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Safety and efficacy of drug-eluting devices :Where do we stand ?What are the concerns?
Dr. Marc BosiersLINC AP 2019 – Hong Kong
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My disclosures
o I do not have any potential conflicts of interest to report
o I have the following potential conflicts of interest to report:
x
❑Consulting❑Employment in industry❑Stockholder of a healthcare company❑Owner of a healthcare company❑Other(s)
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DCB in SFA Evidence / proof-of-concept
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Significant and sustained TLR reduction up to 5 years!
Long-term outcome of DCB in TASC A&B lesions
THUNDERFreedom from CD-TLR through 5 years
IN.PACT SFA Trial:Freedom from CD-TLR through 5 years
1. Gunnar Tepe et al., 5-year Follow-Up of the THUNDER Trial2. John R. Laird et al., 5 year results from the IN.Pact SFA randomized trial
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Significant and sustained TLR reduction up to 5 years!
IN.PACT SFA Trial:Freedom from CD-TLR through 5 years
ZILVER PTX vs Standard Care:Freedom from TLR through 5 years
Long-term outcome of DCB & DES
1. John R. Laird et al., 5 year results from the IN.Pact SFA randomized trial
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RCT DCB versus DES in fempop lesions
Yvonne Bausback et al., Drug-Eluting Stent versus Drug-Coated Balloon Revascularization in Patients with Femoropopliteal Arterial Disease. JACC Volume 73, Issue6, Feb 2019
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RCT DCB versus DES in fempop lesions – Patency results
Yvonne Bausback et al., Drug-Eluting Stent versus Drug-Coated Balloon Revascularization in Patients with Femoropopliteal Arterial Disease. JACC Volume 73, Issue6, Feb 2019
at 3 years seems to be difference in primarypatency in favor of DES over DCB
@1YFU: +/- 75% for both groups@3YFU: +/- 40% for DCB and +/- 50% for DES
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RCT DCB versus DES in fempop lesions – f-TLR results
Yvonne Bausback et al., Drug-Eluting Stent versus Drug-Coated Balloon Revascularization in Patients with Femoropopliteal Arterial Disease. JACC Volume 73, Issue6, Feb 2019
No significant difference in freedom from CD-TLR between DCB and DES treatment!
@1YFU: +/- 85% for both groups@3YFU: +/- 70% for both groups
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Overall, in this pilot study, results for DCB and DES
were similar at 12 months.
At longer time points, a trend in favor of DES was
observed.
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Until….
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All cause death at 2 years
Konstantinos Katsanos et al., Risk of Death Following Application of Pactlitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review andMeta-Analysis of Randomized Controlled Trials
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All cause death at 4 and 5 years
Konstantinos Katsanos et al., Risk of Death Following Application of Pactlitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review andMeta-Analysis of Randomized Controlled Trials
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Significant relationship?
Meta‐regression showed a significant relationship between exposure to paclitaxel
(dose‐time product) and absolute risk of death (0.4±0.1% excess risk of death per paclitaxel
mg‐year; P<0.001)
Konstantinos Katsanos et al., Risk of Death Following Application of Pactlitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review andMeta-Analysis of Randomized Controlled Trials
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Findings of the article…
• In conclusion, there seems to be an increased long-term risk of death beyond the first year following femoropopliteal application of paclitaxel-coated balloons and stents in the lower limbs.
• Meta-regression showed a significant relationship between exposure to paclitaxel (dose-timeproduct) and absolute risk of death
• Actual causes for this serious late side effect remain unknown
• further investigations with longer-term follow-up are urgently warranted.
Konstantinos Katsanos et al., Risk of Death Following Application of Pactlitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review andMeta-Analysis of Randomized Controlled Trials
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Criticism of the article… (1)
• Meta-analysis reported long-term mortality data at three discrete timepoints: 1, 2, and 4-5 years, with the caution that its source studies were not designed or powered to evaluate mortality this far out. “These findings are really hypothesis-generating at best ´´
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Criticism of the article… (2)
ASSOCIATION ≠ CAUSATION
Meta-analysis can show association, not causation. That’s what RCT’s are for.
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Criticism of the article… (2)
ASSOCIATION ≠ CAUSATION
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Criticism of the article… (3)
Mortality Rates from trials of SFA Therapy
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Criticism of the article… (4)
Summary-level versus Patient-level Meta-Analysis
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Criticism of the article… (5)
• Powered for shorter-term patency, not long-term mortality.
• Control groups are small (some RCTs 2:1).
• Not clear if valid to include DCB and DES in same analysis.
• Expected attrition due to age and co-morbid factors.
• Missing data, censored patients.
• Assumptions about drug kinetics.
Some unique characteristics of the Drug-Eluting trials
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Comparable research? Secemsky et al.
• A multicenter retrospective cohort study included 16.560 patients in 1883 hospitals who where admitted for femoropopliteal artery revascularization in 2016.
• Drug-coated devices (DES/DCB) compared with non-drug-coated devices (BMS/PTA).
• Primary outcome: all-cause mortality
Eric A. Secemsky et al., Association of Survival with femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol. Doi.10.1001
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Results -- Drug vs Nondrug
Eric A. Secemsky et al., Association of Survival with femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol. Doi.10.1001
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Results -- DCB vs PTA
Eric A. Secemsky et al., Association of Survival with femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol. Doi.10.1001
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Results -- DES vs BMS
Eric A. Secemsky et al., Association of Survival with femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol. Doi.10.1001
There was no evidence of increased all-cause mortality following femoropopliteal artery revascularization with drug-
coated devices compared with non–drug-coated devices
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Comparable research? Schneider et al.
• Independently-adjudicated study data of DCB (n=1837) and PTA (n=143).
• Extensive analyses of baseline, procedure, and follow-up data of individual patients.
• Time to survival by paclitaxel dose tercile was analyzed with adjustment of inverse probability weighting to correct baseline imbalances and study as random effect.
Peter A. Schneider et al., Mortality not correlated with paclitaxel exposure. An independent patient-level meta-analysis
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Results -- DCB vs PTA
• No significant difference in all-causemortality between DCB & PTA through5 years (9.3% vs 11.2% ; p=0.399).
• No deaths were adjudicated by anindependent clinical events committeeas device-related.
• A survival analysis stratified nominal paclitaxel dose by low (5.019µg), mid (10.007,5µg) and upper (19.978,2µg) terciles. There was no statistically significant difference in all-cause mortality between the three groups through 5 years (p=0.700).
Peter A. Schneider et al., Mortality not correlated with paclitaxel exposure. An independent patient-level meta-analysis
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Conclusion? FDA decision
“The agency concluded that it believes that the benefitscontinue to outweigh the risks for approved paclitaxel-
coated balloons and paclitaxel-eluting stents when used in accordance with their indications for use”
BENEFITS RISKS
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Safety and efficacy of drug-eluting devices :Where do we stand ?What are the concerns?
Dr. Marc BosiersLINC AP 2019 – Hong Kong