Feature

Pressing Pause on Paclitaxel-Coated Devices

A mortality signal of unknown cause has left clinicians unsure how to best treat PAD.

Months after a meta-analysis linked paclitaxel-coated balloons and stents to increased risk for long-term all-cause mortality in patients with peripheral artery disease, questions remain about use of these devices in practice while physicians and researchers diligently search for answers.

The summary-level meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, EBIR, consultant interventional radiologist 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 an increased mortality risk at 2 years and a nearly twofold greater mortality risk at 5 years (Graphic). The researchers also found the mortality risk rose with higher exposure to paclitaxel. The meta-analysis was published in the Journal of the American Heart Association in December 2018.

Prompted by the analysis by Katsanos and colleagues, the FDA conducted its own analysis. Its preliminary findings, using different data from the JAHA meta-analysis, also uncovered a mortality signal associated with paclitaxel-coated devices. However, the agency has stated that it has not been able to find a “smoking gun” that could explain the cause of the mortality risk.

“We’ve used paclitaxel-eluting stents in the coronaries for a long period of time and have never had a mortality signal. Oncologists, who to treat cancer use 1,000 times the dose of paclitaxel that we use, have also never seen a mortality signal, so we are extremely surprised by these findings,” George L. Adams, MD, MHS, MBA, FACC, FSCAI, associate clinical professor of medicine at the University of North Carolina at Chapel Hill and director of cardiovascular and peripheral vascular research at Rex Hospital, told Cardiology Today’s Intervention.

George L. Adams

Conflicting Data

After the meta-analysis was published, the BASIL-3 and SWEDEPAD 1 and 2 trials were temporarily halted pending further investigation. Then, manufacturers of paclitaxel-coated balloons and stents made their trial data available to researchers for patient-level analyses.

In late January, many of these analyses were presented at the Leipzig Interventional Course, and no presenters reported an elevated mortality risk or a relationship between paclitaxel dose and mortality. Trials analyzed included the IN.PACT series for the IN.PACT Admiral DCB (Medtronic), the RANGER SFA trial of the Ranger DCB (Boston Scientific), the ZILVER PTX trial of the Zilver PTX DES (Cook Medical), various studies of the Stellarex DCB (Spectranetics/Philips) and the LEVANT 2 trial of the Lutonix DCB (BD/Bard).

“What I see is not suggesting to me that there is a safety issue or a mortality issue,” presenter Peter Schneider, MD, vascular surgeon and chief of the vascular therapy division at Kaiser Foundation Hospital, Honolulu, who presented the IN.PACT findings at LINC, told Cardiology Today’s Intervention. “But when an issue of this nature comes up, we need to be secure about whatever conclusion we come to.”

Peter Schneider

A retrospective analysis of a real-world CMS database of patients with PAD published in JAMA Cardiology also did not find a link between exposure to paclitaxel and mortality.

Around this time, the FDA wrote a letter to health care providers advising clinicians to continue monitoring patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents in accordance with the standard of care, and to discuss with patients with PAD the risks and benefits of all available treatment options. In the letter, the agency also announced it launched its own investigation.

In March, the FDA presented its preliminary findings at the Vascular Leaders Forum, which was convened specifically to address the topic. Misti Malone, PhD, chief of the peripheral interventional devices branch of the FDA’s Center for Devices and Radiological Health, said the FDA’s investigation is aimed to confirm the results of the JAHA meta-analysis with all 28 trials included in the meta-analysis and then evaluating all available long-term U.S. and global randomized controlled trial data, using similar and alternative statistical methodologies and assumptions and considering the intention-to-treat and as-treated populations. She noted the FDA does not have access to patient-level data for all 28 trials.

“Following preliminary review of the data and replicating the meta-analysis, we believe that a signal still persists and warrants additional investigation,” Malone said. “We are considering this a potential class effect, while also acknowledging that this may affect other disease states such as [arteriovenous fistulas and critical limb ischemia]. In other words, we are looking at the data from multiple different directions ... to consider what is the possible effect, and how to weigh the benefit and risk.”

‘Gone Back in Time’

On March 15, the FDA issued a follow-up letter warning that paclitaxel-coated products for treatment of PAD in the femoropopliteal artery may increase mortality risk and recommending that alternative treatment options be explored in most patients.

The warning is based on analysis of three trials with 5-year follow-up data in which a 50% increase in mortality risk was observed in those with PAD who were treated with these products, according to the updated letter.

In the aftermath of the warning, Krishna Rocha-Singh, MD, FACC, FAHA, chief scientific officer for the Prairie Heart Institute of Illinois at St. John’s Hospital in Springfield, Illinois, told Cardiology Today’s Intervention he assumed there has been a precipitous drop in use of these devices, which were becoming the “new gold standard” for treatment in this patient population.

“I suspect that use is down anywhere from 40% to 45% and will probably continue to drop,” he said.

Krishna Rocha-Singh

Physicians’ concern about the mortality signal is only one reason for the steep decline, Adams noted.

“The FDA’s letter has put the physician and the health care facility at risk. On the one extreme, some health care systems have completely removed the devices — both drug-eluting stents and drug-coated balloons with paclitaxel — from their shelves. In other cases, even if the devices are available, physicians aren’t using them because of the potential for lawsuits,” he said.

Until they have more definitive answers, physicians have “gone back in time” in terms of treatment, according to Adams (Graphic).

“We’re treating patients similarly to the way we were treating them before we had biologic devices. Or if an antirestenotic agent is needed, we can do direct drug delivery with the Bullfrog Micro-Infusion Device (Mercator MedSystems), in which we directly deliver dexamethasone to prevent restenosis,” he said.

Physicians have also focused more on preventing recoil by preparing the vessel as well as possible.

“We’ve resorted back to the best angioplasty techniques in terms of steadily increasing pressure on the lesion as well as leaving the balloon up for a prolonged period of time. We’ve also used focal-force balloons to make sure we’ve adequately prepped the vessel, and then lastly atherectomy to adequately cause microfissures to prevent that recoil,” Adams said.

For the future, he added, some companies have been considering whether to move forward with new devices that have paclitaxel as their biologic and instead pivot toward a limus-based agent rather than a taxel-based agent.

Weighing Benefits vs. Risks

For now, though concerns remain about the mortality signal, the general belief is that there are patients who would benefit from treatment with paclitaxel-coated devices, albeit with significant caveats, experts told Cardiology Today’s Intervention.

“If somebody really needs a revascularization for limb salvage — if they’re going to lose their leg without revascularization — and if the physician managing the patient feels that surgery carries a potential risk that is too high to accept — and if they believe that the patient needs durable patency, that might be a situation where you would consider use of a paclitaxel-coated device. But, I’m drawing lots of narrow bands around that clinical scenario,” Michael R. Jaff, DO, FACC, FSCAI, president of Newton-Wellesley Hospital, professor of medicine at Harvard Medical School and a Cardiology Today’s Intervention Editorial Board Member, said in an interview.

It boils down to carefully considering risks vs. benefits, according to Rocha-Singh.

Michael R. Jaff

“As physicians, we weigh the risks and benefits of treatment on a daily basis, but in this case, it’s very incremental. We look at the risk first and then measure the benefit, which is going to be important because it allows the physician to better elucidate to the patient what the risk-benefit ratio actually is. And right now, we have to understand the risks a little bit better,” he said.

Important Research

The controversy over paclitaxel-coated devices has opened the door to many questions. For instance, the meta-analysis by Katsanos and colleagues is not so definitive that the entire medical community is swayed by the findings.

“I have concerns that the data may be somewhat misleading in that the analysis didn’t look at patient-level data,” Adams said. “We need to look at the patient-level data in terms of mortality and try to compare apples to apples. In other words, we need to look at truly comparable patients, such as those with similar Rutherford classes, similar demographics in terms of diabetes and disease location, for example, such that we can put patients in similar groups to see if they have similar or different mortality risk, depending on which study arm they were in.”

Further, these analyses may not tell the whole story, Jaff noted.

“I’m personally eager to determine if the findings of the JAHA analysis are statistically relevant and also clinically relevant,” he said.

Importantly, researchers also need to search beyond the increased risk for long-term mortality, according to Rocha-Singh.

“We have to look for a signal with causality and determine if that causality is actually due to a drug effect as it relates to the total amount of drug delivered, the area of vessel wall to which it was delivered, the inflation time, among other factors,” he said.

At the Vascular Leaders Forum, Rocha-Singh announced that VIVA Physicians will conduct and fund a meta-analysis using independent patient data in hopes of providing some answers.

Broad Ramifications

In addition to identifying further areas of research, a light has been shone on the way clinical trials are conducted.

“We now understand that randomized controlled trials that we hold up to be the gold standard in theory may not, in their execution, be ideal. The loss to follow-up issue is a problem and we could improve the Clinical Events Committee adjudication process. Also, we’re going to see that adjudicated registries that better reflect real-world use of devices are critical to understanding safety signals,” Rocha-Singh said.

Jaff agreed, noting that he thinks there will be some changes in the clinical trial process as well.

“There is going to be a greater degree of rigor adopted by the FDA around guideline-directed medical therapy in these trials. I also think loss to follow-up rates in vascular device trials is going to receive a lot of attention and there will be a call to arms to implement strategies to minimize loss to follow-up rates, which in this current situation could have potentially had a real impact,” he said.

Finally, Adams said he hopes that this setback does not dampen the field’s enthusiasm for investigating new devices and therapies for patients with PAD.

“One paper has been published regarding the signal, and it’s hard not to react to the FDA’s response, but at the end of the day, we as physicians need to remain level-headed. Until there are more data, we can’t give a definitive opinion on these devices. We are all hopeful that there will be a treatment strategy for these patients at risk for restenosis because, currently, if these biologics don’t work or there is a mortality signal, then we lose that option. My hope is that this won’t stymie future development and progress in the United States in terms of coming up with a solution to treat restenotic patients,” he told Cardiology Today’s Intervention.

The FDA Circulatory System Devices Panel is scheduled to meet on June 19 and 20 to discuss the data and make recommendations regarding the use of paclitaxel-coated devices, adjustments to trial designs, informed consent labeling and/or postmarket data collection. – by Melissa Foster, with additional reporting by Erik Swain

Disclosures: Adams reports he is a consultant for Cook, Boston Scientific and Medtronic. Jaff reports he is a noncompensated adviser to Abbott Vascular and Boston Scientific; he is a compensated adviser to Biotronik, Medtronic, Philips, Sanofi and Vactronix; and he is an equity investor in Embolitech, Gemini, PQ Bypass and Vascular Therapies. Katsanos reports he receives personal fees from Boston Scientific and personal fees and grants from Medtronic. Rocha-Singh reports he is a consultant for 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.

Months after a meta-analysis linked paclitaxel-coated balloons and stents to increased risk for long-term all-cause mortality in patients with peripheral artery disease, questions remain about use of these devices in practice while physicians and researchers diligently search for answers.

The summary-level meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, EBIR, consultant interventional radiologist 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 an increased mortality risk at 2 years and a nearly twofold greater mortality risk at 5 years (Graphic). The researchers also found the mortality risk rose with higher exposure to paclitaxel. The meta-analysis was published in the Journal of the American Heart Association in December 2018.

Prompted by the analysis by Katsanos and colleagues, the FDA conducted its own analysis. Its preliminary findings, using different data from the JAHA meta-analysis, also uncovered a mortality signal associated with paclitaxel-coated devices. However, the agency has stated that it has not been able to find a “smoking gun” that could explain the cause of the mortality risk.

“We’ve used paclitaxel-eluting stents in the coronaries for a long period of time and have never had a mortality signal. Oncologists, who to treat cancer use 1,000 times the dose of paclitaxel that we use, have also never seen a mortality signal, so we are extremely surprised by these findings,” George L. Adams, MD, MHS, MBA, FACC, FSCAI, associate clinical professor of medicine at the University of North Carolina at Chapel Hill and director of cardiovascular and peripheral vascular research at Rex Hospital, told Cardiology Today’s Intervention.

George L. Adams

Conflicting Data

After the meta-analysis was published, the BASIL-3 and SWEDEPAD 1 and 2 trials were temporarily halted pending further investigation. Then, manufacturers of paclitaxel-coated balloons and stents made their trial data available to researchers for patient-level analyses.

In late January, many of these analyses were presented at the Leipzig Interventional Course, and no presenters reported an elevated mortality risk or a relationship between paclitaxel dose and mortality. Trials analyzed included the IN.PACT series for the IN.PACT Admiral DCB (Medtronic), the RANGER SFA trial of the Ranger DCB (Boston Scientific), the ZILVER PTX trial of the Zilver PTX DES (Cook Medical), various studies of the Stellarex DCB (Spectranetics/Philips) and the LEVANT 2 trial of the Lutonix DCB (BD/Bard).

PAGE BREAK

“What I see is not suggesting to me that there is a safety issue or a mortality issue,” presenter Peter Schneider, MD, vascular surgeon and chief of the vascular therapy division at Kaiser Foundation Hospital, Honolulu, who presented the IN.PACT findings at LINC, told Cardiology Today’s Intervention. “But when an issue of this nature comes up, we need to be secure about whatever conclusion we come to.”

Peter Schneider

A retrospective analysis of a real-world CMS database of patients with PAD published in JAMA Cardiology also did not find a link between exposure to paclitaxel and mortality.

Around this time, the FDA wrote a letter to health care providers advising clinicians to continue monitoring patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents in accordance with the standard of care, and to discuss with patients with PAD the risks and benefits of all available treatment options. In the letter, the agency also announced it launched its own investigation.

In March, the FDA presented its preliminary findings at the Vascular Leaders Forum, which was convened specifically to address the topic. Misti Malone, PhD, chief of the peripheral interventional devices branch of the FDA’s Center for Devices and Radiological Health, said the FDA’s investigation is aimed to confirm the results of the JAHA meta-analysis with all 28 trials included in the meta-analysis and then evaluating all available long-term U.S. and global randomized controlled trial data, using similar and alternative statistical methodologies and assumptions and considering the intention-to-treat and as-treated populations. She noted the FDA does not have access to patient-level data for all 28 trials.

“Following preliminary review of the data and replicating the meta-analysis, we believe that a signal still persists and warrants additional investigation,” Malone said. “We are considering this a potential class effect, while also acknowledging that this may affect other disease states such as [arteriovenous fistulas and critical limb ischemia]. In other words, we are looking at the data from multiple different directions ... to consider what is the possible effect, and how to weigh the benefit and risk.”

‘Gone Back in Time’

On March 15, the FDA issued a follow-up letter warning that paclitaxel-coated products for treatment of PAD in the femoropopliteal artery may increase mortality risk and recommending that alternative treatment options be explored in most patients.

The warning is based on analysis of three trials with 5-year follow-up data in which a 50% increase in mortality risk was observed in those with PAD who were treated with these products, according to the updated letter.

PAGE BREAK

In the aftermath of the warning, Krishna Rocha-Singh, MD, FACC, FAHA, chief scientific officer for the Prairie Heart Institute of Illinois at St. John’s Hospital in Springfield, Illinois, told Cardiology Today’s Intervention he assumed there has been a precipitous drop in use of these devices, which were becoming the “new gold standard” for treatment in this patient population.

“I suspect that use is down anywhere from 40% to 45% and will probably continue to drop,” he said.

Krishna Rocha-Singh

Physicians’ concern about the mortality signal is only one reason for the steep decline, Adams noted.

“The FDA’s letter has put the physician and the health care facility at risk. On the one extreme, some health care systems have completely removed the devices — both drug-eluting stents and drug-coated balloons with paclitaxel — from their shelves. In other cases, even if the devices are available, physicians aren’t using them because of the potential for lawsuits,” he said.

Until they have more definitive answers, physicians have “gone back in time” in terms of treatment, according to Adams (Graphic).

“We’re treating patients similarly to the way we were treating them before we had biologic devices. Or if an antirestenotic agent is needed, we can do direct drug delivery with the Bullfrog Micro-Infusion Device (Mercator MedSystems), in which we directly deliver dexamethasone to prevent restenosis,” he said.

Physicians have also focused more on preventing recoil by preparing the vessel as well as possible.

“We’ve resorted back to the best angioplasty techniques in terms of steadily increasing pressure on the lesion as well as leaving the balloon up for a prolonged period of time. We’ve also used focal-force balloons to make sure we’ve adequately prepped the vessel, and then lastly atherectomy to adequately cause microfissures to prevent that recoil,” Adams said.

For the future, he added, some companies have been considering whether to move forward with new devices that have paclitaxel as their biologic and instead pivot toward a limus-based agent rather than a taxel-based agent.

Weighing Benefits vs. Risks

For now, though concerns remain about the mortality signal, the general belief is that there are patients who would benefit from treatment with paclitaxel-coated devices, albeit with significant caveats, experts told Cardiology Today’s Intervention.

PAGE BREAK

“If somebody really needs a revascularization for limb salvage — if they’re going to lose their leg without revascularization — and if the physician managing the patient feels that surgery carries a potential risk that is too high to accept — and if they believe that the patient needs durable patency, that might be a situation where you would consider use of a paclitaxel-coated device. But, I’m drawing lots of narrow bands around that clinical scenario,” Michael R. Jaff, DO, FACC, FSCAI, president of Newton-Wellesley Hospital, professor of medicine at Harvard Medical School and a Cardiology Today’s Intervention Editorial Board Member, said in an interview.

It boils down to carefully considering risks vs. benefits, according to Rocha-Singh.

Michael R. Jaff

“As physicians, we weigh the risks and benefits of treatment on a daily basis, but in this case, it’s very incremental. We look at the risk first and then measure the benefit, which is going to be important because it allows the physician to better elucidate to the patient what the risk-benefit ratio actually is. And right now, we have to understand the risks a little bit better,” he said.

Important Research

The controversy over paclitaxel-coated devices has opened the door to many questions. For instance, the meta-analysis by Katsanos and colleagues is not so definitive that the entire medical community is swayed by the findings.

“I have concerns that the data may be somewhat misleading in that the analysis didn’t look at patient-level data,” Adams said. “We need to look at the patient-level data in terms of mortality and try to compare apples to apples. In other words, we need to look at truly comparable patients, such as those with similar Rutherford classes, similar demographics in terms of diabetes and disease location, for example, such that we can put patients in similar groups to see if they have similar or different mortality risk, depending on which study arm they were in.”

Further, these analyses may not tell the whole story, Jaff noted.

“I’m personally eager to determine if the findings of the JAHA analysis are statistically relevant and also clinically relevant,” he said.

Importantly, researchers also need to search beyond the increased risk for long-term mortality, according to Rocha-Singh.

“We have to look for a signal with causality and determine if that causality is actually due to a drug effect as it relates to the total amount of drug delivered, the area of vessel wall to which it was delivered, the inflation time, among other factors,” he said.

At the Vascular Leaders Forum, Rocha-Singh announced that VIVA Physicians will conduct and fund a meta-analysis using independent patient data in hopes of providing some answers.

Broad Ramifications

In addition to identifying further areas of research, a light has been shone on the way clinical trials are conducted.

“We now understand that randomized controlled trials that we hold up to be the gold standard in theory may not, in their execution, be ideal. The loss to follow-up issue is a problem and we could improve the Clinical Events Committee adjudication process. Also, we’re going to see that adjudicated registries that better reflect real-world use of devices are critical to understanding safety signals,” Rocha-Singh said.

PAGE BREAK

Jaff agreed, noting that he thinks there will be some changes in the clinical trial process as well.

“There is going to be a greater degree of rigor adopted by the FDA around guideline-directed medical therapy in these trials. I also think loss to follow-up rates in vascular device trials is going to receive a lot of attention and there will be a call to arms to implement strategies to minimize loss to follow-up rates, which in this current situation could have potentially had a real impact,” he said.

Finally, Adams said he hopes that this setback does not dampen the field’s enthusiasm for investigating new devices and therapies for patients with PAD.

“One paper has been published regarding the signal, and it’s hard not to react to the FDA’s response, but at the end of the day, we as physicians need to remain level-headed. Until there are more data, we can’t give a definitive opinion on these devices. We are all hopeful that there will be a treatment strategy for these patients at risk for restenosis because, currently, if these biologics don’t work or there is a mortality signal, then we lose that option. My hope is that this won’t stymie future development and progress in the United States in terms of coming up with a solution to treat restenotic patients,” he told Cardiology Today’s Intervention.

The FDA Circulatory System Devices Panel is scheduled to meet on June 19 and 20 to discuss the data and make recommendations regarding the use of paclitaxel-coated devices, adjustments to trial designs, informed consent labeling and/or postmarket data collection. – by Melissa Foster, with additional reporting by Erik Swain

Disclosures: Adams reports he is a consultant for Cook, Boston Scientific and Medtronic. Jaff reports he is a noncompensated adviser to Abbott Vascular and Boston Scientific; he is a compensated adviser to Biotronik, Medtronic, Philips, Sanofi and Vactronix; and he is an equity investor in Embolitech, Gemini, PQ Bypass and Vascular Therapies. Katsanos reports he receives personal fees from Boston Scientific and personal fees and grants from Medtronic. Rocha-Singh reports he is a consultant for 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.

PAGE BREAK