In the Journals

Possible mortality risk from paclitaxel-coated devices spurs debate, pauses trials

Michael R. Jaff
Michael R. Jaff

A meta-analysis finding long-term death risk associated with paclitaxel-coated devices in patients with peripheral artery disease has prompted much debate among vascular interventionalists and caused a temporary halt to enrollment in two ongoing trials.

The meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, EBIR, of the department of interventional radiology at Patras University Hospital in Rion, Greece, and colleagues found no difference in mortality in the paclitaxel-coated device arm vs. the control arm at 1 year, but a 68% increased mortality risk at 2 years and a nearly twofold increased mortality risk at 5 years.

Trials halted

After publication of the meta-analysis, the steering committees of the BASIL-3 trial and SWEDEPAD 1 and 2 trials announced they would temporarily halt enrollment pending further review of the data.

The BASIL-3 steering committee wrote: “Whilst the population of the reviewed trials differs from those in the BASIL-3 trial, it is clearly important new information that may cause concerns for the BASIL-3 trial in relation to patient safety. As such, it raises the need to consider whether changes to the trial protocol and patient information are required.”

The steering committee in a letter to participating centers wrote that it is reviewing data from the individual trials that comprised the meta-analysis, and that trial statisticians are examining the BASIL-3 data collected so far to determine whether there are any signals of mortality risk.

The SWEDEPAD 1 and 2 steering committee wrote: “The results of the meta-analysis, and of our own interim safety analysis, prompted us to ... temporarily halt recruitment of patients to SWEDEPAD 1 and 2. We are now conducting a thorough in-depth analysis of all patients randomized in SWEDEPAD 1 and 2 with respect to this safety warning.”

Major implications

In response to a Cardiology Today’s Intervention survey of its Editorial Board Members on trends to watch for 2019, two prominent figures in vascular intervention said the fallout from the meta-analysis will have major implications in the coming year.
“With the recent publication of a meta-analysis suggesting increased mortality when drug-coated devices are used in patients with symptomatic femoropopliteal artery disease, there is a frenzy of concern about the use of these devices across the world,” Michael R. Jaff, DO, president of Newton-Wellesley Hospital and professor of medicine at Harvard Medical School, wrote to Cardiology Today’s Intervention. “I anticipate a number of publications in the first quarter of 2019 that will shed more light on this subject, so that the practicing vascular specialist can make an informed decision for their patients.”

Kenneth Rosenfeld
Kenneth Rosenfeld

Kenneth Rosenfield, MD, MHCDS, section head of vascular medicine and intervention at Massachusetts General Hospital, agreed.

“The recent furor over paclitaxel-based therapy for PAD, in which a meta-analysis showed a signal of late mortality associated with paclitaxel-coated balloons and stents, has raised concerns that will need to be addressed quickly to better understand any potential downside,” he wrote. “These devices are so prominent that this will dominate the airwaves for the first half of the year.”

Katsanos and colleagues analyzed 28 randomized controlled trials covering 4,663 patients, 89% of whom had claudication, in which patients were assigned to treatment with a paclitaxel-coated balloon or stent or a control arm.

At 1 year, there was no difference between the paclitaxel and control arms for all-cause mortality (RR = 1.08; 95% CI, 0.72-1.61).

However, in a 2-year analysis of 12 trials with 2,316 patients, the paclitaxel arm had elevated risk for all-cause mortality (RR = 1.68; 95% CI, 1.15-2.47; number needed to harm = 29), and in a 5-year analysis of three trials with 863 patients, the risk difference had widened (RR = 1.93; 95% CI, 1.27-2.93; number needed to harm = 14).

In a meta-regression analysis, Katsanos and colleagues found a relationship between exposure to paclitaxel and absolute risk for death (0.4% excess death risk per paclitaxel milligram-year; P < .001).

“Actual causes for this serious late side effect remain unknown, and further investigations with longer-term follow-up are urgently warranted,” the researchers wrote. – by Erik Swain

For more information:

Michael R. Jaff, DO, can be reached at mjaff@partners.org; Twitter: @docmrjaff.

Kenneth Rosenfield, MD, MHCDS, can be reached at krosenfield1@mgh.harvard.edu; Twitter: @krosenfieldmd.

Disclosures: Katsanos reports he receives personal fees from Boston Scientific and personal fees and grants from Medtronic. Please see the study for all other authors’ relevant financial disclosures. Jaff reports he is a consultant for Abbott Vascular, AOPA, Boston Scientific, Cordis, Medtronic, Micell, Primacea, Silk Road Medical, Vactronix, Venarum and Volcano/Philips, and holds equity in Embolitech, Gemini, Janacare, MC10, Northwind Medical, PQ Bypass, Primacea, Sano V and Vascular Therapies. Rosenfield reports he has financial ties with Abbott Vascular, Access Vascular, Amgen, BIO2 Medical, Capture Vascular, Cardinal Health, Contego Medical, Cook Medical, Cordis, Cruzar Systems, Embolitech, Eximo, Endospan, Icon Interventional, InspireMD, Janacare, MD Insider, Micell Technologies, PQ Bypass, Philips, Primacea, Shockwave Medical, Silk Road Medical, SimSuite, Surmodics and Vortex Medical.

 

Michael R. Jaff
Michael R. Jaff

A meta-analysis finding long-term death risk associated with paclitaxel-coated devices in patients with peripheral artery disease has prompted much debate among vascular interventionalists and caused a temporary halt to enrollment in two ongoing trials.

The meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, EBIR, of the department of interventional radiology at Patras University Hospital in Rion, Greece, and colleagues found no difference in mortality in the paclitaxel-coated device arm vs. the control arm at 1 year, but a 68% increased mortality risk at 2 years and a nearly twofold increased mortality risk at 5 years.

Trials halted

After publication of the meta-analysis, the steering committees of the BASIL-3 trial and SWEDEPAD 1 and 2 trials announced they would temporarily halt enrollment pending further review of the data.

The BASIL-3 steering committee wrote: “Whilst the population of the reviewed trials differs from those in the BASIL-3 trial, it is clearly important new information that may cause concerns for the BASIL-3 trial in relation to patient safety. As such, it raises the need to consider whether changes to the trial protocol and patient information are required.”

The steering committee in a letter to participating centers wrote that it is reviewing data from the individual trials that comprised the meta-analysis, and that trial statisticians are examining the BASIL-3 data collected so far to determine whether there are any signals of mortality risk.

The SWEDEPAD 1 and 2 steering committee wrote: “The results of the meta-analysis, and of our own interim safety analysis, prompted us to ... temporarily halt recruitment of patients to SWEDEPAD 1 and 2. We are now conducting a thorough in-depth analysis of all patients randomized in SWEDEPAD 1 and 2 with respect to this safety warning.”

Major implications

In response to a Cardiology Today’s Intervention survey of its Editorial Board Members on trends to watch for 2019, two prominent figures in vascular intervention said the fallout from the meta-analysis will have major implications in the coming year.
“With the recent publication of a meta-analysis suggesting increased mortality when drug-coated devices are used in patients with symptomatic femoropopliteal artery disease, there is a frenzy of concern about the use of these devices across the world,” Michael R. Jaff, DO, president of Newton-Wellesley Hospital and professor of medicine at Harvard Medical School, wrote to Cardiology Today’s Intervention. “I anticipate a number of publications in the first quarter of 2019 that will shed more light on this subject, so that the practicing vascular specialist can make an informed decision for their patients.”

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Kenneth Rosenfeld
Kenneth Rosenfeld

Kenneth Rosenfield, MD, MHCDS, section head of vascular medicine and intervention at Massachusetts General Hospital, agreed.

“The recent furor over paclitaxel-based therapy for PAD, in which a meta-analysis showed a signal of late mortality associated with paclitaxel-coated balloons and stents, has raised concerns that will need to be addressed quickly to better understand any potential downside,” he wrote. “These devices are so prominent that this will dominate the airwaves for the first half of the year.”

Katsanos and colleagues analyzed 28 randomized controlled trials covering 4,663 patients, 89% of whom had claudication, in which patients were assigned to treatment with a paclitaxel-coated balloon or stent or a control arm.

At 1 year, there was no difference between the paclitaxel and control arms for all-cause mortality (RR = 1.08; 95% CI, 0.72-1.61).

However, in a 2-year analysis of 12 trials with 2,316 patients, the paclitaxel arm had elevated risk for all-cause mortality (RR = 1.68; 95% CI, 1.15-2.47; number needed to harm = 29), and in a 5-year analysis of three trials with 863 patients, the risk difference had widened (RR = 1.93; 95% CI, 1.27-2.93; number needed to harm = 14).

In a meta-regression analysis, Katsanos and colleagues found a relationship between exposure to paclitaxel and absolute risk for death (0.4% excess death risk per paclitaxel milligram-year; P < .001).

“Actual causes for this serious late side effect remain unknown, and further investigations with longer-term follow-up are urgently warranted,” the researchers wrote. – by Erik Swain

For more information:

Michael R. Jaff, DO, can be reached at mjaff@partners.org; Twitter: @docmrjaff.

Kenneth Rosenfield, MD, MHCDS, can be reached at krosenfield1@mgh.harvard.edu; Twitter: @krosenfieldmd.

Disclosures: Katsanos reports he receives personal fees from Boston Scientific and personal fees and grants from Medtronic. Please see the study for all other authors’ relevant financial disclosures. Jaff reports he is a consultant for Abbott Vascular, AOPA, Boston Scientific, Cordis, Medtronic, Micell, Primacea, Silk Road Medical, Vactronix, Venarum and Volcano/Philips, and holds equity in Embolitech, Gemini, Janacare, MC10, Northwind Medical, PQ Bypass, Primacea, Sano V and Vascular Therapies. Rosenfield reports he has financial ties with Abbott Vascular, Access Vascular, Amgen, BIO2 Medical, Capture Vascular, Cardinal Health, Contego Medical, Cook Medical, Cordis, Cruzar Systems, Embolitech, Eximo, Endospan, Icon Interventional, InspireMD, Janacare, MD Insider, Micell Technologies, PQ Bypass, Philips, Primacea, Shockwave Medical, Silk Road Medical, SimSuite, Surmodics and Vortex Medical.