Author + information
- Gregg W. Stone, MD∗ ()
- Columbia University Medical Center, NewYork-Presbyterian Hospital, and the Cardiovascular Research Foundation, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Gregg W. Stone, Columbia University Medical Center, Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022.
Last week I was watching the classic film Back to School, in which Rodney Dangerfield plays successful middle-age entrepreneur, Thornton Melon, a high school dropout who attends college to support his struggling son and in the process restores his own self-dignity. He is attracted to one of his professors and asks her out, but is repeatedly rebuffed because she is busy teaching class, to which he replies “Why don’t you call me sometime when you have no class?” (Rodney Dangerfield to Sally Kellerman in Back to School) (1).
In this context, in this issue of JACC: Cardiovascular Interventions, I reviewed the fascinating report by Abizaid et al. (2) detailing the 6-month and 2-year results with the DESolve bioresorbable vascular scaffold (BRS) (Elixir Medical, Sunnyvale, California), which led to my reflecting on the extent to which there is a “class” effect with different BRS.
But first some background. Contemporary metallic drug-eluting stents (DES) have markedly improved the 1-year rates of event-free survival after percutaneous coronary intervention (PCI) compared with first-generation DES and earlier angioplasty devices. Yet study after study demonstrates that after the first year, all metallic stents are associated with 2% to 3% per year rates of very late target lesion–related events due to an ongoing risk of restenosis or stent thrombosis, a phenomenon that has been documented to occur for at least 5 years for DES and 15 to 20 years for bare metal stents, with no plateau in sight (3,4). The mechanisms underlying these very late events likely relate to the presence of a permanent metallic frame that straightens the vessel, causes abnormal shear stress and loss of cyclic strain relief, impairs vasomotion at the stent site (and distally), serves as a source of chronic inflammation, inhibits complete endothelialization, provides a structure for neoatherosclerosis, and affords the opportunity for late strut fracture.
To overcome these limitations, BRS have been developed that offer the mechanical support and drug delivery functions of metallic DES within the first 3 to 12 months, then completely resorb over the next few years, theoretically restoring normal vascular function and removing the nidus for very late adverse events. Exquisite serial imaging studies with the prototypical BRS, the poly-l-lactic acid (PLLA)-based everolimus-eluting ABSORB BVS (Abbott Vascular, Santa Clara, California) have demonstrated return of cyclic pulsatility and restoration of vasomotion at the scaffold site by 12 months, an increase in scaffold and lumen areas between 12 and 24 months, and complete resorption within 3 years, with return of adaptive vascular responses (Glagovian remodeling) (5). More than 20 BRS are under development, and close inspection reveals substantial differences between these devices. The first major distinction is whether the principal BRS component is polymer or metal. Polymers tend to have lower tensile strength and ductility than metals, often requiring thicker and wider struts to provide acceptable mechanical support, although the ratio of crystalline to amorphous polymer and processing methods can increase stiffness. Most BRS polymers absorb by bulk erosion, with the surface and interior of the material degrading at similar rates, a nonenzymatic process, which for most polymers is controlled mainly by temperature and water concentration. In contrast, most metallic BRS (magnesium and iron alloys) degrade (“corrode”) by surface erosion. BRS strut dimensions (thickness and width), surface area coverage ratio (substantially greater than for contemporary metallic DES), cell design, configuration, and expansion capability before fracture vary greatly between devices. Most BRS are radiolucent, relying on radiopaque metallic markers at the device ends to delineate their position. An exception is the Fantom (Reva Medical, San Diego, California), composed of an iodinated polytyrosine–derived polycarbonate polymer, which is as visible as a metallic DES. Most BRS elute an antiproliferative agent to inhibit the neointimal vascular response to injury, similar to metallic DES, although the drug type, carrier vehicle, concentration, and elution rate vary from device to device. Importantly, the duration required for complete scaffold absorption (mass loss) has ranged from 3 months to 4 years or longer for different BRS, which has major implications for the scaffold’s ability to resist early recoil and constrictive remodeling and for the time to restoration of normal vascular physiology and function when potentially improved clinical outcomes compared with metallic DES might emerge.
Abizaid et al. (2) describe the intermediate-term imaging and clinical results with the DESolve novolimus-eluting BRS (Elixir Medical), a novel device composed of multiple polymers (including PLLA), which, along with proprietary material processing, confers several differentiating features. Composed of 150-μm thick struts (with 165-μm wide hoops), DESolve has slightly less radial strength than ABSORB, but demonstrates an initial “self-correction” property such that any tendency for initial recoiling is offset within the first few hours after deployment as the unconstrained device expands toward its nominal diameter (6). This “pre-programmed memory” function as the crimped device hydrates would be expected to increase scaffold dimensions and minimize malapposition, attributes that may be especially useful after device underdeployment or in ST-segment elevation myocardial infarction (STEMI), in which infarct-related vessel dimensions tend to increase over time after PCI. DESolve is designed to provide structural integrity and radial support for at least 3 months and then completely bioabsorb within 1 to 2 years (7). DESolve also has greater expansion capability than other PLLA-based BRS, capable of diameters of 5.0 mm without fracturing (6), although hoop strength will be substantially reduced at these dimensions. DESolve is meant to be stored at 0°C to 8°C to prolong shelf life and consistency and is warmed in the body for 60 s before deployment.
In the DESolve NX registry, 126 patients with noncomplex de novo native coronary artery lesions (2.75 to 3.5 mm reference vessel diameter, ≤14 mm in length) were treated with a single DESolve scaffold. Device success was 97%; in 4 patients with fibrocalcific vessels, the scaffolds could not reach or cross the lesion, attributable to the relatively high profile of this first-generation device (6). All 4 were treated successfully with metallic DES, including 1 case in which the scaffold detached from the balloon. The primary endpoint was in-scaffold late lumen loss at 6 months determined by quantitative coronary angiography (QCA), which at 0.20 ± 0.32 mm is in the range of that expected from potent metallic DES (and similar to ABSORB). There were 4 cases (3.5%) of binary restenosis at 6 months. Major adverse cardiac events (MACE) occurred in 3.3%, 5.7%, and 7.4% of patients at 6, 12, and 24 months, respectively, with only 1 case (0.8%) adjudicated as a definite or probable scaffold thrombosis. Most interestingly, intravascular ultrasound (IVUS) and optical coherence tomography (OCT) were performed at baseline and 6 months in 40 and 38 patients, respectively, demonstrating a significant increase in scaffold and luminal dimensions at this early time point (faster than is seen with the ABSORB scaffold). How much of this is due to the DESolve’s self-correction property within the first few hours after implantation versus accelerated scaffold absorption and remodeling is uncertain. On OCT, a high proportion of struts had tissue coverage at 6 months (98.8 ± 1.7% per patient, with a mean thickness of 100.5 ± 30.6 μm), although whether this represents healthy endothelium and protects against device thrombosis is unknown.
Three-year follow-up has been reported for this study (8). Paired QCA was repeated at 6 and 18 months in 19 patients from a single center, demonstrating a nonsignificant increase in in-scaffold late lumen loss from 0.23 ± 0.33 mm to 0.29 ± 0.34 mm over time (p = 0.10). Paired QCA follow-up at 6 and 36 months in 19 patients from a second center again showed a nonsignificant increase in late lumen loss from 0.12 ± 0.14 mm to 0.22 ± 0.33 mm (p = 0.20). By IVUS and OCT, the scaffold area continued to increase from 6 to 18 months, as did the neointimal area and vessel area; as such, the lumen area was preserved (Glagovian remodeling). There was only 1 additional adverse event after 2 years, bringing the total 3-year MACE rate to 8.2%, including 0 definite and 1 (0.8%) probable scaffold thromboses.
Although BRS may circumvent some of the shortcomings of metallic stents, 1 novel failure mode of BRS that does not occur with DES is that of intraluminal scaffold dismantling (ILSD), the protrusion of sections of the scaffold into the lumen due to segmental bulk erosion, which may occur when little neointimal tissue is present to otherwise restrain the scaffold struts (9). ILSD has been associated with several cases of very late (>1 year) scaffold thrombosis with ABSORB (9,10), and its frequency may be increased and time course shortened with devices that absorb more rapidly. In this regard, OCT in 38 DESolve scaffolds at 6 months demonstrated misaligned struts otherwise fully constrained by neointimal tissue in 12 cases (31.6%) and nonconstrained free-floating struts with loss of scaffold geometry (ILSD) in 5 cases (13.6%) (2). Although the relationship between these findings and adverse events in this registry is uncertain, at least 1 case of ILSD with a DESolve resulting in scaffold collapse at 5 months with subtotal occlusion has been reported (11). The frequency and clinical implications of this phenomenon should be carefully studied in all future BRS studies.
In conclusion, the vast array of BRS devices that have been developed for human investigation are in many ways more different than alike, and the concept of a class effect must be rejected. Trials comparing different BRS will be useful in identifying which of their unique properties are most beneficial to patients (e.g. defining the optimal rate of structural support and bioresorption). However, further complicating this task is the fact that all first-generation BRS are being rapidly iterated to enhance deliverability and otherwise optimize their mechanical and biologic performance. In this regard, the DESolve CX scaffold with a 120-μm strut thickness is currently undergoing human evaluation, and a specific DESolve scaffold (the Amity), which self-corrects by up to 0.6 mm in diameter over 3 days, has been developed for use in STEMI. Ultimately, whether all BRS are as safe and effective as best-in-class metallic DES within the first year of implantation and thereafter provide superior long-term clinical outcomes can only be answered by large-scale randomized trials.
↵∗ 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. Stone is the chairman of the Abbott Vascular sponsored ABSORB III and IV trials (uncompensated) and a consultant to Reva Corp.
- American College of Cardiology Foundation
- ↵Back to School - Call Me When You Have No Class. Available at: http://youtu.be/bJaz_S4deTM. Accessed January 29, 2016.
- Abizaid A.,
- Costa R.A.,
- Schofer J.,
- et al.
- Gada H.,
- Kirtane A.J.,
- Newman W.,
- et al.
- Yamaji K.,
- Kimura T.,
- Morimoto T.,
- et al.
- ↵Onuma Y, Nakatani S, van Geuns RJ, Lara JG, Serruys PW. Scaffolds vs Stents: 5-Year Insights from Longitudinal Imaging Studies. Available at: http://www.tctmd.com/show.aspx?id=126636. Accessed January 10, 2016.
- Verheye S.,
- Ormiston J.A.,
- Stewart J.,
- et al.
- ↵Abizaid A. Prospective, Multi-Center Evaluation of the DESolve Novolimus-Eluting Bioresorbable Coronary Scaffold: 3-Year Clinical and Imaging Results. Available at: http://www.tctmd.com/show.aspx?id=131943. Accessed January 10, 2016.
- Stone G.W.,
- Granada J.F.
- Räber L.,
- Brugaletta S.,
- Yamaji K.,
- et al.
- Braun D.,
- Baquet M.,
- Massberg S.,
- Mehilli J.,
- Hausleiter J.