Is Paclitaxel Safe in Patients with CLTI?

2. September 2021
Jeff Hall, Senior Contributing Editor

Do paclitaxel-coated devices significantly increase amputation-free survival rates, or do they increase the risk of major amputation in patients with chronic limb-threatening ischemia (CLTI)?

Two recently published studies may contribute to the ongoing debate about the efficacy and reported risks of paclitaxel-coated modalities in this high-risk patient population.

In a retrospective review involving nearly 1,000 patients with CLTI, Kumins and colleagues examined four-year outcomes with the use of paclitaxel-coated devices in femoropopliteal artery angioplasty, atherectomy, stent or a combination of procedures.1 In their study, published by the Journal of Vascular Surgery (JVS), they found that the paclitaxel group had a 13.3 percent higher overall survival rate as well as a 16.5 percent higher rate of amputation-free survival. The researchers also noted an 8.7 percent higher rate of freedom from major amputation in patients treated with paclitaxel-coated devices.

However, a separate recently published meta-analysis of 21 randomized controlled trials (RCTs) found that the use of paclitaxel-coated balloons in peripheral arteries for the treatment of intermittent claudication or critical limb ischemia (CLI) had a heightened risk of major amputation.2 In this study, published in the European Journal of Vascular and Endovascular Surgery (EJVES), Katsanos and colleagues drew upon data from a total of 3,760 patients with 52 percent having intermittent claudication and 48 percent having CLI.

Norman H. Kumins, MD, the lead author of the JVS study, says the meta-analysis by Katsanos and colleagues has similar methodologic flaws as a 2018 meta-analysis by Katsanos and coworkers that suggested an association between paclitaxel use and long-term mortality.2,3

“Both of these meta-analyses were based on published trials that were designed to study patency, not mortality or amputation,” notes Dr. Kumins, a Clinical Assistant Professor in the Department of Surgery at the Case Western Reserve University School of Medicine in Cleveland.

He adds that the researchers did not employ a time to event analysis (Kaplan Meier) to study outcome measures and instead reported events at a crude rate, which was calculated differently for each study.2,3 The authors of the aforementioned meta-analyses also accounted for patients in an intention to treat analysis (not as treated), according to Dr. Kumins. He says this is an important point to consider with the 2018 meta-analysis “because many of the control patients crossed over and were actually treated with a paclitaxel-coated device.” Dr. Kumins also notes that many patients who were initially reported as lost to follow up were alive.4,5

“When these missing patients in the 2018 study by Katsanos and colleagues were included, analyzed using a Kaplan Meier model and accounted for in an as-treated analysis instead of an intention to treat analysis, the reported mortality risk evaporated,” maintains Dr. Kumins.3-5

He adds that Dinh and coworkers published another recent meta-analysis patterned off the 2018 Katsanos and colleagues report, included most of the missing patients and found no mortality association.6

When one addresses the potential methodological factors in the EJVES meta-analysis, Dr. Kumins believes there could be a similar pattern with an ultimate finding that paclitaxel is not associated with increasing amputation rates, “at least in the femoropopliteal segment using FDA-approved devices.”

Konstantinos Katsanos, MSc, MD, PhD, EBIR, the lead author of the EJVES meta-analysis, says the “level and quality of evidence (between the two recent studies) are very different.” He notes that the Kumins and colleagues study is a retrospective, single-center analysis that employed Cox regression to control confounding factors.1 Referencing a recent opinion review he co-authored earlier this year, Dr. Katsanos suggests that epidemiological bias factors into the ongoing debate over paclitaxel, and the conflict between prospective, randomized studies and retrospective real-world analyses.7

“A biased emphasis on survival rates because of underlying ‘healthy user’ bias appears to be ubiquitous in non-randomized observational analyses of paclitaxel in patients with PAD,” notes Dr. Katsanos, an Associate Professor of Interventional Radiology at the University of Patras School of Medicine in Patras, Greece. “‘Early adopter,’ ‘healthy user’ and ‘healthy adherer’ biases all relate to the fact that healthier patients tend to receive new, better treatments (like, for example, paclitaxel-coated devices) and consequently demonstrate better clinical results.”

Having utilized and studied paclitaxel-coated balloons and stents for several years, Dr. Katsanos says three meta-analyses that he has co-authored have demonstrated “significantly increased mortality with paclitaxel-coated devices, and amputations with paclitaxel-coated balloons in particular.”2,3,8 That said, Dr. Katsanos says each device stands on the merits and limitations of each design and available RCTs.

“For example, our latest meta-analysis reports a higher risk of amputations with paclitaxel-coated balloons, not stents,” emphasizes Dr. Katsanos.2 “I remain a heavy user of polymer-coated paclitaxel-eluting stents in cases of CLTI because those devices do not suffer from distal paclitaxel particulate embolization and allow for polymer-protected prolonged release of paclitaxel contrary to the paclitaxel showers of coated balloons.”

Dr. Kumins acknowledges that the “optimal design of a balloon for below-the-knee vessels is still being studied,” and notes that some below-knee trials have found increased amputation rates in the trial arm.9 However, Dr. Kumins emphasizes that these patients should not be grouped with those who were treated with FDA-approved balloons.

“The Barmer insurance database trial found that in patients with CLTI, paclitaxel use was associated with improved overall survival, amputation-free survival and freedom from major cardiovascular events,” notes Dr. Kumins, who is affiliated with the Division of Vascular Surgery and Endovascular Therapy at the Harrington Heart and Vascular Institute at the University Hospitals Ahuja Medical Center in Beachwood, Ohio.10

After the publication of the 2018 study from Katsanos and colleagues that linked paclitaxel use with long-term mortality risk, Dr. Kumins says he and his fellow researchers carefully reviewed their own data and found no increased risk of mortality in patients treated with paclitaxel-coated peripheral artery devices.3,11

“We in fact found improved survival in patients treated with paclitaxel-coated devices mostly due to the beneficial effect in patients with CLTI,” adds Dr. Kumins. “ … We also analyzed our patients and performed a propensity match to correct for confounding factors and similarly found no increased risk for mortality and a similar reduction of amputation rates in patients with CLTI.”11

Dr. Kumins concedes, however, that the mechanism of how paclitaxel affects both survival and amputation in patients with CLTI is “unclear.” Noting that it is well established that paclitaxel decreases restenosis, Dr. Kumins suggests that “perhaps the uninterrupted improvement in arterial perfusion leads to a reduction in amputations.”12

Dr. Katsanos notes that the latest EJVES study provides a detailed description of paclitaxel particulate showers that occur with drug-coated balloons.2

“It has been long shown that less than 10 percent of the paclitaxel load is being transferred to the treated vessel wall in the case of drug-coated balloon catheters and as much as 90 percent escapes into the distal circulation,” points out Dr. Katsanos.13 “Hence, downstream embolization of cytotoxic solid state paclitaxel material combined with its long-lasting tissue residence remains the most likely explanation for the detected higher rate of major limb loss, as well as for literature-reported cases of vascular fibrinoid necrosis, aneurysmal degeneration, small vessel inflammation, and focal downstream skeletal muscle necrosis.14-16

Dr. Kumins cautions that findings from animal studies may not be applicable to the diseased arteries treated in humans.13,14,16 Additionally, he says it is not accurate to group all paclitaxel balloons together as a class. Citing a previous editorial by Katsanos, Dr. Kumins says there are significant differences in outcome based on the paclitaxel composition and excipient used.17

“Balloons that use a more predominantly amorphous form of paclitaxel embolize less but have shorter drug half-life in the arterial wall while a more crystalline formulation may embolize more but persist in the arterial wall far longer,” notes Dr. Kumins.17 “Interestingly, balloons that use a higher proportion of the crystalline form have demonstrated improved patency.”18,19

“Still, high-dose crystalline formulations are associated with a more pronounced risk of major amputations and mortality as well,” emphasizes Dr. Katsanos.2,3

Given the current research, Dr. Katsanos has stopped using paclitaxel-coated balloons above and below the knee both in patients with claudication and those with CLTI. Dr. Katsanos reiterates this is not the case for newer-generation paclitaxel-eluting stents that he considers “a completely different technology in terms of stent design, pharmacokinetics and tissue bioavailability.”

In regard to the current JVJES meta-analysis he co-authored, Dr. Katsanos says he was surprised by the higher amputation signal being dominated by the higher 3.5 μg/mm2 urea design.2 While he notes this is in line with the drug-response relationship analysis, Dr. Katsanos says this finding could also be attributed to the fact that more randomized studies have been conducted so far with this particular device in comparison to other devices.

“I personally feel there are key differences in the performance (safety and efficacy) of the first-generation drug-coated balloons compared to the newer generation ones,” maintains Dr. Katsanos. “Still, it is quite alarming that in spite of the high potency of paclitaxel in averting vascular restenosis, the local efficacy has not been able to translate to improved limb and systemic results in well-designed controlled trials. If anything, the opposite seems to be observed so far.”


1. Kumins NH, King AH, Ambani RN, et al. Paclitaxel-coated peripheral arterial devices are associated with improved overall survival and limb salvage in patients with chronic limb-threatening ischemia. J Vasc Surg. 2021 Jun 6;S0741-5214(21)00851-X. doi: 10:1016/j.jvs.2021.05.035. Online ahead of print.

2. Katsanos K, Spiliopoulos S, Teichgraber U, et al. Risk of major amputation following application of paclitaxel coated balloons in the lower limb arteries: a systematic review and meta-analysis of randomized controlled trials. Eur J Vasc Endovasc Surg. 2021 July 26;S1078-5884(21)00443-3. doi: 10:1016/j.ejvs.2021.05.027. Online ahead of print.

3. 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;7(24):e011245. doi: 10.1161/JAHA.118.011245.

4. Rocha-Singh K, Duval S, Jaff MR, et al. Mortality and paclitaxel-coated devices: an individual patient data meta-analysis. Circulation. 2020;141(23):1859-1869.

5. Dake MD, Ansel GM, Bosiers M, et al. Paclitaxel-coated Zilver PTX drug-eluting stent treatment does not result in increased long-term all-cause mortality compared to uncoated devices. Cardiovasc Intervent Radiol. 2020;43(1):8-19.

6. Dinh K, Limmer AM, Chen AZL, et al. Mortality rates after paclitaxel-coated device use in patients with occlusive femoropopliteal disease: an updated systematic review and meta-analysis of randomized controlled trials. J Endovasc Ther. 2021 Jun 9;15266028211023505. doi: 10.1177/1526602821023505.

7. Katsanos K, Kitrou P, Spiliopoulos S. The rollercoaster of paclitaxel in the lower limbs and skeletons in the closet: an opinion review. J Vasc Interv Radiol. 2021;32(6):785-791.

8. Katsanos K, Spiliopoulos S, Kitrou K, 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;31(2):202-212.

9. Zeller T, Micari A, Scheinert D, et al. The IN.PACT DEEP clinical drug-coated balloon trial: 5-year outcomes. JACC Cardiovasc Interv. 2020;13(4):431-443.

10. Behrendt CA, Sedrakyan A, Peters F, et al. Editor’s choice – long-term survival after femoropopliteal artery revascularization with paclitaxel coated devices: a propensity-score matched cohort analysis. Eur J Vasc Endovasc Surg. 2020;59(4):587-596.

11. Kumins NH, King AH, Ambani RN, et al. Paclitaxel-coated peripheral artery devices are not associated with increased mortality. J Vasc Surg. 2020;72(3):968-976.

12. Wu R, Li Z, Wang M, Chang G, Yao C, Wang S. Paclitaxel-coated versus uncoated balloon angioplasty for femoropopliteal artery in-stent restenosis. Int J Surg. 2017 Jun;42:72-82.

13. Stolzenburg N, Breini J, Bienek S, et al. Paclitaxel-coated balloons: investigation of drug transfer in healthy and atherosclerotic arteries – first experimental results in rabbits at low inflation pressure. Cardiovasc Drugs Ther. 2016;30(3):263-270.

14. Kolodgie FD, Pacheco E, Yahagi K, Mori H, Ladich E, Virmani R. Comparison of particulate embolization after femoral artery treatment with IN.PACT Admiral versus Lutonix 035 paclitaxel-coated balloons in healthy swine. J Vasc Interv Radiol. 2016;27(11):1676-1685.e2.

15. Chen W, Dyniewski B, Bobka T, Kraemer C, Tan TW, Zhou W. Aneurysmal degeneration after paclitaxel-eluting balloon angioplasty. Vasc Endovascular Surg. 2021;55(4):410-414.

16. Torii S, Yahagi K, Mori H, et al. Biologic drug effect and particulate embolization of drug-eluting stents versus drug-coated balloons in healthy swine femoropopliteal arteries. J Vasc Interv Radiol. 2018;29(7):1041-1049.

17. Katsanos K. Paclitaxel-coated balloons in the femoropopliteal artery: it is all about the pharmacokinetic profile and vessel tissue bioavailability. JACC Cardiovasc Interv. 2016;9(16):1743-5.

18. Granada JF, Stenoien M, Buszman PP, et al. Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing. Open Heart. 2014 Aug 6;1(1):e000117. doi: 10.1136/openhrt-2014-000117. eCollection 2014.

19. Tzafriri AR, Parikh SA, Edelman ER. Taking paclitaxel coated balloons to a higher level: predicting coating dissolution kinetics, tissue retention and dosing dynamics. J Control Release. 2019 Sep 28;310:94-102. doi: 10.1016/j.jconrel.2019.08.019.

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