Swirling Flow®: Nature's Ideal Alternative to Drug Elution

When the Katsanos et al meta-analysis was published in Journal of the American Heart Association in 2018,¹ it would have been difficult to predict the impact on the use of drug-coated/drug-eluting devices by the summer of 2019. At the time of this writing, several regulatory bodies have made statements relating to the use of paclitaxel devices. At a panel meeting in June 2019, FDA continued to indicate that paclitaxel-coated and paclitaxel-eluting devices should be used with caution in peripheral artery disease (PAD) and that available data will continue to be reviewed. The United Kingdom Medicines & Healthcare Products Regulatory Agency has advised physicians to “not use paclitaxel drug-coated balloons (DCBs) or drug-eluting stents in the routine treatment of patients with intermittent claudication until further notice.”² Germany’s Federal Institute for Drugs and Medical Devices stated, “In all cases, other than in patients with a particularly high risk of restenosis, alternative treatments should preferably be considered.”³ The Cardiovascular and Interventional Radiological Society of Europe’s position statement on the controversy said, “In the majority of patients undergoing lower limb recanalization therapies, alternatives to drug-eluting devices should be used.”⁴

Fortunately, the challenging issue of limiting restenosis has a drug-free solution: swirling flow—nature’s own vascular protection mechanism and the ideal alternative to drug elution.

USING SWIRLING FLOW IN THE FEMOROPOPLITEAL ARTERY

The distribution of atherosclerosis and the tendency of an artery to develop restenosis varies throughout the human arterial system. The femoropopliteal artery has both a high prevalence of atherosclerosis and a high tendency to develop restenosis.^5,6 Part of the reason for the variable distribution of native arterial disease was explained by Caro et al, who drew attention to the relationship between wall shear stress (WSS) and a reduced tendency toward atherosclerosis.⁵ It is understood that normal arterial blood flow is laminar. In addition, the normal pattern of that laminar blood flow in the aorta and proximal branches is also spiral, and it is referred to as swirling flow.⁶ WSS can be thought of as the velocity of blood against the internal wall of the vessel. Swirling flow increases WSS when compared with nonswirling flow, resulting in a reduced propensity to develop atherosclerosis and restenosis. Blood flow in the superficial femoral artery (SFA)—where natural curvature is limited, particularly when straightened by a straight stent—is naturally less swirling and has a reduced WSS (Figure 1)⁷, hence the high prevalence of native disease and proliferative response to endovascular injury.

Figure 1. A computational fluid dynamics (CFD) model of swirling flow, showing it becoming dampened in the iliac arteries, resulting in straight laminar flow in the SFA (A). A CFD model of high WSS in the iliac arteries (as a consequence of swirling flow) and low WSS in the SFA; low WSS (pathogenic) represented in red, suboptimal WSS represented in blue, and high WSS (protective) represented in green (B).⁷ Reproduced from Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999;282:2035-2042.

Figure 2. The BioMimics 3D stent.

Figure 3. Thirty-day histology of a straight nitinol stent (A) and the same stent with a 3D helical shape (B) in a porcine carotid model. Overall, in 10 animals studied, there was a 45% reduction in neointimal thickness (P < .001).¹²

Animal studies have confirmed that areas of low WSS predict the development of neointimal hyperplasia (NIH) in grafts and stents.⁸ Using straight nitinol stents to treat the SFA of patients with PAD has been shown to reduce WSS.⁹ Evaluation of coronary stents in humans showed that the pattern of in-stent restenosis is determined by the distribution of WSS.^10,11 These observations led to the development of the BioMimics three-dimensional (3D) self-expanding nitinol stent (Veryan Medical Ltd.), which has a helical centerline that is capable of inducing swirling flow (Figure 2). The ability of this stent to reduce restenosis was first tested in a porcine model in which a straight stent was placed in one carotid artery and a helically formed version of the same stent was placed in the other carotid artery. The study demonstrated that (1) the helical centerline stent imparted nonplanar curvature to the implanted segment and generated swirling flow; (2) the swirling flow significantly reduced the development of NIH (Figure 3)¹²; and (3) a correlation between the degree of curvature and the reduction in NIH was established.¹³

The BioMimics 3D stent was subsequently tested in the first randomized controlled trial (RCT) to directly compare two nitinol stents in the femoropopliteal segment.¹⁴ MIMICS-RCT was a multicenter, core lab–controlled, prospective, randomized trial in which the BioMimics 3D stent was compared with a conventional straight stent control (LifeStent, BD Interventional) in 76 patients with symptomatic occlusive disease of the SFA and proximal popliteal artery. Conventional radiographs and angiograms confirmed that the BioMimics 3D stent imparts nonplanar curvature to the diseased artery. Compared with the straight stent control, the BioMimics 3D stent had significantly better primary patency through 2 years (Figure 4). There was no clinically driven target lesion revascularization (CDTLR) in the BioMimics 3D arm between 12 and 24 months, whereas there was a threefold increase in CDTLR in the straight stent control arm over the same time period. This represents a significant difference between the two stents (Figure 5). The clinical validation of the BioMimics 3D swirling flow stent is continuing across a range of studies in the MIMICS clinical program. Recently presented 2-year data from the MIMICS-2 investigational device exemption study have validated the clinical outcomes of the earlier randomized study in a larger (271 patient), more challenging patient population.¹³

Figure 4. Kaplan-Meier survival estimate from loss of patency (MIMICS-RCT study).

Figure 5. Kaplan-Meier estimate of survival from CDTLR between 1 and 2 years (MIMICS-RCT study).

DRUG-COATED BALLOONS

Current DCBs use paclitaxel to address the biological mechanisms that lead to restenosis. The drug is combined with an excipient or carrier to provide uniform dosage and rapid uptake into the vessel wall. Variations in the excipient, formulation, and dosage of the paclitaxel result in the different behavior of individual DCBs.

The pivotal DCB trials showed improved performance over simple angioplasty, but these were regulatory studies in carefully selected patients with uncomplicated lesions, and the importance of that in terms of the generalizability of DCBs’ value deserves some attention.^15-19 Severe calcification and an inability to completely predilate the lesion were exclusions in these studies, and they effectively removed those lesions from any analysis. Furthermore, because only 12% to 26% of lesions were total occlusions, vessels in these populations were predominantly noncalcified, with simple disease that was unlikely to recoil after angioplasty, resulting in a bailout stent rate of only 2.5% to 7%.

When the same DCBs are used in patients who are more representative of routine clinical practice and documented within the global registries, the lesion patency and CDTLR rates remain good because these more clinically generalizable cohorts are measuring the outcome of using a DCB plus a stent.^20,21 Registry patients were characterized by more complex disease than those who were recruited to the pivotal regulatory trials, resulting in an average stent rate of 28% to 35.5%.^20-23 This stent rate was related to both lesion length and the chronic total occlusion rate. For instance, in IN.PACT Global, the stent rate was 53% when the length of lesion exceeded 25 cm and 47% in total occlusions.^22,23 The Kaplan-Meier survival estimates from the pivotal regulatory trials demonstrated that the patency benefit and reduction in CDTLR over simple angioplasty occur between 6 and 12 months; but after 1 year in IN.PACT SFA, the Kaplan-Meier curves were parallel.²⁴ This trend is also seen in the global registries.^20-23

A DCB-only approach has never been an adequate solution for clinical practice outside of pivotal trials. Although the bailout stent rate was low in pivotal trials, the global registries demonstrate that a much higher use of stents is required to maintain patency and low CDTLR rates. Vessel recoil and late negative remodeling are common contributory factors in the loss of patency, which compromises a DCB-only strategy.

CONCLUSION

Besides providing the required scaffolding, swirling flow generated by the BioMimics 3D stent has been shown in the MIMICS-RCT trial to significantly reduce the need for revascularization compared with a straight nitinol stent over 2 years of follow-up.¹⁴

With physicians now being advised to find alternatives to the use of paclitaxel in femoropopliteal intervention, swirling flow induced by the BioMimics 3D stent would appear to be nature’s ideal substitute.²⁵

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. United Kingdom Medicines & Healthcare Products Regulatory Agency. Medical device alert: recommendations for ongoing use of paclitaxel drug coated balloons (DCBs) and implantable drug eluting stents (DESs) in the treatment of patients with peripheral artery disease (PAD). https://assets.publishing.service.gov.uk/media/5cf53bb240f0b63b01a86734/MDA-2019-023.pdf. Accessed August 20, 2019.

3. Bundesinstitut für Arzneimittel und Medizinprodukte. Empfehlung für die verwendung von paclitaxel-beschichteten stents (DES) und ballons (DCB) in der behandlung der peripheren arteriellen verschlusskrankheit (pAVK). https://www.bfarm.de/SharedDocs/Risikoinformationen/Medizinprodukte/DE/paclitaxel_stents_ballons_pavk.html. Accessed August 20, 2019.

4. Cardiovascular and Interventional Radiological Society of Europe. CIRSE position on the use of paclitaxel-coated balloons and stents in PAD. https://www.cirse.org/research/current-updates/. Accessed August 20, 2019.

5. Caro CG, Fitz-Gerald JM, Schroter RC. Arterial wall shear and distribution of early atheroma in man. Nature. 1969;223:1159-1160.

6. Caro CG, Doorly DJ, Tarnawski M, et al. Non-planar curvature and branching of arteries and non-planar-type flow. Proc R Soc Lond. 1996;452:185-197.

7. Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999;282:2035-2042.

8. LaDisa JF Jr, Olson LE, Molthen RC, et al. Alterations in wall shear stress predict sites of neointimal hyperplasia after stent implantation in rabbit iliac arteries. Am J Physiol Heart Circ Physiol. 2005;288:H2465-H2475.

9. Schlager O, Zehetmayer S, Seidinger D, et al. Wall shear stress in the stented superficial femoral artery in peripheral arterial disease. Atherosclerosis. 2014;233:76-82.

10. Sanmartín M, Goicolea J, García C, et al. Influence of shear stress on in-stent restenosis: in vivo study using 3D reconstruction and computational fluid dynamics. Rev Esp Cardiol. 2006;59:20-27.

11. Wentzel JJ, Whelan DM, van der Giessen WJ, et al. Coronary stent implantation changes 3-D vessel geometry and 3-D shear stress distribution. J Biomech. 2000;33:1287-1295.

12. Caro CG, Seneviratne A, Heraty KB, et al. Intimal hyperplasia following implantation of helical-centreline and straight-centreline stents in common carotid arteries in healthy pigs: influence of intraluminal flow. J R Soc Interface. 2013;10:20130578.

13. Data on file at Veryan Medical.

14. Zeller T, Gaines PA, Ansel GM, Caro CG. Helical centerline stent improves patency: two-year results from the randomized Mimics trial. Circ Cardiovasc Interv. 2016;9:e002930.

15. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and/or popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2015;131:495-502.

16. Laird JR, Schneider PA, Tepe G et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol. 2015;66:2329-2338.

17. Scheinert D, Schulte KL, Zeller T, et al. Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial. J Endovasc Ther. 2015;22:14-21.

18. Schroeder H, Meyer DR, Lux B, et al. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc Interv. 2015;86:278-286.

19. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med. 2015;373:145-153.

20. Scheinert D. Latest results from the Levant Global registry on challenging, real world lesions including long lesions, CTOs and ISR & lesions learned from Levant II. Presented at: Leipzig Interventional Course (LINC) Asia-Pacific 2016; March 8–10, 2016; Lantau Island, Hong Kong.

21. Scheinert D. Strengths and weaknesses of DCBs: insights from the global registries. Presented at: Vascular Interventional Advances (VIVA) 2016; September 18–22, 2016; Las Vegas, Nevada.

22. Scheinert D, Micari A, Brodmann M, et al. Drug-coated balloon treatment for femoropopliteal artery disease. Circ Cardiovasc Interv. 2018;11: e005654.

23. Tepe G, Micari A, Keirse K, et al. Drug-coated balloon treatment for femoropopliteal artery disease: the chronic total occlusion cohort in the IN.PACT Global study. JACC Cardiovasc Interv. 2019;12:484-493.

24. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol. 2015;66:2329-2338.

25. Sullivan TM, Zeller T, Nakamura M, et al. Swirling flow and wall shear: evaluating the BioMimics 3D helical centerline stent for the femoropopliteal segment. Int J Vasc Med. 2018;2018:9795174.

PAM 217 Issue 00

The BioMimics 3D Vascular Stent System has FDA and CE Mark approval. Not available for sale in Japan.

US Federal law restricts this device to sale by or on the order of a physician.