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Vascular restoration: Is there a window of opportunity?
Medical Hypotheses 85 (2015) 972–975
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Vascular restoration: Is there a window of opportunity? Jianhua Sun ⇑, Xiaoran Kang, Tianzhu Li Tianjin Advanced Laboratory for Interventional Medical Devices, Tianjin 300457, China
a r t i c l e
i n f o
Article history: Received 22 October 2014 Accepted 30 August 2015
a b s t r a c t The usage of drug eluting stents (DES) has markedly reduced the rates of coronary revascularization procedures compared with bare metal stents (BMS). However, this technology still faces challenges in terms of the prevention of late stent thrombosis, major adverse cardiac events (MACE) progression, and the catch-up phenomenon of restenosis. Restoration of endothelial function upon after stenting, therefore, is the key to mitigating the risk of these toxicities and determining the level of the efficacy and safety of an implant. Review of the clinical studies of multiple DES, has suggested that there exists a window of opportunity, within the first two to three months after stent implantation, for restoring vascular function. If re-endothelialization reaches sufficient level within this period, vascular restoration can occur; however, if this opportunity is missed, re-endothelialization is unlikely to reach the level of endothelial maturation necessary to prevent the late stent thrombosis, MACE progression and the catch-up on restenosis. This hypothesis could aid in explaining variable clinical responses for revascularization treatments such as plain old balloon angioplasty (POBA), BMS, or DES. Patients could be grouped according to responses to the different treatment modalities: for Type 1 patients, POBA is sufficient and safe because they possess the capacity with effective endothelial response; for Type 2 patients, re-endothelialization occurs within the window but BMS are needed to maintain the arterial lumen open; for Type 3 individuals, overly accelerated vascular smooth muscle proliferation render sufficient re-endothelialization impossible. Designing based on this principle predicts that the next technology advancement for the interventional cardiology will not be biodegradable DES by default, but rather a DES that can spur early restoration of the endothelial function within the window period. Ó 2015 Elsevier Ltd. All rights reserved.
Background The introduction of drug eluting stents (DES) in the early 2000s markedly reduced the rates of coronary revascularization procedures compared with bare metal stents (BMS). Restenosis was lowered from 35.4% to 3.2% with the usage of DES in the first year [1]. However, the massive introduction of DES revealed two major challenges: the phenomenon of late thrombosis after stent implantation [2] and continued presence restenosis (catch-up) in select patient subgroups [3]. With usage of DES, numerous cases of arterial thrombosis were reported after interruption of dual anti-platelet therapy (DAPT), leading to current guidelines to recommend DAPT for several months to year post stenting. Through extensive research [4–6], poor re-endothelialization of the first generation DES was identified as the main cause for this late stage complication. As a result,
⇑ Corresponding author at: Tianjin Advanced Laboratory for Interventional Medical Devices, 2nd Floor, Building B, TEDA Biopharm Res, #5, 4th St, TEDA, Tianjin 300457, China. Tel.: +86 22 59993327; fax: +86 22 62000060. E-mail address: [email protected] (J. Sun). http://dx.doi.org/10.1016/j.mehy.2015.08.024 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
the level of stent coverage could be as an indicator of the risk of late stent thrombosis [5]. Late stage restenosis was also reported as associated with DES usage. This phenomenon was reported for both first and second generation DES [3,7]. The SPIRIT II trial, reported that the lumen loss for Xience VTM increased substantially from 6 months to 2 years (0.17 ± 0.32 to 0.33 ± 0.37 mm respectively). As a consequence of these first clinical results, second generation DES were introduced with thinner struts, lower dosage of anti-proliferative drugs, and more biocompatible polymer coatings than the first generation products [8]. However, even within this generation DES, significant long term complications were noted to occur. Four year results for the Resolute All Comers Trial showed 2–3% annual increase of target lesion failure (TLF) both for zotarolimus eluting stent (Endeavor ResoluteTM) and everolimus eluting stent (Xience VTM) patient populations [9]. The Leaders ‘‘All Comers” clinical trial demonstrated that the BioMatrix FlexTM, a newer biolimus eluting stent (BES) with a biodegradable abluminal polylactic acid coating, reduced the incidence of very late stent thrombosis (>1 year) compared with the first generation sirolimus eluting stent. However, this study also reported a 3–4% annual increase
J. Sun et al. / Medical Hypotheses 85 (2015) 972–975
of major adverse cardiac events (MACE including cardiac death, myocardial infarction, and clinically-indicated target vessel revascularization) for the BES at 5 years [10]. Thus currently available DES have succeeded in reducing the risk of late stage thrombosis and delaying restenosis, but their use may lead to further, perhaps more serious, late state complications. Fully biodegradable DES were therefore introduced as new strategy to reduce the risk of the aforementioned complications. The rationale of this new approach was that the elimination of the permanent stent materials and polymer coatings could improve both short and long term outcomes by providing the early benefits of a drug eluting scaffold without the need for a permanent device implant [11]. Ideally, this strategy would eliminate vessel wall vasomotor dysfunction, changes in vessel geometry and changes in local hemodynamics [12]. Several fully biodegradable stents are presently in development with different stent materials such as poly-L-lactide or magnesium alloy [11,13,14]. The BVS (Bioabsorbable Vascular Scaffold) everolimus eluting stent from Abbott Vascular was the first fully biodegradable DES approved in Europe with data showing it provided radial support at one year and was fully degraded at three years in vivo [14]. Small scale clinical studies for BVS showed equivalent angiographic results compared to the metallic DES at 6 months (0.19 ± 0.18 mm). At two years, late lumen loss was 0.27 ± 0.20 mm [15]. Furthermore, a recently published large scale registry study (GHOST-EU) indicated that the scaffold thrombosis rate of the BVS within 6 months was 2.1%, exceeding the incidence rate typically reported for metallic DES [16]. This data has prompted further need to evaluate the suitability of fully biodegradable DES in terms of lesion types and procedural factors. The biphasic nature of the complications associated with coronary stenting presents a unique technical and regulatory challenge. Currently, device efficacy and safety is assessed considering 9month late lumen loss and MACE rate. Several new products are validated on this basis but several important of the above mentioned complications can take place up to five years after implantation. However, to consider a longer period for evaluation would hinder the development of new and possibly improved technology while costing prohibitive amounts. As a result, to the design, the development, the testing and the approval of a safe stent has become an ethically challenging issue. A series of new markers for the clinical endpoints in the first year after stenting could serve a surrogate for long term outcomes and help address the current technical and regulatory questions regarding long term device efficacy and safety. Therefore, we present a hypothesis of why current DES continues to be associated with late stent thrombosis, MACE progression and catch-up on restenosis and offers a possible solution to the problems. We will present clinical studies that helped to develop the hypothesis of window of opportunity for vascular restoration. Utilizing this approach, a series of predictive markers of later consequences could be identified and analyzed to assess whether a given stent will be both safe and efficacious allowing for the possibility of early intervention.
Hypothesis The importance of endothelium in vascular function In a normal artery, the endothelium has a well organized structure that includes endothelial cells (ECs), vascular smooth muscle cells (VSMCs), proteins, and extracellular matrix [17] that provide a single layer cover to the inner surface of the vessel. These ‘‘active” endothelial cells are connected by tight, adherens, and gap junctions and are linked to the extracellular matrix [18,19]. The functional
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endothelium plays important roles in regulating many vital functions including vascular tone, inflammation, lipid and tissue-fluid homeostasis, and anti-thrombosis properties [20]. A functional vascular endothelium could prevent thrombosis from occurring and help to regulate VSMCs proliferation or quiescence [21]. Vessel injuries caused by the intervention procedures disrupt the endothelial layer of the artery wall leading to a cascade of cellular responses [22]. Vascular restoration, or properly restored endothelium function, is a necessary factor contributing to device efficacy and long-term safety [23]. Achieving vascular restoration requires re-endothelialization that not only has sufficient coverage at the wounded sites by ECs, but also has the proper connection among newly assembled ECs. Failure to realize this goal will result in dysfunctional endothelium which could be the cause of the current limitations of DES. Clinical studies have shown that normal endothelial function is associated with significantly improved overall and event-free survival compared to patients with endothelial dysfunction [24]. The window of opportunity for vascular restoration An effective DES must balance VSMC proliferation triggered by the vessel injury inherent in stenting with sufficient reendothelialization to achieve vascular restoration. This device must sufficiently inhibit VSMC proliferation at an early stage but then provide an environment on the stent surface that successfully promotes endothelial growth within a key window of opportunity. Recently, research by Dr. J. Hou et al. reported on a novel biodegradable polymer coated sirolimus eluting stent (BPC-SES) in comparison with. the Xience VTM from Abbott Vascular using optical coherence tomography (OCT) [25]. This novel DES features an electro-grafted poly (n-butyl methacrylate) base layer (200 nm) and top coated with a poly (lactic-co-glycolic acid) biodegradable layer containing sirolimus. The drug release profile of this stent is similar to that of the CypherTM DES but achieves 100% release within 30 days in vivo. The results of this well controlled trial showed that this novel DES resulted in early endothelial healing and at 12 months, had significantly better coverage of struts (BPC-SES 99.2% vs. Xience VTM 98.2%, p < 0.001) and a thicker and more uniform neo-intima (BPC-SES 0.15 ± 0.10 mm vs. Xience VTM 0.12 ± 0.56 mm, p < 0.001). Assessment of strut malapposition and strut embedding also favored the BPC-SES stent at this time (strut malapposition: BPC-SES 0.1% vs. Xience VTM 0.5%, p < 0.001; strut embedding: BPC-SES 91.4% vs. Xience VTM 87.7%, p < 0.001). The above results indicated that the BPC-SES most likely achieved a greater level of vascular restoration at 12 months than the Xience VTM stent. In contrary, at the 3 month time point, the OCT results indicated that there was no difference in relation to the coverage of struts or neo-intimal thickness between the two stents. Trying to understand why the two stents initially showed similar results on cell coverage via OCT at 3 months and then significantly different results at 12 months, prompted the realization that an unassessed factor within the first 3 months was differentially affecting later endothelial restoration. Failure to detect the difference could be due to the limitation of OCT. Based on this realization, we proposed the hypothesis that a certain level of reendothelialization within the first 2–3 months, the window of opportunity, is essential to achieve vascular restoration at 12 months. Insufficient endothelial response during this time frame results in the long term impairment of endothelial restoration. This hypothesis is supported by clinical data for the current DES on the market. As first and second generation DES miss the window of opportunity, their long term efficacy is hindered by late stent thrombosis and catch-up on restenosis. Correspondingly, these stents have improved long term outcomes as observed. For example, Xience VTM has a longer drug release curve [26], likely
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J. Sun et al. / Medical Hypotheses 85 (2015) 972–975
impairing endothelial growth during the window of opportunity and possibly contributing to MACE progression. Therefore, optimizing device design to maximize this window of opportunity for endothelial restoration is critical. Applying the hypothesis Using the framework provided by this window of opportunity concept for vascular restoration, patients can be categorized in distinct groups based on their endothelial responses to interventional procedures: Type 1. This type of patients is likely to respond to POBA (Plain Old Balloon Angioplasty) treatment. These patients have natural ability to achieve proper level of reendothelialization within the window of opportunity. Type 2. This type of patients is likely to respond to BMS. These patients will achieve a proper level of reendothelialization within the target time frame but require the assistance of a BMS to maintain the arterial lumen open. Type 3. This type of patients will have restenosis when treating with BMS. These patients have overly accelerated VSMC proliferation and growth making it impossible to reach the proper level of re-endothelialization within the window of opportunity. The last type of patient is the most challenging. In the absence of any pre-screening method to assess to which of above categories a patient belongs to, one should use a device capable of being effective in all three groups. However, ideally, given the limitations of first and second generation DES, next generation DES should be sought. Based on the principle of the window of opportunity, an ideal DES should have a combination of the following features: A complete drug release, ending at 20–30 days after implantation. A process or processes which will produce a stent that provides an optimized environment for a faster re-endothelialization rate when comparing to BMS. This profile is also applicable to fully biodegradable stents. In a recent study comparing two similar Sirolimus eluting stent designs showed significant difference in rate of endothelialization [27]. Both designs incorporated stainless steel platform and biodegradable polymer coating. The difference in the rate of endothelialization could be due to different drug release curve and stent surface processing. Furthermore, using this hypothesis, several of the problems of the first and second generation DES can be explained: Why are –limus derivatives more effective than paclitaxel? The window of opportunity is a limited period in which the inhibition of VSMC proliferation must be balanced with the promotion of re-endothelialization. As paclitaxel requires a longer endothelial cell recovery [28] than –limus drugs there is less opportunity for re-endothelialization resulting in the latter drugs have improved outcomes. Why is the assessment of late lumen loss via quantitative coronary angiography (QCA) at 9 months an insufficient marker of successful long term outcomes? Endothelium has a well organized structure that includes endothelial cells (ECs), vascular smooth muscle cells (VSMCs),
proteins, and extracellular matrix. Vascular restoration therefore requires re-establishment of the endothelium. A proper level of proliferation of VSMC and of deposition of the extra-cellular matrix is required for re-establishing the proper connection among the EC and in vascular restoration. A low late lumen loss value via QCA at 9 months (i.e. Cypher) is an indicator for poor vascular restoration. Why are improved clinical results seen with a thinner strut and lower drug dosage? Strut height and drug dosage both have a negative impact on reendothelialization [29]. A thinner strut provides less of an impediment for endothelial growth and a lower drug dosage can improve the likelihood of re-endothelialization occurring within the window of opportunity. Why do polymer free DES produce less than promised outcomes? The real target of the DES is the type 3 patients. The higher rate on restenosis in patients with BMS is the result of a failure to achieve a proper level of re-endothelialization. Therefore, even though polymer free DES might control VSMC proliferation with drug release, the remaining BMS does not provide the environment necessary to achieve the proper level of re-endothelialization within the window of opportunity resulting in impaired long term outcomes. Why might DES with a biodegradable drug containing layer not necessarily produce improved outcomes relative to bio-stable coated DES? A biodegradable drug containing layer allows for the possibility of achieving complete drug release favoring re-endothelialization. However, if the drug release curve is longer than 30 days, then the DES is likely comparable to bio-stable DES in terms of endothelial effect. Furthermore, as before, the environment of the stent surface after the polymer degrades might not be suitable for promoting re-endothelialization within the window of opportunity. Therefore, the terms bio-stable coated, biodegradable coated or fully biodegradable DES only provide a partial picture of the impact of a device. Why might a fully biodegradable DES by default not be able to deliver its proposed benefits? For a fully biodegradable DES with slow drug release curve (more than 30 days) or with a surface which cannot promote a better re-endothelialization than BMS, it would be unlikely to allow endothelial growth within the window of opportunity resulting in poor vascular restoration and likely impaired safety outcomes. Therefore, an ideal DES should achieve vascular restoration first and then reach complete degradation. Conclusion We propose there is a window of opportunity for vascular restoration based on basis of current clinical study results. Endothelial response to the injury within first two to three months plays a significant role in long term outcomes. Ensuring that sufficient endothelialization occurs within this window is crucial patient outcomes likely for interventions throughout the vascular system. Validation of this hypothesis is still required. A device built based on the principle of window of opportunity should significantly reduce late stent thrombosis, device related MACE progression and catch up on restenosis. Positive clinical outcome is a
J. Sun et al. / Medical Hypotheses 85 (2015) 972–975
validation of this hypothesis. Furthermore, with this hypothesis, it is possible to identify the appropriate markers within the first year of implantation that might predict later device safety and efficacy resulting in the prevention, not just the management, of adverse effects. Conflict of interest statement
[13] [14]
[15]
None declared. [16]
Acknowledgments The authors thank Christophe Bureau, PhD, Eric Cao and Cindy Zheng, for their critical review and valuable suggestions for the manuscript.
[17]
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[1] Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. New Engl J Med 2003;349:1315–23. [2] Maisel WH. Unanswered questions–drug-eluting stents and the risk of late thrombosis. New Engl J Med 2007;356:981–4. [3] Byrne RA, Iijima R, Mehilli J, Pinieck S, Bruskina O, Schomig A, et al. Durability of antirestenotic efficacy in drug-eluting stents with and without permanent polymer. JACC Cardiovasc Interven 2009;2:291–9. [4] Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193–202. [5] Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435–41. [6] Virmani R, Kolodgie FD, Farb A. Drug-eluting stents: are they really safe? Am Heart Hospital J 2004;2:85–8. [7] Claessen BE, Beijk MA, Legrand V, Ruzyllo W, Manari A, Varenne O, et al. Twoyear clinical, angiographic, and intravascular ultrasound follow-up of the xience v everolimus-eluting stent in the treatment of patients with de novo native coronary artery lesions: the spirit ii trial. Circul Cardiovasc Interven 2009;2:339–47. [8] Sun D, Zheng Y, Yin T, Tang C, Yu Q, Wang G. Coronary drug-eluting stents: from design optimization to newer strategies. J Biomed Mater Res A 2013. [9] Serruys PW. Four-year outcomes from the randomized comparison of a zotarolimus-eluting and an everolimus-eluting stent in the resolute all comers trial. EUROPCR; 2013. [10] Serruys PW, Farooq V, Kalesan B, de Vries T, Buszman P, Linke A, et al. Improved safety and reduction in stent thrombosis associated with biodegradable polymer-based biolimus-eluting stents versus durable polymer-based sirolimus-eluting stents in patients with coronary artery disease: final 5-year report of the leaders (limus eluted from a durable versus erodable stent coating) randomized, noninferiority trial. JACC Cardiovasc Interven 2013;6:777–89. [11] Kahn J. Bioabsorbable stents. J Interven Cardiol 2007;20:564–5. [12] Bourantas CV, Onuma Y, Farooq V, Zhang Y, Garcia-Garcia HM, Serruys PW. Bioresorbable scaffolds: current knowledge, potentialities and limitations
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Vascular restoration: Is there a window of opportunity? Jianhua Sun ⇑, Xiaoran Kang, Tianzhu Li Tianjin Advanced Laboratory for Interventional Medical Devices, Tianjin 300457, China
a r t i c l e
i n f o
Article history: Received 22 October 2014 Accepted 30 August 2015
a b s t r a c t The usage of drug eluting stents (DES) has markedly reduced the rates of coronary revascularization procedures compared with bare metal stents (BMS). However, this technology still faces challenges in terms of the prevention of late stent thrombosis, major adverse cardiac events (MACE) progression, and the catch-up phenomenon of restenosis. Restoration of endothelial function upon after stenting, therefore, is the key to mitigating the risk of these toxicities and determining the level of the efficacy and safety of an implant. Review of the clinical studies of multiple DES, has suggested that there exists a window of opportunity, within the first two to three months after stent implantation, for restoring vascular function. If re-endothelialization reaches sufficient level within this period, vascular restoration can occur; however, if this opportunity is missed, re-endothelialization is unlikely to reach the level of endothelial maturation necessary to prevent the late stent thrombosis, MACE progression and the catch-up on restenosis. This hypothesis could aid in explaining variable clinical responses for revascularization treatments such as plain old balloon angioplasty (POBA), BMS, or DES. Patients could be grouped according to responses to the different treatment modalities: for Type 1 patients, POBA is sufficient and safe because they possess the capacity with effective endothelial response; for Type 2 patients, re-endothelialization occurs within the window but BMS are needed to maintain the arterial lumen open; for Type 3 individuals, overly accelerated vascular smooth muscle proliferation render sufficient re-endothelialization impossible. Designing based on this principle predicts that the next technology advancement for the interventional cardiology will not be biodegradable DES by default, but rather a DES that can spur early restoration of the endothelial function within the window period. Ó 2015 Elsevier Ltd. All rights reserved.
Background The introduction of drug eluting stents (DES) in the early 2000s markedly reduced the rates of coronary revascularization procedures compared with bare metal stents (BMS). Restenosis was lowered from 35.4% to 3.2% with the usage of DES in the first year [1]. However, the massive introduction of DES revealed two major challenges: the phenomenon of late thrombosis after stent implantation [2] and continued presence restenosis (catch-up) in select patient subgroups [3]. With usage of DES, numerous cases of arterial thrombosis were reported after interruption of dual anti-platelet therapy (DAPT), leading to current guidelines to recommend DAPT for several months to year post stenting. Through extensive research [4–6], poor re-endothelialization of the first generation DES was identified as the main cause for this late stage complication. As a result,
⇑ Corresponding author at: Tianjin Advanced Laboratory for Interventional Medical Devices, 2nd Floor, Building B, TEDA Biopharm Res, #5, 4th St, TEDA, Tianjin 300457, China. Tel.: +86 22 59993327; fax: +86 22 62000060. E-mail address: [email protected] (J. Sun). http://dx.doi.org/10.1016/j.mehy.2015.08.024 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
the level of stent coverage could be as an indicator of the risk of late stent thrombosis [5]. Late stage restenosis was also reported as associated with DES usage. This phenomenon was reported for both first and second generation DES [3,7]. The SPIRIT II trial, reported that the lumen loss for Xience VTM increased substantially from 6 months to 2 years (0.17 ± 0.32 to 0.33 ± 0.37 mm respectively). As a consequence of these first clinical results, second generation DES were introduced with thinner struts, lower dosage of anti-proliferative drugs, and more biocompatible polymer coatings than the first generation products [8]. However, even within this generation DES, significant long term complications were noted to occur. Four year results for the Resolute All Comers Trial showed 2–3% annual increase of target lesion failure (TLF) both for zotarolimus eluting stent (Endeavor ResoluteTM) and everolimus eluting stent (Xience VTM) patient populations [9]. The Leaders ‘‘All Comers” clinical trial demonstrated that the BioMatrix FlexTM, a newer biolimus eluting stent (BES) with a biodegradable abluminal polylactic acid coating, reduced the incidence of very late stent thrombosis (>1 year) compared with the first generation sirolimus eluting stent. However, this study also reported a 3–4% annual increase
J. Sun et al. / Medical Hypotheses 85 (2015) 972–975
of major adverse cardiac events (MACE including cardiac death, myocardial infarction, and clinically-indicated target vessel revascularization) for the BES at 5 years [10]. Thus currently available DES have succeeded in reducing the risk of late stage thrombosis and delaying restenosis, but their use may lead to further, perhaps more serious, late state complications. Fully biodegradable DES were therefore introduced as new strategy to reduce the risk of the aforementioned complications. The rationale of this new approach was that the elimination of the permanent stent materials and polymer coatings could improve both short and long term outcomes by providing the early benefits of a drug eluting scaffold without the need for a permanent device implant [11]. Ideally, this strategy would eliminate vessel wall vasomotor dysfunction, changes in vessel geometry and changes in local hemodynamics [12]. Several fully biodegradable stents are presently in development with different stent materials such as poly-L-lactide or magnesium alloy [11,13,14]. The BVS (Bioabsorbable Vascular Scaffold) everolimus eluting stent from Abbott Vascular was the first fully biodegradable DES approved in Europe with data showing it provided radial support at one year and was fully degraded at three years in vivo [14]. Small scale clinical studies for BVS showed equivalent angiographic results compared to the metallic DES at 6 months (0.19 ± 0.18 mm). At two years, late lumen loss was 0.27 ± 0.20 mm [15]. Furthermore, a recently published large scale registry study (GHOST-EU) indicated that the scaffold thrombosis rate of the BVS within 6 months was 2.1%, exceeding the incidence rate typically reported for metallic DES [16]. This data has prompted further need to evaluate the suitability of fully biodegradable DES in terms of lesion types and procedural factors. The biphasic nature of the complications associated with coronary stenting presents a unique technical and regulatory challenge. Currently, device efficacy and safety is assessed considering 9month late lumen loss and MACE rate. Several new products are validated on this basis but several important of the above mentioned complications can take place up to five years after implantation. However, to consider a longer period for evaluation would hinder the development of new and possibly improved technology while costing prohibitive amounts. As a result, to the design, the development, the testing and the approval of a safe stent has become an ethically challenging issue. A series of new markers for the clinical endpoints in the first year after stenting could serve a surrogate for long term outcomes and help address the current technical and regulatory questions regarding long term device efficacy and safety. Therefore, we present a hypothesis of why current DES continues to be associated with late stent thrombosis, MACE progression and catch-up on restenosis and offers a possible solution to the problems. We will present clinical studies that helped to develop the hypothesis of window of opportunity for vascular restoration. Utilizing this approach, a series of predictive markers of later consequences could be identified and analyzed to assess whether a given stent will be both safe and efficacious allowing for the possibility of early intervention.
Hypothesis The importance of endothelium in vascular function In a normal artery, the endothelium has a well organized structure that includes endothelial cells (ECs), vascular smooth muscle cells (VSMCs), proteins, and extracellular matrix [17] that provide a single layer cover to the inner surface of the vessel. These ‘‘active” endothelial cells are connected by tight, adherens, and gap junctions and are linked to the extracellular matrix [18,19]. The functional
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endothelium plays important roles in regulating many vital functions including vascular tone, inflammation, lipid and tissue-fluid homeostasis, and anti-thrombosis properties [20]. A functional vascular endothelium could prevent thrombosis from occurring and help to regulate VSMCs proliferation or quiescence [21]. Vessel injuries caused by the intervention procedures disrupt the endothelial layer of the artery wall leading to a cascade of cellular responses [22]. Vascular restoration, or properly restored endothelium function, is a necessary factor contributing to device efficacy and long-term safety [23]. Achieving vascular restoration requires re-endothelialization that not only has sufficient coverage at the wounded sites by ECs, but also has the proper connection among newly assembled ECs. Failure to realize this goal will result in dysfunctional endothelium which could be the cause of the current limitations of DES. Clinical studies have shown that normal endothelial function is associated with significantly improved overall and event-free survival compared to patients with endothelial dysfunction [24]. The window of opportunity for vascular restoration An effective DES must balance VSMC proliferation triggered by the vessel injury inherent in stenting with sufficient reendothelialization to achieve vascular restoration. This device must sufficiently inhibit VSMC proliferation at an early stage but then provide an environment on the stent surface that successfully promotes endothelial growth within a key window of opportunity. Recently, research by Dr. J. Hou et al. reported on a novel biodegradable polymer coated sirolimus eluting stent (BPC-SES) in comparison with. the Xience VTM from Abbott Vascular using optical coherence tomography (OCT) [25]. This novel DES features an electro-grafted poly (n-butyl methacrylate) base layer (200 nm) and top coated with a poly (lactic-co-glycolic acid) biodegradable layer containing sirolimus. The drug release profile of this stent is similar to that of the CypherTM DES but achieves 100% release within 30 days in vivo. The results of this well controlled trial showed that this novel DES resulted in early endothelial healing and at 12 months, had significantly better coverage of struts (BPC-SES 99.2% vs. Xience VTM 98.2%, p < 0.001) and a thicker and more uniform neo-intima (BPC-SES 0.15 ± 0.10 mm vs. Xience VTM 0.12 ± 0.56 mm, p < 0.001). Assessment of strut malapposition and strut embedding also favored the BPC-SES stent at this time (strut malapposition: BPC-SES 0.1% vs. Xience VTM 0.5%, p < 0.001; strut embedding: BPC-SES 91.4% vs. Xience VTM 87.7%, p < 0.001). The above results indicated that the BPC-SES most likely achieved a greater level of vascular restoration at 12 months than the Xience VTM stent. In contrary, at the 3 month time point, the OCT results indicated that there was no difference in relation to the coverage of struts or neo-intimal thickness between the two stents. Trying to understand why the two stents initially showed similar results on cell coverage via OCT at 3 months and then significantly different results at 12 months, prompted the realization that an unassessed factor within the first 3 months was differentially affecting later endothelial restoration. Failure to detect the difference could be due to the limitation of OCT. Based on this realization, we proposed the hypothesis that a certain level of reendothelialization within the first 2–3 months, the window of opportunity, is essential to achieve vascular restoration at 12 months. Insufficient endothelial response during this time frame results in the long term impairment of endothelial restoration. This hypothesis is supported by clinical data for the current DES on the market. As first and second generation DES miss the window of opportunity, their long term efficacy is hindered by late stent thrombosis and catch-up on restenosis. Correspondingly, these stents have improved long term outcomes as observed. For example, Xience VTM has a longer drug release curve [26], likely
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impairing endothelial growth during the window of opportunity and possibly contributing to MACE progression. Therefore, optimizing device design to maximize this window of opportunity for endothelial restoration is critical. Applying the hypothesis Using the framework provided by this window of opportunity concept for vascular restoration, patients can be categorized in distinct groups based on their endothelial responses to interventional procedures: Type 1. This type of patients is likely to respond to POBA (Plain Old Balloon Angioplasty) treatment. These patients have natural ability to achieve proper level of reendothelialization within the window of opportunity. Type 2. This type of patients is likely to respond to BMS. These patients will achieve a proper level of reendothelialization within the target time frame but require the assistance of a BMS to maintain the arterial lumen open. Type 3. This type of patients will have restenosis when treating with BMS. These patients have overly accelerated VSMC proliferation and growth making it impossible to reach the proper level of re-endothelialization within the window of opportunity. The last type of patient is the most challenging. In the absence of any pre-screening method to assess to which of above categories a patient belongs to, one should use a device capable of being effective in all three groups. However, ideally, given the limitations of first and second generation DES, next generation DES should be sought. Based on the principle of the window of opportunity, an ideal DES should have a combination of the following features: A complete drug release, ending at 20–30 days after implantation. A process or processes which will produce a stent that provides an optimized environment for a faster re-endothelialization rate when comparing to BMS. This profile is also applicable to fully biodegradable stents. In a recent study comparing two similar Sirolimus eluting stent designs showed significant difference in rate of endothelialization [27]. Both designs incorporated stainless steel platform and biodegradable polymer coating. The difference in the rate of endothelialization could be due to different drug release curve and stent surface processing. Furthermore, using this hypothesis, several of the problems of the first and second generation DES can be explained: Why are –limus derivatives more effective than paclitaxel? The window of opportunity is a limited period in which the inhibition of VSMC proliferation must be balanced with the promotion of re-endothelialization. As paclitaxel requires a longer endothelial cell recovery [28] than –limus drugs there is less opportunity for re-endothelialization resulting in the latter drugs have improved outcomes. Why is the assessment of late lumen loss via quantitative coronary angiography (QCA) at 9 months an insufficient marker of successful long term outcomes? Endothelium has a well organized structure that includes endothelial cells (ECs), vascular smooth muscle cells (VSMCs),
proteins, and extracellular matrix. Vascular restoration therefore requires re-establishment of the endothelium. A proper level of proliferation of VSMC and of deposition of the extra-cellular matrix is required for re-establishing the proper connection among the EC and in vascular restoration. A low late lumen loss value via QCA at 9 months (i.e. Cypher) is an indicator for poor vascular restoration. Why are improved clinical results seen with a thinner strut and lower drug dosage? Strut height and drug dosage both have a negative impact on reendothelialization [29]. A thinner strut provides less of an impediment for endothelial growth and a lower drug dosage can improve the likelihood of re-endothelialization occurring within the window of opportunity. Why do polymer free DES produce less than promised outcomes? The real target of the DES is the type 3 patients. The higher rate on restenosis in patients with BMS is the result of a failure to achieve a proper level of re-endothelialization. Therefore, even though polymer free DES might control VSMC proliferation with drug release, the remaining BMS does not provide the environment necessary to achieve the proper level of re-endothelialization within the window of opportunity resulting in impaired long term outcomes. Why might DES with a biodegradable drug containing layer not necessarily produce improved outcomes relative to bio-stable coated DES? A biodegradable drug containing layer allows for the possibility of achieving complete drug release favoring re-endothelialization. However, if the drug release curve is longer than 30 days, then the DES is likely comparable to bio-stable DES in terms of endothelial effect. Furthermore, as before, the environment of the stent surface after the polymer degrades might not be suitable for promoting re-endothelialization within the window of opportunity. Therefore, the terms bio-stable coated, biodegradable coated or fully biodegradable DES only provide a partial picture of the impact of a device. Why might a fully biodegradable DES by default not be able to deliver its proposed benefits? For a fully biodegradable DES with slow drug release curve (more than 30 days) or with a surface which cannot promote a better re-endothelialization than BMS, it would be unlikely to allow endothelial growth within the window of opportunity resulting in poor vascular restoration and likely impaired safety outcomes. Therefore, an ideal DES should achieve vascular restoration first and then reach complete degradation. Conclusion We propose there is a window of opportunity for vascular restoration based on basis of current clinical study results. Endothelial response to the injury within first two to three months plays a significant role in long term outcomes. Ensuring that sufficient endothelialization occurs within this window is crucial patient outcomes likely for interventions throughout the vascular system. Validation of this hypothesis is still required. A device built based on the principle of window of opportunity should significantly reduce late stent thrombosis, device related MACE progression and catch up on restenosis. Positive clinical outcome is a
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validation of this hypothesis. Furthermore, with this hypothesis, it is possible to identify the appropriate markers within the first year of implantation that might predict later device safety and efficacy resulting in the prevention, not just the management, of adverse effects. Conflict of interest statement
[13] [14]
[15]
None declared. [16]
Acknowledgments The authors thank Christophe Bureau, PhD, Eric Cao and Cindy Zheng, for their critical review and valuable suggestions for the manuscript.
[17]
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