“Unfortunately, we are doing worse for our patients today,” were the sobering words of Eric Secemsky (Boston, United States) during a late-breaking presentation at the Charing Cross (CX) International Symposium (23-25 April, London, UK).
Among several speakers to address the controversy on paclitaxel safety, Secemsky reported that regulatory restrictions subsequent to the Katsanos et al meta-analysis on paclitaxel-coated devices did cause harm through relegating patients to “less durable” device treatment, increasing the incidence of adverse events post-revascularisation.
In a session focused on reaching resolution on the paclitaxel controversy, early presentations given by Thomas Zeller (Bad Krozingen, Germany) and Peter Schneider (San Francisco, United States)—concerning paclitaxel-coated balloon safety in femoropopliteal occlusive disease and paclitaxel mortality across randomised controlled trials—established the “lack” of paclitaxel-coated device mortality risk in the most recent available data.
Secemsky gave a timeline of the use of paclitaxel-coated devices, noting that there had been a “significant, rapid” change in practice in the United States, corresponding to a sharp decline in the use of these devices following the Konstantinos Katsanos (Patras, Greece) et al 2018 meta-analysis which reported an increased mortality risk, leading to subsequent regulatory restrictions in the United States and Europe.
Using both Medicare data and the IQVIA: Medical Device Supply Audit database, Secemsky and colleagues looked at paclitaxel device use in US hospitals between Q3 2013 and Q3 2023. He reported that, following the pivotal Katsanos et al meta-analysis, drug-coated balloon (DCB) and drug-eluting stent (DES) use did not recover to pre-meta-analysis levels until Q3 2023—a period of four and a half years—showing the “parallel” trajectory between device use and data, Secemsky said. Furthermore, of note, the speaker displayed a “shrunken” downward trend in overall femoropopliteal procedural counts in the United States following the controversy, despite PAD-related amputations remaining “stable” in the same period.
Then, Secemsky and colleagues followed 275,009 Medicare beneficiaries who underwent femoropopliteal intervention, comparing the risk of major amputation and death in the period prior to and following the paclitaxel controversy. Risk of amputation or death was reported in 40.4% and 43.2% of patients in the pre- and post-paclitaxel period, respectively. Secemsky also reported a 43.9% risk of major amputation and death in the post-COVID-19 period, establishing that risks following femoropopliteal intervention were “not driven by COVID-19 alone”, he said.
“Did the paclitaxel meta-analysis cause harm? There are many data here to support that it did, and you can see that global restrictions resulted in less durable treatment, more amputation and death post paclitaxel controversy, [and] an increase in economic burden,” said Secemsky.
Although the meta-analysis and regulatory restrictions on paclitaxel devices caused harm, Secemsky—flipping the coin—stated that it also resulted in some positive outcomes by underscoring the need for better clinical trial practices and complete study participant follow-up.
“The paclitaxel controversy not only instigated interest in non-paclitaxel therapies such as sirolimus-based treatments, but it also demonstrated that the vascular community could quickly band together to address a dispute, and particularly displayed the collaborative nature of [the] US Food and Drug Administration (FDA) who ensured regulatory concerns were addressed,” Secemsky finalised. “These lessons can help guide the vascular community through the next controversy and to further develop evidence to shape clinical practice.”
The discussion was then opened to the FDA and UK Medicines and Healthcare products Regulatory Agency (MHRA) to provide a conclusive perspective on the matter. Representing the FDA, Ariel Ash-Shakoor (Washington, United States) stated that, based on the “totality of available evidence” the FDA has determined that the data do not support an excess mortality risk for paclitaxel-coated devices.
Ash-Shakoor noted that lessons can be learned from the paclitaxel mortality controversy, including the importance of long-term follow-up, prespecified plans concerning missing data, and proactive patient monitoring to ensure “complete” reporting.
Providing the perspective of the MHRA, Alexander McLaren (London, United Kingdom) confirmed that no increased risk in mortality with paclitaxel-coated devices has been observed in their review of available randomised controlled trial data.
“Looking back with a critical eye to our own management of the long-running complex topic, I do feel the MHRA response was swift and decisive with the establishment and advice that we received by the expert advisory group,” McLaren stated. In his view, as “quality, robust data were slow to emerge”, delays in decision-making were inevitable. However, taking what has been learnt forward, McLaren said that the MHRA intends on improving premarket clinical investigation and ensuring studies are “sufficiently powered and supported” to collect real-world follow-up data.
