The importance of scientific evidence. Prof. I. Baumgartner Head Clinical & Interventional Angiology University Hospital Bern

Transcription

1 The importance of scientific evidence Prof. I. Baumgartner Head Clinical & Interventional Angiology University Hospital Bern

2 Disclosure Speaker name:...i. Baumgartner... I have the following potential conflicts of interest to report: Consulting Employment in industry Stockholder of a healthcare company Owner of a healthcare company X X Other(s) - educational grant COOK I do not have any potential conflict of interest

3 Understanding strengths and shortcomings of each trial... is more important and challenging than ever Prof. M. Jaff

4 all DCBs passed «Proof-of-Concept» Test 6-month LLL from 7 Trials / 6 DCB Technologies Paccocath PTX 3 µg/mm 2 + Ultravist Lutonix PTX 2 µg/mm 2 + Polysorbate & Sorbitol Passeo 18 Lux PTX 3.0 µg/mm 2 + BTHC In.Pact PTX 3.5 µg/mm 2 + Urea Advance PTX PTX 3.0 µg/mm 2 NO Excipient Stellarex PTX 2.0 µg/mm 2 PEG 1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med Feb 14;358(7): Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation Sep 23;118(13): Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv Jan;7(1): Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-Releasing Balloon in Femoropopliteal Lesions Using a BTHC Excipient: Twelve-Month Results From the BIOLUX P-I Randomized Trial. J Endovasc Ther Feb;22(1): Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv Dec;5(6): D.Scheinert LINC 2013 oral presentation 7. Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: Outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc Interv Feb 23

5 Drug eluting balloon angioplasty versus uncoated balloon angioplasty for peripheral arterial disease of the lower limbs Cochrane Database of Systematic Reviews 4 AUG 2016 DOI: / CD pub2

6 Scientific evidence Trials had differences in the way in which they inserted the balloons, and in the type and duration of additional antiplatelet (anticlotting) therapy, leading to downgrading of the quality of the evidence. Cochrane Database of Systematic Reviews 4 AUG 2016 DOI: / CD pub2

7 Why you can t compare trials: Trial Design Zilver PTX Randomized Trial DCB Trial Designs Included in PTX Trial Excluded in DCB Trials

8 Why you can t compare trials: PSVR threshold Zilver PTX Supera 500 In.Pact Admiral Lutonix PSVR PSVR 2.0 ( ~40% stenosis) PSVR 2.5 ( ~50% stenosis) Lutonix 035 Drug Coated Balloon Catheter [package insert]. New Hope, MN: C.R. Bard Inc.; Medtronic IN.PACT Admiral Pactlitaxel-coated PTA Balloon Catheter [package insert]. Santa Rosa, CA: Medtronic Vascular, Inc.; Zilver PTX Drug-Eluting Peripheral Stent [package insert]. Limerick Ireland: Cook Ireland LTD; 2012.

9 Why you can t compare trials: PSVR threshold Department of Health and Human Services. FDA executive summary P130024: Bard LUTONIX 035 Drug Coated Balloon PTA Catheter. Food and Drug Administration Web site. Published June 12, Accessed May 14, 2015.

10 So, if we don t compare trials, what s the basis for device selection? Two things: 1. Long-term performance in RCTs (Level 1 data). 2. Consistent performance across multiple trials.

11 Global Clinical Program Pre-Market Studies Post-Market Studies Enrolling RCT Moderate lesions SAS More complex lesions China Similar lesions to RCT Japan PMS All-comers US PAS Similar lesions to RCT EU Longer Lesions XPEDITE Next Generation Coating PTA Zilver PTX n=242 Optimal n=118 Sub-optimal Zilver Flex n=56 Zilver PTX n=63 Zilver PTX n=787 Zilver PTX n=178 Zilver PTX n=905 Zilver PTX n=200 Zilver PTX n=45 Zilver PTX n=150 More than 2500 patients included in current Zilver PTX clinical program

12 Zilver PTX Study Design Enrollment Primary Randomization PTA Zilver PTX n=252 n=124 Suboptimal PTA Optimal PTA n=125 n=62 Provisional BMS Provisional Zilver PTX Secondary Randomization

13 Long-term performance in RCTs (Level 1 data) 5-year Freedom from TLR Zilver PTX vs. Standard Care 83.1% Zilver PTX p < 0.01 log-rank 67.6% Optimal PTA + BMS At 5 years, Zilver PTX demonstrates a 48% reduction in reintervention compared to standard care

14 Long-term performance in RCTs (Level 1 data) 5-year Freedom from TLR Provisional Zilver PTX vs. BMS 84.9% 71.6% Provisional Zilver PTX Provisional BMS p = 0.06 log-rank At 5 years, Zilver PTX demonstrates a 47% reduction in reintervention compared to BMS

15 Long-term performance in RCTs (Level 1 data) 4-Year Primary Patency (PSVR 2.0) Zilver PTX in Diabetic Patients 69.3% 65.9% Non-Diabetics Diabetics p = 0.50 log-rank Zilver PTX results are similar in diabetic and non-diabetic patients

16 Long-term performance in RCTs (Level 1 data) Consistent performance across multiple trials Zilver PTX RCT Zilver PTX SAS Zilver PTX Japan PMS No significant untreated inflow tract stenosis At least one patent runoff vessel Maximum 2 Zilver PTX Maximum 4 Zilver PTX ALL patients treated with stents per lesion stents per patient Zilver PTX enrolled (up Key Study Lesion length 14 cm No exclusions to enrollment limit), NO Criteria One lesion per limb exclusion criteria No prior stent in SFA ISR included Excluded if serum creatinine > 2.0, renal No exclusions failure, or dialysis Antiplatelets Clopidogrel or ticlopidine recommended for 60 days, aspirin indefinitely Follow-up 5 years 2 years 5 years Patency DUS core laboratory analysis DUS site analysis Stent Integrity X-ray core laboratory analysis Increasingly complex patients and lesions a These studies included previously stented lesions that are outside of the approved indication for use in the US.

17 Consistent performance across multiple trials Lesion Characteristics RCT SAS Japan PMS Lesions Lesion length (cm) 6.6 ± 3.9 * 10.0 ± 8.2 * 14.6 ± 9.6 Diameter stenosis (%) 81 ± 16 * 85 ± 16 * 92 ± 11 Total occlusions 30% * 38% 41% In-stent restenosis 0% * 15%* 19% Patent runoff vessels 0 0%* 0%* 7% 1 22%* 19%* 32% Critical Limb Ischemia 9%* 11%* 21% ABI 0.67 ± 0.20* 0.64 ± ± 0.18 * p < 0.01 compared to Japan PMS p-value for patent runoff vessels calculated based on 0 to 3 vessels p-value for CLI based on all reported Rutherford values (1 to 6)

18 Consistent performance across multiple trials Demographics & Comorbidities RCT SAS Japan PMS Patients Age (years) 68 ± 10 * 67 ± 10 * 74 ± 9 Male 66% 73% 70% Diabetes 50% * 36% * 59% High cholesterol 76% * 58% 61% Hypertension 89% 80% * 85% Pulmonary disease 19% * 9% 8% Renal disease 10% * 11% * 44% Renal failure a 0% * Not assessed 35% * p < 0.01 compared to Japan PMS a egfr < 60 ml/min/1.73m 2 and/or on dialysis

19 Consistent performance across multiple trials Freedom from TLR TLR rate consistent despite more complex lesions Freedom from TLR Years (n=patients) RCT SAS Japan PMS (n=305) (n=787) (n=904) % 89.8% 90.9% % 83.3% 83.7% % 79.4% n/a % 78.3%

20 Consistent performance across multiple trials Subgroup Analyses Chronic Renal Failure egfr< 60mL/min/1.73m 2 and/or dialysis CRF n = 321 (35%) Japan PMS n = 905 No CRF n = 584 Higher incidence of diabetes (69% vs. 53%) in the CRF group Lower rate of total occlusions (34% vs. 45%) in the CRF group No other significant demographic or lesion differences

21 Consistent performance across multiple trials Subgroup Analyses Chronic Renal Failure 91.5% 90.8% 84.9% 81.4% p = 0.24 Freedom from TLR rates are similar through 2 years

22 Consistent performance across multiple trials Subgroup Analyses No Patent Runoff Vessels Patients who did not have any continuous patent runoff vessels to the foot Japan PMS n = 905 Higher incidence of CLI (45% vs. 20%) in the no runoff group No other significant demographic or lesion differences No runoff vessels n = 54 (7%) 1 runoff vessel n = 846

23 Consistent performance across multiple trials Subgroup Analyses No Patent Runoff Vessels 91.0% 89.5% 83.8% 81.3% p = 0.87 Freedom from TLR rates are similar through 2 years

24 Consistent performance across multiple trials Subgroup Analyses In-Stent Restenosis In-stent restenosis is outside of the approved indication for use in the US ISR n = 175 (19%) Japan PMS n = 905 Non ISR n = 730 Higher incidence of hypercholesterolemia (70% vs. 59%) and lower ABI (0.59 vs. 0.64) in the ISR group Longer lesion length (17.8 vs cm) in the ISR group No other significant demographic or lesion differences

25 Consistent performance across multiple trials Subgroup Analyses In-Stent Restenosis 92.4% 84.2% 85.3% 76.6% p = 0.05 Nearly similar outcomes for ISR and non-isr patients

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27 The importance of scientific evidence Prof. I. Baumgartner Head Clinical & Interventional Angiology University Hospital Bern