Paclitaxel-coated balloons and stents were the standard of care for interventions in the superficial femoral and popliteal arteries. Then in December 2018, a meta-analysis from Greece by Katsanos and colleagues[1] suggested an increased risk for late mortality with the paclitaxel-coated devices versus uncoated devices.
This led the US Food and Drug Administration (FDA) to do a preliminary analysis of long-term follow-up data, which found an approximate 50% increased risk for mortality in persons treated with paclitaxel-coated devices versus those treated with control devices (20.1% vs 13.4% crude risk for death at 5 years). Their current recommendation is that "alternative treatment options should generally be used for most patients while we continue to further evaluate."
There is a déjà vu–all-over-again feeling to the controversy for those who recall the stent thrombosis scare surrounding first-generation coronary drug-eluting stents, which was also triggered by meta-analyses.[2,3]
At the 2019 European Association of Percutaneous Cardiovascular Interventions (EuroPCR) conference, the world's leading interventional cardiology meeting, the methodology of the Katsanos analysis came in for criticism in a PCR statement on the topic.[4]
Speaking on behalf of PCR, Alexandra J. Lansky, MD (Yale University) noted that it was a study-level analysis that did not account for paclitaxel exposure in the control arms and that more than 80% of patients were lost to follow-up at 4-5 years, when the mortality signal is seen.
Her presentation also reviewed four subsequent patient-level analyses and a Centers for Medicare & Medicaid Services claims data analysis[5] which have failed to replicate the finding.
Is There a Plausible Mechanism?
Paclitaxel has a checkered past in the cardiovascular space; it was the antiproliferative drug on the weakest drug-eluting stent, which has since been surpassed by stents eluting limus analogs. The PCR statement also noted a lack of explanation for the late mortality.
So could the mortality signal be real? In an interview with Medscape, interventional cardiologist Robert Byrne, MB BCh, PhD (Deutsches Herzzentrum, Munich) was skeptical. "The main problem with the meta-analyses is that we've lacked a plausible reason why paclitaxel in the dosage that it's been administered, locally applied, should result in an increase in all-cause mortality...there's a missing step."
Aloke Finn, MD (University of Maryland School of Medicine), who has conducted preclinical work on drug-eluting stents and balloons, was similarly stumped. "There can be no mechanism that is known that explains the mortality, especially the mortality in the meta-analysis that is at 2 years and at 5 years," he told Medscape. He noted that the paclitaxel doses are very low, much lower than those used for chemotherapy, and that animal models developed for approval of these devices show that the levels in the organs drop very quickly.
If there had been a signal of more amputations or critical limb ischemia, that might have made sense to Byrne because it was seen with some of the first-generation paclitaxel balloons that had high particulate shedding during inflation.[6] "The rather large crystals and the excipient material can cause problems with the microvessels and the downstream vascular bed," he explained.
Lumping vs Splitting Balloons and Stents
Compounding matters was the fact that when the manufacturers went back to investigate the peripheral paclitaxel device data, they found errors. The Zilver PTX Randomized Trial published a correction and now shows significantly higher all-cause mortality with the paclitaxel stent, and Medtronic announced that it had omitted some mortality data from safety-outcomes tables for the IN.PACT Admiral paclitaxel-coated balloon.
Byrne commented that "with the best will in the world these things can happen, but it's bad when they come out in this setting."
The PCR statement criticized the Greek meta-analysis for lumping stents and balloons and assuming a class effect. Lansky described it as "messy" because "the data suggest that the stent is worse than the balloon."
It is debatable whether paclitaxel-coated balloons can even be considered a single class, as they have different drug doses, crystallinity, and excipient.[7] The paclitaxel coating comes in an amorphous form that provides an initial burst of drug, and a crystalline form which enables slower release over time. One animal study of five different paclitaxel-coated balloons suggested differences in distal embolization profiles.[8]
Table. Paclitaxel-Coated Balloons Approved by the US Food and Drug Administration for Peripheral Interventions
| Device Company | Excipient | Paclitaxel Dose (μg/mm2) |
|---|---|---|
| IN.PACT Admiral (Medtronic Vascular; Santa Clara, California) | Urea | 3.5 |
| Lutonix (BARD; Murray Hill, New Jersey) | Polysorbate/sorbitol | 2.0 |
| Stellarex (Spectranetics; Colorado Springs, Colorado) | Polyethylene glycol | 2.0 |
The role of the excipient is to facilitate drug transfer into the vessel wall and, to some extent, to facilitate the dissolution of the crystalline paclitaxel over time, explained Finn, adding that the drug transfer from a balloon is not as efficient as with a stent, which can retain paclitaxel within a polymer matrix. "For the modern-day balloons... I would say on the order of 80% of the drug is lost downstream or remains on the balloon, and maybe 20% is transferred [into the arterial wall]."
Finn conceded that "there's a lot of room to make a better balloon, and that's part of what needs to happen. But does that explain the mortality? I don't think so."
Are Limus Devices the Answer?
Paclitaxel is a harsher drug than limus analogs such as sirolimus. Byrne recalled that the histology studies from the coronary stent era "seem to show that with paclitaxel you do get more pronounced delayed healing and fibrin deposition for sure." Commenting on its lower therapeutic index, Finn noted that "it's easy to overdose it, and it can cause problems such as malapposition in the arterial wall—this was all seen with Taxus [coronary] stents."
With the cloud hanging over paclitaxel-coated balloons and stents in the periphery, why not just switch to limus analogs, as has happened in the coronary space?
Byrne agreed that "if you offer people an effective sirolimus balloon, they're going to prefer it, but it's not a trivial problem getting an effective sirolimus balloon; that's why hardly anyone has managed it yet."
Finn explained that sirolimus doesn't bind well to tissues. "You need a depot. That doesn't mean it won't happen," he noted. "People are making inroads with sirolimus-coated balloons by using such clever things as nano- or microparticle reservoirs that are themselves transferred to the vessel wall. They stick and that allows sustained drug release." There were some presentations at EuroPCR on such novel sirolimus-coated balloons.
Drug-Coated Balloons in the Coronaries
Drug-coated balloons are not yet approved by the FDA for applications in the coronaries, but they are widely used in that setting in Europe, mostly for treating in-stent restenosis—although some "enthusiastic adopters," as described by Byrne, use them in de novo lesions.
A patient-level meta-analysis of 10 randomized clinical trials comparing drug-coated balloons with bare-metal or drug-eluting stents for coronary in-stent restenosis was presented at EuroPCR in 2018. It did not find anything untoward safetywise, but given the recent hoopla, Byrne and colleagues revisited those data and contacted individual investigators for additional follow-up.
Overall, they found no sign of a mortality signal; if anything, there was a slight trend toward lower mortality with the paclitaxel-coated balloons, said Byrne. However, the control group included paclitaxel-coated stents. When they compared the coated balloons against only limus-coated stents, there was a numerically higher rate of death with the paclitaxel balloon that did not reach statistical significance.
What Now?
So where does this leave clinicians?
The PCR statement called for the resumption of the suspended clinical trials of paclitaxel-coated balloons in the periphery, namely BASIL-3 and the SWEDEPAD series. SWEDEPAD's data safety monitoring committee did an analysis of patients randomized and has recommended that the trial resume. PCR also concluded that there were not enough data to change clinical practice.
Given the FDA warning, Finn said that there was no current availability of paclitaxel devices at his hospital. The bottom line for him is that the care of the patients has improved because of drug-eluting technologies. "We've improved the [coronary] stents. There is less restenosis; you don't have to come back all the time to have repeat procedures. That's a big deal for anybody."
He believes that the latest controversy may be a wake-up call for the manufacturers to develop better balloons, because ultimately they offer an advantage over stents, "which is that they don't cage the vessel wall. We used to have this idea of the [bioresorbable scaffolds] being the solution. We know what happened with that," he lamented, referring to the withdrawal of bioresorbable stents from the US marketplace due to efficacy and safety concerns.
On June 19 and 20, the FDA will convene an Advisory Committee meeting of the Circulatory System Devices Panel to review the topic; a patient-level pooled analysis of the data will be presented.
Paclitaxel-coated devices continue to be used in Europe. "There's an unmet need; you don't have a good way of treating these patients otherwise and the efficacy data are good. Our colleagues who do the peripheral interventions are still using them," said Byrne.
In his opinion, the mortality signal might be a chance finding. "You have to take it seriously at the same time. Let's see what the FDA says in their panel; they might take some of the heat out of the situation."
Finn was more pessimistic. "I don't know that this will ever go away...it's so hard to fix now."
Disclosures: Lansky reported research grant support from AstraZeneca, Abiomed, Abbott Vascular, Bard, Boston Scientific, Biocardia, Biotronik, Cagent, Cardiatis, Conformal, Gore, Intact Vascular, KeyStone Heart, Venous, Lifetech, Limflow, Medinol, Micell, Microport, Myocardia, Reva, Shockwave Medical, Surmodics, TriReme, Venus, and Veryan Medical. Byrne reported financial relationships with Boston Scientific and Celonova Biosciences. Finn reported research grants support from Abbott Vascular, Biosensors, Biotronik, Boston Scientific, Concept Medical Research Pvt. Ltd., Edwards Lifesciences, Medtronic, MicroPort, Mitralign, OrbusNeich, Shockwave Medical, Sinomed BV, Medis Medical Imaging Systems BV, and Terumo.
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Cite this: Paclitaxel in PAD Warnings Echo Past Drug-Eluting Stent Scare - Medscape - Jun 10, 2019.
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