Stents

Long-Term Clinical Safety and Efficacy: The Orsiro Ultrathin Bioresorbable Polymer Sirolimus-Eluting Stent

Cath Lab Digest talks with David E. Kandzari, MD, Director of Interventional Cardiology and Cardiovascular Research, Piedmont Heart Institute, Atlanta, Georgia.

Cath Lab Digest talks with David E. Kandzari, MD, Director of Interventional Cardiology and Cardiovascular Research, Piedmont Heart Institute, Atlanta, Georgia.

Can you describe the Orsiro stent?

The Orsiro stent (Biotronik) is comprised of three elements: the metallic stent structure, the polymer, and the antiproliferative drug. The drug is a well-proven antiproliferative agent, sirolimus, which has been used effectively and safely in many drug-eluting stents over several different generations. The polymer is bioresorbable; along with drug elution after stent implantation, the polymer resorbs over time, returning the stent characteristics to those of a bare-metal stent, which may confer a safety advantage over the long term, particularly in comparison to what we call “permanent” polymer drug-eluting stents. In selected instances, durable or permanent polymers have been associated with a higher risk of inflammation that may lead to outcomes such as stent thrombosis or neoatherosclerosis, and a progressive “catch-up” phenomenon of late repeat revascularization. The third element, the stent itself, is perhaps the most distinctive element of Orsiro compared to contemporary drug-eluting stents, with an ultrathin-strut stent design. The strut thickness of 60 microns is the lowest among commercially available drug-eluting stents. Most contemporary drug-eluting stents used in clinical practice today range between 80 and 90 microns in strut thickness. There is increasing awareness, both in preclinical study as well as in human clinical trials, that ultrathin-strut stents may confer an advantage not only in regard to safety outcomes such as stent thrombosis and myocardial infarction1, but also in lower risks of repeat revascularization and restenosis. The premise is that ultrathin-strut stents produce less inflammation, less injury to the vessel wall, and are also more permissive of rapid healing, all of which would confer both a safety and efficacy advantage compared with thicker strut stents. Indeed, when we look back at over 15 years of drug-eluting stent iteration, the progression to thinner and thinner stent struts has been associated with lower rates of stent thrombosis, lower rates of myocardial infarction, and lower rates of repeat revascularization.2-10 The Orsiro stent represents the first and only commercially available drug-eluting stent in the United States with an ultrathin-strut design, and is only one of two drug-eluting stents with the bioresorbable polymer technology.

What have clinical trials with Orsiro shown thus far?

To date, about 37,500 patients worldwide have been included in clinical trials involving the Orsiro stent. The pivotal trial for United States approval, the BIOFLOW V trial (Biotronik Prospective Randomized Multicenter Study to Assess the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in the Treatment of Subjects with Up to Three De Novo or Restenotic Coronary Artery Lesions V)11 has been completed and led to the recent FDA approval. We now have 2 years of follow-up published and presented from the BIOFLOW V trial. These findings are very relevant, first, because the standard benchmark for comparison in drug-eluting stent clinical trials has been the durable polymer, everolimus-eluting Xience V (Abbott Vascular) drug-eluting stents. Xience has been the comparator for alternative drug-eluting stents as well bioresorbable scaffolds. Until the Orsiro program, no previous stent had ever demonstrated superiority to Xience stents. Trials previously had demonstrated non-inferiority or clinical equivalence to the Xience stent; again, none had demonstrated superiority. Now, through the BIOFLOW V trial, the Orsiro stent has demonstrated improved outcomes at both 1-year and 2-year follow-up. More specifically, at 2 years of follow-up, the Orsiro stent has demonstrated superiority compared with the Xience stent for a composite outcome of target lesion failure and the components of that primary endpoint, including superiority with regard to myocardial infarction, target lesion revascularization, and even significantly lower late and very late stent thrombosis with the Orsiro stent compared with the Xience stent. For many clinicians and investigators, the BIOFLOW V results have also established a new standard of comparison for drug-eluting stents. Other ongoing trials or recently completed trials performed in other countries have now used the Orsiro stent as the primary or standard comparison.12-14

Can you describe other characteristics of the Orsiro stent?

With regard to deliverability, if anything, the ultrathin-strut stent design permits even greater deliverability and trackability of the stent delivery system. Operators now have experience using the stent in over a million patients elsewhere in the world and many operators would claim this is one of the most deliverable, if not the most deliverable, drug-eluting stents that exists. With regard to the ultrathin-strut stent design, some of the concerns for physicians unfamiliar with the use of the Orsiro stent would relate to the visibility of the stent under x-ray imaging, and radial strength or scaffolding properties of the stent. Clinical experience shows visibility is not an issue with this stent. Bench testing also demonstrates that despite the ultrathin-strut stent design, the radial strength is at least comparable to other contemporary drug-eluting stents with thicker struts.15 The reason is because the radial strength of stents is often not simply a function of the thinness of the struts, but of the stent design itself.

Are there any concerns regarding stent fracture?

Stent fracture will always be a point of discussion in interventional cardiology. It seems to be less frequently identified with newer, contemporary generation drug-eluting stents. It was more commonly associated with thicker strut stents and more rigid stent architecture. Stent fracture is not an event that has been associated with the Orsiro stent.

What do we know about the stent’s performance in complex lesions and patients?

Like other commercially available drug-eluting stents, the Orsiro stent is intended to be what many might consider a ‘workhorse’ stent; that is, a stent designed for all applications, both simple and complex. Orsiro has been studied in patient and lesion complexities that extend well beyond those of the BIOFLOW V trial in all-comer and real-world registries.16-20 FDA approval means more studies will be performed in specific patient and lesion subsets due to the safety and efficacy that has been observed with the Orsiro stent, including a study of a shorter duration of dual antiplatelet therapy in patients at high bleeding risk.

What are current dual antiplatelet therapy guidelines?

It depends on the presentation of the patient. In general, for patients undergoing percutaneous revascularization for standard angina, current guidelines in the United States recommend a minimum of at least 6 months of dual antiplatelet therapy. There are selected instances in which shorter durations may be considered clinically appropriate for patients at high bleeding risk. For patients who present with acute coronary syndromes, 12 months of dual antiplatelet therapy is advocated by the guidelines. Duration varies, based on the patient’s presentation and complexity, but in high bleeding risk patients, there are ongoing clinical trials with other drug-eluting stents, examining one month or three months’ duration of dual antiplatelet therapy. It may be an intended trial in the future for the Orsiro program. The stent has a bioresorbable polymer, and the ultra-thin struts confer a safety advantage, so in the high bleeding risk patient, Orsiro may offer a particular indication or be of special-use interest.21

Can you tell us about your experience with the Orsiro stent?

I had previous experience with the stent outside the United States in both coronary interventional procedures as well as in clinical testing. Since recent approval in the United States, my colleagues and I have a very favorable experience treating patients in a variety of clinical settings and lesion complexities. Combining an emerging body of evidence suggesting the benefits of an ultrathin-strut stent with the deliverability properties of this particular stent seemed to justify the reasons for bringing Orsiro for further clinical study and ultimately, bringing it to the United States. Especially with the superior results now demonstrated with the stent in a large, randomized, international clinical trial, I am excited about offering this stent to patients and its entry into the United States market.

Could the stent’s clinical advantages also have an economic impact?

Current clinical trials with the Orsiro stent, whether BIOFLOW V or other clinical trials, demonstrate low event rates of myocardial infarction and repeat revascularization, ranging from 1-2% in fairly complex patients at one year and beyond. Certainly that is not only an important aspect for our patients, but it could have an economic impact with regard to cost savings. The current implications of recurrent hospitalization for myocardial infarction and undergoing repeat procedures, including repeat revascularization, do translate to an economic impact for U.S. hospitals and the healthcare system. In that regard, we are currently performing some analyses to explore how the reduction in those events could translate into a cost savings to the healthcare system.

Any final thoughts?

The introduction of the Orsiro stent to the U.S. interventional community is welcomed, because we have entered into a phase, in a positive sense, where we are realizing the best outcomes ever achieved in interventional cardiology. We are observing these outcomes across the variety of different stents available in the United States. It seemed in many ways that we had plateaued with regard to the levels of safety and efficacy that could be surpassed, and that there was a class effect of current-generation drug-eluting stents. In other words, there was the perception among some clinicians perhaps that all stents were alike. These data from the BIOFLOW V trial and with the introduction of the Orsiro stent remind us that we actually can do better and achieve superiority over the existing standards with the Orsiro stent, and that we can further incrementally improve the outcomes for our patients. 

Disclosure: Dr. Kandzari reports institutional research/grant support from Biotronik, Boston Scientific, Medtronic, Orbus Neich and Teleflex; and personal consulting honoraria from Biotronik, Cardinal Health, Cardiovascular Systems, Inc. and Medtronic.

Dr. Kandzari can be contacted at david.kandzari@piedmont.org.

References
  1. Bangalore S, Toklu B, Patel N, et al. Newer-generation ultrathin strut drug-eluting stents versus older second-generation thicker strut drug-eluting stents for coronary artery disease. Circulation. 2018 Nov 13;138(20):2216-2226. doi: 10.1161/CIRCULATIONAHA.118.034456.
  2. Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombogenicity early in high- risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation. 2011; 123: 1400-1409.
  3. Kawamoto H, Panoulas VF, Sato K, et al. Impact of strut width in periprocedural myocardial infarction: a propensity-matched comparison between bioresorbable scaffolds and the first-generation sirolimus-eluting stent. J Am Coll Cardiol Intv. 2015; 8: 900-909.
  4. Kandzari DE, Leon MB, Popma JJ, et al; for the ENDEAVOR III Investigators. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease. J Am Coll Cardiol. 2006; 48: 2440-2447.
  5. Stone GW, Midei M, Newman W, et al; for the SPIRIT III Investigators. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA. 2008; 299: 1903-1913.
  6. Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the Endeavor zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary lesions. J Am Coll Cardiol. 2010; 55: 543-554.
  7. Kandzari DE, Leon MB, Meredith I, Fajadet J, Wijns W, Mauri L. Final 5-year outcomes from the Endeavor zotarolimus-eluting stent clinical trial program. J Am Coll Cardiol Intv. 2013; 6: 504-512.
  8. Stone GW, Rizvi A, Newman W, et al; for the SPIRIT IV Investigators. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med. 2010; 362: 1663-1674.
  9. Botelho R. Outcomes with a thin-strut PLLA-based sirolimus-eluting stent: Biomime. Paper presented at: TCT 2017; October 31, 2017; Denver CO. Available at: https://www.tctmd.com/slide/outcomes-thin-strut-plla-based-sirolimus-eluting-stent-1-biomime. Accessed August 22, 2018.
  10. Jensen LO, Thayssen P, Maeng M, et al. Randomized comparison of a biodegradable polymer ultrathin strut sirolimus-eluting stent with a biodegradable polymer biolimus-eluting stent in patients treated with percutaneous coronary intervention: the SORT OUT VII trial. Circ Cardiovasc Interv. 2016; 9:e003610.
  11. Kandzari DE, Koolen JJ, Doros G, et al; BIOFLOW V Investigators. Ultrathin bioresorbable polymer sirolimus-eluting stents versus thin durable polymer everolimus-eluting stents. J Am Coll Cardiol. 2018 Dec 25; 72(25): 3287-3297. doi: 10.1016/j.jacc.2018.09.019.
  12. van der Heijden LC, Kok MM, Zocca P, et al. Bioresorbable polymer-coated Orsiro versus durable polymer-coated Resolute Onyx stents (BIONYX): rationale and design of the randomized TWENTE IV multicenter trial. Am Heart J. 2018 Apr; 198: 25-32. doi: 10.1016/j.ahj.2017.12.011.
  13. Jakobsen L, Christiansen EH, Maeng M, et al. Randomized clinical comparison of the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent with the sirolimus-eluting Orsiro stent in patients treated with percutaneous coronary intervention: Rationale and study design of the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) X trial. Am Heart J. 2018 Aug; 202: 49-53. doi: 10.1016/j.ahj.2018.04.019.
  14. Jensen LO, Maeng M, Raungaard B, et al. A randomized trial comparing a polymer-free coronary drug-eluting stent with an ultra-thin strut bioresorbable polymer-based drug-eluting stent in an allcomers patient population: SORT OUT IX. Presented at: TCT 2018. September 22, 2018. San Diego, CA.
  15. Bonin M, Guerin P, Olive JM, Jordana F, Huchet F. Standardized bench test evaluation of coronary stents: biomechanical characteristics. Catheter Cardiovasc Interv. 2018 Dec 1; 92(7): E465-E470. doi: 10.1002/ccd.27912.
  16. Bartorelli AL, Versaci F, Briguori C, et al. The BIOFLOW-III Italian Satellite Registry: 18-month results of the Orsiro stent in an all-comer high-risk population. J Cardiovasc Med (Hagerstown). 2019 Apr 15. doi: 10.2459/JCM.0000000000000795.
  17. Waltenberger J, Brachmann J, van der Heyden J, et al; BIOFLOW-III Investigators. Five-year results of the BIOFLOW-III Registry: real-world experience with a biodegradable polymer sirolimus-eluting stent. Cardiovasc Revasc Med. 2019 Mar 15. pii: S1553-8389(19)30166-6. doi: 10.1016/j.carrev.2019.03.004.
  18. S Pilgrim T, Heg D, Roffi M, et al. Ultrathin strut biodegradable polymer sirolimus-eluting stent versus durable polymer everolimus-eluting stent for percutaneous coronary revascularisation (BIOSCIENCE): a randomised, single-blind, non-inferiority trial. Lancet. 2014; 384: 2111-2122.
  19. Jensen LO, Thayssen P, Maeng M, et al. Randomized comparison of a biodegradable polymer ultrathin strut sirolimus-eluting stent with a biodegradable polymer biolimus-eluting stent in patients treated with percutaneous coronary intervention: the SORT OUT VII Trial. Circ Cardiovasc Interv. 2016;e003610.
  20. Kok MM, Zocca P, Buiten RA, et al. Two-year clinical outcome of all-comers treated with three highly dissimilar contemporary coronary drug-eluting stents in the randomized BIO-RESORT trial. EuroIntervention. 2018 Oct 20; 14(8): 915-923. doi: 10.4244/EIJ-D-18-00336.
  21. Zocca P, Kok MM, van der Heijden LC, et al. High bleeding risk patients treated with very thin-strut biodegradable polymer or thin-strut durable polymer drug-eluting stents in the BIO-RESORT trial. Cardiovasc Drugs Ther. 2018 Dec; 32(6): 567-576. doi: 10.1007/s10557.