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Current Antiproliferative Considerations: The Eluvia Stent
Results from a meta-analysis published last year by Katsanos et al in the Journal of the American Heart Association (JAHA) have led to a discussion in the peripheral vascular community about the use of paclitaxel-coated devices to treat peripheral artery disease. On March 15th, the FDA published a letter to health care providers following their own initial review of several of the paclitaxel-coated devices available in the United States. In the letter, the FDA stated that there are known benefits to paclitaxel-coated devices. However, given the potentially concerning safety signal of all-cause mortality at the 5-year interval observed in both analyses, they recommended that alternative treatment options should be used for most patients until more information is available. They also indicated that clinicians may determine that the benefits of using a paclitaxel device could outweigh the risks for some patients at high risk for restenosis. In the follow-up FDA panel hearing on June 19th and 20th, they recommended paclitaxel device use could proceed with caution.
As we move forward and continue to care for this challenging patient population, antiproliferative therapy should remain an important treatment modality. In the current climate, it is imperative that each vascular specialist have a full understanding of the relative differences of paclitaxel delivery and dosage when considering appropriate options for each patient. While Cook’s Zilver PTX drug-eluting stent (DES), Bard’s Lutonix drug-coated balloon (DCB) and Medtronic’s IN.PACT DCB have been available since 2012, it is important to note that studies of the recently approved Boston Scientific Eluvia DES were not included in the JAHA meta-analysis, nor in the FDA analysis, and yet may have properties that are even more important to acknowledge in this controversial era of peripheral arterial disease (PAD) management.
Polymer-Based Drug Delivery
Eluvia (Boston Scientific) is a next-generation device for peripheral artery disease that is uniquely different from other paclitaxel-coated devices, including the Zilver PTX (Cook Medical) drug-coated stent and the drug-coated balloons (DCBs), due to its controlled, localized, and sustained drug delivery. While each product delivers paclitaxel to the vessel wall, there are substantial differences between Eluvia and other paclitaxel-coated devices in the coating design, drug dose and release mechanism.
Eluvia is the only product for the treatment of peripheral artery disease that uses a polymer-based drug delivery system. Eluvia utilizes the same polymer used on the Promus (Boston Scientific) and Xience (Abbott Vascular) coronary stents, the world’s most commonly used drug-eluting stents. This biocompatible and thrombo-resistant fluoropolymer (PVDF-HFP) has been implanted in more than 20 million patients1 and studied in more than 100,000 patients2 for more than a decade. Polymer-based drug delivery allows for a highly controlled and localized mechanism to deliver the lowest effective dose of paclitaxel to the lesion. Eluvia contains the lowest drug dose of any paclitaxel device on the market, with a drug dose density of 0.167 μg/mm2. By comparison, this is about 18 times lower than the drug dose density for Zilver PTX (3.0 μg/mm2) and more than 20 times lower compared to Medtronic’s IN.PACT DCB (3.5 μg/mm2).3
Eluvia’s polymer also significantly minimizes downstream drug particulates and ensures that nearly all the drug is delivered to the targeted lesion. In an in vitro simulated use model, the Zilver PTX stent, which does not use a carrier to deliver drug, has been shown to release 19 times as many 10-25 μm particulates and 32 times as many 25-50 μm particulates compared to Eluvia. DCBs, which use an excipient rather than a polymer to deliver drug to the tissue, are even less efficient in their transfer of drug. In the same simulated use model, the IN.PACT DCB released 640 times as many 10-25 μm particulates and 1,143 times as many 25-50 μm particulates compared to Eluvia.4 Preclinical studies with DCBs have shown that approximately 5 to 30% of the drug is washed off during transit to the treatment site, 40 to 70% is lost in runoff during balloon inflation, and up to 30% remains on the balloon after withdrawal from the vessel. An estimated 5 to 20% of the drug load on a DCB is transferred to the arterial wall.5 In the IMPERIAL pharmacokinetic sub-study, paclitaxel was undetectable in the plasma after 10 minutes and blood concentrations were too low to measure drug half-life.6 By comparison, half-life for other paclitaxel devices range from 2.4 hours (Zilver PTX) to 72.5 hours (IN.PACT DCB).7
Polymer-based drug delivery also allows drug concentrations to be sustained in the lesion long enough to match the restenotic process. In a study that looked at restenosis of nitinol stents in the SFA, restenosis was shown to peak at about 12 months.8 This is different from the disease process in the coronary arteries, where restenosis tends to peak at about 6 months.9 Preclinical studies have shown that the Eluvia DES sustains drug tissue concentrations in the targeted lesion for about one year.10 By comparison, drug tissue concentrations are sustained for 56 days with the Zilver PTX stent and for about 60 to 90 days with DCBs.11
Efficacy and Safety
The nature and severity of the disease in the patients in a study have generally been seen to have a heavy influence on the results of the trial. Patients with diabetes, for instance, commonly achieve poorer outcomes in superficial femoral artery (SFA) device trials compared to patients who are not diabetic. Likewise, the greater the extent of calcification, the longer the lesion length, or the higher the percentage of total occlusions, the worse the results tend to be. Consequently, it is remarkable that Eluvia has demonstrated consistently high primary patency rates regardless of lesion or patient complexity. In the IMPERIAL trial, Eluvia demonstrated a statistically significantly higher primary patency rate compared to Zilver PTX at 12 months (88.5% vs. 79.5%, P=.0119).12 Eluvia also demonstrated an 87.4% primary patency rate in the IMPERIAL Diabetic Subgroup13 and an 89.2% primary patency rate in the IMPERIAL Severe/Moderate Calcium Subgroup.14 In the single-arm IMPERIAL Long Lesion Sub-study, Eluvia demonstrated an 87.9% primary patency rate in lesions with an average length of 163 mm.15 This is an exceptional result, considering the loss of efficacy typically observed in studies looking at longer lesion lengths. In the Münster All-Comers Registry, a study with an average lesion length of 200 mm, 79% total occlusions, and 46% of patients with critical limb ischemia (CLI), Eluvia achieved an 87% primary patency rate. Eluvia demonstrated a 4.5% target lesion revascularization (TLR) rate at 12 months in IMPERIAL (vs 9.0% in the Zilver PTX arm, P=.0672).16
The long-term durability of the Eluvia stent was demonstrated in the single-arm MAJESTIC trial, which reported a 14.7% TLR rate at 3 years.17
With respect to mortality, the IMPERIAL trial reported a 2.0% all-cause mortality rate at 1 year in the Eluvia arm (vs 3.9% for Zilver PTX).12 This rate is not greater than rates observed with contemporary non-coated devices. Of the six deaths of patients in the Eluvia arm, three of the deaths were related to cardiac problems, and three were non-cardiovascular related. IMPERIAL will include a 5-year follow-up.
Eluvia demonstrated a 3.6% all-cause mortality rate at 3 years in the MAJESTIC trial.17 Of the two patients who died, one death was due to cardiac problems and the other was related to complications from metastatic squamous cell carcinoma. To put this in perspective, the 3-year mortality rate reported for Eluvia in the MAJESTIC trial was slightly lower than the 3.8% 2-year mortality rate reported for noncoated devices in the Katsanos meta-analysis.18
Long-Term Safety of Coronary Polymer-Based Paclitaxel-Eluting Stents
Survival data for the Eluvia DES beyond 3 years is currently not available. However, because Eluvia has a similar paclitaxel distribution and concentration compared to the Taxus coronary stent, signals of any long-term systemic effect of paclitaxel eluted from Eluvia should be observable among patients who were treated with Taxus. The first-generation Taxus stent was commercially launched in 2002 and was implanted in more than 6 million during its time on the market.
Paclitaxel-based treatment with the Taxus stent did not differentially affect long-term mortality compared to bare metal stents (BMS) and other drug-eluting stents. Specifically, 5-year results from a patient-level randomized pooled analysis of 2,797 patients showed no difference in mortality compared to BMS (all-cause mortality rate of 9.8% vs 9.1%, P=.53).19 The SIRTAX trial, another large randomized trial, showed no difference in 10-year all-cause mortality between coronary paclitaxel-eluting stents and sirolimus-eluting stents (23.4% vs 25.0%, P=.52), and both stents had similar stent thrombosis rates at 5 and 10 years (4.3% vs 4.7% at 5 years, 5.6% vs 5.6% at 10 years, P=.97).20
In the same manner, the PADI study, which evaluated the Taxus Liberty stent in 137 patients with CLI, reported no difference in survival rates at 5 years for paclitaxel-eluting stents vs BMS (37.7% vs 37.0%, P=.45).21 The overall low survival rates in this study highlight the morbidity of patients with severe PAD and CLI who were included in this study.
As the treatment of coronary artery disease (CAD) evolved, coronary stents eventually shifted from paclitaxel to the limus family of drugs. Importantly, this change was not driven by concerns about the safety of paclitaxel, but rather by changing market preferences for limus due to lower late lumen loss in the coronary arteries. The SPIRIT III trial showed a lower late lumen loss at 8 months for everolimus-eluting stents compared to paclitaxel-eluting stents in the treatment of CAD (0.16 mm vs 0.31 mm, P=.006).22 The SIRIUS trial also showed a lower late lumen loss for sirolimus-eluting stents at 8 months (0.17 mm vs 1.0 mm for BMS, P=.001).23 The integration of more biocompatible and thrombo-resistant polymers, like the PVDF-HFP used in the Eluvia stent, also encouraged the shift to newer generation coronary stents, because they were shown to significantly reduce the risk of late stent thrombosis.
Conclusion
As stated at the conclusion of the recent FDA panel, more long-term data is required to elucidate the true nature of the paclitaxel mortality signal. While the controversy regarding paclitaxel failed to demonstrate a dose relationship with and a mechanism for mortality, a thoughtful and strategic approach to antiproliferative therapy should include a consideration for minimizing paclitaxel dosage and promoting efficient delivery to the target lesion. A drug-eluting stent with an enhanced polymer-based design and targeted dosing customized for the treatment of PAD, as seen in the Eluvia device, may be a better alternative to traditional options.
Disclosure: Dr. Steve Henao reports he is a member of the speaker’s bureau for Abbott, Boston Scientific and Endologix. He is a member of the medical/scientific boards for Abbott and Boston Scientific. He has no stock ownership to report.
Dr. Steve Henao can be contacted at steveh@nmhi.com.
REFERENCES
1. Represents total global sales of the PROMUS (Boston Scientific) and XIENCE (Abbott) stents since 2008.
2. Represents total population of patients studied in the PROMUS and XIENCE series of clinical trials.
3. Data from Eluvia, Zilver PTX and IN.PACT Directions for Use.
4. Data on file at Boston Scientific. Simulated use in a tortuous vessel model under clinically relevant flow conditions.
5. Schneider PA. Presented at the Leipzig Interventional Course (LINC) 2017.
6. Gray WA. Presented at the Leipzig Interventional Course (LINC) 2019. Paclitaxel plasma concentrations measured at 10 and 30 minutes and 1, 2, 3, 4, 6, 12, 24, and 48 hours post-implant. Drug levels for Eluvia were too low to measure a plasma half-life.
7. Data from Zilver PTX and IN.PACT Directions for Use.
8. Iida O, Uematsu M, Soga Y, et al. Timing of the restenosis following nitinol stenting in the superficial femoral artery and the factors associated with early and late restenoses. Catheter Cardiovasc Interv. 2011 Oct 1; 78(4): 611-617. doi: 10.1002/ccd.23064
9. Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med. 1996; 334: 561-567.
10. Data on file at Boston Scientific.
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12. Gray WA, Keirse K, Soga Y, et al; IMPERIAL investigators. A polymer-coated, paclitaxel-eluting stent (Eluvia) versus a polymer-free, paclitaxel-coated stent (Zilver PTX) for endovascular femoropopliteal intervention (IMPERIAL): a randomised, non-inferiority trial. Lancet. 2018 Oct 27; 392(10157): 1541-1551. doi: 10.1016/S0140-6736(18)32262-1
13. Müller-Hülsbeck S. Presented at the Leipzig Interventional Course (LINC) 2019.
14. Vermassen F. Presented at Charing Cross Symposium 2019.
15. Gray WA. Presented at the Vascular Intervention Advances (VIVA) Conference 2018.
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17. Müller-Hülsbeck S, Keirse K, Zeller T, Schroë H, Diaz-Cartelle J. Long-term results from the MAJESTIC trial of the Eluvia paclitaxel-eluting stent for femoropopliteal treatment: 3-year follow-up. Cardiovasc Intervent Radiol. 2017 Dec; 40(12): 1832-1838. doi: 10.1007/s00270-017-1771-5
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20. Yamaji K, Räber L1, Zanchin T, et al. Ten-year clinical outcomes of first-generation drug-eluting stents: the Sirolimus-Eluting vs. Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) VERY LATE trial. Eur Heart J. 2016 Dec 1; 37(45): 3386-3395. doi: 10.1093/eurheartj/ehw343
21. Spreen MI, Martens JM, Knippenberg B, et al. Long-term follow-up of the PADI trial: percutaneous transluminal angioplasty versus drug-eluting stents for infrapopliteal lesions in critical limb ischemia. J Am Heart Assoc. 2017 Apr 14; 6(4). pii: e004877. doi: 10.1161/JAHA.116.004877
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23. Moses JW, Leon MB, Popma JJ, et al; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003 Oct 2; 349(14): 1315-1323.
