June 18, 2019
JEVT Editorial Challenges Drug Dosing and Exposure Time Assumptions in Paclitaxel Mortality Meta-Analysis
June 17, 2019—A recent editorial in the Journal of Endovascular Therapy (JEVT) challenges several key assumptions and findings of the recent meta-analysis by Konstantinos Katsanos, MD, et al published in December 2018 in the Journal of the American Heart Association (JAHA). The JAHA study found an increased long-term risk of mortality using paclitaxel-based devices to treat peripheral artery disease in the superficial femoral artery. Those findings raised significant concerns with clinicians, trial investigators, and regulatory authorities on the use of these devices in routine clinical practice and clinical trials.
The JEVT editorial—entitled "Paclitaxel and Mortality: The Dose Argument Is Critical"—is authored by Andrew Holden, MBChB, FRANZCR, EBIR; Ramon L. Varcoe, MBBS, MS (Vasc), FRACS (Vasc), PhD; Michael R. Jaff, DO; Peter A. Schneider, MD; Gunnar Tepe, MD; and Thomas Zeller, MD.
One assertion of the JEVT editorial is that Katsanos et al incorrectly assumed that drug-eluting stents (DES) liberate paclitaxel over the entire lumen surface of the vessel. Holden et al note that only 14% of the abluminal surface of the Zilver PTX DES (Cook Medical) is coated with the drug, resulting in far less paclitaxel exposure than postulated by Katsanos et al. Based on the instructions for use for 6-mm X 120-mm devices, the JEVT authors calculate that of the three devices with 5-year pivotal trial data, the Zilver PTX DES carries the lowest dose of paclitaxel (1.1 mg of paclitaxel). By comparison, the Lutonix drug-coated balloon (BD [Becton, Dickinson and Company]) has 4.5 mg of paclitaxel and the In.Pact Admiral drug-coated balloon (Medtronic) has 8.4 mg of paclitaxel.
The editorial also addresses the concept of paclitaxel exposure over time as defined by the authors of the meta-analysis.
In JEVT, Holden et al stated, "[T]he exposure equation devised by the authors included time. This time variable corresponds to study follow-up time reported in the publication or presentation, not drug residence in the target tissue or systemic circulation. The time relationship posed by the authors assumes that the dose is stable and remains constant over time. There is no evidence in any preclinical or clinical study to suggest that this is true. The concept is fundamentally flawed, as the time parameter used in this way penalizes older studies with longer follow-up. Thus, studies at shorter follow-up will be biased toward the null and longer follow- up studies biased toward finding a stronger association between paclitaxel-coated devices and greater mortality."
To directly compare 5-year mortality data using consistent methodology, Holden et al asked the three companies with data out to this point to calculate and provide their 5-year mortality figures using Medtronic's “proportion method”: the total number of patients who died divided by the number of patients followed to 5 years. This allowed for a direct comparison of product dose to test the dose-response theory proposed by the meta-analysis.
Tying the data points together, Holden et al report that, "The highest 5-year mortality was found to be associated with the lowest paclitaxel dose device (Zilver PTX), while the lowest mortality was associated with the highest dose device (In.Pact). It is our view that this directly refutes the causal relationship theory between paclitaxel dose and all-cause mortality."
To see all of the articles in our continuing coverage of the paclitaxel safety data review, please visit this page.