In December 2018, Katsanos et al. surprised the vascular community in publishing a meta-analysis demonstrating a late mortality signal for patients treated with paclitaxel-coated devices (PCDs) relative to non-coated devices.¹ Specifically, they performed a meta-analysis of summary-level data from randomized-controlled trials that showed an increase in mortality at 2 and 5 years (68% and 93% increase in risk, respectively) in patients treated with PCDs relative to uncoated percutaneous transluminal angioplasty (PTA) and bare metal stenting (BMS) in the femoropopliteal artery segment.

This meta-analysis has several methodological flaws for which it has been criticized. For example, the individual randomized controlled trials (RCTs) included in the study were designed to evaluate short-term safety endpoints. Therefore, there was significant loss to follow-up after the specified short-term endpoints were met. This is evident in the meta-analysis as the 1-year analysis included 28 trials and 4,432 patients whereas the 5-year analysis included only 3 trials and 863 patients. The patient populations in the individual RCTs were also heterogeneous in terms of their comorbidities and lesion characteristics as well as the endovascular devices used. Because individual-level data were not analyzed, these differences in patient populations were not accounted for and may have biased the results of the meta-analysis.

Despite its flaws, the consequences of the Katsanos meta-analysis were far-reaching. RCTs including BASIL III and SWEDEPAD I and II were stopped.² The US Food and Drug Administration (FDA) recommended that healthcare providers restrict the use of PCDs to high-risk patient populations.³ Prior to the publication of the Katsanos meta-analysis, PCDs had emerged as the standard of care for patients undergoing endovascular revascularization because they increase primary patency rates and reduce target-lesion revascularization relative to PTA and BMS.^4,5,6

The FDA convened a Medical Device Advisory Panel in June of 2019 to investigate the possibility of a late mortality signal associated with PCDs. In preparation, the FDA had analyzed internal pivotal trial data of FDA-approved PCDs, which included several trials that had been analyzed in the Katsanos meta-analysis. In their analysis, they did identify a late mortality signal associated with PCDs. However, they felt that no overarching conclusion could be drawn as there was substantial residual missing data, small patient sample sizes, and no clear relationship between paclitaxel dose and mortality.⁷ The FDA also reviewed observational data from Medicare claims, Optum claims, and the Vascular Quality Initiative registry.⁸ These analyses did not identify an association between PCDs and mortality. The FDA concluded from the advisory panel that there was a signal of harm present, but a causal relationship could not yet be established. The FDA requested more long-term data to evaluate the possibility of a late mortality signal. They allowed these devices to remain on the market, but published a revised FDA to Healthcare Providers that reinforced the recommendations that PCDs should be reserved for patients at the highest risk of restenosis and alternative treatment options should be considered.⁹

Since the FDA advisory panel, several additional studies have evaluated the association of mortality with paclitaxel. These include large observational studies, longer-term follow up data from RCTs, and a meta-analysis of clinical trials (Table 1).

Table 1: Key studies investigating the safety of paclitaxel-coated devices (PCDs) relative to non-PCDs. Studies that did not find an increase in mortality associated with PCDs are highlighted in blue. Studies that found an increase in mortality associated with PCDs are highlighted in orange.

	Key Studies of Mortality in PCDs	Time to Follow Up	Mortality Difference?
Observational Studies	Secemsky et al. JAMA. 2019.10	Median 389 days, up to 600 days	No Increase in Mortality for PCDs - unadjusted cumulative incidence through 600 days: 32.5% PCD vs. 34.3% non-PCD (P=0.007) - aHR 0.97, 95% CI 0.91-1.04 (p=0.43)
	Secemsky et al. JACC. 2019.11	Median 2 years, up to 4.1 years	No Increase in Mortality for PCDs - unadjusted cumulative incidence through 4.1 years: 51.7% PES vs. 50.1% BMS (P=0.16) - aHR 0.98; 95%CI 0.93-1.03 (p=0.53)
	OPTUM Claims Data presented at VIVA LBCT Webinar 2020.18	Median 2.66 years, up to 4.75 years	No Increase in Mortality for PCDs - aHR for mortality of PCDs relative to non-PCDs: 1.03, 95% CI 0.96-1.10 (p=0.39)
	Freisinger et al. ESC. 2019.12	Median 92 months, up to 11 years	No Increase in Mortality for PCDs - HR at 5 years for PES vs. non-PCD: 1.01, 95% CI 0.83-12.3 (p=0.91) - HR at 5 years for PCB vs non-PCD: 0.97, 95% CI 0.89-1.06 (p=0.492)
	Behrendt et al. Eur. J. Vasc. Surg. 2020.13	5 years	No Increase in Mortality for PCDs - aHR for survival in PCD vs non-PCD in patients with IC: 0.87, 95% CI 0.76-0.99 - aHR for survival in PCD vs. non-PCD in patients with CLTI: 0.83, 95% CI 0.77-0.90
	Bohme et al. JACC CI. 2020.23	Median 51 months	No Increase in Mortality for PCDs - Mortality rate 27.5% after PTA vs. 16.9% after PCB (p<0.001)
	Hess et al. TCT Connect. 2020.21	Median of 31 months	No Increase in Mortality for PCDs - adjusted HR 0.95, 95% CI 0.83-1.09 (p=0.49)
Meta-Analysis	Rocha-Singh et al. Circ. 2020.16	Median of 4 years, up to 5 years	PCDs Conferred an Increased Risk of Mortality - aHR for PCDs vs. non-PCDs with 27% and 25% loss-to-follow-up, respectively: 1.38, 95% CI 1.06-1.8 - aHR for PCDs vs. non-PCDs with 10% and 9% loss-to-follow-up, respectively: 1.27, 95% CI 1.03-1.58
Clinical Trials	Schneider et al. CCI. 2020. (IN.PACT).17	5 years	No Increase in Mortality for PCDs - cumulative incidence of mortality for PCD was 14.7 vs. 12.0 for PTA, HR 1.39, 95% CI 0.76-2.57 (log-rank p=0.286)
	Gray et al. Circ. 2019 and Lyden LBCT 2020 VIVA presentation (ILLUMENATE).24,18	4 years	No Increase in Mortality for PCDs - All-cause death for PCB was 17.7% vs. 14.1% for PTA (p=0.494)
	Ouriel et al. JACC CI. 2019. (LEVANT).19	5 years	No Increase in Mortality for PCDs - HR for survival for PCB vs PTA: 1.01, 95% CI 0.68-1.52 (p=0.95)
	Dake et al. 2020. (Cook Zilver PTX).20	5 years	No Increase in Mortality for PCDs - All-cause mortality for DES was 19.1% vs. 17.1% for PTA/BMS (p=0.60)
PCB = paclitaxel-coated balloon, PES = paclitaxel-eluting stent, BMS = bare-metal stent, PTA = percutaneous transluminal angioplasty, HR = hazard ratio, CI = confidence interval, IC = intermittent claudication, CLTI = chronic limb-threatening ischemia

There have been multiple additional real-world observational studies published, all of which have not demonstrated an increase in mortality among patients treated with PCDs compared with those treated with non-coated devices. These include studies performed in the Medicare database,^10,11 German BARMER insurance claims database,^12,13 and a study in the Society for Vascular Surgery Vascular Quality Initiative registry.¹⁴ The ongoing Safety Assessment of Femoropopliteal Endovascular treatment with Paclitaxel-coated Devices (SAFE-PAD)¹⁵ includes pre-specified sensitivity analyses to assess the influence of unmeasured confounding as well as subgroup analyses to examine low-risk populations, inpatients versus outpatients, critical limb ischemia (CLI), and device type among Medicare patients. The first report from this study has reaffirmed findings from prior Medicare analyses, with no evidence of long-term harm associated with these devices.

Rocha-Singh et al. performed a meta-analysis of individual patient-level data from eight RCTs.¹⁶ As part of this analysis, the investigators were able to gather follow-up data that reduced the loss-to-follow-up present in the original studies. With 27% and 25% loss-to-follow-up in treatment and control arms, respectively, they reported a mortality hazard ratio associates with PCDs of 1.38 (95% CI 1.06-1.80). When loss-to-follow-up was reduced to 10% and 9% for treatment and control arms, respectively, the hazard ratio decreased to 1.27 (95% CI 1.03-1.58). Hence, although the authors demonstrate that there remained a relationship between treatment with PCDs and mortality, they showed that this association attenuated as loss-to-follow-up was reduced. This is suggestive that patients missing long-term follow-up may not have been lost at random. Notably, there was no evidence of a dose-response relationship between paclitaxel and mortality.

Long-term follow up from industry sponsored RCTs have also been reassuring. This includes 5-year data from IN.PACT SFA and IN.PACT Japan,¹⁷ 4-year results from the Illumenate Pivotal trial,¹⁸ and 5-year follow up data from the LEVANT trials.¹⁹ A 5-year as treated analysis from the Zilver PTX trial comparing 336 patients who were treated with DES to 143 patients treated with PTA showed no difference in mortality between the two groups.²⁰ For all these analyses, causes of death were analyzed between each treatment arm and no significant differences were identified.

More recently, Hess et al. performed a subgroup analysis of patients who underwent endovascular revascularization with PCDs or non-PCDs in patients from the VOYAGER PAD trial.²¹ The VOYAGER PAD trial was a double-blind, placebo-controlled trial of patients with peripheral artery disease (PAD) undergoing lower-extremity revascularization who were randomized post-treatment to receive rivaroxaban 2.5 mg bid or placebo on a background of aspirin 100 mg daily.²² Of the 4,379 patients in the trial who underwent endovascular revascularization, 31% (1,358) were treated with a PCD. Patients were followed for a median of 31 months and vital status was ascertained for 99.6% of patients. After adjusting for confounders using inverse probability of treatment weighting, the investigators found no association between treatment with PCDs and mortality.

In summary, since the publication of the Katsanos meta-analysis, there has been ample data published or presented from large, observational datasets, subgroup analyses from RCTs, and long-term follow-up from the pivotal PCD RCTs. None of these studies has been able to replicate an association between PCDs and mortality. Furthermore, several studies have now analyzed causes of death in patients who were treated with PCDs versus non-PCDs and have not found significant differences between groups. Lastly, no clear mechanism relating paclitaxel to death has been described and a dose-response relationship between paclitaxel and mortality has not been established. As this controversy is now approaching 2 years, the vascular community awaits next steps from the FDA and other regulatory bodies in determining the long-term future of PCDs.

References

1. 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:e011245.
2. McKeown LA. Two Trials Halted in Wake of Study Linking Paclitaxel-Coated Devices to Deaths in PAD. 2018. Available at: https://www.tctmd.com/news/two-trials-halted-wake-study-linking-paclitaxel-coated-devices-deaths-pad. Accessed 11/15/2020.
3. Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality - Letter to Health Care Providers (FDA.gov). 2019 Available at: https://www.fda.gov/MedicalDevices/Safety/LetterstoHealthCareProviders/ucm629589.htm. Accessed 11/15/2020.
4. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial. JACC Cardiovasc Interv 2015;8:102–08.
5. SCAI Releases Consensus Guidelines for Device Selection in Femoral-Popliteal Arterial Interventions (SCAI website). 2018. Available at: https://scai.org/scai-releases-consensus-guidelines-device-selection-femoral-popliteal-arterial-interventions. Accessed 11/15/2020.
6. Mohapatra A, Saadeddin Z, Bertges DJ, et al. Nationwide trends in drug-coated balloon and drug-eluting stent utilization in the femoropopliteal arteries. J Vasc Surg 2020;71:560–66.
7. June 19-20, 2019: Circulatory System Devices Panel of the Medical Device Advisory Committee Meeting Announcement (FDA.gov). 2019. Available at: https://www.fda.gov/advisory-committees/advisory-committeecalendar/june-19-20-2019-circulatory-systemdevices-panel-medical-devices-advisory-committee-meeting. Accessed 11/15/2020.
8. FDA Executive Summary (FDA.gov). 2019. Available at: https://www.fda.gov/media/127698/download. Accessed 11/15/2020.
9. August 7, 2019 UPDATE: Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality (FDA.gov). 2019. Available at: https://www.fda.gov/medical-devices/letters-health-care-providers/august-7-2019-update-treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel. Accessed 11/15/2020.
10. Secemsky EA, Kundi H, Weinberg I, et al. Association of survival with femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol 2019;4:332-40.
11. Secemsky EA, Kundi H, Weinberg I, et al. Drug-eluting stent implantation and long-term survival following peripheral artery revascularization. J Am Coll Cardiol 2019;73:2636–38.
12. Freisinger E, Koeppe J, Gerss J, et al. Mortality after use of paclitaxel-based devices in peripheral arteries: a real-world safety analysis. Eur Heart J 2020;41:3732-39.
13. Behrendt CA, Sedrakyan A, Peters F, et al. Long-term survival after femoropopliteal artery revascularisation with paclitaxel coated devices: a propensity score matched cohort analysis. Eur J Vasc Endovasc Surg 2020;59:587-96.
14. Bertges DJ, Sedrakyan A, Sun T, et al. Mortality after paclitaxel coated balloon angioplasty and stenting of superficial femoral and popliteal artery in the Vascular Quality Initiative. Circ Cardiovasc Interv 2020:13;e008528.
15. Safety Assessment of Femoropopliteal Endovascular Treatment with PAclitaxel-coated Devices (SAFE-PAD Study) (SAFE-PAD)(Clinicaltrials website). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04496544. Accessed 11/15/2020.
16. Rocha-Singh KJ, Duval S, Jaff MR, et al. Mortality and paclitaxel-coated devices: an individual patient data meta-analysis. Circulation 2020;141:1859–69.
17. Schneider PA, Brodmann M, Mauri L, et al. Paclitaxel exposure: Long-term safety and effectiveness of a drug-coated balloon for claudication in pooled randomized trials. Catheter Cardiovasc Interv 2020;Aug 24:[Epub ahead of print].
18. VIVA Late-Breaking Clinical Trials Livestream (YouTube). 2020. Available at: https://www.youtube.com/watch?v=hH4EVFl7mPE. Accessed 11/15/2020.
19. Ouriel K, Adelman MA, Rosenfield K, et al. Safety of paclitaxel-coated balloon angioplasty for femoropopliteal peripheral artery disease. JACC Cardiovasc Interv 2019;12:2515–24.
20. 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;43:8–19.
21. Hess CN, Patel MR, Bauersach RM, et al. TCT Connect 2020: Late Breaking Clinical Trials and Science. Long-term Safety of Drug-Coated Devices for Peripheral Artery Revascularization: Insights from Voyager-PAD (tctMD website). 2020. Available at: https://www.tctmd.com/slide/voyager-pad-long-term-safety-drug-coated-devices-peripheral-artery-revascularization. Accessed 11/15/2020.
22. Bonaca MP, Bauersach RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994–2004.
23. Böhme T, Noory E, Beschorner U, et al. Evaluation of mortality following paclitaxel drug-coated balloon angioplasty of femoropopliteal lesions in the real world. JACC Cardiovasc Interv 2020;13:2052–61.
24. Gray WA, Jaff MR, Parikh SA, et al. Mortality assessment of paclitaxel-coated balloons: patient-level meta-analysis of the ILLUMENATE clinical program at 3 years. Circulation 2019;140:1145–55 .

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and Vascular Medicine

Keywords: Ocimum basilicum, Peripheral Arterial Disease, United States Food and Drug Administration, Paclitaxel, Outpatients, Inpatients, Double-Blind Method, Aspirin, Citrus sinensis, Follow-Up Studies, Cause of Death, Standard of Care, Medicare, Angioplasty, Lower Extremity, Health Personnel, Probability, Registries, Ischemia, Publishing

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