Paclitaxel was first used as an antiproliferative coating on coronary stents around 15 years ago, and though it has been superseded by more effective drugs there has been little question of its safety in this setting. Not so in the peripheral vasculature: a meta-analysis published at the end of last year suggested peripheral stents and balloons coated with paclitaxel carry a greater risk of death in patients with femoropopliteal artery disease than uncoated devices.
In the study’s wake sales of these products fell, though none was removed from market, and ongoing trials of new paclitaxel-eluting devices were put on hold. This week an FDA panel will evaluate the risk level of these devices and recommend regulatory steps – and the agency has stated that its analyses have confirmed the increased risk seen in the study.
The meta-analysis collated data from 28 randomised trials of various paclitaxel-coated devices developed by groups including Medtronic, Philips and Cook Medical.
The study assessed 14 devices from 12 manufacturers. The most significant are summarised below. The table also includes the fifth paclitaxel-coated peripheral device that is approved in the US: Boston Scientific’s Eluvia stent. This was not included in the original meta-analysis.
|Selected paclitaxel-coated peripheral devices|
|Company||Device||Type||EU approval||FDA approval|
|Cook Medical||Zilver‐PTX||Stent||Aug 2009||Nov 2012|
|Becton Dickinson||Lutonix*||Balloon||Jun 2011||Oct 2014|
|Medtronic||In.Pact Admiral*||Balloon||May 2009||Dec 2014|
|Philips||Stellarex||Balloon||Dec 2014||Jul 2017|
|Boston Scientific||Eluvia**||Stent||Feb 2016||Sep 2018|
|B. Braun||SeQuent Please||Balloon||Mar 2009||-|
|Bayer||Cotavance Balloon||Balloon||May 2011||-|
|Biotronik||Passeo‐18 Lux||Balloon||Jan 2014||-|
|Boston Scientific||Ranger||Balloon||Jul 2014||-|
|*Also used in the coronary arteries. **Not included in the meta-analysis. Source: EvaluateMedTech, FDA website, company communications.|
The rate of all‐cause death at one year was similar between paclitaxel‐coated devices and control arms – which used uncoated balloons or stents or, in one case, surgical implantation of a plastic graft. At two years, however, all-cause death rates were significantly higher, at 7.2% with the drug-coated devices versus 3.8% with control. By five years the difference had widened further.
The real crunch came in March, however, when the FDA wrote to doctors that its preliminary review of the data had identified a “potentially concerning” signal of increased long-term mortality. Of 975 patients in three trials with five-year follow-up data there was an increased risk of mortality of around 50% in those treated with paclitaxel-coated devices versus control, the agency said. The figures for crude risk of death were 20% versus 13%.
The agency stated that, for most patients, other treatments should generally be used until further analyses of the safety signal were complete, and announced the panel meeting.
Sales of the devices were immediately hit. Reporting its 2019 results last month, Medtronic said uncertainty about safety of the devices had led to sales of its drug-coated balloons declining by around a quarter in the US, that the slowdown was expected to continue in the first quarter, and that there was a “low-20s” percentage decline in Western Europe. This was partly offset by sales growth in Japan.
Becton Dickinson, meanwhile, cut its full-year guidance last month, explicitly citing regulatory and market pressures related to paclitaxel-coated devices. On a conference call its chief financial officer, Chris Reidy, said sales of drug-coated balloons were expected to halve.
Stifel analysts estimate that Medtronic has around two thirds of the US drug-coated peripheral balloon market to Becton Dickinson’s one third; the other balloon approved in the US is Philips’s Stellarex, but the Dutch group has not reported any sales for the device.
Exact sales figures for these products are hard to come by, but the table below shows how important peripheral devices are to the two US groups with FDA-approved paclitaxel-coated balloons. It should be noted that these segments will include other devices too, such as uncoated balloons, so it is a fairly crude measure.
|Medtronic and Becton Dickinson's peripheral devices|
|Annual sales ($bn)|
|% of total company sales||4%||4%||4%||4%||4%||4%||4%|
|% of total company sales||7%||8%||8%||8%||9%||9%||9%|
It is just conceivable that the adcom, which will run on June 19-20, will conclude that the devices are worth using after all, and sales will rise once more. The cardiovascular industry organisation PCR issued a statement last month saying the meta-analysis was “subject to major inherent methodological limitations”, and insisting that paclitaxel-coated balloons and stents were safe.
In briefing documents the FDA said its analyses had found an increase in mortality between two and five years with paclitaxel-coated devices intended to treat femoropopliteal disease. But it added that the cause of this increase in deaths could not be determined, and said more data might help it determine the causes and update benefit-risk considerations for these products.
Most interested parties seem to expect the FDA to err on the side of caution. Even Medtronic’s chief executive Omar Ishrak is fatalistic.
“We’re basically assuming that what FDA has stated is going to remain for the entire balance of the year,” he said last month. “If FDA were to become more favourable in their commentary obviously that could improve outcomes. But right now our guidance would assume there will be no change coming out of it.”