From IMPERIALism to EMINENence: The Noble Rise of the Second-Generation Peripheral Drug Eluting Stent

The femoropopliteal arterial segment remains the most common culprit of symptomatic peripheral arterial disease and the most frequent target for revascularization. The advancement of novel revascularization techniques and devices have allowed an endovascular first approach in treating most femoropopliteal lesion subtypes, including long-segment disease (>15cm), chronic total occlusions, in-stent restenosis (ISR), and popliteal and proximal trifurcation disease (classified as Trans-Atlantic Society II Class [TASCII] C and D lesions), all of which were historically recommended for surgical revascularization.¹ (Figure) However, despite these changes in the treatment paradigm, the complex vasomotion of the femoropopliteal arterial segment, in addition to the high burden of advanced lesions, continue to pose major challenges to long-term patency, particularly when a vascular scaffold is required.

Figure. Broadening Endovascular Indications for the Treatment of Femoropopliteal Artery Disease.

Evolving treatment paradigms of revascularization approach for femoropopliteal artery disease marked by progressive expansion of an endovascular approach to treat increasingly complex disease.

Paclitaxel-coated peripheral stents were designed with the intent of improving patency through use of antiproliferative elution. The principle of delaying restenosis through antiproliferative therapy is similar to how drug-eluting stents in the coronaries perform, yet the femoropopliteal artery has a tendency for comparatively accelerated restenosis. The Zilver PTX paclitaxel-coated stent (Cook Medical) approved in the US in 2012 and involving a scaffold without a polymer, was the first and only approved paclitaxel-coated peripheral stent until recently. It gained market approval based on demonstration of improved patency compared to balloon angioplasty (PTA), with or without bailout bare metal stents (BMS), in the treatment of femoropopliteal disease.² While not a prespecified endpoint, when compared to provisional bare metal stenting in the PTA arm, Zilver PTX showed improved patency and freedom from target lesion revascularization, suggesting incremental benefit over BMS.² More recently, the Eluvia drug-coated stent (Boston Scientific) was approved in 2018 and is a newer generation drug-coated stent that includes a fluoropolymer, allowing for long-term elution of paclitaxel. This provides drug coverage during a period of highest risk for restenosis. With this advancement, the IMPERIAL trial was conducted to compare the Eluvia stent to the Zilver PTX stent, and demonstrated improved primary patency with decreased major adverse events at 1 year.³

While contemporary drug-coated stents afford promise in improving patency in femoropopliteal interventions, advances in BMS technology with purpose-built stents that conform better to the external forces applied to the femoropopliteal artery (termed biomimetics) raise question as to whether the addition of drug coating is required. For instance, in a randomized trial comparing Zilver PTX to the Misago BMS (Terumo), there was no difference in rates of ISR at 1-year, a finding that was sustained at 2-years.⁴ The results of this trial, which was initially designed as a superiority trial for Zilver PTX, were surprising and highlights the strengths of the contemporary peripheral BMS. Whether second generation drug-eluting stents, such as the Eluvia stent, can provide added benefit over the contemporary BMS has remained an area of uncertainty requiring evaluation.

In this issue of Circulation, Goueffic et al presented the results from the EMINENT Trial (Efficacy of Drug-Eluting versus Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease), a prospective, randomized, multicenter study assessing patency outcomes in patients treated with the Eluvia stent compared to contemporary BMS.⁵ This trial, which recruited patients from 58 European sites, randomized 775 patients (Rutherford category 2-4) in a 2:1 assignment to Eluvia versus BMS, making this the largest trial to evaluate the performance of a drug-coated stent versus BMS for symptomatic femoropopliteal artery disease. The primary outcome of primary patency at 12 months (defined as duplex ultrasound peak systolic velocity ratio </= 2.4 m/s in the absence of clinically driven target lesion revascularization or surgical bypass) was significantly improved in the Eluvia stent arm compared to the BMS arm (83.2% vs. 74.3%, p <0.01).

Outside of these primary findings, a notable feature of this trial included the evaluation of quality-of-life (QoL) metrics as secondary endpoints. While improvement in QoL is a primary aim of peripheral vascular intervention, patient reported QoL metrics have not been widely applied in PAD trials. In EMINENT, intervention with both Eluvia and BMS improved life dimensions of mobility and pain/discomfort for a majority of patients, without significant differences between groups. EMINENT sets an important precedent of incorporating prospectively gathered QoL outcomes. Long-term follow-up of QoL in relation to patency outcomes, which is crucial to delineating the impact of interventions, may help stratify devices that optimize patient experience.

EMINENT also touched on two areas of controversy that remain active in the peripheral vascular space. First, there has been a question of the long-term safety of paclitaxel-coated devices after a meta-analysis of randomized trials of paclitaxel-coated balloons and stents found a relationship with worse long-term survival compared with uncoated devices⁶. Although this has not been replicated in a randomized trial and observational data, a warning from the Food & Drug Administration remains that paclitaxel-coated devices should be reserved for those at highest risk of restenosis. Although this analysis included a shorter time point to assess survival, the lack of difference in mortality and causes-of death between the Eluvia versus BMS groups is reassuring.

Second, there has been recent concern that the Eluvia stent is associated with the accelerated development of aneurysmal degeneration, sometimes termed the “halo sign”. In a porcine model, the Eluvia stent was found to be associated with increased aneurysmal degeneration in comparison to Zilver PTX⁷. While there was no difference in halo prevalence between Eluvia and Zilver PTX in the IMPERIAL trial, ultrasonographic follow-up to assess this endpoint was only available for 27.5% of patients.³ In the CAPSICUM (Contemporary Outcomes Achieved with Paclitaxel-Eluting Peripheral Stents to Treat Symptomatic Lower Limb Ischemia and Lesions in the Superficial Femoral Artery or Proximal Popliteal Artery) registry of fluoropolymer based drug-eluting stents, aneurysmal degeneration was noted to be high at 16.8%. ⁸ However, in this report from EMINENT, halo prevalence was not significantly different between Eluvia and BMS cohorts (26.1% vs 17.9%, p=0.21). These data suggest that aneurysmal degeneration may be related to femoropopliteal artery stents as a class, and its association with meaningful clinical endpoints has not been established.

Although there are important findings in this large and well-designed prospective trial, several limitations should be noted. The most notable limitation is the heterogeneity of stents included in the BMS arm. Only a minority were the more modern biomimetic Supera stent (Abbot Vascular), which has some of the highest patency rates to date.⁹ Second, the patient and lesion characteristics were notable for a lack of patients with chronic limb threatening ischemia and long lesion lengths, despite allowance of lesions from 30-210mmm. Importantly, the IMPERIAL Long Lesion sub-study included lesion lengths >140mm and <190mm treated with Eluvia and demonstrated excellent patency at 12 months (91.0% [95% CI 82.5% to 99.6%])¹⁰. If these lengths were included in EMINENT, it may have further emphasized the patency benefit of Eluvia compared to BMS. Lastly, as we look to improve the function and lives of our peripheral vascular patients, we need to move beyond celebrating patency milestones at 1 year. Longer term data with an emphasis on sustained QoL improvements are required to further support the benefit of the Eluvia stent over competitor devices.

The investigators should be congratulated on conducting the largest drug-coated stent versus BMS trial for symptomatic femoropopliteal disease. These findings advance the peripheral vascular interventional space by demonstrating the incremental benefit of drug elution for revascularization of the femoropopliteal segment. Future studies that incorporate emerging biomimetic BMS technology and other drug-coated platforms, such as novel sirolimus-coated stents, will further inform the comparative efficacy of this device. Long-term follow-up of the primary endpoints will also be crucial. If benefits in patency and metrics such as QoL persist, it will strengthen the body of evidence supporting first line use of paclitaxel-coated devices, which currently have the strongest randomized trial data among approved peripheral devices.

Abbreviations:

BMS

Bare Metal Stent

DES

Drug Eluting Stent

ISR

In-stent Restenosis

PTA

Percutaneous Transluminal Angioplasty

QoL

Quality of Life