By Mike Schroeder and Kamran Zamanian, Ph.D., iData Research Inc.
Following the publication of a meta-analysis by Konstantinos Katsanos et al. in the Journal of the American Heart Association (JAHA) in December 2018,1 the markets for drug-coated balloons (DCB) and drug-eluting stents (DES) experienced a large negative shock and still await their recovery.
Despite numerous studies released in the past year validating the use of paclitaxel in the peripheries, as well as the Food and Drug Administration’s (FDA) August statement that conclusive evidence did not exist to fully evaluate the late mortality signal, sales of devices that incorporate paclitaxel remain low. The last months of 2019 showed a slow return to these devices, and nuanced use has improved physician comfort. Still, many care providers refuse to use these devices until further evidence is available.
Meta-Analysis Publication and the FDA’s Initial Statement
Katsanos’ meta-analysis found “a significant relationship between exposure to paclitaxel and absolute risk of death (0.4± 0.1% excess risk of death per paclitaxel mg-year; P>0.001).” The increased risk of death appears after the first year following treatment; however, a direct cause for the increased risk of death had not been identified.
An initial FDA statement, released about a month after publication of this meta-analysis, shared the Katsanos paper’s findings and urged physicians to continue surveillance of paclitaxel-treated patients, as well as discuss the risks and benefits of all treatment options during clinical decision-making. The FDA remarked that it was independently evaluating long-term follow-up data from studies in the U.S. and other available data sets. In the statement, the FDA also claimed, “the benefits continue to outweigh the risks for approved paclitaxel-coated balloons and paclitaxel-eluting stents when used in accordance with their indications for use.”
This initial FDA statement had an immediate, powerful effect on the market. In the U.S., Paclitaxel Q1 2019 unit sales decreased by approximately 10 percent versus Q4 2018 unit sales, and dipped 13 percent compared to Q1 2018. Many hospitals and physicians refused to use DCBs due to worries about litigation. Some physicians continued to use the devices only on the most complicated patients, and even then only after serious discussion of alternatives. Other care providers continued use under the justification that paclitaxel devices still provided the best patency rates (i.e., likelihood the vessel would remain open) for patients they were treating.
Movement away from paclitaxel devices continued through 2019, deepening the negative shock. Annual unit sales for DCBs in the superficial femoral artery (SFA) were most impacted by this, experiencing an approximate 20 percent decline in European unit sales2 and almost a 40 percent drop in U.S. unit sales.3 Drug-eluting stents experienced a more moderate 9 percent decline in Europe and 11 percent decline in the U.S.
Companies Defend Paclitaxel and the FDA Clears Use
In response to the rapidly evaporating market, most companies republished their data with additional analysis to support continued use of their devices. Apart from an inadvertent earlier error in released data for Cook Medical’s Zilver PTX,4 all the re-released studies found no significant late-mortality signal.
Boston Scientific, Medtronic, C. R. Bard, and Philips all updated their original studies and stood by their evidence supporting the use of paclitaxel devices in the peripheries.
A June 2019 FDA panel meeting presented the agency’s independent investigation results and sought responses from manufacturers. Katsanos also joined with additional research on the associated co-morbidities within the original study. Throughout the two-day meeting, the FDA pleaded with manufacturers to continue long-term data gathering, and to actively share the results.
However, questions about co-morbidities and path of treatment were often raised, preventing causal demonstration within any analysis. In August 2019, a final FDA statement was issued, allowing for continued use of paclitaxel devices within the peripheries. However, the agency once again warned about the potential for late mortality arising from these devices.
Eva Freisinger’s Study and Physicians’ Response
Physicians, especially in Europe, were hesitant to reintroduce paclitaxel-coated devices to their regular treatment strategies. Instead, they tended to revert to older treatment strategies, employing plain balloons and bare metal stents (BMS) with other conjunctive treatments. Many European physicians requested additional clinical evidence — specifically, evidence testing the efficacy of dosage and concentration within these devices. Physicians in some regions, such as Germany and Benelux, also needed to wait for their governmental regulatory agencies to once again clear these devices.
An exception to the paclitaxel retreat was below-the-knee treatments, which have few other available treatment options demonstrating sustained patency. Atherectomy and DCB use was common, employing off-label coronary DCB use within the U.S., as no paclitaxel-coated devices had been approved. While usage in below-the-knee treatments did decline, the observed 10 percent reduction paled in comparison to the shock seen in other indications.
In an attempt to rectify the ambiguity that remained after the FDA’s meetings due to a lack of long-term data, Eva Fresinger et al. published a study5 in the European Heart Journal following Germany health insurance data over 11 years of past application. This study, unique in its scope, suggested paclitaxel use in the peripheries has a limited-time benefit of between two and three years, after which patency and mortality rates return to similar rates seen by percutaneous transluminal angioplasty (PTA) or bare-metal stenting.
What Can We Expect?
Now, about a year after the FDA’s initial statement was released, the market appears to be recovering. While paclitaxel usage has not regained its previous usage peaks, physician and manufacturer sentiments both seem to suggest a healthy market recovery within five to seven years. However, heavy investment likely will be required to prompt similar historical growth rates.
A few studies in coronary applications6,7 have shown a late mortality with paclitaxel, up to five years after treatment, which has prompted some manufacturers to adopt alternatives for their coronary stents and balloons. While these drugs have not fully transitioned over to peripheral applications, several non-paclitaxel devices have been approved in recent years. iVascular and Reva Medical obtained CE mark approval for the Angiolite® BTK stent in 2017 and the MOTIV® BTK stent in 2018, respectively. In October 2019, Concept Medical received CE mark approval for its sirolimus-covered MagicTouch® balloon, indicated for use in arteriovenous (AV) applications and peripheral arteries. The spotlight on paclitaxel over the past year is only expected to increase innovation in alternatives.
Further, additional clinical investment is expected to investigate the causality between dosage, length of patency, timing of mortality signal, and concentration of the drug during application. DCB and DES treatment techniques were solidifying prior to 2019, but research in BTK treatments had not yet concluded an optimal strategy.
Therefore, as the market returns to use of these devices, manufacturers of paclitaxel devices may wish to promote BTK usage through comparison to alternative treatments and capitalize on increasing treatment of critical limb ischemia (CLI) resultant of aging populations and increasing diabetic rates in Europe and the U.S.
About The Authors
Mike Schroeder is an Senior Analyst at iData Research. He has been involved in custom and syndicated medical device market research projects, publishing the entire Peripheral Vascular Global Series, and now supports custom research and updates for the impacts of the COVID19 pandemic.
Kamran Zamanian, Ph.D., is CEO and founding partner of iData Research. He has spent over 20 years working in the market research industry with a dedication to the study of medical devices used in the health of patients all over the globe.
About iData Research
For 15 years, iData Research has been a strong advocate for data-driven decision-making within the global medical device, dental, and pharmaceutical industries. By providing custom research and consulting solutions, iData empowers their clients to trust the source of data and make important strategic decisions with confidence.
- Katsanos, K. S., Spiliopoulos, S., Kitrou, P., Kokidis, M., Karnabatidis, D. (2018). 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. Journal of the American Heart Association.
- European Market Report Suite for Peripheral Vascular Devices – 2020, iData Research Inc.
- US Market Report Suite for Peripheral Vascular Devices – 2020, iData Research Inc.
- McKeown, L.A. “'Inadvertent Reversal' of Late Mortality Data Flips Advantage From Paclitaxel Zilver PTX Stent in PAD to PTA.” TCTMD.com, TCTMD, 20 Feb. 2019, www.tctmd.com/news/inadvertent-reversal-late-mortality-data-flips-advantage-paclitaxel-zilver-ptx-stent-pad-pta
- Freisinger, E. K. et al. (2019). Mortality after use of paclitaxel-based devices in peripheral arteries: a real-world safety analysis. European Heart Journal, https://doi.org/10.1093/eurheartj/ehz698
- Serruys, P. W., Mohr, F. W., Hanisch, M. (2010). SYNTAX study: TAXUS drug-eluting stent versus coronary artery bypass surgery for the treatment of narrowed arteries (SYNTAX). U.S. National Library of Medice. https://clinicaltrials.gov/ct2/show/NCT00114972
- Stone, G. W., et al. (2011). Long-term safety and efficacy of paclitaxel-eluting stents final 5-year analysis from the TAXUS Clinical Trial Program. JACC: Cardiovascular Interventions, 10.1016/j.jcin.2011.03.005. https://pubmed.ncbi.nlm.nih.gov/21596326/