Understanding Benefits and Risks of Drug-Eluting Stents
Ongoing clinical studies will shed light on patient outcomes in real-world settings.
The past 15 years have borne witness to a number of new devices and surgical techniques for the treatment of peripheral artery disease (PAD). However, to offer the best care and achieve the best possible patient outcomes, the medical community must continue to break barriers and innovate not only the therapies we offer but also the ways we study those therapies—and in whom we study them.
Boston Scientific, an innovator in advanced paclitaxel-eluting stents, is currently running clinical studies that will expand medical knowledge about treatments for PAD. In our clinical trials, inclusion criteria are as broad as possible to ensure we enroll a patient population that is as similar as possible to the patients physicians care for in real-world practice. The hope is that innovations in trial design and subgroup analysis will, over time, yield insights into relevant treatment and outcomes.
In December 2018, the Journal of the American Heart Association (JAHA) published a meta-analysis by researchers at Patras University and Attikon University in Greece presenting “strong evidence from statistical inference” that the risk of death increases for patients treated with paclitaxel-coated balloons and stents after the first year of care.1 In response, the FDA initiated its own analysis of randomized trials for such products that have been approved in the United States. Its preliminary findings identified “a potentially concerning signal” of increased mortality.2 The FDA is convening a meeting of the Circulatory System Devices Panel in June 2019 to discuss and make recommendations on the information.3
It is important to note that Boston Scientific’s Eluvia™ Drug-Eluting Vascular Stent System was not included in the JAHA meta-analysis, the subsequent analysis by the FDA, or in the patient-level meta-analysis undertaken by VIVA Physicians.
The starting point for any discussion of risk in a PAD trial is to understand that enrolled patients are already at increased risk of mortality due to certain comorbidities. The expected mortality for PAD at 5 years ranges from 18% to 45%,4 depending on a number of factors such as age, diabetic status, renal function, history of congestive heart failure, and degree of vascular calcification. As a newly available product, 5-year follow-up data are still being collected on the Eluvia stent. However, no mortality signal has been observed in any of the 5-year data on Boston Scientific’s TAXUS™ family of coronary drug-eluting stents, which, like Eluvia, employ a polymer-based mechanism that elutes a low dose of paclitaxel.
WORLD OF DIFFERENCES
Boston Scientific’s device differs from those discussed in the JAHA meta-analysis, FDA analysis, or VIVA Physicians review with regard to drug-release mechanism, formulation of the drug, initial dose, and dose over time.
The Eluvia stent is the only peripheral device designed with a polymer matrix, which allows for controlled, localized, low-dose amorphous paclitaxel delivery to lesions over time. This ensures minimal systemic distribution or particulate loss. Other FDA-approved peripheral devices utilize paclitaxel coatings that result in a higher initial bolus release.5
Furthermore, as previously noted, the safety profile of our Eluvia stent correlates with safety data from patients treated with Boston Scientific TAXUS paclitaxel-eluting stents studied in the coronary and peripheral vasculature. The two stents have identical design principles. They both deliver a very low dose of paclitaxel in the same controlled manner via a similar polymer mechanism. In fact, TAXUS (1 µg/mm2) has a higher drug dose density than Eluvia (0.167 µg/mm2) (Figure 1).
For the TAXUS stent, we have patient-level safety data on more than 4,000 patients in well-controlled trials followed out to 5 years. One would expect that an increase in all-cause mortality would have been observed in these coronary applications if paclitaxel exposure via a polymer truly impacts all-cause mortality rates, but there was no such signal (Figure 2).6,7
Data on the performance of the Eluvia stent has demonstrated highly consistent patency in patients with a number of major risk factors, including diabetes, occlusions, moderate and severe calcification, renal insufficiency, and a history of smoking. We strive to learn about these patient differences and risk factors in our global, multicenter prospective study, the ongoing IMPERIAL trial (Table 1).8 For example, nearly 42% of IMPERIAL trial participants have diabetes. Half of participants are former smokers, and 35% continue to smoke. More than 40% had calcification classified as severe, and 31% had total occlusions. In the separate Münster All-Comers Eluvia Registry, in which the 12-month primary patency rate was 87% in lesions with an average length of 200 mm in Eluvia-treated patients, 79% of patients had total occlusions and nearly half had critical limb ischemia.9 The data we gather will shed light on stratified patient cohorts that have not previously been examined with this level of rigor.
“INTERPRET WITH CAUTION”
To date, FDA communications underscore the limitations of the meta-analysis. “These data should be interpreted with caution for several reasons,” the FDA says.2 “First, there is large variability in the risk estimate of mortality due to the limited amount of long-term data. Second, these studies were not originally designed to be pooled, introducing greater uncertainty in the results.”
In the clinical perspective section of the JAHA meta-analysis triggering the FDA panel, the authors are circumspect in their recommendations. Primarily, they call for “the collection and reporting of longer-term follow-up” for all commercial clinical studies.8 The authors appear to acknowledge the need for long-term research in this area, in line with our commitment to running a 5-year clinical trial for Eluvia.
A PERSONALIZED APPROACH
As we enter an era of precision medicine in which treatment is tailored to provide the best and safest outcomes, endovascular specialists must obtain a better understanding of which treatment strategies are most effective for which patients.
This is the foundation on which our research efforts are based. Our ongoing analyses in long-term and postmarketing surveillance studies may also shed light on subsets of patients, including those with advanced disease, for whom drug-eluting stents could prevent significant morbidity.
The advances of the past decade and a half have provided a great deal of forward movement in the treatment of PAD, yet work remains to be done. Our highest priority is patient care and safety, and as we continue to progress in this area, we must do so for all patients with PAD—not just those who fit within the traditional parameters of clinical trial populations.
It remains the responsibility of the medical community at large to broaden the armamentarium against PAD in concert with the real-world expertise of treating physicians. Although the FDA approval of our Eluvia stent just last year represented a major advance in the treatment options available for patients with PAD, the availability of different therapies does not mean our work is done. These technologic advances must be coupled with the concepts of precision medicine and the development of an evidence-based treatment algorithm to refine treatment strategies that work for specific patient cohorts. Together with our innovative devices, ongoing studies and analysis by Boston Scientific aim to fulfill this mission. Patient safety and patient centricity are at the core of our mission of advancing science for life.
1. Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018;7:e011245.
2. US Food & Drug Administration. Update: treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality – letter to health care providers. https://www.fda.gov/medical-devices/letters-health-care-providers/update-treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel-eluting. Accessed June 5, 2019.
3. US Food & Drug Administration. June 19-20, 2019: Circulatory system devices panel of the Medical Devices Advisory Committee meeting announcement. Accessed June 5, 2019.
4. Feringa HH, Bax JJ, Hoeks S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med. 2007;167:2482-2489.
5. Gongora CA, Shibuya M, Wessler JD, et al. Impact of paclitaxel dose on tissue pharmacokinetics and vascular healing: a comparative drug-coated balloon study in the familial hypercholesterolemic swine model of superficial femoral in-stent restenosis. JACC Cardiovasc Interv. 2015;8:1115-1123.
6. Stone GW, Ellis SG, Colombo A, et al. Long-term safety and efficacy of paclitaxel-eluting stents final 5-year analysis from the TAXUS clinical trial program. JACC Cardiovasc Interv. 2011;4:530-542.
7. Kaplan-Meier data on file with Boston Scientific Corporation.
8. Gray AW, Keirse K, Soga Y, et al. 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;392:1541-1551.
9. Bisdas T, Beropoulis E, Argyriou A, et al. 1-year all-comers analysis of the Eluvia drug-eluting stent for long femoropopliteal lesions after suboptimal angioplasty. JACC Cardiovasc Interv. 2018;11:957-966.
Ian T. Meredith, MBBS, PhD, AM
Executive Vice President and Global Chief Medical Officer
Boston Scientific Corporation