered at 6 months, and this figure increased to 23% at 12 months and 82% at 24 months. Although these authors had previously reported short-term favorable healing after BES implantation, the long-term healing is more relevant, because improved long-term healing is the reason for this stent design. Indeed, at 24 months, on average, less than 1% of struts were uncovered. The biodegradable polymer DESs have been shown to be noninferior to the durable thin-strut second-generation DESs regarding clinical events within the first year after implantation when compared with the second-generation everolimuseluting DES, although interestingly not when compared with the first-generation sirolimus-eluting stent (SES).5,12,13 Stents with biodegradable polymer were developed with the hope of a reduction in stent thrombosis beyond 1 year. The randomized trials were not powered to show a difference in stent thrombosis within the first 12 months. Results from Limus Eluted From a Durable Versus Erodable Stent Coating (LEADERS), another study comparing a biodegradable to a durable polymer, suggest that if differences in the occurrence of stent thrombosis exist, they become apparent only later.14 OCT findings from LEADERS showed that stent coverage was more complete at 9 months with the BES compared with the SES.15 Although the use of biodegradable material appears intriguing, clinical trials provide inconsistent results, and a meta-analysis suggests that stents using newer durable polymers are at least as good as the biodegradable ones.16 Recently, the third-generation Resolute Integrity (Medtronic, Minneapolis, MN), composed of a durable polymer-coated zotarolimus-eluting stent, was found to be noninferior to the biodegradable polymer-based Biomatrix Flex (BIOSENSORS, Singapore) biolimus-eluting stent up to 12 months in The Scandinavian Organization for Randomized Trials with Clinical Outcome 6 (SORT OUT VI) trial.17 The potential advantage of an abluminally coated biodegradable polymer is better anatomic healing that includes more stent coverage and functional healing with a higher likelihood of normal vasomotion once the polymer has dissolved. Local endothelial-dependent vasomotion after implantation of coronary stents depends on the stent platform design, polymer, and drug. Three months after implantation, coronary vasodilator response remains abnormal in a large proportion of patients after implantation of either a biodegradable or durable DES.18 After 9-12 months, newergeneration DESs such as the biolimus A9-eluting and
Canadian Journal of Cardiology Volume 31 2015
zotarolimus-eluting stents demonstrate normal vasodilation, as opposed to the first-generation SES and paclitaxel-eluting stents.19 It is likely that the imaging OCT findings up to 24 months in the study by Konishi et al.11 represent nearly final healing of the Nobori stent regarding stent coverage. A recent study demonstrated full stent coverage of the Nobori stent in 91.6% of cases at 5 years compared with 63.6% after implantation of the first-generation SES. In contrast, coverage of BMSs was complete. The difference between BMSs and BESs may be related to patient selection or to differences in stent design, particularly strut thickness.20 With superior healing of the BES compared with previous-generation DESs, it is possible that shorter duration of DAPT may be a reasonable approach with this type of stent. However, this is yet to be proved. OCT follow-up adds important mechanistic dimension to the overall assessment of new-generation DESs, and therefore Konishi et al. should be commended for performing this meticulous study. They demonstrate continuous arterial healing after implantation of the Nobori BES at different time points after stent implantation, with excellent strut coverage at 2 years. The implications of this study include the need to verify arterial healing before the widespread use of new stent platforms. Serial imaging studies should be performed until acceptable and maintained healing is observed. Furthermore, OCT mechanistic substudies should be incorporated routinely into randomized clinical trials evaluating new stent platforms. Disclosures The authors have no conflicts of interest to disclose. References 1. Simard T, Hibbert B, Ramirez FD, et al. The evolution of coronary stents: a brief review. Can J Cardiol 2014;30:35-45. 2. Kastrati A, Schomig A, Dirschinger J, et al. Increased risk of restenosis after placement of gold-coated stents: results of a randomized trial comparing gold-coated with uncoated steel stents in patients with coronary artery disease. Circulation 2000;101:2478-83. 3. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202. 4. Stone GW, Midei M, Newman W, et al. Comparison of an everolimuseluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA 2008;299:1903-13. 5. 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;381:651-60. 6. Pendyala LK, Matsumoto D, Shinke T, et al. Nobori stent shows less vascular inflammation and early recovery of endothelial function compared with Cypher stent. JACC Cardiovasc Interv 2012;5:436-44. 7. Nakagawa M, Otake H, Shinke T, et al. Analysis by optical coherence tomography of long-term arterial healing after implantation of different types of stents. Can J Cardiol 2014;30:904-11. 8. Lavi S, Camuglia AC. Illuminating and alarming insights into vascular healing. Can J Cardiol 2014;30:855-7.
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9. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371: 2155-66.
15. 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.
10. Garratt KN, Weaver WD, Jenkins RG, et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel-eluting coronary stent placement. Circulation 2015;131:62-73.
16. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes with bioabsorbable polymer- versus durable polymer-based drug-eluting and bare-metal stents: evidence from a comprehensive network metaanalysis. J Am Coll Cardiol 2014;63:299-307.
11. Konishi A, Shinke T, Otake H, et al. Serial optical coherence tomography evaluation at 6, 12, and 24 months after biolimus A9-eluting biodegradable polymer-coated stent implantation. Can J Cardiol 2015;31:980-8
17. Raungaard B, Jensen LO, Tilsted HH, et al. Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradablepolymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial. Lancet 2015;385:1527-35.
12. Natsuaki M, Kozuma K, Morimoto T, et al. Biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent: a randomized, controlled, noninferiority trial. J Am Coll Cardiol 2013;62: 181-90. 13. Christiansen EH, Jensen LO, Thayssen P, et al. Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial. Lancet 2013;381:661-9. 14. Stefanini GG, Kalesan B, Serruys PW, 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;378:1940-8.
18. Karjalainen PP, Varho V, Nammas W, et al. Early neointimal coverage and vasodilator response following biodegradable polymer sirolimuseluting vs. durable polymer zotarolimus-eluting stents in patients with acute coronary syndrome. Circulation 2015;79:360-7. 19. Hamilos M, Sarma J, Ostojic M, et al. Interference of drug-eluting stents with endothelium-dependent coronary vasomotion: evidence for devicespecific responses. Circulation 2008;1:193-200. 20. Kuramitsu S, Sonoda S, Yokoi H, et al. Long-term coronary arterial response to biodegradable polymer biolimus-eluting stents in comparison with durable polymer sirolimus-eluting stents and bare-metal stents: fiveyear follow-up optical coherence tomography study. Atherosclerosis 2014;237:23-9.
