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Paclitaxel in PAD Warnings Echo Past Drug-Eluting Stent Scare…………

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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 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.

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.

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 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 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 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.

-GDMeds, an India Pharmacy Service company
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