Bioresorbable Scaffolds: The New Tool in PCI

Coronary Artery Disease and Durable Metallic Stents

Coronary artery disease (CAD) is the leading cause of death among all forms of heart disease and accounts for one in every five deaths in the United States.1 Given the profound impact of CAD-related morbidity and mortality, the development of improved therapies for CAD is critical. Coronary artery stenting is now an established therapy for patients with obstructive CAD ranging from stable angina to acute coronary syndromes. Clinical trials have demonstrated that drug-eluting stents (DES) significantly reduced in-stent restenosis and target lesion revascularization compared with bare-metal stents (BMS).2,3 However, conerns remain about the risk of late and very late stent thrombosis after DES implantation, which can result from delayed stent endothelialization as well as hypersensitivity reactions to the durable polymers employed in drug delivery, leading to poor intimal healing and providing a substrate for stent thrombosis.4 Furthermore, DES leave a permanent metal implant in the coronary vessel wall that could interfere with vasomotion, endothelial function, and vessel remodeling. Although the rigid structure of BMS and DES is helpful to prevent acute or threatened arterial closure after percutaneous coronary intervention (PCI), it does not allow for restoration of normal arterial function after the procedure. Additionally, when BMS or DES are placed at coronary artery bifurcations, there is a risk of side branch vessel compromise by the stent struts.

Bioresorbable Coronary Scaffolds

The limitations of current coronary metallic stent designs have triggered interest in improved stent designs using fully bioresorbable vascular scaffolds (BVS). Scaffolds are designed to provide 1) vessel support acutely to prevent acute vessel closure and 2) anti-proliferative drugs transiently to prevent neointimal hyperplasia but be completely absorbed and integrated into the vessel wall in the long term, providing several potential advantages over existing permanent DES implants, including the following:

  • Restoration of physiologic vasomotion
  • Late expansive remodeling
  • Reduced risk of stent thrombosis
  • Ability to graft scaffolded segments of coronary artery
  • Avoidance of problems associated with jailing side branches
  • Improved imaging with computed tomography or magnetic resonance imaging

In general, two major approaches to the material construction of BVS have been investigated: metallic and polymer-based. For polymer-based scaffolds, multiple polymers are available with different chemical compositions and mechanical properties including bioabsorption times. Poly-L-lactic acid (PLLA) is the most commonly used polymer in BVS given its widespread use in other clinical arenas such as sutures and biological implants. PLLA is broken down via depolymerization and hydrolysis. The smaller chains are then metabolized by phagocytes into soluble monomers that are metabolized into pyruvate. Pyruvate is able to enter the Krebs cycle and is metabolized into carbon dioxide and water.5

Metallic BVS are an appealing concept because they may be expected to have performance characteristics similar to conventional metallic stents such as profile, deliverability, and radial strength. There are two types of metallic BVS that have been attempted: iron alloys and magnesium alloys. Magnesium alloys are the most commonly used bioresorbable metallic substrate due to their biocompatibility. Given their increased initial radial strength compared with polymeric scaffolds, magnesium bioresorbable stents are able to have thinner struts. Degradation products from magnesium alloy stents are not expected to cause adverse effects given that magnesium itself has been investigated.6

Table 1: Summary of Available Bioresorbable Scaffolds

Device
(Manufacturer)

Scaffold Material

Ancillary Medicinal Substance

Strut Thickness (mcm)

Resorption Timeframe (months)

Regulatory Status

Absorb BVS 1.0
(Abbott Vascular, Santa Clara, CA)

PLLA

Everolimus

156

18-24

Discontinued

Absorb BVS 1.1
(Abbott Vascular, Santa Clara, CA)

PLLA

Everolimus

156

24-48

FDA approved, CE marked

DESolve
(Elixir Medical Corporation, Sunnyvale, CA)

PLLA

Myolimus

150

12-2

CE marked

ART PBS
(Arterial Remodeling Technologies, Paris, France)

PLLA

None

170

3-6

CE marked

REVA
(REVA Medical Inc., San Diego, CA)

Polytyrosine-derived polycarbonate

None

200

24

Discontinued

ReZolve
(REVA Medical Inc., San Diego, CA)

Polytyrosine-derived polycarbonate

Sirolimus

115-230

4-6

Investigational

ReZolve 2
(REVA Medical Inc., San Diego, CA)

Polytyrosine-derived polycarbonate

Sirolimus

115-230

4-6

Investigational

Igaki-Tamai Stent
(Kyoto Medical Planning Co., Kyoto, Japan)

PLLA

None

170

24-36

CE marked (peripheral)

XINSORB
(Shanghai Weite Biotechnology Co., Shanghai Municipality, China)

PLLA

Sirolimus

160

Not reported

Investigational

FORTITUDE
(Amaranth Medical, Inc., Mountain View, CA)

PLLA

None

150-200

3-6

Investigational

Ideal BioStent
(Xenogenics Corporation, Lincoln, RI)

PLLA

Sirolimus

200

6-9

Investigational

AMS-1
(Biotronik SE & Co. KG, Berlin, Germany)

Mg alloy

None

165

<4

Discontinued

DREAMS 1G
(Biotronik SE & Co. KG, Berlin, Germany)

Mg alloy

Paclitaxel

125

9

Investigational

DREAMS 2G
(Biotronik SE & Co. KG, Berlin, Germany)

Mg alloy

Sirolimus

150

9

Investigational

This review focuses on the data supporting the Absorb BVS (Abbott Vascular, Santa Clara, CA), which is currently the only scaffold with US Food and Drug Administration approval.

Absorb BVS

The balloon-expandable Absorb BVS is composed of PLLA with 156 mcm thick stent struts and elutes the anti-proliferative medicinal substance everolimus.7 Because the polymer is not inherently radiopaque, two platinum radiopaque markers are incorporated into the scaffold for visualization and deployment. The scaffold is mounted on the VISION RX delivery system (Abbot Vascular, Santa Clara, CA).

The Absorb BVS has undergone the largest and most extensive evaluation of the polymeric scaffolds. The ABSORB family of clinical studies has demonstrated the feasibility of delivering a BVS with struts that are thicker than conventional durable metallic scaffolds to simple coronary lesions.

Since its first implantation in 2007,8 the performance of the Absorb BVS was evaluated in the ABSORB II9 and ABSORB III trials.10 In the randomized, prospective, multicenter, single-blind ABSORB III trial, 2,008 patients with stable or unstable angina were randomly assigned to either the Absorb BVS or an everolimus-eluting cobalt chromium DES (Xience EES [Abbot Vascular, Santa Clara, CA]).7 Procedural success was high in both the Absorb BVS and Xience EES groups (94.6 vs. 96.2%, p = 0.12). In addition, 1-year target lesion failure rates (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization) were noninferior for the Absorb BVS compared with the Xience EES (7.8 vs. 6.1%, p = 0.007).7 ABSORB III demonstrated no significant difference in 1-year probable/definite stent thrombosis between the Absorb BVS group and Xience EES group (1.5 vs. 0.7%, p = 0.13).7 Although the ABSORB III trial included predominantly stable patients with relatively simple coronary lesions, studies have also revealed high procedural success rates and outcomes of the Absorb BVS in more complicated lesions such as small vessels, longer lesions, and in patients with ST-segment elevation myocardial infarction.11-18 For example, in the large multicenter, real-world GHOST-EU (Gauging coronary Healing with bioresorbable Scaffolding plaTforms in EUrope) registry, 1,189 patients received 1 or more Absorb BVS, and technical success was achieved in 99.7% of patients.19 However, treatment with overlapping Absorb BVS for longer and/or complex lesions may be associated with longer procedure length and fluoroscopy time compared with conventional DES.15

An additional potential benefit of BVS is improved vessel conformability compared with rigid metallic stents, better allowing the vessel to maintain its natural shape. On implantation, the Absorb BVS has improved geometric parameters by intravascular ultrasound (IVUS) compared with durable stents and may allow for normalization of vascular compliance and geometry over time.20-22 Furthermore, because BVS do not leave a rigid structure behind after degradation, normal coronary vasomotion can be restored. Serial imaging evaluations have demonstrated the evolution of vasomotion restoration after the Absorb BVS is implanted and undergoes resorption.23-26 Using intracoronary nitrate and ergonovine injections, there was no significant vasomotion at 6 months follow-up after the Absorb BVS implantation, and there was significant vasoconstriction and vasodilation at 1 year. At 2 and 3 years, significant vasodilation was seen when only intracoronary nitrate was injected.24

Of note, because of the different mechanical properties of BVS, there is a learning curve to optimize implantation.27 Expansion of the scaffold is important because malapposition can be associated with peri-stent evagination, which has been a proposed mechanism for scaffold/stent thrombosis.28,29 Optimal lesion preparation (such as pre-dilatation with a noncompliant balloon) improves procedural and fluoroscopy time and acute results.30-32 Post-dilatation does not appear to impact procedural or clinical outcomes.

The implantation technique for the Absorb BVS is different from that of metallic DES implantation. Adequate lesion preparation is required to facilitate full scaffold expansion. The vessel should be pre-dilated with a noncomplaint balloon with the goal of achieving 20-40% residual stenosis after pre-dilatation. A second inflation is performed to confirm that the vessel is optimal for BVS. If there is no lesion waist present, then the operator can proceed with scaffold implantation. If there continues to be a waist at the lesion, then the operator should consider additional vessel prepation with either cutting balloon, rotational atherectomy, or laser. The vessel should then be sized using either IVUS or optical coherence tomography to select the appropriate scaffold size, particularly in small (<2.7 mm) vessel sizes. Because the Absorb BVS is not radiopaque, two pairs of platinum markers have been incorporated on the balloon and on the scaffold to aid with placement. The proximal scaffold marker is 1 mm from the scaffold edge, and the distal scaffold marker is 0.3 mm from the scaffold edge. It can be useful to use zoomed images and/or 30 frames per second (instead of 15 frames per second) to visualize these markers, in particular for positioning of additional scaffolds to avoid scaffold overlap. In order to deploy the scaffold, the scaffold is expanded slowly using 2 atm over 5 seconds until the scaffold is completely expanded. Once obtained, the target deployment pressure should be held for at least 30 seconds. High pressure post-dilatation should be performed to achieve <10% final residual stenosis and ensure full strut apposition; however, to avoid damaging the scaffold, the scaffold should not be post-dilated beyond its maximum expansion range. IVUS or optical coherence tomography should be used after scaffold implantation to evaluate for complete strut apposition.

Although data have supported multiple benefits of using BVS, studies have suggested some limitations with this new technology. A large meta-analysis of the ABSORB clinical studies, which included 3,738 randomized patients treated with Absorb BVS or everolimus-eluting metallic stents, demonstrated a higher risk of definite or probable stent thrombosis in patients treated with the Absorb BVS than those treated with metallic stents (odds ratio 1.99 [95% confidence interval 1.00-3.98], p = 0.05).33 Similarly, in an expanded meta-analysis that included registry and randomized data, the rate of definite or probable stent thrombosis was higher in patients treated with the Absorb BVS compared with patients treated with DES (odds ratio 2.06 [95% confidence interval 1.07-3.98]; p = 0.03).34 Thus, additional studies and long-term follow-up are required to elucidate whether these scaffolds do indeed have higher stent thrombosis rates and whether there are certain vessel characteristics associated with higher adverse event rates. For example, a post-hoc analysis of the ABSORB III trial demonstrated that there was a higher risk of stent thrombosis rate when either the Absorb BVS or DES were used in vessels with a reference diameter < 2.25 mm.35 This was a non-significant trend; nonetheless, this led to a warning on the Absorb BVS's instructions for use that implantation of this device in small vessels could increase the risk of adverse events.

Table 2: Advantages and Challenges of BVS

Advantages

Challenges

Conformable and flexible to preserve vessel geometry

Developing a scaffold with sufficient radial strength during the critical time period

Once resorbed:

  • No foreign material left behind
  • Restoration of functional endothelial coverage
  • Allows the restoration of physiological vasomotion
  • Avoids jailing of side branches or overhanging at ostial lesions
  • Allows to graft stented segments of coronary artery

Visualization of the scaffold for implantation

Deliverability of the devices

Summary and Conclusions

BVS technology has evolved significantly over the last decade, and multiple clinical trials are currently investigating the efficacy and performance of BVS. The largest clinical trial to date for BVS, ABSORB III, has clearly demonstrated the feasibility of this technology. Nonetheless, there are still limitations that need to be overcome. Current limitations of BVS include ensuring adequate radial support36 and deliverability. In order to provide adequate radial support, polymeric scaffolds have thicker struts (150-250 mcm) than metallic stents (80 mcm). Furthermore, there are challenges with crimping the polymeric scaffolds onto balloon delivery systems, resulting in overall larger crossing profiles of scaffolds (1.4-1.8 mm) compared with DES (approximately 1.0 mm). As a result, scaffolds have largely been used in simple lesions, and delivery to complex and tortuous lesions may be technically challenging. Additionally, polymeric scaffolds made with PLLA are not inherently radiopaque and cannot be seen by fluoroscopy, making accurate delivery/deployment more difficult. Therefore, continued advancements in BVS technology are necessary to provide the maximum benefit to patients with CAD. In addition, long-term safety and efficacy data are still needed for this technology.

References

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Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Magnetic Resonance Imaging, Chronic Angina

Keywords: Acute Coronary Syndrome, Angina, Stable, Angina, Unstable, Atherectomy, Coronary, Biotechnology, Constriction, Pathologic, Coronary Artery Disease, Drug-Eluting Stents, Magnetic Resonance Imaging, Myocardial Infarction, Percutaneous Coronary Intervention, Polycarboxylate Cement, Thrombosis, Tomography, Optical Coherence, Vasoconstriction, Vasodilation


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