Paclitaxel: Should we be concerned about the risks? Rajabrata - PDF document

4/8/19 Paclitaxel: Should we be concerned about the risks? Rajabrata Sarkar M.D. Ph.D. Barbara Baur Dunlap Professor of Surgery and Physiology Interim Chair, Department of Surgery Chief, Division of Vascular Surgery University of Maryland Disclosures • None 1

4/8/19 Objectives • Review the biology of taxol and restenosis • Describe the recent meta-analysis of taxol and mortality • Evaulate the data and responses to it • Discuss the controversy and how to approach patients Paclitaxel (Taxol) • Derived from Pacific yew bark • Targets tubulin and inhibits assembly of the mitotic spindle • Widely used chemotherapy and restenosis agent 2

4/8/19 Vascular uses of paclitaxel • Extensive randomized clinical trials demonstrate that paclitaxel coated angioplasty balloons and stents have superior patency in the peripheral circulation • Widely used by multiple specialties to treat PAD and dialysis restenosis • Multiple major manufacturers 3

4/8/19 The Meta-Analysis Published in Journal of the American Heart Association December 6th, 2018 • Public data on 28 RCTs (24 DCB and 4 DES trials) • 4663 patients • 12 devices (2.0, 3.0 and 3.5 µ g/mm 2 ) One Year Risk of death 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, Volume: 7, Issue: 24, DOI: (10.1161/JAHA.118.011245) 4

4/8/19 Risk of death at two years 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, Volume: 7, Issue: 24, DOI: (10.1161/JAHA.118.011245) Risk of death at 4-5 years 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, Volume: 7, Issue: 24, DOI: (10.1161/JAHA.118.011245) 5

4/8/19 Total Paclitaxel dose vs. risk of death 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, Volume: 7, Issue: 24, DOI: (10.1161/JAHA.118.011245) First FDA letter to doctors • Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality - Letter to Health Care Providers • 1/17/19 6

4/8/19 FDA letter 1/17/19 • In clinical decision-making, discuss the risks and benefits of all available treatment options for PAD with your patients. • Continue surveillance and report adverse events • “Currently, the FDA believes that the benefits continue to outweigh the risks for approved paclitaxel-coated balloons and paclitaxel- eluting stents when used in accordance with their indications for use.” Reactions • BASIL-3, SWEDEPAD 1, SWEDEPAD 2 trials halted enrollment • Manufacturers re-examined data from their clinical trials • Others examined mortality in patients receiving these treatments • Critique of methods in the meta-analysis 7

4/8/19 Critique of methods • A statistical assumption is made that the unknown study-specific log relative risks are normal, i.e. follow a bell-shaped curve. • However, the normality assumption is rejected (p=0.03) for 12 of the 28 studies (43% of the studies) at two years; at five years, the sample of three studies is too small for a meaningful normality test. • When contemporary, more robust methodologies that do not make this assumption are employed, the overall mortality differences are not statistically significant at the one-, two-, and five-year intervals of the study. • Presented by Hanson T, LINC Leipzig, Germany 2019. Critique of methods • Authors propose their own model of drug exposure • Drug dose (Dose i ) is modeled as a constant based on dosage in labeling of respective devices; time (Time i ) is follow-up time in years. • However, paclitaxel demonstrates a transient presence in tissue, not a constant level over years. – Plasma half-life of PTX post-DCB is hours to days – Target tissue PTX residence post-DCB (see figure) is weeks to months 8

4/8/19 Other analysis • Secemsky et al. JAMA Cardiol. 2019: Retrospective study of 16,560 beneficiaries of Centers for Medicare and Medicaid Services with femoropopliteal disease. • Treatment with drug-coated device was associated with a lower incidence of all-cause mortality compared to non-drug coated devices through 600 days (p=0.007) • Authors conclude no evidence of increased all-cause mortality following femoropopliteal artery revascularization with drug-coated devices compared with non–drug-coated devices. 34.3% 32.5% Secemsky et al. JAMA Cardiol. 2019 9

4/8/19 • Individual patient-level analysis on 1980 patients from the IN.PACT Clinical Program to determine any potential connection between paclitaxel exposure and mortality. 1 • Results demonstrate no correlation between paclitaxel exposure and mortality through 5 years. – No difference in mean nominal paclitaxel exposure by survival status. – No difference in survival status stratified by drug exposure (by terciles). – Paclitaxel dose NOT identified as a predictor of mortality (by multivariable analysis). • Preliminary findings suggest that follow-up visit compliance may be associated with a lower risk of mortality Reactions to first letter • William A. Gray, MD (Lankenau Heart Institute, Wynnewood, PA), told TCTMD. “We really need to understand the causes of death at the patient level, but I’m not sure I would change practice at this point.” • Christopher White, MD (Ochsner Medical Center, New Orleans, LA): “We should be paying attention to these signals. We don’t know why it might be harmful [but] we definitely ought to be looking at this.The wrong thing to do right now would be to just deny this like a climate denier,” 10

4/8/19 Reactions • Leipzig Interventional Course (LINC; 22–25 January, Leipzig, Germany): • An independent, third party, pooled analysis of all the IN.PACT Admiral DCB (Medtronic) clinical programmes, published in the Journal of the American College of Cardiology and including 1,980 patients, demonstrated that at five years, there is no statistically significant difference in all-cause mortality between the DCB and the control arm (9.3% vs. 11.2% respectively, p=0.399). • Five-year data from 1,189 patients in the LEVANT 2 trial within the Lutonix DCB (BD) programme showed no statistically significant difference in all-cause mortality between the DCB and the control group (14.2% vs. 10.6% respectively, p=0.22), as described at LINC. • Results from a Cook Medical press release also demonstrated the safety of their drug-eluting stent, the Zilver PTX. Patient- level data found no increased mortality at five years with Zilver PTX compared to non-coated stents and balloons (18.7% vs. 17.6% respectively, p=0.53). The story continues… • However, Medtronic and Cook Medical have since issued corrections to their published data regarding the safety of their devices, the IN.PACT Admiral DCB and the Zilver PTX drug-eluting stent, respectively. 11

4/8/19 FDA letter 3/15/19 • We have now conducted a preliminary analysis of long-term follow-up data (up to five years in some studies) of the pivotal premarket randomized trials for paclitaxel-coated products indicated for PAD. While the analyses are ongoing, our preliminary review of this data has identified a potentially concerning signal of increased long-term mortality in study subjects treated with paclitaxel-coated products compared to patients treated with uncoated devices. • Of the three trials with 5-year follow-up data, each showed higher mortality in subjects treated with paclitaxel-coated products than subjects treated with uncoated devices. In total, among the 975 subjects in these 3 trials, there was an approximately 50% increased risk of mortality in subjects treated with paclitaxel-coated devices versus those treated with control devices (20.1% versus 13.4% crude risk of death at 5 years). IN.PACT IN.PACT SFA IN.PACT Japan IN.PACT China Global DCB PTA DCB PTA (DCB n=143) (DCB n=1406) p-value p-value (n=220) (n=111) (n=68) (n=32) 1 year 1.9% 0.0% 0.926 0.0% 0.0% -- 2.9% 3.5% 2 years 8.1% 0.9% 0.008 6.1% 3.4% 1.000 7.6% 3 years 10.7% 1.9% 0.006 6.0% 6.9% 1.000 11.4% Study completed 4 years 13.0% 6.8% 0.116 one year Complete data Study completed at three years not yet available 5 years 15.8% 9.6% 0.156 12