Sirolimus vs Paclitaxel

In 2002, results of the RAVEL (Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions) trial were published in the New England Journal of Medicine. For the first time, a striking 0% restenosis rate was observed by the use of an intracoronary device,¹ which represented the beginning of the so-called drug-eluting stent (DES) era. Sirolimus, a macrolide antifungal agent, was able to virtually suppress neointimal hyperplasia when eluted from a stainless-steel platform through a durable polymeric coating. Two years later, results of the TAXUS IV (Treatment of De Novo Coronary Disease Using a Single Paclitaxel-Eluting Stent) trial put paclitaxel-eluting stent (PES) in the spotlight.² Paclitaxel, a lipophilic molecule derived from the Pacific yew tree Taxus brevifolia, showed neointimal hyperplasia inhibition and restenosis prevention through microtubule interaction leading to inhibition of cellular division. After that, the battle for being the leading stent was at stake. Numerous trials compared the outcomes of patients being treated with either sirolimus-eluting (SES) or PES stents.^3-5 Overall, no major differences were observed between both devices in terms of hard clinical endpoints, although target lesion revascularization rate and late lumen loss (LLL) were generally higher with PES.⁵ In this regard, SES usually evidenced a mean value of LLL below 0.20 mm, whereas PES used to show a mean value in the range of 0.40 mm.

In 2006, concerns regarding a higher-than-expected increased risk of death and stent thrombosis after DES implantation were presented at the European Society of Cardiology Congress.⁶ These reports lead the scientific community to scrutinize the presented outcomes and standardize the definitions and reporting of the events in contemporary DES trials.^7,8 In parallel, new technological advances improved the performance of DES.⁹ Indeed, second-generation DES with enhanced biocompatibility and reduced thrombogenicity displaced the first-generation SES and PES. Eventually, both seminal DES types were withdrawn from the market. Current-generation DES are generally composed of limus analogues while paclitaxel has been abandoned from being part of any metallic new platform.

In-stent restenosis (ISR) has classically been the Achilles’ heel of percutaneous coronary interventions. Several approaches have been tested to minimize the risk of failure after ISR treatment,¹⁰ being the implantation of additional DES¹¹ or surgical revascularization the only effective alternative in many circumstances. Recently, the drug-coated technology appeared to be an interesting option because it avoided the implantation of a second metallic layer and allowed shortening of dual antiplatelet regimen after percutaneous treatment. As a matter of fact, it currently presents the highest degree of recommendation and level of evidence in the European Society of Cardiology guidelines.¹² Interestingly, paclitaxel was the drug initially selected for balloon coating due to its lipophilic properties and elution capacity. Paclitaxel-coated balloon (PCB) has demonstrated a beneficial effect in many ISR trials with outcomes comparable to those of additional DES implantation.^13-15 The avoidance of a metallic cage was the rationale to expand the indications of this technology to percutaneous treatment of small vessels¹⁶ and to peripheral artery disease. Concerns regarding increased mortality after PCB used in peripheral vasculature were recently raised but subsequently refuted.^17,18 Nonetheless, despite the good results demonstrated by PCB, limus-coated balloons have been designed and are currently being tested in the clinical arena. From the technological point of view, the design of a sirolimus-eluting balloon is challenging due to the hydrophilic nature of the drug and the reversible binding to FKBP 12. These features require the device to express a more controlled release of the drug to reach a proper tissue concentration over time to exert an adequate antirestenotic effect. To tackle that, several approaches have been attempted, including the encapsulation of the sirolimus in phospholipids¹⁹ or the crystalline formulation of the drug.²⁰ Whereas the former resulted in a decline of the initial tissue concentration to about 4% after 2 weeks in preclinical models,¹⁹ the latter allows persistence of sirolimus in the tissue of about 50% of the initial concentration 4 weeks after application.²⁰

Wan Ahmad et al²¹ report in this issue of JACC: Cardiovascular Interventions the first-in-human outcomes of the sirolimus-eluting balloon on a crystalline coating (SeQuent 4 μg/mm², B. Braun Medical) as compared with a clinically proven PCB (SeQuent Please, 3 μg/mm²) for the treatment of de novo coronary lesions. After 6 months, in-segment LLL was 0.01 ± 0.33 mm in the PCB group vs 0.10 ± 0.32 mm in the novel sirolimus-coated balloon group, meeting the predefined, but rather large, noninferiority margin of 0.35 mm. Furthermore, negative LLL indicative of positive vessel remodeling was more frequently observed in the PCB group (56% vs 32%; P = 0.019). No difference in clinical events was observed between the groups. Interestingly, in this second round of the battle between sirolimus and paclitaxel, angiographic results seem to favor paclitaxel as being more efficacious in neointimal suppression. The aforementioned differential features between both drugs and their release properties may account for these results. Whether this differential angiographic behavior will be translated into different hard endpoints has to be dilucidated in larger randomized trials powered for clinical events. In the meantime, other drug-coated balloons using different limus-analogues drugs, such as biolimus A9 or everolimus, are currently being tested in randomized trials (Biolimus A9™ [BA9™] Drug Coated Balloon [DCB] Study [REFORM]; NCT04079192) and registries. Their results will shed light on the potential of these drugs for the treatment of ISR and small vessels.