Background

Symptomatic PAD is associated with significant morbidity and mortality, above and beyond many other chronic diseases.¹ Development of effective, durable endovascular technology has been desperately needed to improve patients' quality of life and limb-related outcomes. In recent years, randomized controlled trials have demonstrated that peripheral devices coated with paclitaxel (balloons [DCBs] and stents [DES]) result in superior patency and decreased target lesion failure compared with standard, non-drug-coated balloons (percutaneous transluminal angioplasty [PTA]) and stents (bare metal stents [BMS]) for the treatment of femoropopliteal artery disease.^2-5 As a result, drug-coated devices, in particular DCBs, have become the first-line treatment for femoropopliteal artery disease among symptomatic patients.⁶

The Katsanos Meta-Analysis

Despite their superior outcomes, the long-term safety of drug-coated devices has not been well-established given their limited time in use in clinical practice. Thus, the vascular community was understandably surprised by the results of a summary-level meta-analysis of randomized trials that demonstrated increased long-term mortality associated with paclitaxel-coated technology. In this study, published by Katsanos et al.,⁷ the authors examined all-cause death from 28 randomized trials at 1, 2, and 4-5 years. At 1 year (4432 patients), there was no mortality difference between DCB/DES and PTA/BMS treatment groups. Yet, in the 2-year analysis, which included 12 trials (2316 patients), and the 4-5 year analysis, which included three trials (863 patients), the authors found a significant increase in the relative risks of mortality (68% and 93% increased risk, respectively) with DCB/DES treatment. The authors also reported a positive association between increasing paclitaxel dose and the absolute risk of death.

In near immediate response to this meta-analysis, two clinical trials were paused (SWEDEPAD [Swedish Drug-elution Trial in Peripheral Arterial Disease] 1,2 and BASIL-3 [Balloon versus Stenting in severe Ischemia of the Leg-3])⁸ and further trials have been challenged by slow enrollment and amendment of the consent process. Furthermore, the FDA issued a series of letters warning clinicians about the possible increased mortality rate associated with DCB/DES,^9,10 the second of which recommend against their use unless treating high-risk patients. This recommendation was secondary to their own review of pre-market approval trial data that demonstrated a similar mortality signal as seen in the Katsanos meta-analysis (among 975 subjects from three trials, 20.1% crude risk of death at 5 years with DCB/DES treatment versus 13.4% with PTA/BMS treatment). The consequence of this letter has been substantial, with drug-coated technology use plummeting since mid-March.

Limitations of the Meta-Analysis

Importantly, since publication, there have been many concerns about the accuracy of the meta-analysis results. From a methodological standpoint, the small, randomized device trials included in the meta-analyses were designed to examine device and limb-related outcomes, not mortality. As such, after achievement of their primary endpoint (most of which occurred at 1 year), these studies had substantial loss to follow-up, withdrawal and patient cross-over. These events were unaccounted for in the meta-analysis, as only summary-level results based on the enrollment population were analyzed. Furthermore, the included trials varied substantially in their patient populations, such as burden of comorbidities and severity of illness, and this heterogeneity raised questions as to whether these patient cohorts could be pooled without introducing substantial bias. Thirdly, the paclitaxel-dose relationship analysis failed to accurately account for the time of drug distribution for each individual device. Lastly, no clear plausible mechanism has been established as to how paclitaxel exposure may influence mortality. This includes a lack of pattern among specific causes of death, as reported in the meta-analysis.

Safety Assessments in Available Patient-Level Data

In response to this paper, there have been multiple attempts to examine the safety of these devices using available patient-level trial data, device registries, and claims-based datasets. These data are summarized in the Table below. Schneider et al. published the first comprehensive meta-analysis of patient-level data using combined data from two prospective randomized controlled trials and two prospective single-arm studies (IN.PACT SFA [Randomized Trial of IN.PACT Admiral Drug Coated Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disesase], IN.PACT SFA Japan, IN.PACT SFA China, and IN.PACT Global). In this study comparing the IN.PACT Admiral DCB (n = 1837) with PTA (n= 143), the authors found no difference in all-cause mortality through 5 years (9.3% vs. 11.2%, respectively; p= 0.399).¹¹ In addition, the investigators examined survival stratified by paclitaxel dose exposure and found no difference in all-cause mortality among patients receiving low, middle, and high paclitaxel doses (p = 0.70). Lastly, the authors demonstrated that patients treated with non-drug coated devices had higher rates of compliance with follow-up compared with those treated with drug-coated technology, and higher compliance rates was associated with improved survival. From this finding, it has been theorized that patients treated with non-drug coated devices, who are often exposed to greater healthcare contact due to worse treatment efficacy, may be more optimally managed, diagnosed, and treated, thus improving their long-term survival.

In a second patient-level meta-analysis, Albrecht et al. pooled four randomized controlled trials (THUNDER [Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries], FEMPAC [Femoral Paclitaxel], PACIFIER [Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis], CONSEQUENT [Clinical Trial on Peripheral Arteries Treated With SeQuent® Please P Paclitaxel Coated Balloon Catheter]) comparing DCBs with PTA. The authors examined all-cause death through 24 months and found no significant difference in the cumulative incidence of survival between groups (8.6% for DCB vs. 7.0% for PTA; p = 0.55).¹² Causes of death were well balanced between the treatment groups with no obvious pattern or trend towards an increase in any specific causes of death with DCB treatment. Furthermore, cumulative paclitaxel exposure was similar between patients who died versus survived in the DCB arm.

In addition to these published meta-analyses, there have been multiple presentations of patient-level data from individual device trial programs, including Lutonix®, Stellarex™, Zilver® PTX®, and Ranger™. These were comprehensively presented at the 2019 Leipzig Interventional (LINC) Course in January.¹³ Results from the LEVANT 2 (Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries) trial (Lutonix®), which examined patients treated with DCB versus PTA at 5 years, found no difference in mortality (14.3% and 10.6%, respectively; p = 0.198). Long-term safety data from Stellarex™ pooled data of 2351 patients (ILLUMENATE [Pivotal Trial of a Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon]) found no difference in all-cause death at 3 years for DCB versus PTA (9.3% vs. 9.9%; p = 0.93). A 5-year mortality analysis performed using data from the Zilver® PTX®, global data analysis showing no difference in mortality between the Zilver® PTX®, DES and PTA/BMS (18.7% vs. 17.6%; p = 0.53). Lastly, the RANGER- SFA (Comparison of the Ranger Paclitaxel-Coated PTA Balloon Catheter and uncoated PTA Balloons in Femoropopliteal Arteries) trial of the Ranger™ DCB showed no difference in mortality over 3 years with DCB compared with PTA (13.8% vs. 10.7%).

Lastly, there have been two large analyses published using Medicare beneficiary claims data, both of which failed to demonstrate an association between drug-coated devices and long-term survival. In the first study, Secemsky et al. performed a retrospective analysis of 16,560 Medicare patients who underwent femoropopliteal artery revascularization, with follow-up of a median 389 days (interquartile range 277-508 days).¹⁴ The authors found that treatment with DCB/DES was associated with lower unadjusted mortality compared with PTA/BMS through 600 days (32.5% vs. 34.3%, respectively; P = 0.007). There was no association between drug-coated devices and all-cause mortality after multivariable adjustment (adjusted HR 0.97 [95% CI, 0.91-1.04]; p = 0.43). Subgroup analyses showed that these results persisted among patients with stable claudication and critical limb ischemia, as well as when stratified by device type (DCB vs. PTA and DES with or without DCB vs. BMS). In the second analysis, Secemsky et al. specifically examined survival after implantation with a DES versus BMS.¹⁵ This analysis included 51,456 Medicare patients, with a median follow up time of 2 years and longest follow-up out to 4.1 years. The authors found no different in unadjusted mortality (51.7% for DES versus 50.1% for BMS; log-rank p-value = 0.16), and this association remained non-significant after multivariable adjustment (adjusted HR 0.98; 95%CI 0.93-1.03; p = 0.53). Although these real-world analyses are limited by non-randomized treatment assignment and the possibility of misclassification due to the use of billing claims to determine exposure, these analyses are strengthened by their large sample size and near complete report of survival.

Where Do We Go From Here

As it currently stands, all presented and published patient-level data since the Katsanos meta-analysis have been supportive of the safety of paclitaxel-coated devices. However, we are left still explaining the results from the meta-analysis as well as the signal seen in the FDA internal analysis. As such, it is critically important that more information be obtained to understand whether a relationship between DCB/DES and mortality truly exists. This is both to protect patients and to ensure that beneficial technology is not unnecessarily restricted. The vascular community is anticipating the upcoming FDA Advisory Meeting on June 19-20 as an opportunity to obtain further guidance of how these devices may be used moving forward. As part of this meeting, there will be updated data presented, including from the independent patient level meta-analysis performed by VIVA Physicians, device-specific patient-level data with more complete follow-up from industry sponsors, and an updated analysis of Medicare beneficiary data. A focus will be trying to understand a potential mechanism of action, which will be examined through cause-specific mortality and further dose-exposure survival analyses. In the interim, physicians have been advised to engage in risk benefit discussion with patients regarding PAD treatment options, monitor patients who have been treated with DCB/DES per the standard of care, and to report any adverse events observed in these patients.

Table 1: Summary of Analyses Examining Survival following Drug-Coated Device Treatment for Femoropopliteal Artery Disease

Long-Term Safety Analyses	Devices Compared	Time to Follow Up	Mortality Difference
Secemsky et al. JAMA 2019.	DCB/DES versus BMS/PTA	Median 389 days, up to 600 days.	No mortality difference: - unadjusted cumulative incidence through 600 days: 32.5% DCB/DES  vs. 34.3% BMS/PTA; P=0.007 - adjusted HR 0.97, 95% CI 0.91-1.04; p = 0.43
Secemsky et al. JACC 2019.	DES versus BMS	Median 2 years, up to 4.1 years.	No mortality difference: - unadjusted cumulative incidence through 4.1 years: 51.7% DES vs. 50.1% BMS; P = 0.16 - adjusted HR 0.98; 95%CI 0.93-1.03; p = 0.53
Schneider et al. JACC 2019. (IN.PACT)	IN.PACT DCB versus PTA	5 years	No mortality difference: - cumulative incidence through 5 years: 9.3% DCB vs. 11.2% PTA; p = 0.399
Albrecht et al. Cardiovasc. Intervent. Radiol 2019.  (THUNDER, FemPac, PACIFIER, CONSEQUENT)	DCB versus POBA	2 years	No mortality difference: -  cumulative incidence through 2 years:  8.6% DCB vs. 7.0% PTA; p = 0.55
Scheinert, MD. Presented at Linc 2019 Leipzig Interventional Course 2019. (Levant 2)	Lutonix® DCB versus PTA	5 years	No mortality difference:   - cumulative incidence through 5 years: 14.3% DCB vs. 10.6% PTA; p =0.198
Lyden, MD. Linc 2019 Leipzig Interventional Course 2019. (ILLUMENATE)	Stellarex™ DCB versus PTA	3 years	No mortality difference: - cumulative incidence through 3 years:  9.3% DCB vs. 9.9% PTA; p =0.93
Dake, MD. Linc 2019. Leipzig Interventional Course 2019. (Zilver® PTX®)	Zilver® PTX® DES versus BMS/PTA	5 years	No mortality difference:  - cumulative incidence through 5 years:  18.7% DES vs. 17.6% BMS/PTA; p =0.53
Gray, MD. Linc 2019 Leipzig Interventional Course 2019. (Ranger™ SFA)	Ranger™ DCB versus PTA	3 years	No mortality difference : - cumulative incidence through 3 years: 13.8% DCB vs. 10.7% PTA
Katsanos et al. JAHA 2018.	DCB/DES versus BMS/PTA	2 and 4-5 years	Higher mortality with DCB/DES: - absolute risks at 2 years: 7.2% DCB/DES vs. 3.8% BMS/PTA; risk ratio 1.68; 95% CI, 1.15-2.47) - absolute risks at 5 years: 14.7% DCB/DES vs. 8.1% BMS/PTA; risk ratio 1.93; 95% CI, 1.27-2.93)
FDA Internal Analysis	DCB/DES versus BMS/PTA	5 years	Higher mortality with DCB/DES: - absolute risk at 5 years: 20.1% DCB/DES vs. 13.4% BMS/PTA

References

1. Wu A, Coresh J, Selvin E, et al. Lower extremity peripheral artery disease and quality of life among older individuals in the community. J Am Heart Assoc. 2017;6.
2. Dake MD, Ansel GM, Jaff MR, et al. Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial. Circulation. 2016;133:1472-83; discussion 1483.
3. Dake MD, Ansel GM, Jaff MR, et al. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv. 2011;4:495-504.
4. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2015;131:495-502.
5. 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.
6. Feldman DN, Armstrong EJ, Aronow HD, et al. SCAI consensus guidelines for device selection in femoral-popliteal arterial interventions. Catheter Cardiovasc Interv. 2018;92:124-40.
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;7:e011245.
8. McKeown, L.A. (2018, December 17). Two trials halted in wake of study linking paclitaxel-coated devices to deaths in PAD. Retrieved from https://www.tctmd.com/news/two-trials-halted-wake-study-linking-paclitaxel-coated-devices-deaths-pad. Accessed 12/19/18.
9. U.S. Food & Drug Administration (2019, January 17). Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality - Letter to Health Care Providers. Retrieved from https://www.fda.gov/MedicalDevices/Safety/LetterstoHealthCareProviders/ucm629589.htm. Accessed 1/21/19.
10. U.S. Food & Drug Administration (2019, March 15). Treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality - letter to health care providers. Retrieved from https://www.fda.gov/MedicalDevices/Safety/LetterstoHealthCareProviders/ucm633614.htm. Accessed 3/26/19.
11. Schneider PA, Laird JR, Doros G, et al. Mortality not correlated with paclitaxel exposure: an independent patient-level meta-analysis of a drug-coated balloon. J Am Coll Cardiol. 2019; 73: 2550-63.
12. Albrecht T, Ukrow A, Werk M, et al. Impact of patient and lesion characteristics on drug-coated balloon angioplasty in the femoropopliteal artery: a pooled analysis of four randomized controlled multicenter trials. Cardiovasc Intervent Radiol. 2019; 42: 495-504.
13. Leipzig Interventional Course (LINC 2019) Programme (2019; January 22-25). Retreived from https://www.leipzig-interventional-course.com/archive/linc-2019/presentations/. Accessed 5/28/19.
14. 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.
15. 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.

Keywords: Peripheral Arterial Disease, Paclitaxel, Risk, Ocimum basilicum, Follow-Up Studies, Quality of Life, Ischemia, Stents, Angioplasty, Angioplasty, Balloon, Angioplasty, Balloon, Coronary, Prospective Studies, Comorbidity, Arteries, Chronic Disease, Informed Consent, Cause of Death, Research Personnel, Treatment Outcome, Survival Analysis, Standard of Care, Medicare, Registries, Sample Size, Femoral Artery, Metals

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