Author + information
- Published online June 5, 2017.
- Ron Waksman, MD∗ ()
- ↵∗Address for correspondence:
Dr. Ron Waksman, MedStar Washington Hospital Center, 110 Irving Street, NW, Room 6D15E, Washington, DC 20010.
The quest to manufacture a safe and effective bioresorbable scaffold (BRS) has been ongoing for nearly 2 decades. Polymers based on poly-l-lactide (PLLA) or poly-d,l-lactide were introduced as the base material for BRS technology. The core polymer technology has distinct differences compared with metallic stents. The immediate challenge of the polymer-based technology was to match its mechanical properties to those of metallic stents to allow adequate expansion and apposition to the vessel wall without recoil or breakage of the struts and maintain stability during degradation. Upfront, there are major differences between the metallic of the struts and PLLA-based polymers. For example, the tensile strength of the polymers ranged from 45 to 70 MPa compared with 1,449 MPa for cobalt chromium. The elongation at break for polymers is 2% to 6% compared with 40% for metallic stents (1,2). These gaps in mechanical properties are a challenge to overcome, and despite improvements in refining the polymer composition, structure, and manufacturing process, the performance of the currently available polymer-based BRS technology falls short compared with second-generation metallic drug-eluting stents. The low tensile and radial strength has the potential to cause early recoil and lack of apposition in addition to mechanical disruption in the integrity of the scaffold. Late dismantling of the polymer can also occur toward the final stages of resorption of the polymer. Those were considered to be attributive factors for the early and late scaffold thrombosis phenomenon and higher rates of myocardial infarction and revascularization as recently reported in the ABSORB II (3) and ABSORB III (4) randomized clinical trials. To overcome the tensile strength and stiffness deficiency, the first-generation BRS technology consisted of thick struts (150 μm). As a result, they are not suitable for small vessels, which are at risk for higher scaffold thrombosis. In addition, the polymeric BRS require meticulous vessel preparation, proper sizing and post-dilatation, which are not well defined in addition to a recommendation for intravascular imaging guidance. These mechanical challenges motivated chemists, engineers, and polymer scientists to modify the processing methods of the polymers to improve the radial strength, allowing the polymer to deform, elongate, and stretch under tensile stress without breakage and to reduce the strut thickness and to improve deliverability of the scaffold.
Manli Cardiology (Singapore) developed a microfiber novel technology to alter the molecular orientation of the polylactide to create a circular single monofilament. The scaffold design consists of a helicoid coil structure in which the monofilament maintains its directional mechanical properties as well as its circular geometry. The technology was incorporated into the Mirage sirolimus-eluting bioresorbable microfiber scaffold (BRMS). The strut thickness of this scaffold is 125 μm, and the tensile strength is nearly 300 MPa, with an elongation at break of 35% and a radial strength of 120 kPa, which is comparable with the radial strength of the Xience V metallic stent with a strut thickness of 81 μm. In this issue of JACC: Cardiovascular Interventions, Tenekecioglu et al. (5) report the results of a study in which the Mirage BRMS was tested in a small clinical trial head to head against the Absorb bioresorbable vascular scaffold (BVS), looking at safety and effectiveness using optical coherence tomographic and angiographic imaging modalities to assess the performance of the device. Despite the improvements to the specifications of the Mirage BRMS, it underperformed compared with Absorb, and the diameter stenosis on angiography and on optical coherence tomography was significantly higher with the Mirage MBRS than the Absorb, with similar 12-month angiographic in-scaffold late loss. More concerning was the high clinically indicated target vessel revascularization rates for both devices (17.2% for the Mirage and 14.8% for the Absorb), the scaffold thrombosis rate for the Mirage (3.4%), and the rate of all death, all myocardial infarction, and all revascularization (patient-oriented composite endpoint) was 27.6% for the Mirage and 29.6% for the ABSORB, which is an alarming rate. It is unfortunate that the investigators did not add a metallic stent arm to compare the performance of the presumed improved BRS technology also with that of a metallic stent to assess whether the changes in the mechanical properties of the polymer are good enough to translate those to angiographic and clinical outcome when compared with metallic stent. Despite the contemporary patient and lesion profile in the study compared with traditional feasibility studies, the clinical outcome was dismal and not acceptable. The investigators attribute the results to suboptimal implantation technique with the Mirage, but it is not clear what would have been the optimal technique and why it was not applied. Arguments for suboptimal deployment techniques were used to explain the underperformance of Absorb against Xience in the ABSORB II and ABSORB III studies. On March 18, 2017, the U.S. Food and Drug Administration (FDA) issued an advisory letter clarifying the following: “An additional preliminary analysis of ABSORB III data suggests improved clinical performance and a lower rate of complications associated with BVS implantation when health care providers follow the recommended implantation methods. The FDA-approved labeling for the ABSORB BVS includes recommendations on selecting appropriately sized heart arteries for BVS implantation and methods to properly implant the device against the vessel wall” (6). To date, no prospective study has demonstrated that adopting these optimal deployment recommendations with BRS will produce equivalent outcomes as the best-in-class metallic drug-eluting stent. Nevertheless, it is imperative to adopt these recommendations when using any BRS technology and to apply them with permanent metallic stents. Obviously, these recommendations are more critical for BRS, because the technology is not forgiving of poor deployment technique.
The results of the present study raise uncertainty as to whether the proprietary changes in the Mirage BRMS indeed improved the performance of the PLAA-based polymer technology. Furthermore, the question is whether under any circumstances polymer-based technology can equate to the clinical performance of metallic stents without closing the gap of the mechanical properties of the scaffold. In this regard, the magnesium bioabsorbable metallic scaffold has better mechanical properties compared with PLLA-based polymers, with tensile strength ranging from 220 to 330 MPa and elongation at break of 40%. Although there is limited experience, no scaffold thrombosis was reported so far with the magnesium-based BRS systems in any of the clinical trials using the magnesium alloy (7).
The promise of the BRS technology remains. However, to date, there is no proof of a clinical advantage to the concept. Although physicians and patients desire a way to avoid the shortcomings of permanent metallic stents, polymeric scaffolds so far offer inferior performance and more events than best-in-class metallic drug-eluting stents. Although the current technology is not good enough and second-generation BRS are in the pipeline, efforts should continue to address the following issues. Is there a technology barrier using the PLLA polymer–based technology? Are we looking for a breakthrough in the technology to overcome the shortcoming of the current PLLA-based technology? If so, what would be the best model to examine the next-generation BRS? What should be the comparator, a first-generation BRS or the best-in-class permanent metallic stent? What should be the optimal deployment technique? Can we rely on imaging as a surrogate endpoint to address these important questions? And finally, will the BRS technology ever be able to demonstrate superiority over permanent metallic stents? Until we find answers to those questions, we should exercise caution on patient and lesion selection and be meticulous on optimal deployment technique when utilizing the polymeric BRS technology. In addition, tight surveillance should apply to the nearly 200,000 patients who have already received polymer-based BRS. Further, investigation of the mechanical properties of the polymer and prospective monitored clinical trials will determine what will be the future role of the polymeric based BRS technology for patients undergoing intervention.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Waksman is a consultant for Abbott Vascular, Amgen, Biosensors International, Biotronik, Boston Scientific, Corindus, Lifetech Medical, Medtronic Vascular, Philips Volcano, and Symetis; is a member of the Speakers Bureau for AstraZeneca; and has received grant support from Biosensors International, Biotronik, Boston Scientific, Edwards Lifesciences, and Abbott Vascular.
- 2017 American College of Cardiology Foundation
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- ↵Ellis SG, Kereiakes DJ, Stone GW. Everolimus-eluting bioresorbable vascular scaffolds in patients with coronary artery disease: ABSORB III trial 2-year results. Presented at: ACC 2017; March 18, 2017; Washington, DC.
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- ↵U.S. Food and Drug Administration. Absorb GT1 bioresorbable vascular scaffold (BVS) by Abbott Vascular: letter to health care providers—FDA investigating increased rate of major adverse cardiac events. Available at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm547256.htm. Accessed March 29, 2017.
- Waksman R.