March 25, 2019
Cook Medical Letter to Physicians Addresses Paclitaxel Data
March 26, 2019—In a letter to physicians, Cook Medical communicated the company's latest information and insights regarding concerns about long-term safety of paclitaxel eluted from the company's Zilver PTX stent for the treatment of peripheral artery disease (PAD). In the letter, the company (1) reiterated the FDA's recent guidance on the matter, (2) outlined ongoing initiatives to address the concerns, and (3) reviewed data from the Zilver PTX randomized controlled trial (RCT) that may account for discrepancies in long-term safety findings.
Cook noted that the Zilver PTX drug-eluting stent was approved by the FDA in 2012 through the premarket approval process. In the letter to physicians, the company outlined safety and effectiveness data from 20 years of research and development of the device—including the design and outcomes of the Zilver PTX RCT—and repeated the FDA's latest guidance for health care providers.
First, Cook Medical recommended that health care providers follow the FDA's current recommendations on treatment decisions with paclitaxel devices that the agency issued in a letter on March 15. These guidelines are based on the FDA's preliminary review of available data that was conducted after an increased long-term mortality with paclitaxel-eluting devices versus percutaneous transluminal angioplasty (PTA) with bare-metal stents (BMS) was seen in findings from a meta-analysis of randomized controlled trials (RCTs). The meta-analysis data were published in December 2018 by Konstantinos Katsanos, MD, et al online in Journal of the American Heart Association.
In the March 15 recommendation letter, the FDA noted that the data used to develop the recommendations should be interpreted with caution for several reasons: (1) there is large variability in the risk estimate of mortality due to the limited amount of long-term data; (2) these studies were not originally designed to be pooled, introducing greater uncertainty in the results; and (3) the specific cause and mechanism of the increased mortality is unknown.
Second, Cook Medical advised that the company is working to provide answers—including providing patient-level data—to questions from the FDA and other global regulatory authorities. The FDA has also asked industry to collaborate and present at an FDA panel meeting in June. An industry-wide working group is preparing data for presentation at this panel meeting. Cook is also collaborating with medical societies and is sharing its data to provide a deeper understanding of its mortality analysis.
Third, Cook Medical explained that the Zilver PTX RCT had a unique trial design that may account for findings of increased mortality risk. The trial included a primary and secondary randomization, as well as an opportunity for patients in the PTA arm to cross over to treatment with Zilver PTX after experiencing a target lesion revascularization in the first 12 months. As a result of this trial design, 40% of patients who were initially assigned to the PTA arm were subsequently treated with Zilver PTX. In total, 70% of the patients enrolled in this trial received a Zilver PTX stent.
Cook advised that to appropriately analyze the role of paclitaxel on mortality, it is important to compare all patients who were treated with Zilver PTX to those treated only with non–drug-eluting devices.
The “intent-to-treat” analysis shows a 5-year all-cause mortality rate of 22.1% for the Zilver PTX primary randomization arm and 15.3% for the PTA primary randomization arm (P = .04). However, Cook noted that this analysis does not recognize that 94 of the 237 patients (40%) in the primary PTA arm were actually treated with a Zilver PTX stent yet were analyzed as PTA patients and not Zilver PTX patients in the intent-to-treat analysis.
The “as-treated” analysis shows a mortality rate of 18.7% for Zilver PTX patients and 17.6% for PTA/BMS patients (P = .53). This “as-treated” Zilver PTX group includes all patients who received a Zilver PTX stent.
Causes of death were examined between the “as-treated” Zilver PTX and PTA/BMS groups. There was no increased rate of cardiovascular, cancer, or other cause of death for Zilver PTX compared to PTA/BMS, reported Cook Medical in its letter to health care providers.
Cook Medical's letter to physicians is available on the company's website here.
For details regarding these data and all news related to the ongoing controversy regarding paclitaxel use in PAD, please visit our comprehensive continuing coverage page.