Meeting News

FDA panel, industry discuss potential long-term mortality with paclitaxel devices

Mitchell W. Krucoff
Mitchell W. Krucoff

Members of the Circulatory System Devices Panel of the Medical Devices Advisory Committee of the FDA discussed the potential for increased long-term mortality in patients with peripheral artery disease who were treated with paclitaxel-coated balloons and paclitaxel-eluting stents compared with those treated with other uncoated devices.

Industry and FDA members presented information during the first day of the 2-day meeting. Several associations participated in the open public hearing session to discuss the potential mortality risk with paclitaxel devices. Questions that were addressed during the first day of this meeting include presence of signal, class effect, impact of missing data, subgroup analyses and cause of death.

“The signal is there; that’s true,” Col. Todd E. Rasmussen, MD, USAF MC, professor of surgery and associate dean for clinical research at The Uniformed Services University F. Edward Hebert School of Medicine in Bethesda, Maryland, said during the panel deliberations of the questions. “The statistics are laudable, they’re impressive, but I don’t find them — with regard to magnitude — practically as important to our patients.”

Regarding a class effect, most of the panel members said they felt that the evidence is low.

“The lack of class effect based on the strength of evidence at this point also leaves the door very importantly open to encouraging that each of these devices and these trial results are as complete and high quality as we can encourage the industry to provide them,” Mitchell W. Krucoff, MD, FACC, FAHA, FSCAI, professor of medicine/cardiology at Duke University Medical Center and director of the cardiovascular devices unit and of the eECG Core Laboratories at Duke Clinical Research Institute, said during the panel deliberation. “These trial results are as complete and high quality as we can encourage the industry to provide them. It provides value that maybe this is not a class effect; maybe there is a better mousetrap in the midst here somewhere.”

The lack of data in these studies on paclitaxel devices can make it difficult to interpret, experts said.

“The missing data clearly tempers the interpretation of the analyses,” Joaquin E. Cigarroa, MD, associate chief of clinical cardiology at Oregon Health and Science University in Portland, said during the panel deliberations.

The panel also discussed how the subgroup analyses did not provide a signal as to who would be at the greatest risk.

“My review of everything that was presented today doesn’t find anything striking that would suggest that some subgroups for whatever the magnitude of the signal that we’ve mentioned may be, that some subgroups are at a lower magnitude or no magnitude and others are at greater,” Kevin E. Kip, PhD, FAHA, distinguished health professor at the University of South Florida in Tampa, said during the panel deliberations. “I don’t see anything that looks compelling enough for any one subgroup to make that statement right now.”

It may be difficult to determine what was the exact cause of death in patients with PAD who were treated with paclitaxel devices, panel members said.

“Cause of death is really hard, but these patients have many different comorbidities to attribute it to one particular cause. It’s even more problematic,” said Karla V. Ballman, PhD, professor of health care policy and research at Weill Cornell Medical College in New York.

This meeting was a result of a meta-analysis published in the Journal of the American Heart Association in December, which found that there was long-term death risk associated with paclitaxel-coated devices in patients with PAD.

The FDA held a meeting in March, in which it announced that its preliminary analysis of the possible link between paclitaxel-coated devices and mortality showed a signal of a link between the two, but there was no evidence that provided definitive proof or was able to pinpoint a cause.

The FDA also released a letter in March, warning that the use of paclitaxel-coated products in the treatment of PAD in the femoropopliteal artery may increase mortality risk and to temporarily halt the use of these devices.

FDA presentation

Daniel G. Clair
Daniel G. Clair

The FDA conducted its own meta-analysis of pivotal randomized controlled trials of paclitaxel devices, which found that there was an increasing trend in the RR of mortality for patients who were treated with paclitaxel-coated devices compared with those who were treated with control devices, Adrijo Chakraborty, PhD, mathematical statistician for the Office of Surveillance and Biometrics at the FDA, said during the agency’s presentation.

Based on a cause-of-death analysis also performed by the FDA, the leading causes of CV death were “other,” HF and sudden death, whereas the leading causes of non-CV death include malignancy, “unknown” and pulmonary, Donna Buckley, MD, MS, interventional radiologist for the Office of Cardiovascular Devices at the FDA, said during the presentation. Patients who received a paclitaxel device had a numerically higher rates of all death types except for trauma and infection.

“There is no clear signal that [paclitaxel]-coated devices are associated with an excess rate of a specific CV or non-CV death subtype,” Buckley said.

In a combined industry presentation by Daniel G. Clair, MD, chair of the department of surgery at the University of South Carolina in Columbia, he said the higher RR for mortality was not demonstrated in all studies. In addition, no mortality signal was seen in studies with 5-year data that underwent a modified as-treated analysis of additional vital status data. The predictors of mortality were those that were expected in patients with PAD and include renal failure, age, CVD and diabetes.

Michael D. Dake
Michael D. Dake

“The primary concern in these efforts has been the safety of our patients and the enhancement of their lives,” Clair said. “Providing benefit with reduced need for repeat procedures and recurrent hospitalization is critical in rendering a long-term advantage for these patients, and drug-eluting technology has proven a dramatic enhancement in this regard.”

A presentation by Cook Medical noted that there was no mortality signal with its paclitaxel device (Zilver PTX). As a result of the FDA halting its use, patient care is being negatively affected, Michael D. Dake, MD, senior vice president of health sciences and professor of medical imaging, surgery and medicine at the University of Arizona, said during Cook Medical’s presentation.

A presentation for Bard Medical also discussed how there was no significant increase in the HR for mortality in any analysis of its paclitaxel device (Lutonix 035), nor was there a plausible mechanism for mortality or the evidence of paclitaxel causation.

“Lutonix 035 DCB continues to offer meaningful benefit relative to risk in patients with PAD,” Kenneth Ouriel, MD, president and CEO of Syntactx, said during Bard Medical’s presentation.

Laura Mauri
Laura Mauri

There was no mortality signal related to a paclitaxel-coated balloon (IN.PACT Admiral, Medtronic), Laura Mauri, MD, MSc, vice president of global clinical research and analysis for Medtronic, said during the company’s presentation. Study design and conduct may be an explanation for the transient mortality signal, as there was biased follow-up study attendance in U.S. patients, lower than expected early percutaneous transluminal angioplasty mortality, updated vital status that reduced differences between both arms at all time points and no significant difference in mortality at 5 years, according to the presentation.

“In my opinion, if we restrict availability of paclitaxel DCBs, we would be turning back the clock to an era of less effective treatments and will likely result in more repeat interventions over the long term,” Peter Schneider, MD, vascular surgeon and chief of the vascular therapy division at Kaiser Foundation Hospital, Honolulu, said during Medtronic’s presentation.

Peter Schneider
Peter Schneider

Philips/Spectranetics also found that there was no mortality signal with its drug-coated balloon (Stellarex). The lack of this signal was further reinforced through the crossover treatments performed in the studies, according to the presentation.

“Stellarex has proven both effectiveness and safety for improved benefit/risk for claudicants and high-risk patients,” William A. Gray, MD, FACC, FSCAI, system chief of cardiovascular services for cardiovascular disease at Main Line Health and president of the Lankenau Heart Institute in Wynnewood, Pennsylvania, said during the Philips/Spectranetics presentation.

William A. Gray
William A. Gray

An increased mortality risk was not seen in studies focused on a PES (Eluvia, Boston Scientific), and, in fact, there were proven benefits of treatment with this device that outweighed the risk, according to Robert A. Lookstein, MD, FSIR, FAHA, professor of radiology and surgery and vice chair and chief of the division of interventional radiology at Mount Sinai Medical Center.

“Eluvia DES demonstrates an excellent safety profile and consistent clinical benefit for patients with PAD,” Lookstein said during Boston Scientific’s presentation.

“We know that paclitaxel is indeed associated with increased mortality for the population of intermittent claudication when we analyzed those studies,” Konstantinos Katsanos, MD, PhD, MSc, EBIR, of the department of interventional radiology at Patras University Hospital in Rion, Greece, said during the open public hearing session. “It seems to demonstrate the strong negative interaction with other patient risk factors. What we propose is patient-risk-stratified analysis in order to be able to better understand this signal and to guide medical decision-making.”

The meeting will continue Thursday, when the panel will discuss additional questions, including the paclitaxel dose/mortality relationship, preclinical studies, benefit-risk profile, postmarket studies/surveillance, labeling, changes to study design and other indications. – by Darlene Dobkowski

Reference:

FDA Executive Summary.

Disclosures: Aside from an industry representative employed by Alpha Medical, the members of the Circulatory System Devices Panel report no relevant financial disclosures. Cardiology Today could not confirm relevant financial disclosures at the time of publication. Buckley and Chakraborty are employees of the FDA. Clair reports he is an adviser for Boston Scientific and Medtronic, consultant and a data safety monitoring board member for Bard, and travel and lodging for this FDA meeting have been compensated by Bard. Dake reports he received honoraria from Bard Peripheral Vascular and Cook Medical, consulted for Cook Medical, Novate Medical and W.L. Gore and Associates, and received research funding from Essential Medical, Novate Medical, Shockwave Medical and W.L. Gore and Associates. Ouriel is an employee of Syntactx. Mauri is an employee of Medtronic. Schneider reports he serves on scientific advisory boards for Abbott, Boston Scientific and Medtronic, consults for Cardinal Health, Cardiovascular Systems Inc., Medtronic, Profusa, Silk Road Medical and Surmodics, and serves as chief medical officer for Cagent and Intact Vascular. Gray reports he is an adviser for Boston Scientific. Lookstein reports he is a consultant for Boston Scientific, Cordis and Medrad Interventional/Possis Partnership and serves on a scientific advisory board for Boston Scientific. Katsanos reports no relevant financial disclosures.

Mitchell W. Krucoff
Mitchell W. Krucoff

Members of the Circulatory System Devices Panel of the Medical Devices Advisory Committee of the FDA discussed the potential for increased long-term mortality in patients with peripheral artery disease who were treated with paclitaxel-coated balloons and paclitaxel-eluting stents compared with those treated with other uncoated devices.

Industry and FDA members presented information during the first day of the 2-day meeting. Several associations participated in the open public hearing session to discuss the potential mortality risk with paclitaxel devices. Questions that were addressed during the first day of this meeting include presence of signal, class effect, impact of missing data, subgroup analyses and cause of death.

“The signal is there; that’s true,” Col. Todd E. Rasmussen, MD, USAF MC, professor of surgery and associate dean for clinical research at The Uniformed Services University F. Edward Hebert School of Medicine in Bethesda, Maryland, said during the panel deliberations of the questions. “The statistics are laudable, they’re impressive, but I don’t find them — with regard to magnitude — practically as important to our patients.”

Regarding a class effect, most of the panel members said they felt that the evidence is low.

“The lack of class effect based on the strength of evidence at this point also leaves the door very importantly open to encouraging that each of these devices and these trial results are as complete and high quality as we can encourage the industry to provide them,” Mitchell W. Krucoff, MD, FACC, FAHA, FSCAI, professor of medicine/cardiology at Duke University Medical Center and director of the cardiovascular devices unit and of the eECG Core Laboratories at Duke Clinical Research Institute, said during the panel deliberation. “These trial results are as complete and high quality as we can encourage the industry to provide them. It provides value that maybe this is not a class effect; maybe there is a better mousetrap in the midst here somewhere.”

The lack of data in these studies on paclitaxel devices can make it difficult to interpret, experts said.

“The missing data clearly tempers the interpretation of the analyses,” Joaquin E. Cigarroa, MD, associate chief of clinical cardiology at Oregon Health and Science University in Portland, said during the panel deliberations.

The panel also discussed how the subgroup analyses did not provide a signal as to who would be at the greatest risk.

“My review of everything that was presented today doesn’t find anything striking that would suggest that some subgroups for whatever the magnitude of the signal that we’ve mentioned may be, that some subgroups are at a lower magnitude or no magnitude and others are at greater,” Kevin E. Kip, PhD, FAHA, distinguished health professor at the University of South Florida in Tampa, said during the panel deliberations. “I don’t see anything that looks compelling enough for any one subgroup to make that statement right now.”

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It may be difficult to determine what was the exact cause of death in patients with PAD who were treated with paclitaxel devices, panel members said.

“Cause of death is really hard, but these patients have many different comorbidities to attribute it to one particular cause. It’s even more problematic,” said Karla V. Ballman, PhD, professor of health care policy and research at Weill Cornell Medical College in New York.

This meeting was a result of a meta-analysis published in the Journal of the American Heart Association in December, which found that there was long-term death risk associated with paclitaxel-coated devices in patients with PAD.

The FDA held a meeting in March, in which it announced that its preliminary analysis of the possible link between paclitaxel-coated devices and mortality showed a signal of a link between the two, but there was no evidence that provided definitive proof or was able to pinpoint a cause.

The FDA also released a letter in March, warning that the use of paclitaxel-coated products in the treatment of PAD in the femoropopliteal artery may increase mortality risk and to temporarily halt the use of these devices.

FDA presentation

Daniel G. Clair
Daniel G. Clair

The FDA conducted its own meta-analysis of pivotal randomized controlled trials of paclitaxel devices, which found that there was an increasing trend in the RR of mortality for patients who were treated with paclitaxel-coated devices compared with those who were treated with control devices, Adrijo Chakraborty, PhD, mathematical statistician for the Office of Surveillance and Biometrics at the FDA, said during the agency’s presentation.

Based on a cause-of-death analysis also performed by the FDA, the leading causes of CV death were “other,” HF and sudden death, whereas the leading causes of non-CV death include malignancy, “unknown” and pulmonary, Donna Buckley, MD, MS, interventional radiologist for the Office of Cardiovascular Devices at the FDA, said during the presentation. Patients who received a paclitaxel device had a numerically higher rates of all death types except for trauma and infection.

“There is no clear signal that [paclitaxel]-coated devices are associated with an excess rate of a specific CV or non-CV death subtype,” Buckley said.

In a combined industry presentation by Daniel G. Clair, MD, chair of the department of surgery at the University of South Carolina in Columbia, he said the higher RR for mortality was not demonstrated in all studies. In addition, no mortality signal was seen in studies with 5-year data that underwent a modified as-treated analysis of additional vital status data. The predictors of mortality were those that were expected in patients with PAD and include renal failure, age, CVD and diabetes.

PAGE BREAK
Michael D. Dake
Michael D. Dake

“The primary concern in these efforts has been the safety of our patients and the enhancement of their lives,” Clair said. “Providing benefit with reduced need for repeat procedures and recurrent hospitalization is critical in rendering a long-term advantage for these patients, and drug-eluting technology has proven a dramatic enhancement in this regard.”

A presentation by Cook Medical noted that there was no mortality signal with its paclitaxel device (Zilver PTX). As a result of the FDA halting its use, patient care is being negatively affected, Michael D. Dake, MD, senior vice president of health sciences and professor of medical imaging, surgery and medicine at the University of Arizona, said during Cook Medical’s presentation.

A presentation for Bard Medical also discussed how there was no significant increase in the HR for mortality in any analysis of its paclitaxel device (Lutonix 035), nor was there a plausible mechanism for mortality or the evidence of paclitaxel causation.

“Lutonix 035 DCB continues to offer meaningful benefit relative to risk in patients with PAD,” Kenneth Ouriel, MD, president and CEO of Syntactx, said during Bard Medical’s presentation.

Laura Mauri
Laura Mauri

There was no mortality signal related to a paclitaxel-coated balloon (IN.PACT Admiral, Medtronic), Laura Mauri, MD, MSc, vice president of global clinical research and analysis for Medtronic, said during the company’s presentation. Study design and conduct may be an explanation for the transient mortality signal, as there was biased follow-up study attendance in U.S. patients, lower than expected early percutaneous transluminal angioplasty mortality, updated vital status that reduced differences between both arms at all time points and no significant difference in mortality at 5 years, according to the presentation.

“In my opinion, if we restrict availability of paclitaxel DCBs, we would be turning back the clock to an era of less effective treatments and will likely result in more repeat interventions over the long term,” Peter Schneider, MD, vascular surgeon and chief of the vascular therapy division at Kaiser Foundation Hospital, Honolulu, said during Medtronic’s presentation.

Peter Schneider
Peter Schneider

Philips/Spectranetics also found that there was no mortality signal with its drug-coated balloon (Stellarex). The lack of this signal was further reinforced through the crossover treatments performed in the studies, according to the presentation.

“Stellarex has proven both effectiveness and safety for improved benefit/risk for claudicants and high-risk patients,” William A. Gray, MD, FACC, FSCAI, system chief of cardiovascular services for cardiovascular disease at Main Line Health and president of the Lankenau Heart Institute in Wynnewood, Pennsylvania, said during the Philips/Spectranetics presentation.

PAGE BREAK
William A. Gray
William A. Gray

An increased mortality risk was not seen in studies focused on a PES (Eluvia, Boston Scientific), and, in fact, there were proven benefits of treatment with this device that outweighed the risk, according to Robert A. Lookstein, MD, FSIR, FAHA, professor of radiology and surgery and vice chair and chief of the division of interventional radiology at Mount Sinai Medical Center.

“Eluvia DES demonstrates an excellent safety profile and consistent clinical benefit for patients with PAD,” Lookstein said during Boston Scientific’s presentation.

“We know that paclitaxel is indeed associated with increased mortality for the population of intermittent claudication when we analyzed those studies,” Konstantinos Katsanos, MD, PhD, MSc, EBIR, of the department of interventional radiology at Patras University Hospital in Rion, Greece, said during the open public hearing session. “It seems to demonstrate the strong negative interaction with other patient risk factors. What we propose is patient-risk-stratified analysis in order to be able to better understand this signal and to guide medical decision-making.”

The meeting will continue Thursday, when the panel will discuss additional questions, including the paclitaxel dose/mortality relationship, preclinical studies, benefit-risk profile, postmarket studies/surveillance, labeling, changes to study design and other indications. – by Darlene Dobkowski

Reference:

FDA Executive Summary.

Disclosures: Aside from an industry representative employed by Alpha Medical, the members of the Circulatory System Devices Panel report no relevant financial disclosures. Cardiology Today could not confirm relevant financial disclosures at the time of publication. Buckley and Chakraborty are employees of the FDA. Clair reports he is an adviser for Boston Scientific and Medtronic, consultant and a data safety monitoring board member for Bard, and travel and lodging for this FDA meeting have been compensated by Bard. Dake reports he received honoraria from Bard Peripheral Vascular and Cook Medical, consulted for Cook Medical, Novate Medical and W.L. Gore and Associates, and received research funding from Essential Medical, Novate Medical, Shockwave Medical and W.L. Gore and Associates. Ouriel is an employee of Syntactx. Mauri is an employee of Medtronic. Schneider reports he serves on scientific advisory boards for Abbott, Boston Scientific and Medtronic, consults for Cardinal Health, Cardiovascular Systems Inc., Medtronic, Profusa, Silk Road Medical and Surmodics, and serves as chief medical officer for Cagent and Intact Vascular. Gray reports he is an adviser for Boston Scientific. Lookstein reports he is a consultant for Boston Scientific, Cordis and Medrad Interventional/Possis Partnership and serves on a scientific advisory board for Boston Scientific. Katsanos reports no relevant financial disclosures.