Update on paclitaxel use

By fall 2018, three drug-coated balloons and two drug-eluting stents had been approved by the FDA for use in the femoral-popliteal circulation for PAD. These approvals were based on prospective randomized trials that uniformly demonstrated superiority over plain balloon angioplasty at achieving higher rates of primary patency and freedom from clinically driven target lesion revascularization.1–5 Clinical use of these products had increased dramatically since the first device was approved in 2015, to the point where it was estimated that, by late 2018, over 50% of peripheral femoral popliteal intervention used a paclitaxel-based device.6

In winter 2018, an article published on the Journal of the American Heart Association website provided a meta-analysis statistical review of all published reports of peripheral paclitaxel use. This study reported a significant statistical correlation between the use of peripheral paclitaxel devices and mortality at 2- and 5-year follow-ups. The article also implied that devices that were believed to use higher doses of paclitaxel were associated with higher mortality rates when compared to those with relatively lower doses of the drug.7

This article has brought the global vascular community to a near standstill in the last 18 months with many international regulatory bodies issuing warnings and hospitals, as well individual physicians, choosing to not offer the technology to their respective patients. The FDA held a Circulatory System Device panel meeting in summer 2019 to review the findings of this controversial article and attempt to make recommendations on potential pathways forward. The panel consisted of expert physicians from multiple vascular specialties who heard presentations from the medical device industry offering supplemental clinical data and statistical review. Vascular medical specialty representatives, including SIR and ACR, offered a patient-centered clinical perspective on the impact of this technology on comprehensive vascular care.

The FDA panel concluded and reported in their own independent analysis and review of the industry data the following points:

  1. There was a statistical signal, or correlation, with peripheral paclitaxel use that appeared to be less dramatic than that reported in the JAHA article.
  2. There was no dose effect after the FDA reviewed the patient-level data supplied by the medical device industry from the pivotal randomized trials that led to FDA approval.
  3. There was no plausible mechanism that had been described or theorized to account for this statistical signal.

At the conclusion of the panel, there was uniform consensus that the technology should remain available for clinical use but that a potential patient should undergo a detailed informed consent process to review the statistical association for mortality at 2 and 5 years before undergoing a therapeutic procedure.8

Since the panel meeting last summer, several publications have attempted to supplement the original findings of the JAHA article. A review of Medicare claims data found no correlation between peripheral paclitaxel use and mortality when compared to patients treated with non-drug-based devices.9 A second independent meta-analysis that incorporated a more thorough review of patient follow-up data showed a persistent signal but at far greater significance than the original report.10 Several European reports have demonstrated no correlation between paclitaxel use and late mortality.11–12 A recent drug-coated balloon trial with 3-year follow-up has shown no difference with late mortality when compared to plain balloon angioplasty.13

While the persistent statistical signal in the follow-up meta-analysis is concerning, several theories have been put forward to explain this finding. The most intriguing theory suggests that ascertainment bias or the different levels of clinical follow-up for the two randomized groups in the early trials may have led to different reporting of adverse events. It is also possible that patients in the control groups that met the primary endpoint for loss of patency may have received better medical therapy and shown lower mortality rates. These theories may explain why trials completed in the last few years have failed to repeat the findings of the original meta-analysis.14

Earlier this year, another publication by the authors of the original meta-analysis suggested that paclitaxel-based peripheral devices, when used for infrapopliteal disease for limb salvage, may confer increased mortality and limb loss for patients with critical limb ischemia (CLI) or chronic limb threatening ischemia (CLTI).15 This publication was met with the same level of concern and controversy. At present, there are no FDA-approved paclitaxel-based devices for use in the below-knee circulation. From a practical perspective, this is more of a theoretical concern. Several criticisms have been raised in response to this publication as well. First, the only prospective randomized trial evaluating paclitaxel eluting stents in the below-knee circulation showed both clinical efficacy at achieving limb salvage but also no effect on mortality.16 This trial was not included for consideration in this meta-analysis. Second, the most widely studied drug-coated balloon for the infrapopliteal circulation recently published 5-year data from the pivotal European trial. This data showed a lack of clinical efficacy and, most notably, no correlation with late mortality in the population studied.17 At present, this product is currently not available for clinical use in the global market due to a lack of clinical efficacy.

Currently, an ongoing multispecialty (including representatives from SIR and ACR) and multistakeholder working group is meeting with the FDA on a regular basis to resolve this issue after the panel last summer. A repeat statistical analysis including recent datasets is planned for later this year. The patient’s perspective is being increasingly considered for preference for therapy as well as their quality of life before and following treatment.

As an interventional radiologist and practicing vascular specialist, I believe this issue will be resolved in the near future. SIR remains committed to advocating for patients and will continue to assist the FDA to make decisions that will protect our patients and improve care now and in the future.

References

  1. Rosenfield K, Jaff MR, White CJ, Rocha-Singh K, Mena-Hurtado C, Metzger DC, Brodmann M, Pilger E, Zeller T, Krishnan P, Gammon R, Müller-Hülsbeck S, Nehler MR, Benenati JF, Scheinert D; LEVANT 2 Investigators. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med. 2015 Jul 9;373(2):145–53.
  2. Laird JR, Schneider PA, Tepe G, Brodmann M, Zeller T, Metzger C, Krishnan P, Scheinert D, Micari A, Cohen DJ, Wang H, Hasenbank MS, Jaff MR; IN.PACT SFA Trial Investigators. Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA. J Am Coll Cardiol. 2015 Dec 1;66(21):2329–2338.
  3. Krishnan P, Faries P, Niazi K, Jain A, Sachar R, Bachinsky WB, Cardenas J, Werner M, Brodmann M, Mustapha JA, Mena-Hurtado C, Jaff MR, Holden AH, Lyden SP. Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies. Circulation. 2017 Sep 19;136(12):1102–1113.
  4. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, Machan LS, Snyder SA, O’Leary EE, Ragheb AO, Zeller T; Zilver PTX Investigators. Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery: 5-Year Results of the Zilver PTX Randomized Trial. Circulation. 2016 Apr 12;133(15):1472–83; discussion 1483. Epub 2016 Mar 11. Erratum in: Circulation. 2019 Feb 19;139(8):e42. PMID: 26969758; PMCID: PMC4823823.
  5. Gray WA, Keirse K, Soga Y, Benko A, Babaev A, Yokoi Y, Schroeder H, Prem JT, Holden A, Popma J, Jaff MR, Diaz-Cartelle J, Müller-Hülsbeck S; 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. 1. Epub 2018 Sep 24. PMID: 30262332.
  6. fda.gov/media/127698/download.
  7. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. 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 Dec 18;7(24):e011245. PMID: 30561254; PMCID: PMC6405619.
  8. fda.gov/medical-devices/letters-health-care-providers/august-7-2019-updatetreatment-peripheral-arterial-disease-paclitaxelcoated-balloons-and-paclitaxel.
  9. Secemsky EA, Kundi H, Weinberg I, Jaff MR, Krawisz A, Parikh SA, Beckman JA, Mustapha J, Rosenfield K, Yeh RW. Association of Survival With Femoropopliteal Artery Revascularization With Drug-Coated Devices. JAMA Cardiol. 2019 Apr 1;4(4):332–340. PMID: 30747949; PMCID: PMC6484791.
  10. Rocha-Singh KJ, Duval S, Jaff MR, Schneider PA, Ansel GM, Lyden SP, Mullin CM, Ioannidis JPA, Misra S, Tzafriri AR, Edelman ER, Granada JF, White CJ, Beckman JA; VIVA Physicians, Inc. Mortality and Paclitaxel-Coated Devices: An Individual Patient Data Meta-Analysis. Circulation. 2020 Jun 9;141(23):1859–1869. PMID: 32370548.
  11. Freisinger E, Koeppe J, Gerss J, Goerlich D, Malyar NM, Marschall U, Faldum A, Reinecke H. Mortality after use of paclitaxel-based devices in peripheral arteries: a real-world safety analysis. Eur Heart J. 2019 Oct 8:ehz698. Epub ahead of print. PMID: 31593987.
  12. Saratzis A, Lea T, Yap T, Batchelder A, Thomson B, Saha P, Diamantopoulos A, Saratzis N, Davies R, Zayed H. Paclitaxel and Mortality Following Peripheral Angioplasty: An Adjusted and Case Matched Multicentre Analysis. Eur J Vasc Endovasc Surg. 2020 May 1:S1078–5884(20)30330-0. Epub ahead of print. PMID: 32370918.
  13. Gray WA, Jaff MR, Parikh SA, Ansel GM, Brodmann M, Krishnan P, Razavi MK, Vermassen F, Zeller T, White R, Ouriel K, Adelman MA, Lyden SP. Mortality Assessment of Paclitaxel-Coated Balloons: Patient-Level Meta-Analysis of the ILLUMENATE Clinical Program at 3 Years. Circulation. 2019 Oct;140(14):1145–1155. Epub 2019 Sep 30. PMID: 31567024; PMCID: PMC6784772.
  14. Holden A, Varcoe RL, Jaff MR, Schneider PA, Tepe G, Zeller T. Paclitaxel and Mortality: The Dose Argument Is Critical. J Endovasc Ther. 2019 Aug;26(4):467–470. Epub 2019 Jun 9. PMID: 31179816.
  15. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Paraskevopoulos I, Karnabatidis D. Risk of Death and Amputation with Use of Paclitaxel-Coated Balloons in the Infrapopliteal Arteries for Treatment of Critical Limb Ischemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Vasc Interv Radiol. 2020 Feb;31(2):202–212. doi: 10.1016/j.jvir.2019.11.015. Epub 2020 Jan 15. PMID: 31954604.
  16. Spreen MI, Martens JM, Knippenberg B, van Dijk LC, de Vries JPM, Vos JA, de Borst GJ, Vonken EPA, Bijlstra OD, Wever JJ, Statius van Eps RG, Mali WPTM, van Overhagen H. 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):e004877. doi: 10.1161/JAHA.116.004877. PMID: 28411244; PMCID: PMC5533004.
  17. Zeller T, Micari A, Scheinert D, Baumgartner I, Bosiers M, Vermassen FEG, Banyai M, Shishehbor MH, Wang H, Brodmann M; IN.PACT DEEP Trial Investigators. The IN.PACT DEEP Clinical Drug-Coated Balloon Trial: 5-Year Outcomes. JACC Cardiovasc Interv. 2020 Feb 24;13(4):431–443. doi: 10.1016/j.jcin.2019.10.059. PMID: 32081236.