Bioresorbable Scaffolds　― A Ray of Hope in the Darkness ―

Bioresorbable scaffold (BRS) technology is a highly innovative therapeutic approach because it provides transient vessel support and is biologically resorbed over time in contrast to permanent metallic prostheses. BRS technology is expected to allow restoration of vasomotor function, adaptive shear stress, and late luminal enlargement of the coronary vasculature without the risk of traumatic vessel occlusion or acute elastic recoil during percutaneous coronary interventions (PCI).¹ The concept of this technology was introduced in the 1980s, and the Igaki-Tamai BRS, consisting of poly-L-lactide monofilament, was first implanted in human coronary arteries in Japan in 1988, demonstrating acceptable long-term clinical safety and efficacy, despite the lack of a drug elution profile, and certainly provided proof-of-concept for the technology.² After the ABSORB clinical investigation program, the everolimus-eluting polymeric Absorb^® BVS (Abbott Vascular, Santa Clara, CA, USA) was launched in September 2012. The ABSORB Japan randomized trial demonstrated the non-inferiority of the BVS to the best-in-class cobalt-chromium everolimus-eluting stent (CoCr-EES: XIENCE^®, Abbott Vascular) in terms of composite target lesion failure at 12 months.³ The Absorb GT1^® was approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) in November 2016 based on the data, but the early enthusiasm for this device has gradually waned after pivotal randomized trials against the CoCr-EES conducted in Western countries.^4,5 Finally, the company called a halt on the Absorb BVS on 14 September, 2017, attributing the decision to low commercial sales.

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The major drawback of the Absorb BVS – scaffold thrombosis (ScT) – is considered to be multifactorial: the larger strut thickness of the BVS than that of the drug-eluting metallic stents (DES) is associated with reversal flow behind the struts, poorer ability to embed into the vessel wall, and slower neointimal coverage.⁶ During the bioresorption process of the polymer, focal inflammation and replaced provisional matrix (e.g., proteoglycan) can also promote local thrombogenicity. In vivo investigations using optical coherence tomography (OCT) have suggested that late scaffold discontinuity/dismantling is the leading mechanism of very late ScT.⁷ These findings drove physicians to seek better implantation techniques for this device to overcome the risk of ScT. The P-S-P technique, comprising lesion Preparation, appropriate Sizing of the device, and Postdilatation, was encouraged and prospectively tested in the USA (ABSORB IV trial).⁸ The incidence rate of ScT was 1.7% in the BVS group and 1.1% in the DES group throughout the 5-year follow-up (P=0.15). It should be noted, however, that intracoronary imaging modalities (i.e., IVUS or OCT) were used in only 14%, while the incidence of ScT became almost neutral after the completion of the bioresorption process (3 years).

In this issue of the Journal, Nakamura et al⁹ report the 5-year follow-up of the Absorb GT1 post-market surveillance (PMS) study in Japan. Unfortunately, study enrollment had to cease after 135 patients due to discontinuation of the study device in 2017. In this PMS, all patients were treated under intracoronary imaging guidance and the P-S-P technique was rigorously executed with 100% for predilatation and 98.6% for postdilatation at a mean pressure of 18.8 atm. Cumulative incidence of target lesion failure was 5.1% and no definite/probable ScT was observed through the 5 years. First of all, the authors should be commended for their tremendous effort. In order to expand the number of facilities implementing the reimbursement program in Japan, they had to minimize the incidence of ScT even during the post-marketing phase. They report that the average age of patients was 64 years, only 3.7% had renal failure, lesion length was 13.8 mm, percentage struts with incomplete scaffold apposition on postprocedural OCT was 1.9%, and dual antiplatelet therapy (DAPT) was continued in >70% of patients up to 3 years after BVS implantation. Selection of appropriate patients, meticulous implantation technique, intracoronary imaging assessment, and careful clinical follow-up after PCI, including DAPT continuation – all of which may have contributed to the elimination of ScT for the first time under prospective observation. Conversely, in the ABSORB IV and the COMPARE-ABSORB trials, the dedicated implantation techniques were implemented but there were still a gap in clinical event rates between the BVS and CoCr-EES. For both trials, the intracoronary imaging use was not mandated (frequency of use: 15% in the ABSORB IV and 23% in the COMPARE-ABSORB).^8,10 Hence, intracoronary imaging guidance is of paramount importance for the clinical application of future generations of BRS technologies.

Given the excellent clinical performance of the current generation of DES, one may argue whether BRS technology is needed anymore? Specifically for patients who do not want to have a permanently implanted medical device or those with suspected metallic allergy, the “leave-nothing-behind” strategy sounds attractive for eliminating the nidus for long-term device-related complications. The “leave-nothing-behind” revascularization strategy would work synergistically with concomitant optimal medical therapy (e.g., lipid-lowering agents), which could reduce the amount of coronary plaque (Figure 1).¹¹ This concept can be achieved either by BRS, drug-coated balloons (DCB), or their combination. The former is still under development or investigation, while the latter has gained clinical evidence in coronary and lower extremity arterial diseases. In the nationwide J-PCI registry, 17.2% of lesions were treated with a DCB in 2021, and a clear trend of increasing usage in Japan was revealed.¹² A possible reason of frequent use of the DCB is that it is less likely to necessitate long-term DAPT or to limit future therapeutic options compared with standard DES. Similarly to the BRS, the recent AGENT Japan trial demonstrated that late luminal enlargement was observed in ≈50% of lesions regardless of the type of paclitaxel-coated balloon.¹³ But a technical challenge for the DCB is that a certain proportion of cases require bail-out stenting due to inappropriate lesion preparation such as dissection, hematoma or acute elastic recoil.

Figure 1.

“Leave-nothing-behind” revascularization strategies with optimal medical therapies based on the pathophysiological patterns of coronary artery disease. PCI, percutaneous coronary intervention; PPG, pullback pressure gradient; QFR, quantitative flow ratio.

The present study clearly demonstrated the long-term safety of the Absorb GT1 in selected patients with native coronary artery disease. Nevertheless, the optimal patient/lesion selection and duration of DAPT need to be clarified, and technological improvements are obviously warranted. Recently, in the the LIFE BTK trial the ESPRIT^® BTK everolimus-eluting resorbable scaffold (Abbott Vascular) with thinner struts (99 μm) than the Absorb BVS (157 μm) demonstrated superior clinical outcomes over conventional balloon angioplasty in patients with lower limb ischemia due to infrapopliteal arterial disease.¹⁴ The new iteration of the magnesium alloy BRS (DREAMS-3) showed a significant improvement in angiographic late loss and acquired the CE mark in February 2024.¹⁵ The iron-based BRS with 70-μm strut thickness demonstrated stable late lumen loss up to 3 years.¹⁶ Furthermore, the JFK-01 magnesium alloy BRS (KANEKA Medix, Tokyo, Japan) is currently being tested in a first-in-man trial.

BRS technology has the technical challenge of finding the balance between duration of mechanical integrity and bioresorption time in the clinical setting (Figure 2). Manufacturing thinner struts with enough radial strength and acceptable bioresorption time is expected. In conclusion, the present study had a small sample size but represents a great step forward for this novel technology in interventional cardiology.

Figure 2.

Duration of mechanical integrity and bioresorption time in bioresorbable scaffold technologies.

Disclosures

None.

References

• 1.   Muramatsu T, Onuma Y, Zhang YJ, Bourantas CV, Kharlamov A, Diletti R, et al. Progress in treatment by percutaneous coronary intervention: The stent of the future. Rev Esp Cardiol 2013; 66: 483–496, doi:10.1016/j.rec.2012.12.009.
• 2.   Nishio S, Kosuga K, Igaki K, Okada M, Kyo E, Tsuji T, et al. Long-term (>10 years) clinical outcomes of first-in-human biodegradable poly-l-lactic acid coronary stents: Igaki-Tamai stents. Circulation 2012; 125: 2343–2353, doi:CIRCULATIONAHA.110.000901.
• 3.   Kimura T, Kozuma K, Tanabe K, Nakamura S, Yamane M, Muramatsu T, et al. A randomized trial evaluating everolimus-eluting absorb bioresorbable scaffolds vs. everolimus-eluting metallic stents in patients with coronary artery disease: ABSORB Japan. Eur Heart J 2015; 36: 3332–3342, doi:10.1093/eurheartj/ehv435.
• 4.   Serruys PW, Chevalier B, Sotomi Y, Cequier A, Carrie D, Piek JJ, et al. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): A 3 year, randomised, controlled, single-blind, multicentre clinical trial. Lancet 2016; 388: 2479–2491, doi:10.1016/S0140-6736(16)32050-5.
• 5.   Wykrzykowska JJ, Kraak RP, Hofma SH, van der Schaaf RJ, Arkenbout EK, IJsselmuiden AJ, et al. Bioresorbable scaffolds versus metallic stents in routine PCI. N Engl J Med 2017; 376: 2319–2328, doi:10.1056/NEJMoa1614954.
• 6.   Sotomi Y, Onuma Y, Collet C, Tenekecioglu E, Virmani R, Kleiman NS, et al. Bioresorbable scaffold: The emerging reality and future directions. Circ Res 2017; 120: 1341–1352, doi:10.1161/CIRCRESAHA.117.310275.
• 7.   Yamaji K, Ueki Y, Souteyrand G, Daemen J, Wiebe J, Nef H, et al. Mechanisms of very late bioresorbable scaffold thrombosis: The INVEST registry. J Am Coll Cardiol 2017; 70: 2330–2344, doi:10.1016/j.jacc.2017.09.014.
• 8.   Stone GW, Kereiakes DJ, Gori T, Metzger DC, Stein B, Erickson M, et al. 5-year outcomes after bioresorbable coronary scaffolds implanted with improved technique. J Am Coll Cardiol 2023; 82: 183–195, doi:10.1016/j.jacc.2023.05.003.
• 9.   Nakamura M, Suzuki N, Fujii K, Furuya J, Kawasaki T, Kimura T, et al. The Absorb GT1 bioresorbable vascular scaffold system: 5-year post-market surveillance study in Japan. Circ J 2024; 88: 863–872, doi:10.1253/circj.CJ-23-0877.
• 10.   Smits PC, Chang CC, Chevalier B, West NEJ, Gori T, Barbato E, et al. Bioresorbable vascular scaffold versus metallic drug-eluting stent in patients at high risk of restenosis: The COMPARE-ABSORB randomised clinical trial. EuroIntervention 2020; 16: 645–653, doi:10.4244/EIJ-D-19-01079.
• 11.   Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV randomized clinical trial. JAMA 2016; 316: 2373–2384, doi:10.1001/jama.2016.16951.
• 12.   Muramatsu T, Kozuma K, Tanabe K, Morino Y, Ako J, Nakamura S, et al. Clinical expert consensus document on drug-coated balloon for coronary artery disease from the Japanese Association of Cardiovascular Intervention and Therapeutics. Cardiovasc Interv Ther 2023; 38: 166–176, doi:10.1007/s12928-023-00921-2.
• 13.   Nakamura M, Isawa T, Nakamura S, Ando K, Namiki A, Shibata Y, et al. Drug-coated balloon for the treatment of small vessel coronary artery disease: A randomized non-inferiority trial. Circ J 2023; 87: 287–295, doi:10.1253/circj.CJ-22-0584.
• 14.   Varcoe RL, DeRubertis BG, Kolluri R, Krishnan P, Metzger DC, Bonaca MP, et al. Drug-eluting resorbable scaffold versus angioplasty for infrapopliteal artery disease. N Engl J Med 2024; 390: 9–19, doi:10.1056/NEJMoa2305637.
• 15.   Haude M, Wlodarczak A, van der Schaaf RJ, Torzewski J, Ferdinande B, Escaned J, et al. A new resorbable magnesium scaffold for de novo coronary lesions (DREAMS 3): One-year results of the BIOMAG-I first-in-human study. EuroIntervention 2023; 19: e414–e422, doi:10.4244/EIJ-D-23-00326.
• 16.   Gao RL, Xu B, Sun Z, Guan C, Song L, Gao L, et al. First-in-human evaluation of a novel ultrathin sirolimus-eluting iron bioresorbable scaffold: 3-year outcomes of the IBS-FIM trial. EuroIntervention 2023; 19: 222–231, doi:10.4244/EIJ-D-22-00919.