Bioresorbable Scaffolds: Fading Away or Hope for the Future?

Since the development of the first metallic stents in the mid-1980s, there have been continued improvements in stent technology. However, all permanent metallic scaffolds have the inherent limitation of leaving a foreign metallic stent within the vessel. This not only has the potential for an adverse host response to the foreign object, such as neointimal hyperplasia leading to in-stent restenosis or stent thrombosis from failed endothelialization, but also imposes physical restraints, such as altering vessel physiology, jailing of side branches, undersizing/malapposition, and continued luminal encroachment with stenting for treatment of in-stent restenosis. Thus, there has been growing interest in developing bioresorbable scaffolds. We believe that interventional cardiology is at a critical crossroads due to the recent disappointments with the Absorb (Abbott Vascular; Santa Clara, CA) bioresorbable vascular scaffold (BVS), which failed to live up to its promise.

Bioresorbable scaffolds are intended do all that drug-eluting stent (DES) can do; they provide the radial support needed to prevent vessel recoil, seal intimal dissection flaps that may result from balloon angioplasty, and allow for secretion of the anti-proliferative drug. Bioresorbable scaffold systems have the added benefit of completely degrading, which allows for recovery of vessel vasoreactivity and endothelial function.1 For these reasons, bioresorbable scaffold systems represent a crucial next step in stent technology development.

Lactate-based polymer systems provide the majority of data to date for bioresorbable scaffold systems. Poly-L-lactic acid (PLLA) is a thermoplastic aliphatic polyester that undergoes hydrolysis into shorter lactic acid molecules, which are then converted into water and carbon dioxide via Krebs cycle. Other lactate-based polymers such as poly-D,L-lactic acid (PDLLA) undergo a similar breakdown process but at a faster rate due to decreased crystalline structure compared with PLLA. Bioresorbable metallic scaffolds are also being pursued and may serve as an alternative to lactate-based polymer systems.

The most widely studied and clinically utilized bioresorbable scaffold is the Absorb BVS, which consists of a PLLA scaffold coated with a layer of everolimus-eluting PDLLA. To provide adequate radial strength given the absence of a metallic backbone, the strut thickness of the Absorb BVS is quite large at over 150 microns.2 Due in part to its strut thickness, the Absorb BVS can take up to 4 years to fully resorb.3 As it resorbs, the device can create a potential nidus for very late scaffold thrombosis, necessitating prolonged dual antiplatelet therapy.

The initial studies of the Absorb BVS were isolated to patients with stable angina and largely excluded complicated lesion characteristics.4 After Conformité Européenne (CE) mark approval, registry data began to raise concern for scaffold thrombosis,5 particularly in the setting of acute coronary syndromes. A subsequent systematic review and meta-analysis including over 10,000 patients demonstrated a twofold increase in the rate of both myocardial infarction and definite or probable scaffold thrombosis compared with DES.6 These results, coupled with the ABSORB III (A Bioresorbable Everolimus-Eluting Scaffold Versus a Metallic Everolimus-Eluting Stent III) trial showing a trend toward more target lesion failure at 12 months compared with DES7 and the AIDA (Amsterdam Investigator-Initiated Absorb Strategy All-Comers) trial showing an almost fourfold increase in the rate of definite or probable scaffold thrombosis,8 led Abbott Vascular to restrict the use of its Absorb BVS in Europe to registry patients only. Shortly thereafter, Boston Scientific announced it was abandoning its research into its Renuvia bioresorbable scaffold system.

There are several proposed mechanisms that lead to scaffold thrombosis and target lesion failure. Although thicker scaffold struts may enhance radial strength, preventing vessel recoil, this may be at the expense of decreased luminal area and prolonged resorption time.1 Thicker struts prolong endothelialization9 and increase thrombogenicity,10 which is only exacerbated in the setting of malapposition when the struts do not overlie the endothelium, preventing resorption of the scaffold. Furthermore, the Absorb BVS may have prothrombogenic characteristics that need to be explored further. A recent preclinical study compared the acute thrombogenicity of the Absorb BVS and the Magmaris (BIOTRONIK AG; Bülach, Switzerland) resorbable magnesium scaffold, a fully bioabsorbable magnesium scaffold with sirolimus-eluting bioresorbable PLLA coating and a 150 mcm strut thickness. After running for a maximum of 1 hour in a porcine arteriovenous shunt with an activated clotting time of 150-200 seconds, 21% of the Absorb BVS surface was covered in platelets while only 3% of the Magmaris scaffold surface had platelet adherence.11 Conversely, these data also raise the question whether magnesium-based scaffolds have inherent platelet-repelling properties.

The regulatory framework in Europe led to the early granting of a CE mark and release. The original device approval was granted based on the Medical Device Directive dating back to 1993. Following the emergence of trends toward increased scaffold thrombosis, the European Commission, in conjunction with the European Society of Cardiology and the European Association of Percutaneous Coronary Intervention, formed a task force to assess new stent and scaffold technologies. This led to the recommendation and adoption of a two-stage clinical evaluation, which includes initial premarket trials with pre-established invasive imaging requirements and mandatory large-scale trials before the granting of an unconditional CE mark.12 Recently, the US Food and Drug Administration issued a letter to physicians warning them of an increased rate of major cardiac events with the Absorb BVS, leading Abbott Vascular to pull the device.13

The recently presented 3-year data for the ABSORB III trial and the 30-day data for the ABSORB IV (A Bioresorbable Everolimus-Eluting Scaffold Versus a Metallic Everolimus-Eluting Stent IV) trial presented at the Transcatheter Cardiovascular Therapeutics Congress 2017 have reinforced these concerns. In the ABSORB III trial, the target lesion failure rate at 3 years was 13.4% for BVS compared with 10.4% in the everolimus-eluting stent group (p = 0.06).14 Target vessel myocardial infarction (8.6 vs. 5.9% respectively, p = 0.03) and scaffold thrombosis (2.3 vs. 0.7% respectively, p = 0.01) were also significantly higher in the BVS arm, which is consistent with previously published meta-analysis. The ABSORB IV trial demonstrated that the incidence of scaffold thrombosis at 30 days was 0.6% with BVS compared with 0.2% in the DES arm.15 Though appropriate implantation technique (pre-dilation, vessel sizing, and post-dilation) was associated with a reduced incidence of target lesion failure and scaffold thrombosis,16 this is unlikely to salvage the Absorb BVS.

Despite this setback for the Absorb BVS, DESolve (Elixir Medical Corporation; Milpitas, CA) and ART Pure (Arterial Remodeling Technologies SA; Paris, France) remain as poly-lactide scaffold alternatives, and Magmaris and Fantom (REVA Medical, Inc.; San Diego, CA) scaffolds are magnesium-based bioresorbable scaffold alternatives.17 Characteristics of these bioresorbable scaffolds can be found in Table 1. The price of failure is extremely high for these developing bioresorbable scaffold technologies. Not only is the financial cost extremely high to conduct well-controlled and appropriately powered randomized clinical trials, but further setbacks in bioresorbable scaffold technology, as seen this Halloween at the Transcatheter Cardiovascular Therapeutics Congress 2017, may limit the desire of other companies to invest in the necessary research and development resources. It is important to acknowledge that the initial concerns for stent thrombosis following the development of DES were alleviated with subsequent technological advances, resulting in our current "gold standard" second-generation DES. If companies had abandoned DES technology after 2006 due to concerns over stent thrombosis, it is hard to imagine where the field would stand if we were limited to the use of bare-metal stents. We believe more in-depth preclinical investigation of novel scaffold technologies published in peer-reviewed scientific journals may enable further refinement of these technologies, limit premature initiation of clinical studies, and allow for a greater chance of success. In summary, we look forward to further improvements in bioresorbable scaffold technology and eagerly anticipate the successful utilization of alternative bioresorbable scaffold platforms in appropriately powered randomized controlled trials.

Table 1: Scaffold Characteristics of Currently Available Bioresorbable Scaffolds With CE Mark

Bioresorbable Scaffolds

Absorb BVS

DESolve

ART Pure

Magmaris

Fantom

Backbone

PLLA

PLLA

PDLLA

Magnesium

Tyrosine polycarbonate

Drug-elution

Everolimus

Novolimus

None

Sirolimus

Sirolimus

Strut thickness (mcm)

157

120

170

150

125

Resorption (months)

24-48

<24

6

9-12

36

References

  1. Lipinski MJ, Escarcega RO, Lhermusier T, Waksman R. The effects of novel, bioresorbable scaffolds on coronary vascular pathophysiology. J Cardiovasc Transl Res 2014;7:413-25.
  2. Sheehy A, Gutiérrez-Chico JL, Diletti R, et al. In vivo characterisation of bioresorbable vascular scaffold strut interfaces using optical coherence tomography with Gaussian line spread function analysis. EuroIntervention 2012;7:1227-35.
  3. Onuma Y, Serruys PW, Perkins LE, et al. Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial. Circulation 2010;122:2288-300.
  4. Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 2008;371:899-907.
  5. Capodanno D, Gori T, Nef H, et al. Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-EU registry. EuroIntervention 2015;10:1144-53.
  6. Lipinski MJ, Escarcega RO, Baker NC, et al. Scaffold Thrombosis After Percutaneous Coronary Intervention With ABSORB Bioresorbable Vascular Scaffold: A Systematic Review and Meta-Analysis. JACC Cardiovasc Interv 2016;9:12-24.
  7. Ellis SG, Kereiakes DJ, Metzger DC, et al. Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease. N Engl J Med 2015;373:1905-15.
  8. Wykrzykowska JJ, Kraak RP, Hofma SH, et al. Bioresorbable Scaffolds versus Metallic Stents in Routine PCI. N Engl J Med 2017;376:2319-28.
  9. Otsuka F, Vorpahl M, Nakano M, et al. Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. Circulation 2014;129:211-23.
  10. Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011;123:1400-9.
  11. Waksman R, Lipinski MJ, Acampado E, et al. Comparison of Acute Thrombogenicity for Metallic and Polymeric Bioabsorbable Scaffolds: Magmaris Versus Absorb in a Porcine Arteriovenous Shunt Model. Circ Cardiovasc Interv 2017;10:e004762.
  12. Byrne RA, Stefanini GG, Capodanno D, et al. Report of an ESC-EAPCI Task Force on the evaluation and use of bioresorbable scaffolds for percutaneous coronary intervention: executive summary. Eur Heart J 2017;Aug 28:[Epub ahead of print].
  13. FDA Investigating Increased Rate of Major Adverse Cardiac Events Observed in Patients Receiving Abbott Vascular's Absorb GT1 Bioresorbable Vascular Scaffold (BVS) - Letter to Health Care Providers. (US Food and Drug Administration website). March 18, 2017. Available at: https://www.fda.gov/MedicalDevices/Safety/LetterstoHealthCareProviders/ucm546808.htm. Accessed 11/07/2017.
  14. Kereiakes DJ, Ellis SG, Metzger C, et al. 3-Year Clinical Outcomes With Everolimus-Eluting Bioresorbable Coronary Scaffolds: The ABSORB III Trial. J Am Coll Cardiol 2017;70:2852-62.
  15. Stone GW. ABSORB IV: 30-Day Outcomes From a Randomized Trial of a Bioresorbable Scaffold vs a Metallic DES in Patients With Coronary Artery Disease. October 31, 2017. Presented at Transcatheter Cardiovascular Therapeutics Congress 2017.
  16. Stone GW, Abizaid A, Onuma Y, et al. Effect of Technique on Outcomes Following Bioresorbable Vascular Scaffold Implantation: Analysis From the ABSORB Trials. J Am Coll Cardiol 2017;70:2863-74.
  17. Onuma Y, Serruys PW. Rather Thick, Yet Antithrombogenic: Is the Magmaris Scaffold a New Hope for Bioresorbable Coronary Scaffold? Circ Cardiovasc Interv 2017;10:e005663.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Interventions and ACS, Chronic Angina

Keywords: Drug-Eluting Stents, Lactic Acid, Sirolimus, Absorbable Implants, Blood Platelets, Magnesium, Carbon Dioxide, Angina, Stable, Acute Coronary Syndrome, Polymers, Hyperplasia, Hydrolysis, Citric Acid Cycle, Dilatation, Angioplasty, Balloon, Coronary, Percutaneous Coronary Intervention, Stents, Myocardial Infarction, Thrombosis, Registries, Endothelium


< Back to Listings