Industry, Investigators Push Back With Patient-Level Data Showing No Increased Death From Paclitaxel-Based PAD Therapies

More than a month after a controversial meta-analysis suggested a late mortality signal in patients with PAD treated with paclitaxel-based balloons and stents, a session convened at the Leipzig Interventional Course (LINC) 2019 this week revealed further details—newly-released patient-level data from the pivotal trials show low and comparable mortality rates for paclitaxel-treated and uncoated balloon-treated patients.

The meta-analysis that first sounded the alarm was led by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), and suggested that within 2 years of treatment, the paclitaxel groups had a 68% relative risk increase in all-cause death compared with patients treated with an uncoated balloon. At 5 years, the relative risk increase was 93% in comparison with uncoated balloons. Since then, researchers have struggled to explain the Katsanos results, which were based on summary-level pooled data from 28 trials of DES and drug-coated balloons (DCBs) for PAD.

Katsanos, who spoke at LINC yesterday, theorized that the explanation behind the mortality increase lies in a fine line between the effective therapeutic dose of paclitaxel and a toxic dose.

“I would put it to you that there is no question that [paclitaxel] is effective, but on the other side it can increase the risk of death,” he said during his presentation.

Building on the concept that paclitaxel interferes with mitosis and causes cell death and the rise of aneuploid daughter cells, Katsanos said as-yet unpublished work from his group also shows consistently increased risk of cardiovascular events in paclitaxel-treated patients at 1 year in pooled US Food and Drug Administration-submitted data from ZILVER PTX, LUTONIX, STELLAREX, and IN.PACT, as well as greater risks of GI events, infectious diseases, and respiratory events. “There is a consistent finding of certain groups of adverse events across all those studies up to 1 year,” he observed, adding that the incidence of cancer was similar between groups.

In a separate analysis of dose subgroups, one that also that has not yet been published, Katsanos showed data indicating that devices that deliver less than 3.5 mg of paclitaxel are associated with a lower risk of death at 2 years than those that deliver more than 3.5 mg (RR 1.38; 95% CI 0.97-2.19 vs RR 2.31; 95% CI 1.23-4.33).

We do not know what we do not know. Konstantinos Katsanos

“Our research is mainly a word of caution and an awakening call for the endovascular community,” he told TCMTD in an email. “We do not know what we do not know.”

Asked if he was reassured by the response of industry to the meta-analysis, he said the new data presented by various researchers at the LINC session on behalf of the pivotal RCTs shows that they are taking the issue seriously. “A wealth of new data has emerged that we need to look at carefully,” Katsanos said. “My first impression, however, is that questionable statistical analyses may have been performed (eg, violating the intention-to-treat principle, or not reporting the hazard ratios at individual time points like we did in our meta-analysis) that may lead to biased overall results. In addition, in spite of the proclaimed spirit of transparency, we are still being refused access to individual patient data to conduct our own analyses.”

Bioavailability and Digging Deeper

Katsanos also suggested in the email that cautious use of paclitaxel in the legs is warranted based on data indicating that the drug is readily detectable at low traces in nontarget organs like the kidneys and liver at up to 18 months postprocedure.

But Juan Granada, MD (Cardiovascular Research Foundation, New York, NY), who presented experimental data on nontarget tissue drug concentrations of paclitaxel during the LINC session, disagreed with that assessment.

"Our data show that the levels in organs are so exceedingly low that it would be difficult to attribute residual paclitaxel present in the tissue as the cause of adverse events years after treatment with a balloon or stent," he told TCTMD. "I'm not going to say it's impossible, because there is nothing impossible in science, but it's highly unlikely that residual paclitaxel is a cause of increased mortality at 5 years. The science does not match up."

A slide from Granada’s presentation showed that liver and kidney concentrations of paclitaxel at 540 days were 0.001 ng/mg and 0.0003 ng/mg, respectively, which are far below the therapeutic level of paclitaxel. In fact, Granada said the only reason those levels are even detectable is due to the high sensitivity of the available tests.

"We need to go with what we know, and what we know right now is that these technologies are only used once in the large majority of patients and the concentration that is used for PAD—even in the worst-case scenarios—is several orders of magnitude lower than how paclitaxel is used for cancer treatment,” Granada told TCTMD. “I don’t believe there is a plausible biological explanation for an increase in mortality in paclitaxel-treated patients. Now, that does not mean that there is no mortality difference. Perhaps we should start looking at other causes that may be related to that imbalance.”

If this paclitaxel thing is a runaway train, we need to know it right away. Peter Schneider

Presenting new data from the IN.PACT clinical trial series, Peter Schneider, MD (Hawaii Permanente Group, Honolulu), said evaluating the raw data from patients treated with paclitaxel technologies is a key first step in digging deeper into the mortality issue. Results of an independently adjudicated patient-level analysis of individuals enrolled across the entire IN.PACT Admiral clinical program showed no correlation between exposure to paclitaxel and mortality through 5 years. Schneider said an alternative hypothesis for the better mortality rates of the percutaneous transluminal angioplasty (PTA) group seen in the Katsanos meta-analysis could be that follow-up compliance is associated with lower mortality risk, possibly because it puts patients in more frequent touch with the healthcare system.

In an interview with TCTMD, Schneider said the full analysis of the IN.PACT groups, with longer follow-up data that have not previously been made public, will be published soon in the Journal of the American College of Cardiology. He added that his group performed extensive analyses to look for mortality differences by paclitaxel dose and could find nothing. "We tried to use paclitaxel dosage as a predictor of mortality, and the model for multivariable analysis kept kicking it back to us,” Schneider observed.

In another presentation during the same LINC session, Schneider outlined plans for an upcoming vascular leaders’ forum headed by VIVA, saying he believes there is an opportunity for the vascular community to come together to generate answers to the questions raised by the meta-analysis.

The leaders’ forum will collaborate with five US companies that produce commercially available paclitaxel-based DCB and DES products (Medtronic, Cook, Boston Scientific, Bard, and Philips), all of whom have agreed to a data-sharing arrangement in which the patient-level data will be transferred to a third-party statistical consultant for a pooled meta-analysis.

“If this paclitaxel thing is a runaway train, we need to know it right away,” he said during his presentation.

Industry Responds With Data

In addition to the new IN.PACT data, attendees at the LINC session heard from the principal investigators or co-principal investigators of trials testing the Lutonix DCB, Stellarex DCB, Zilver PTX, Eluvia DES, and Ranger DCB. All of the presentations included patient-level data from their respective trial groups and reached similar conclusions, namely that there were no differences in rates of all-cause death between the DCB or DES arms and the PTA groups. Some also looked for and failed to find differences in mortality by applied paclitaxel dose.

Some of the investigators took the opportunity to point out additional data shortfalls of the Katsanos meta-analysis. Taking an in-depth look at the Zilver PTX studies, Michael D. Dake, MD (University of Arizona, Tucson), said the data used by Katsanos et al did not include all patients treated with the Zilver stent. According to Dake, 31 patients initially randomized to PTA or BMS who had suboptimal results in the first year crossed over to the device arm, data that were not available to Katsanos. When numbers on all patients was included in a patient-level analysis, Dake reported that there was no difference in long-term mortality out to5 years with the device compared with PTA or BMS, challenging the results of the Katsanos meta-analysis.

To TCTMD Schneider said that as a whole, the findings presented at the session "suggested strongly that there is no safety signal, and if there is one, it's got to be a little bit smaller than was claimed by the summary-level meta-analysis. It's going to be quite difficult to find. If there is anything to find I think we will find it with the larger pool of patient-level data.”

Safety data for Eluvia DES and Ranger DCB presented by William A. Gray, MD (Lankenau Heart Institute, Wynnewood, PA), also were consistent with the findings of the other devices. Mortality rates with Eluvia were not greater than contemporary rates seen with non-drug-coated devices at 1 and 2 years. Additionally, 3-year mortality data in the RANGER SFA study showed no difference between DCB and PTA groups and patient-level data showed no differences in causes of death.

In an interview with TCTMD, Gray pointed out that the Eluvia stent is intended to retain paclitaxel for 12 months, longer than any of the other devices, and yet it was not associated with increased mortality.

Still, he said the planned patient-level meta-analysis “needs to be done and it should be done with the appropriate methodology.” More time, he added, “will give us more data as well.”

Schneider agreed. “I still think we need to go through these next steps, because I would like everyone to feel great confidence that we're making the right decisions and that the right things are driving those decisions,” he told TCTMD.

At the end of the LINC session, co-moderator John Laird, MD (Adventist St. Helena Hospital, St. Helena, CA), asked Katsanos about his current clinical practice with regard to paclitaxel.

“I’m still using a little bit of paclitaxel,” he said. “Paclitaxel is here to stay. We’re not dismissing paclitaxel. It is an amazing medication. I have a feeling it has a narrow therapeutic index and we need to find out more about that.” For the time being, Laird said, he is restricting the use to “as low as necessary” and not using it for very long lesions. Nor is he using multiple paclitaxel DES.

Note: Granada is CEO of the Cardiovascular Research Foundation, the publisher of TCTMD.