It’s been over a decade since drug-eluting stents (DES) were introduced into the clinical practice of percutaneous coronary intervention for the treatment of coronary artery lesions. With significant reductions in restenosis rates and the need for repeat revascularizations, the technology was disseminated globally at an unprecedented rate . Soon after, reports of early and late stent thrombosis curbed the enthusiasm and mandated selective DES uses and prolonged dual antiplatelet therapy (DAPT) for at least 12 months . This strategy significantly reduced stent thrombosis rates, albeit at the price of bleeding, which has often led to premature DAPT discontinuation . Additionally, first-generation DES, Cypher and Taxus, reported a stent thrombosis increasing hazard of 0.6 per year up to 5 years and even higher rates of target lesion failure . First-generation DES were then replaced with second-generation DES that utilize a thinner cobalt chromium or platinum chromium alloy, sirolimus analogue drugs, such as everolimus and zotarolimus, and a thinner and more biocompatible polymer layer. Despite these iterations, the requirement for prolonged DAPT did not change. At the same time, the hazard ratios for stent thrombosis and target vessel failure were attenuated, but not eliminated, especially in the more complex patient and lesion subsets .

The question remains, “What factors contribute to the development of the late events seen in second-generation DES?” Is it the metal? The polymer? Or is it the drug? For BMS, target vessel failure occurs within the first 6–12 months, and events beyond that are rare. With second-generation DES, the drug is gone within the first 6 months and complete healing is usually attained at 12 months. This suggests that the culprit for these late events (> 12 months) is most likely the polymer, which continues to irritate the vessel wall causing low grade inflammation and subsequently neoatherosclerosis. The polymers used in first-generation DES were associated with a high degree of inflammation, which often resulted in vessel wall toxicity, target lesion failure, and late stent thrombosis. Nevertheless, the polymers used in the second-generation DES, such as BioLinx and fluoropolymer, are proven to be more biocompatible. More specifically, the fluoropolymer used in Xience V (Abbott Vascular) and Promus Element stents (Boston Scientific) have further claimed to have antithrombotic properties and protection from stent thrombosis when compared to BMS . However, the data to support this claim are rather weak and did not result in a change in the recommended duration of DAPT for such stents. Further, in the Prospective, Randomized, Multicenter Trial to Assess an Everolimus-Eluting Coronary Stent System (PROMUS Element™) for the Treatment of up to Two De Novo Coronary Artery Lesions (PLATINUM) study, the rate of target vessel failure from 12 to 24 months was 3.0% and 1.2% for the Xience and Promus Element stents, respectively.

If the polymer is indeed the culprit for these late events, the strategy should be to minimize or eliminate its use. Proposed methods to minimize the use of polymer for drug elution include: 1) Substitute durable polymers with bioabsorbable ones; 2) Design a DES that is polymer free; and 3) Design a completely bioabsorbable stent, also known as a scaffold. Among the first DES with bioabsorbable polymer technology is the BioMatrix stent (Biosensors International), which utilizes an abluminal coating of PLA and the biolimus A9 drug. In a head-to-head landmark analysis with an all-comers population [Limus Eluted from a Durable versus Erodable Stent Coating (LEADERS)] that compared BioMatrix and Cypher stents, the BioMatrix stent showed superiority in the reduction of stent thrombosis and overall major adverse cardiac events from 1 to 5 years . Further, data from a meta analysis comparing durable DES to bioabsorbable DES corroborated the observation that a bioabsorbable polymer DES has improved safety and efficacy compared to durable polymer sirolimus-eluting stents at 4 years .

The study by Tada et al., published in this issue of CRM , aimed to compare the healing patterns of a novel, rapid breakdown (≤ 8 weeks) bioabsorbable polymer sirolimus-eluting stent to a durable polymer everolimus-eluting stent using intravascular optical coherence tomography at 4 months. Data demonstrated improved tissue coverage with the bioabsorbable polymer but no difference in suppression of neointima formation between the durable and bioabsorbable polymer stent systems.

The widespread development of DES with bioabsorbable polymers is evident. Several bioabsorbable stent programs are being launched into clinical practice, including the Synergy stent (Boston Scientific) that uses a thin bioabsorbable PLGA abluminal coating with everolimus, and the Orsiro stent (Biotronik) that uses a thin PLLA bioabsorbable coating with sirolimus. Both received CE Mark and are available commercially outside of the US. These platforms are currently being tested in head-to-head pivotal trials against second-generation DES with durable polymers (Synergy versus Promus Element and Orsiro versus Xience V). In these trials, the aim is to demonstrate non-inferiority of durable polymer DES at 1 year and superiority in reduction of target vessel failure at 5 years. If these observations materialize as a reduction in clinical events, such as in LEADERS, bioabsorbable polymer DES will dominate the market and make durable polymer DES obsolete.

Another question also presents itself, “Will bioabsorbable polymer technology on a DES reduce the dependency on DAPT from 12 to 3 months or less?” Since stent thrombosis rates beyond 1 month are low, it would take thousands of patients to address this question. However, a reduction in DAPT duration may be safe once the polymer and drug are completely gone.

A further step in the efforts to eliminate polymer use is the development polymer-free DES. These include the polymer-free BioFreedom stent (Biosensors) and the drug-filled stent developed by Medtronic. While the BioFreedom DES demonstrated similar late loss indices to durable polymer DES and is now used in pivotal clinical trials, the drug-filled stent has not yet been tested in humans. It remains to be seen whether polymer-free DES can reproduce similar clinical and angiographic results to those seen with durable polymer DES and whether they’re safe for use with a shorter duration of DAPT (30 days) as is currently seen with the BioFreedom DES in the LEADERS FREE trial.

Ultimately, bioabsorbable scaffolds may be the decisive device since the entire device is eliminated, including the polymer, drug, and the backbone. This process may take up to 3 years from implantation; however, the vessel remains cage free and regains its vasoreactivity properties. The drug-eluting bioabsorbable scaffold must show improved performance with regards to safety and efficacy, including reduced target vessel failure over time. The scaffold technology should be compared to bioabsorbable polymer- or non-polymeric DES since the current durable polymer DES technology may be obsolete by the time the bioabsorbable scaffold is available for marketing in the US.