The ongoing quest for optimal coronary stenting provides further innovations in stent designs and material properties utilizing biodegradable polymers or biocorrodible metals for engineering coronary scaffolds. The impetus for developing drug-eluting bioresorbable scaffolds (BRS) has been driven by the need for elastic and transient platforms instead of stiff and permanent metallic implants in diseased coronary anatomies that enable prevention of acute recoil or occlusion, allow sealing of post-procedural dissections following acute barotrauma, and provide inhibition of in-segment restenosis through efficient drug-elution. After the acute revascularization and mid-term healing phase, the long-term restoration phase follows as the biological elimination of the implanted scaffold is anticipated over a three-year time interval.

This technological endeavor promises to overcome long-term implications of non-compliant metal caging over a pulsatile vascular tissue. Indeed, the clinical endpoints following deployment of first-generation drug-eluting BRS for mechanically treating coronary artery disease are anticipated to be non-inferior when compared with current-generation drug-eluting stents (DES), as well as the rates of late clinical events attributed to either late restenosis (late catch-up) or late and very late scaffold thrombosis are expected to be reduced. Preliminary observations derived from multicenter registries such as the ABSORB Cohorts A and B^1-3 and ABSORB Extend,⁴ assessing the clinical safety and efficacy of the Absorb™ BVS, as well as the BIOSOLVE-I⁵ and DeSolve-1 studies which assessed the clinical safety and efficacy of the DREAMS-1 and DESolve scaffolds (Figure 1) have indicated the potentialities of these technologies.

Figure 1: BRS Family Illustrating the Major Clinical and Imaging Findings

Physiologic Restoration (Restoration of Function)

The liberation of the treated segment from its permanent metal cage will provide physiologic recovery of both vasomotor function and vessel pulsatility through repaired endothelial cell signaling and restored mechanotransduction (translation of mechanical forces in chemical signals). In addition, the compensatory mechanisms of adaptive expansive remodeling as well as lumen gain will be reactivated allowing a more physiologic response to the underlying flow-mediated stimuli.

Thrombogenic Risk Attenuation

The risk of late or very late scaffold thrombosis is expected to be eliminated following scaffold degradation (platform + coating) by replacing the resorption sites (sites previously occupied by polymeric struts) with connective tissue and minimizing the risk of late acquired strut malapposition. Late or very late stent thrombosis remains a major concern even with newer-generation DES; while older-generation DES retain a stent thrombosis risk of 0.4-0.6%/year.⁶

Elimination of the Risk of In-Scaffold Neoatherosclerosis and Its Clinical Implications

In-stent neoatherosclerosis has been observed with both metallic DES and bare-metal stents (BMS). Delayed endothelial healing associated with inefficient or sustained endothelial dysfunction are the most prevalent precipitating mechanisms; meanwhile, the complete mechanism of delayed plaque growth has not been fully elucidated. Despite the paucity of long-term imaging data following BRS implantation, the combination of complete scaffold resorption, regenerated intact endothelium with restored vasomotor function and plaque passivation^7,8 will potentially eliminate the risk and the subsequent clinical implications of in-scaffold neoatherosclerosis.

Anatomic Restoration (Restoration of Form)

BRS are more compliant platforms compared to metallic stents, diminishing the extent of disturbed flow patterns and associated vascular responses over the scaffolded segments and the proximal and distal edges by limiting vascular straightening. Both vessel angulation and curvature are anticipated to be restored by the time the scaffold eliminates its radial strength. In addition, any area/diameter mismatch causing step-up (proximal edge) or step-down (distal edge) regions, which generate local anatomic alterations with subsequent disturbances in fluid mechanics (wall shear stress) are expected to subside following scaffold resorption.

A recent observation derived from the one-year interim analysis of the ABSORB II randomized clinical trial, which compared a fully resorbable scaffold with a metallic stent showed significantly reduced anginal episodes in patients treated with a biodegradable scaffold. Although this preliminary observation indicates a new era of novel clinical endpoints, further studies are needed to identify whether this is associated with the anatomic and functional recovery of the treated segments potentially linked to the restored fluid and solid mechanical microenvironment following gradual scaffold resorption.⁹

Pediatric Applications

Absorbable scaffolds appear as more appropriate technologies for the treatment of pediatric obstructive vascular lesions, such as aortic coarctation and pulmonary artery stenosis. Permanent metallic implants limit vessel growth and require future surgical removal in contrast to bioresorbable devices, which are able to allow natural vessel growth after the time of radial strength elimination and further resorption.

Despite the overall encouraging results following deployment of BRS in non-complex lesions of highly selective patients and the hypothetic beneficial properties over DES, the paucity of randomized clinical trials with hard clinical endpoints (cardiac death, target vessel myocardial infarction, or clinically-driven target lesion revascularization) following head-to-head comparisons of BRS with current generation DES generated skepticism among the interventional community. Only recently, the results of the first large-scale ABSORB III randomized clinical trial as well as ABSORB China and ABSORB JAPAN were reported and solidified the merit of BRS technologies in the interventional treatment armamentarium.

ABSORB III is the largest multicenter randomized clinical trial and enrolled 2,008 patients assigned in a 2:1 ratio to receive either an everolimus-eluting Absorb BVS or a cobalt-chromium Xience stent. The primary endpoint of non-inferiority was target lesion failure (composite of cardiac death; target-vessel myocardial infarction; or ischemia-driven, target-lesion revascularization) at one year, occurring in 7.8% in the Absorb BVS arm and in 6.1% in the Xience arm (difference, 1.7 percentage points; 95% confidence interval, −0.5 to 3.9; p = 0.007 for non-inferiority). Device thrombosis at one year among both arms was not statistically different occurring in 1.5% of patients in the Absorb BVS arm versus 0.7% of patients in the Xience group (p = 0.13).¹⁰

The ABSORB China trial was reported simultaneously with ABSORB III. Four hundred eighty patients scheduled for elective percutaneous intervention were randomized in a 1:1 fashion to either Absorb BVS or Xience stent. The primary endpoint of in-segment late lumen loss (LLL), which was powered for non-inferiority at one year was 0.19 ± 0.38 mm vs. 0.13 ± 0.37 mm (P_{non-inferiority} = 0.01).¹¹

Finally, the ABSORB Japan was another trial that enrolled 400 patients randomized in a 2:1 fashion to either Absorb BVS or Xience stent. The study met its primary endpoint of non-inferior target lesion failure among the two arms at one year reaching 4.2% in the Absorb arm versus 3.8% in the Xience arm. The secondary endpoint of in-segment LLL at one year was 0.13 ± 0.30 mm versus 0.12 ± 0.32 mm (P_{non-inferiority} = 0.0001).¹²

ABSORB III, ABORB China, and ABSORB Japan proved the clinical safety and non-inferior efficacy of Absorb BVS versus current-generation DES at one year. Although further improvements in next-generation BRS technologies are anticipated to meet superiority endpoints when compared with current-generation DES, these data will most likely suffice for regulatory approval in the U.S. and China.

Clinical Applicability and Special Considerations

Although BRS appear appealing alternatives to metal stents in specific lesions and population subsets with potential long-term benefits attributed to full resorption and subsequent long-term functional and anatomic vessel restoration, current generation DES have revolutionized the practice of interventional cardiology and remain the standard of care. As of now, only the Absorb BVS has acquired clearance for U.S. pre-market approval, which allows safety and efficacy testing in the U.S. based large-scale randomized clinical trials such as the ABORB III and ABSORB IV.

Strut design (rectangular, circular, elliptical, or tear-drop) and more in particular strut thickness is an important determinant of target vessel revascularization;¹³ thus, current-generation DES are engineered with thinner struts in the range of 90-μm. Bulky struts are prone to side-branch jailing or occlusion, delayed endothelialization in particular when overlapped scaffolds are implanted and increased mechanical stresses over the vessel wall. First-generation BRS technologies have been introduced with a strut thickness similar to that of Cypher metallic stents (150-μm) to maintain their mechanical properties, as bioresorbable polymers or biocorrodible metals have inferior tensile strength compared to metallic materials.

This design increases their overall crossing profile at the crimped stage (~1.4-mm); restricts deliverability in tortuous anatomies, calcified lesions, and small vessels (vessel diameter <2.5-mm); and induces a more robust vascular response as opposed to stents with thinner cells. Indeed, the evidence derived thus far from phase I and II clinical trials after BRS implantation has been acquired with observations in de novo coronary lesions in vessels 2.5 to 3.5-mm in diameter.

Polymer-based scaffolds and, to a lesser extent, scaffolds made of biocorrodible metals have limited expansion properties, and over-dilation entails the risk of strut fracture or discontinuity. It is imperative for operators who implant drug-eluting BRS to perform aggressive lesion preparation by adequate pre-dilatation with a near-optimal size, non-compliant balloon to high pressures. Since biodegradable scaffolds have limited tensile strength as compared to metallic stents resulting in acute scaffold recoil and potentially under expansion increasing the risk for sub-clinical or clinical restenosis, the operator should consider lesion preparation with high balloon inflation pressures using non-compliant balloons, scoring balloons and/or rotational atherectomy according to the anatomic substrate.^14-16 The accurate scaffold to artery sizing ratio of 1:1 by quantitative coronary angiography is mandatory to precisely select the most appropriate scaffold diameter. Post-dilation should not exceed a 0.5-mm diameter overstretch of the deployed scaffold, with inflation pressures not exceeding 18-20 atm. Intravascular imaging with light-based modalities, such as optical coherence tomography (OCT), appears an imperative tool to assess plaque modification after balloon angioplasty and coronary atherectomy procedures prior to scaffold deployment, as well as scaffold expansion or edge dissections following deployment.

The use of BRS in complex lesions, such as bifurcation scaffolding, has been only investigated in vitro with bifurcation phantom models. Provisional scaffolding is the standard approach with sequential non-compliant balloon inflations in the side branch followed by the main branch, reserving final kissing balloon inflations, if necessary. Two-scaffold BVS crush and culotte techniques require careful evaluation, and should only be considered in patients with large-caliber main vessels.¹⁷ The mid- and long-term clinical outcomes were carefully evaluated in a recent "real-world" European BVS registry (GHOST-EU), which enrolled 1,189 patients and included complex percutaneous interventions, such as acute coronary syndromes (ST-elevation myocardial infarction) and left main interventions.¹⁸ The reported cumulative incidence of definite/probable scaffold thrombosis was 1.5% at 30 days and 2.1% at 6 months, raising concerns over the appropriateness of BRS utilization in complex lesions despite the predefined recommendation of one year of dual antiplatelet therapy.¹⁸

The incremental cost effectiveness ration is of particular importance in the setting of U.S. health care reform with the use of novel interventional devices. Prior experience demonstrated that more than 1 million interventional procedures were performed in the U.S. health care system in 2004 following Food and Drug Administration approval of first-generation DES with costs generally 3- to 4-times more compared to costs of BMS. Meanwhile the overall projected cost with first-generation DES was compensated by reducing the economic burden of clinical restenosis associated with BMS of 16.9% in the first year. Increased competition further reduced the costs of newer generation DES, and it was recently demonstrated that higher index expenditures of DES were completely offset by lower costs due to lower rates of clinical restenosis. BRS in Europe, Asia-Pacific, and South America are priced generally 2 times more compared to the price of newer-generation DES. Subsequently, the comparable cost effectiveness and quality-adjusted life years with current generation DES is another barrier that these novel technologies have to overcome, if the broad clinical application and wide U.S. market penetration need to be achieved.

Conclusion

Next-generation BRS technologies are expected to revolutionize the treatment of coronary artery disease. Current evidence from first-in-man and large-scale randomized clinical trials indicate their non-inferiority to current-generation DES and their unique reparative properties. Meanwhile, there is not clear superiority yet. Experienced operators should handle these technologies in selected lesions and clinical subsets. Future design improvements are anticipated and additional randomized trial results will further solidify whether these novel scaffolds will acquire a place in the treatment armamentarium of interventional cardiology.

References

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Keywords: Angiography, Acute Coronary Syndrome, Angioplasty, Balloon, Coronary, Aortic Coarctation, Atherectomy, Coronary, Barotrauma, Chromium, Cobalt, Confidence Intervals, Connective Tissue, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Cost-Benefit Analysis, Dilatation, Drug-Eluting Stents, Endothelial Cells, Endothelium, Health Care Reform, Health Expenditures, Incidence, Mechanotransduction, Cellular, Myocardial Infarction, Polymers, Pulmonary Artery, Registries, Sirolimus, Standard of Care, Stress, Mechanical, Tensile Strength, Thrombosis, Tomography, Optical Coherence, United States Food and Drug Administration, omega-Chloroacetophenone

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