Paclitaxel Devices in PAD: Debate Continues, but Risk 'Cannot Be Ignored'

A European Heart Journal paper adds to the tally of conflicting data in the ongoing controversy about the safety of drug-coated balloons (DCBs) and drug-eluting stents (DESs) in peripheral intervention. This latest "real world" analysis from Germany included almost 65,000 patients who underwent more than 105,000 lower-limb interventions and found no association between paclitaxel-coated device use and increased mortality.

However, it is unlikely to settle the debate that erupted last year when a Greek meta-analysis of the randomized controlled trials (RCTs) showed a late mortality signal. This triggered a spate of additional analyses, suspension of ongoing trials, and a 2-day Food and Drug Administration (FDA) panel hearing. The FDA assessment of the RCT data and an individual patient level data analysis from VIVA/NAMSA also show a consistent late mortality signal.

This new paper from Freisinger and colleagues looked at German BARMER Health Insurance data for all patients with a first endovascular procedure between 2007 and 2015 and followed through December 2017. Its finding aligns with a Centers for Medicare & Medicaid Services (CMS) analysis that did not show increased mortality with coated devices.

Konstantinos Katsanos, MD, PhD, from Patras University Hospital, Rion, Greece, lead author of the meta-analysis that set off the firestorm, told theheart.org | Medscape Cardiology via email that the latter two datasets "have some distinct differences and limitations compared to our analysis." In the Freisinger paper, he noted that only 5.1% of patients received paclitaxel devices at their index procedure. This increased to just over 10% with the inclusion of additional procedures during follow-up.

Konstantinos Katsanos, MD, PhD.

Unlike the RCTs, the German cases were not limited to femoropopliteal interventions, and both the German and Medicare databases included a relatively high percentage of patients with critical limb ischemia. Katsanos also pointed out that another paper using the CMS data showed higher rates of revascularization in the DCB arm, which contradicts the results of the RCTs.

An updated analyses of the Medicare beneficiary data presented at the recent Transcatheter Cardiovascular Therapeutics (TCT) 2019 meeting in San Francisco by Eric Secemsky, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, showed no difference in survival by device type, peripheral artery disease (PAD) severity, or place of service or among low-risk patients. The update had a median follow-up of 799 days compared with just over a year for the original publication; the mortality signal seen in the RCT data emerges at 2 years and later.

The controversy was addressed during various sessions at TCT, including a presentation titled "The Case for Ongoing Use of Drug-Eluting Technologies for PAD" by William Gray, MD, from Lankenau Heart Institute, Wynnewood, Pennsylvania. He highlighted the fact that 80% of the initial patients and 90% of the studies were missing from the Greek meta-analysis at 5 years. To his mind, this negates the strength of numbers and increases the risk for type I error. As missing data were filled in, the hazard ratio declined, adding to his suspicions that the mortality signal was a false positive.

Updates to a VIVA/NAMSA analysis presented by Krishna Rocha-Singh from the Prairie Heart Institute, Springfield, Illinois, also showed lower hazard ratios as the rate of missing data declined (Table).

Analysis	Risk or HazardRatio (95% CI)	Lost to Follow-up/Withdrawn (%): Paclitaxel	Lost to Follow-up/Withdrawn (%): Control
Katsanos, JAHA 2018	1.93 (1.27 - 2.93)	NR	NR
Katsanos, June 2019 update	1.62^a (1.21 - 2.17)	NR	NR
FDA, original as treated	1.72 (1.22 - 2.38)	25	23
FDA, as treated June 2019	1.57 (1.16 - 2.13)	15	15
VIVA/NAMSA, May 2019	1.30^a (1.03 - 1.63)	15	16
VIAV/NAMSA, update August 2019	1.27^a	9	10
CI = confidence interval; JAHA = Journal of the American Heart Association; NR = not reported. ^aHazard ratio.

When asked about this observation, Katsanos countered that "there is still wide overlap between the original and revised confidence intervals and the direction and consistency of the findings have remained stable." He also pointed out that the VIVA analysis was limited to the major industry-sponsored trials.

Controls and Crossovers

Another criticism from Gray was that the high rate of crossover to paclitaxel devices in the control arms of the studies limited any assessment of risk by intention-to-treat and that "our understanding of exposure to paclitaxel is really limited" given that information on contralateral treatment and treatment before randomization was not available.

Katsanos acknowledged that this was a valid point but one that was "still rebutted by the beauty of the randomization element…the probability of contralateral limb treatment (with or without paclitaxel) should be approximately the same among active and control study groups." Since the risk of revascularization is significantly higher with uncoated devices, the control group is more likely to be exposed to paclitaxel, which "would introduce more biased estimates in case of control treatment," he added.

As for the charge leveled at the Greek professor of interventional radiology that he didn't use patient-level data: "I will reiterate once again that with the exception of COOK Medical (whom I kindly thank), we have been shamefully declined access to the individual-patient data by other companies time and time again."

Dose Response Is Extremely Complicated

The Katsanos analysis suggested a dose-response effect that other researchers have been unable to replicate. According to a basic science presentation by Elazer Edelman, MD, PhD, from Brigham and Women's Hospital in Boston, Massachusetts, "dose response is extremely complicated." The dose on the device is no indication of the dose the patients retain, he explained, because for a nonsoluble drug like paclitaxel, retention is influenced by conditions that cause receptor overexpression, such as inflammation, and others that hinder drug diffusion, such as calcification: "A hypercholesterolemic diet will actually profoundly change the amount of paclitaxel in the artery," he said.

Katsanos applauded Edelman's work and said that "long-term tissue bioavailability of paclitaxel very much depends on the solubility properties (ie, crystallinity) and the total amount of paclitaxel delivered to begin with." The various approved paclitaxel-coated balloons have different drug doses, crystallinity, and excipient.

Because of coding limitations, the German researchers did not know the exact product used in each case, which included early iterations of devices not used in the United States. Drug-coated devices were first approved by the FDA for use in PAD in November 2012. Almost seven times more of the German patients got DCBs than DESs, but the individual paclitaxel load or length of device was not known.

David Kandzari, MD, from Piedmont Heart Institute, Atlanta, Georgia, who was on the FDA panel that sat through 2 days of data poring and discussion, told theheart.org | Medscape Cardiology via email "I don't think we have enough information to suggest there is a differential risk between DCB and DES. Moreover, there does not seem to be a compelling relationship between paclitaxel dose and risk."

Moving On

One thing everyone seems to agree on is that endovascular trialists need to do a better job in terms of the quality and completeness of follow-up. In a session at TCT, Bram Zuckerman, MD, from the FDA, said, "I really want to complement Dr Katsanos for really challenging us…to do better science." He reiterated the FDA's position that "there is a mortality signal that cannot be ignored at this point in time."

Paclitaxel-coated devices remain on the market with revised labeling that addresses the mortality signal and the data uncertainty. The BASIL-3, SWEDEPAD 1, and SWEDEPAD 2 trials have resumed. The most recent Letter to Healthcare Providers emphasized the need for a benefit-risk discussion with patients before using the devices.

Kandzari confirmed that he continues to use the devices in his patients after a thorough discussion on the mortality issue. "It is certainly more effort intensive, but also a welcomed opportunity to revisit the positives of the patient-physician relationship," he said, adding that most patients ask him to "do for me what you would do for your family members." Katsanos supports judicious use, saying that "paclitaxel is very effective in treating vascular restenosis, but not as safe as we previously thought."

With the need for more high-quality data and analyses, the FDA is also working with Secemsky and others on the SAFE-PAD CMS study, which will have a median follow-up of over 5 years and will incorporate a variety of subgroup analyses and sensitivity analyses to evaluate potential unmeasured confounders.

Katsanos sees the controversy as "a unique opportunity for the whole industry to release all anonymized patient data in an open, ethical, and transparent way for everybody to test and compare in order to better serve patient safety and the advancement of science."

However, he admitted that he was not optimistic that this would happen anytime soon. His next steps? "We are monitoring the space very closely like everybody else!"

Disclosures: Edelman reports research support from Abiomed, Edwards Lifesciences, Cardiatis, Boston Scientific Corporation, Medtronic, and consultancy for Abbott Vascular. Freisinger reports grants from Bayer and Pfizer. Gray reports research support from SurModics and Philips and consultancy for WI Gore, SurModics, Abbott Vascular, Boston Scientific, Medtronic, and Philips. Kandzari reports consulting for and research support from Biotronik and Medtronic. Katsanos reports no relevant disclosures. Rocha Singh reports research support from Medtronic and VIVA Physicians , consulting for Medtronic and Alucent BioMedical, and stock/equity in PQ Bypass and is the founder of Convergence Consulting, LLC. Secemsky reports research grants from BIDMC, AstraZeneca, BD Bard, Cook Medical, CSI, and Medtronic and consultancy for Cook Medical, CSI, Medtronic, and Philips.

Tricia Ward is Executive Editor of theheart.org | Medscape Cardiology. She last wrote about paclitaxel devices in PAD in June.

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