‘Inadvertent Reversal’ of Late Mortality Data Flips Advantage From Paclitaxel Zilver PTX Stent in PAD to PTA

(UPDATED) A serious error in data reporting in the Zilver PTX trial reverses the conclusion that there was a long-term mortality advantage for the paclitaxel-based stent compared with percutaneous transluminal angioplasty (PTA) in patients with PAD. The journal Circulation says the all-cause mortality data for the study arms were “inadvertently reversed” by the authors in their original manuscript and have been corrected, along with one additional mistake.

The trial has the longest follow-up of patients randomized to an endovascular device for treatment of femoropopliteal artery disease and has been referenced multiple times in recent months as strong evidence to refute claims linking increased mortality and paclitaxel-based devices in a controversial meta-analysis by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece).

In their paper published in Circulation in 2016, the Zilver PTX investigators led by Michael D. Dake, MD (University of Arizona, Tucson), reported that the 5-year all-cause mortality rate in the 474-patient trial was 10.2% for the DES group and 16.9% for the PTA group (P = 0.03). The correction, published February 19, 2019, on the journal’s website, reverses those numbers, giving the mortality advantage to the PTA group.

This marks the second time in less than a week that a major trial of a paclitaxel-coated device for PAD has acknowledged a serious data error. On February 15, 2019, Medtronic revealed that some mortality data on patients treated in its IN.PACT Global Study were not included in two recent publications.

One PAD researcher who spoke with TCTMD on condition of anonymity was speechless at the news of the Circulation correction, noting that the Zilver PTX data have repeatedly been held up as strong evidence of the long-term safety of paclitaxel-coated devices and adding that “this is really too bad.”

Indeed, the Zilver PTX trial was a focal point at a recent special session at LINC 2019 at which investigators from various studies of paclitaxel-based devices for PAD presented patient-level meta-analyses that uniformly showed no mortality signal compared with an uncoated device. At that time, Dake presented additional data from Zilver PTX on crossover patients who had not been included in the Katsanos meta-analysis.

In an email response to a TCTMD question, asking when the errors were first discovered, a spokesperson for Cook Vascular said corrections of the transposed data were submitted to Circulation in December 2018. At the same time, the company requested correction of an erroneous diagram that was published in the original manuscript as well.

“When high-resolution files were requested during production, an incorrect version of Figure 1 was mistakenly provided,” the Circulation correction reads. “Subsequently, the published version of the flow chart in Figure 1 contained incorrect numbers.”

The email from Cook Vascular to TCTMD further states, “Although this is a mistake that needed to be addressed, the underlying data that was published in Circulation is correct.” The company adds: “The safety data that we submitted to FDA, other regulatory authorities around the world, and that we use in presentations of 5-year data have been correct. Our patient level data confirms the safety of Zilver PTX, showing no significant difference in mortality between Zilver PTX and uncoated balloons and stents.”

In an interview with TCTMD, William A. Gray, MD (Lankenau Heart Institute, Wynnewood, PA), said the errors are “unfortunate” and will have to be taken into account as efforts to pool the patient-level analytics on all of the paclitaxel-based DCB and stent trials move forward. VIVA Physicians is set to oversee the data collection from trial sponsors, and the FDA has said it is evaluating long-term follow-up data from all of the studies that supported approval of paclitaxel-coated balloons or stents for the treatment of femoropopliteal artery disease.

“I don't think this, by itself, changes much of the current activity or perspective. We're still in the process of sorting this out,” Gray noted. “We have to remember that any differences seen at 5 years in relatively small numbers of patients may be problematic because they are too small to see a mortality effect.”

Requests for comment from Cook Medical, sponsor of the Zilver PTX trial, were not returned before this story went online.