Drug matrix coatings play the critical role in determining the clinical efficacy of drug-eluting stent (DES) devices. In fact, although various surface modifications have been investigated as a means of facilitating loading and controlling release of the active drug, most success has been seen with matrix coatings that combine active drug with a polymeric carrier . Effective DES devices are typically characterized by controlled drug release: approximately 50% of the drug load is eluted in the first 10–14 days and the bulk of the remainder in the first 30–60 days. DES platforms without polymer usually exhibit a release kinetic that is too rapid in the initial weeks after implantation, and this results in a suboptimal suppression of neointimal hyperplasia . Indeed, to date all DESs that have been approved for use in the United States have made use of nonerodable polymer coatings .
Although the clinical effects of DES result from interplay of various design elements, including stent backbone, matrix coating, and drug load and concentration, nonerodable polymer coatings have been implicated as a central factor contributing to the delayed arterial healing that seems to occur systematically with DES therapy . The most likely mechanistic explanation is that chronic inflammatory reaction to the polymer layer that remains on the DES after the active drug has been eluted delays endothelial regeneration . In fact, delayed healing underlies a spectrum of adverse events ranging from late stent thrombosis to delayed catch-up restenosis. In addition, it is likely an important trigger for the development of de novo in-stent atherosclerosis . These observations have provided the impetus for the development of newer generation DES devices that do not depend on durable polymer matrices.
One successful approach to target the problem of delayed arterial healing has been to use DES coated with biodegradable polymer. In fact, although DES with biodegradable polymer are not approved for use in the United States at present, we and other investigators began testing these devices in clinical trials about 10 years ago with largely encouraging results . The hypothesized clinical advantage is intuitively attractive: biodegradable polymer coatings that are made of polylactic acid (PLA) or polylactic-co-glycolic acid control the elution of drug in the critical initial weeks after stent implantation and then degrade to carbon dioxide and water after their useful function has been served. As a result, the long-term footprint of the device is expected to be similar to that of a bare metal stent. Moreover, as some nonclinical evidence suggests that certain nonerodable methacrylate-based polymer coatings may improve stent-blood interactions directly after stent implantation , patients might still theoretically derive the benefit of polymer in the acute phase without incurring the long-term costs of delayed healing.
In the current issue of the journal, Sumida and colleagues present a preclinical investigation comparing data from pigs implanted with biodegradable polymer DES (Nobori, Terumo, Tokyo, Japan) versus durable polymer DES (Xience, Abbott Vascular, Santa Clara, CA) with angiography and euthanasia at 28 days after implantation . The main findings were that: (i) histopathology-derived inflammatory scores were significantly lower with the biodegradable polymer DES as compared with the nonerodable polymer DES; (ii) angiographic analysis showed lower late loss with the biodegradable polymer DES as well as improved vasomotor function; (iii) gene expression of inflammatory cytokines were up-regulated after nonerodable polymer DES in comparison with biodegradable polymer DES.
What are the implications of these data, and how should we interpret the findings in light of the large volume of clinical data already available with both of these stents? First, the results of Sumida et al. extend the observations of other investigators in relation to biocompatibility of biodegradable polymer DES. In addition, there is no signal that degradation of the PLA polymer is associated with adverse effects, though the time point of follow-up at 28 days is probably too short to detect such effects. Amongst others, investigators from our group and another study from St. Joseph’s Translational Institute previously showed lower inflammatory scores in pigs treated with PLA-based DES, though both studies used the early-generation durable polymer Cypher DES as control . The present study shows that these differences can also be seen when newer generation Xience DES is used as comparator. Indeed although this latter stent shows good results in clinical practice, similar to the Cypher stent the durable polymer used contains methacrylate components, which might be responsible for cellular toxic effects . Notwithstanding this, it should be noted that other preclinical studies with Xience show a generally favourable healing profile . Furthermore, the inflammatory reactions after stenting in the porcine coronary model can be quite marked and characterized by granulomatous reactions that are out of line with experiences from clinical studies . Indeed, in the study of Sumida et al., it seems likely that most of the differences in the inflammation scores were due to the presence of higher numbers of granulomas in the nonerodable polymer group; this would be consistent with marked differences in injury scores between the groups at 28 days, which indicate significant disruption of the vessel wall architecture. In this respect, it would have been appropriate to present a sensitivity analysis comparing inflammation scores when granulomas were excluded (as they give a score of 4 and skew the dataset). An alternative approach would have been to present statistical analysis taking into account granulomas as a covariate.
Second, the findings in relation to angiographic data should be interpreted with some caution. Although preclinical studies are very useful in evaluating the safety of coronary stents, they are generally not appropriate for assessment of comparative efficacy . Amongst other factors, efficacy is difficult to reliably assess when stents are implanted in non-stenosed animal arteries. Indeed clinical studies with invasive imaging follow-up as well as large-scale trials powered for clinical endpoints failed to support significant differences in antirestenotic efficacy between the two stents in human use . Moreover, in the present study much of the difference in late loss was likely driven by differences in the incidence of granulomatous reaction. On the other hand, the interesting differences observed in relation to vasomotor dysfunction—with biodegradable polymer DES showing lower rates of paradoxical vasoconstriction to acetylcholine—are concordant with previous observations from trials of vasomotor testing in man . However, again the comparable results seen with both stents in large-scale clinical trials undermine the real clinical relevance of this observation.
Third, the overall relevance of the preclinical results reported here are somewhat limited by the time lag between availability of this device and publication of these data. Indeed, the field of coronary stent development is characterized by rapid iterative development with devices often superseded by newer generation stents in as little as five years . In actual fact, the particular biodegradable polymer stent investigated by Sumida et al. is likely being phased out of clinical practice and replaced by a newer generation device from the same manufacturer .
So as we look to the future, what is the role for biodegradable polymer DES in daily practice in the coming years? Certainly, a variety of new generation biodegradable polymer DES is available (see Fig. 1 ) and in widespread clinical use in catheterization labs around the world. Most of these devices leverage the overall improvements in DES technology over the last 10–15 years, not just regarding polymer coatings but also in relation to choice and dosing of drug as well as strut thickness and stent geometry. In addition to preclinical data and results from modest-sized trials powered for imaging endpoints, the clinical efficacy of many of these biodegradable polymer DESs is supported by data from large-scale clinical trials powered for clinical endpoints. The results at primary endpoint assessment after 12 months are generally consistent in showing non-inferiority against current generation durable polymer DES . Indeed this should be a pre-requisite for their use in practice. Moreover, although network meta-analyses raised some questions regarding a higher risk of stent thrombosis in the first year with biodegradable polymer DES versus newer generation nonerodable polymer stents, this is not borne out by examination of the individual direct comparison studies .
