Meeting News

ISET town hall calls attention to paclitaxel-coated devices

Thomas Zeller
Thomas Zeller

HOLLYWOOD, Fla. — Increased attention on the mortality risk associated with paclitaxel-coated devices used in patients with peripheral artery disease has prompted much debate in the vascular intervention community. Leaders in the area took the stage during a town hall opening session at the International Symposium on Endovascular Therapy to discuss recent data and what this means for current standards of practice and further investigation.

As Cardiology Today’s Intervention previously reported, a summary-level meta-analysis published in the Journal of the American Heart Association in December prompted two ongoing trials of paclitaxel-coated devices to pause pending further investigation and the FDA to announce it was launching its own investigation. At the Leipzig Interventional Course in January, patient-level data from studies of various paclitaxel-coated balloons and paclitaxel-eluting stents were presented showing no long-term elevated mortality risk associated with any of the devices.

Those speaking at the ISET town hall said the recent data raise questions that require further investigation.

“There is no reason to panic,” Thomas Zeller, MD, PhD, head of the department of angiology at the University Heart Center Freiburg-Bad Krozingen in Germany, said during a presentation.

In a poll of the audience at the end of the town hall, 80% of attendees said their use of paclitaxel-coated devices would not change, but 65% said they would discuss the possible mortality risk with their patients.

Statistical methods

The JAHA meta-analysis included 28 randomized controlled trials covering 4,663 patients (89% with claudication) in which patients were assigned to treatment with a paclitaxel-coated balloon or stent or to a control arm. There was no difference in all-cause mortality at 1 year, but in a 2-year analysis of 12 trials with 2,316 patients, the paclitaxel arm had elevated risk for all-cause mortality, and in a 5-year analysis of three trials with 863 patients, the risk difference widened. In a meta-regression analysis, researchers found a relationship between paclitaxel exposure and absolute risk for death (0.4% excess risk per paclitaxel milligram-year).

Jihad A. Mustapha
Jihad A Mustapha

In an analysis of the JAHA meta-analysis, Jihad A. Mustapha, MD, FACC, FSCAI, CEO of Advanced Cardiac and Vascular Amputation Prevention Centers in Grand Rapids, Michigan, noted that “metrics such as number of withdrawals, number of patients remaining at risk and timing of deaths were not considered in these calculations. Mortality rates drawn from time-to-event data are preferred in meta-analyses.”

He noted that not using time-to-event data led to reporting of very different 5-year mortality rates of patients treated with the Zilver PTX DES (Cook Medical) vs. controls compared with the original study.

“It therefore seems plausible that similar discrepancies between crude vs. time-to-event mortality rates may exist among other studies included in the meta-analysis, particularly those with longer follow-up periods during which higher rates of patient withdrawal might be expected,” Mustapha said.

It may be worth re-analyzing the meta-analysis findings using time-to-event data to see if the conclusion remains, Mustapha said.

“Additionally, potential mechanisms by which paclitaxel might contribute to excess mortality should be explored, given that the causes of late deaths were mostly unreported or deemed unrelated to the device or procedure,” he said.

‘Warrants further investigation’

In his presentation, Zeller noted several flaws of the meta-analysis, including that DES and DCB were analyzed together despite “substantial differences across device features,” that there were no patient-level data and that the primary outcome was all-cause mortality and there was no distinction of deaths adjudicated by clinical events committees as not related to the device or procedure.

He noted that an analysis of DCBs compared with plain balloon angioplasty angioplasty in a population of more than 82,000 patients documented in CMS inpatient and outpatient files in 2015 and 2016 using Inverse Probability of Treatment Weighting came to a different conclusion, finding that at 1 year, DCBs were associated with lower rates of all-cause mortality, all-cause hospitalization and major amputation. Inverse Probability of Treatment Weighting means that characteristics between patient groups are similar, with the only difference being the treatment itself, Zeller said.

Also of concern, Zeller said, is that the JAHA meta-analysis related 5-year mortality to the entire patient population instead of the number of patients actually at risk at 5 years.

“With numbers, you can prove everything depending on how you apply the method of analysis,” he said.

What is known, he said, is that “paclitaxel is a toxic drug that results in cell death, local vessel wall damage is noted but not understood in detail and systemic toxicity with low-dose paclitaxel from DCB or DES seems unlikely but warrants further investigation.”

Discussion continues

Michael R. Jaff
Michael R. Jaff

Cardiology Today’s Intervention Editorial Board Member Michael R. Jaff, DO, MSVM, FSCAI, FACP, FACC, president of Newton-Wellesley Hospital and professor of medicine at Harvard Medical School, said the JAHA meta-analysis was “surprising” because no prior studies, including meta-analyses, had detected a mortality signal associated with paclitaxel-coated devices.

“I just don’t know if this is real or not, but we must take this seriously,” Jaff said during a presentation. “I have no doubt that each commercial sponsor will publish its patient-level results. There is an effort to merge all of the data into one independent database to answer the question.”

However, he said, he has two criticisms.

“First, this meta-analysis was leaked to media outlets weeks before publication,” he said. “I find that completely unacceptable. It led to all sorts of speculation and frenzy long before the paper actually hit the press. Second, as the article states, ‘further investigations are urgently warranted.’ In my opinion, the word ‘urgently’ was alarmist and added to the frenzy which exists today. I don’t think there was enough here to call the situation ‘urgent’. It has led to reactions that could potentially hurt the field.” – by Erik Swain

References:

Jaff MR.

Mustapha JA.

Zeller T. Townhall on paclitaxel: What should practitioners do in light of recent information released and is there enough information to alter current standards of practice? All presented at: the International Symposium on Endovascular Therapy (ISET); Jan. 27-30, 2019; Hollywood, Fla.

Disclosures: Jaff reports he is a paid consultant to American Orthotics and Prosthetics Association, Medtronic Vascular, Philips/Volcano, Silk Road Medical, Vactronix, and Venarum; is an equity shareholder in Embolitech, Gemini, Janacare, MC10, Micell, PQ Bypass, Primacea, Sano V and Vascular Therapies; and is a non-compensated advisor to Abbott Vascular and Boston Scientific. Mustapha reports he has financial ties with 480 Biomedical, BD/Bard, Bioendothelium, Boston Scientific, Cagent Vascular, Cardio Flow, Cardiovascular Systems Inc., Medtronic, Micromedical Solutions, Philips, PQ Bypass, Reflow Medical and Terumo. Zeller reports he has financial ties with Abbott Vascular, Biotronik, Boston Scientific, Cook Medical, Medtronic, Philips/Spectranetics, QT Medical, Shockwave Medical, Terumo, TriReme, Veryan and W.L. Gore and Associates.

Thomas Zeller
Thomas Zeller

HOLLYWOOD, Fla. — Increased attention on the mortality risk associated with paclitaxel-coated devices used in patients with peripheral artery disease has prompted much debate in the vascular intervention community. Leaders in the area took the stage during a town hall opening session at the International Symposium on Endovascular Therapy to discuss recent data and what this means for current standards of practice and further investigation.

As Cardiology Today’s Intervention previously reported, a summary-level meta-analysis published in the Journal of the American Heart Association in December prompted two ongoing trials of paclitaxel-coated devices to pause pending further investigation and the FDA to announce it was launching its own investigation. At the Leipzig Interventional Course in January, patient-level data from studies of various paclitaxel-coated balloons and paclitaxel-eluting stents were presented showing no long-term elevated mortality risk associated with any of the devices.

Those speaking at the ISET town hall said the recent data raise questions that require further investigation.

“There is no reason to panic,” Thomas Zeller, MD, PhD, head of the department of angiology at the University Heart Center Freiburg-Bad Krozingen in Germany, said during a presentation.

In a poll of the audience at the end of the town hall, 80% of attendees said their use of paclitaxel-coated devices would not change, but 65% said they would discuss the possible mortality risk with their patients.

Statistical methods

The JAHA meta-analysis included 28 randomized controlled trials covering 4,663 patients (89% with claudication) in which patients were assigned to treatment with a paclitaxel-coated balloon or stent or to a control arm. There was no difference in all-cause mortality at 1 year, but in a 2-year analysis of 12 trials with 2,316 patients, the paclitaxel arm had elevated risk for all-cause mortality, and in a 5-year analysis of three trials with 863 patients, the risk difference widened. In a meta-regression analysis, researchers found a relationship between paclitaxel exposure and absolute risk for death (0.4% excess risk per paclitaxel milligram-year).

Jihad A. Mustapha
Jihad A Mustapha

In an analysis of the JAHA meta-analysis, Jihad A. Mustapha, MD, FACC, FSCAI, CEO of Advanced Cardiac and Vascular Amputation Prevention Centers in Grand Rapids, Michigan, noted that “metrics such as number of withdrawals, number of patients remaining at risk and timing of deaths were not considered in these calculations. Mortality rates drawn from time-to-event data are preferred in meta-analyses.”

He noted that not using time-to-event data led to reporting of very different 5-year mortality rates of patients treated with the Zilver PTX DES (Cook Medical) vs. controls compared with the original study.

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“It therefore seems plausible that similar discrepancies between crude vs. time-to-event mortality rates may exist among other studies included in the meta-analysis, particularly those with longer follow-up periods during which higher rates of patient withdrawal might be expected,” Mustapha said.

It may be worth re-analyzing the meta-analysis findings using time-to-event data to see if the conclusion remains, Mustapha said.

“Additionally, potential mechanisms by which paclitaxel might contribute to excess mortality should be explored, given that the causes of late deaths were mostly unreported or deemed unrelated to the device or procedure,” he said.

‘Warrants further investigation’

In his presentation, Zeller noted several flaws of the meta-analysis, including that DES and DCB were analyzed together despite “substantial differences across device features,” that there were no patient-level data and that the primary outcome was all-cause mortality and there was no distinction of deaths adjudicated by clinical events committees as not related to the device or procedure.

He noted that an analysis of DCBs compared with plain balloon angioplasty angioplasty in a population of more than 82,000 patients documented in CMS inpatient and outpatient files in 2015 and 2016 using Inverse Probability of Treatment Weighting came to a different conclusion, finding that at 1 year, DCBs were associated with lower rates of all-cause mortality, all-cause hospitalization and major amputation. Inverse Probability of Treatment Weighting means that characteristics between patient groups are similar, with the only difference being the treatment itself, Zeller said.

Also of concern, Zeller said, is that the JAHA meta-analysis related 5-year mortality to the entire patient population instead of the number of patients actually at risk at 5 years.

“With numbers, you can prove everything depending on how you apply the method of analysis,” he said.

What is known, he said, is that “paclitaxel is a toxic drug that results in cell death, local vessel wall damage is noted but not understood in detail and systemic toxicity with low-dose paclitaxel from DCB or DES seems unlikely but warrants further investigation.”

Discussion continues

Michael R. Jaff
Michael R. Jaff

Cardiology Today’s Intervention Editorial Board Member Michael R. Jaff, DO, MSVM, FSCAI, FACP, FACC, president of Newton-Wellesley Hospital and professor of medicine at Harvard Medical School, said the JAHA meta-analysis was “surprising” because no prior studies, including meta-analyses, had detected a mortality signal associated with paclitaxel-coated devices.

“I just don’t know if this is real or not, but we must take this seriously,” Jaff said during a presentation. “I have no doubt that each commercial sponsor will publish its patient-level results. There is an effort to merge all of the data into one independent database to answer the question.”

However, he said, he has two criticisms.

“First, this meta-analysis was leaked to media outlets weeks before publication,” he said. “I find that completely unacceptable. It led to all sorts of speculation and frenzy long before the paper actually hit the press. Second, as the article states, ‘further investigations are urgently warranted.’ In my opinion, the word ‘urgently’ was alarmist and added to the frenzy which exists today. I don’t think there was enough here to call the situation ‘urgent’. It has led to reactions that could potentially hurt the field.” – by Erik Swain

References:

Jaff MR.

Mustapha JA.

Zeller T. Townhall on paclitaxel: What should practitioners do in light of recent information released and is there enough information to alter current standards of practice? All presented at: the International Symposium on Endovascular Therapy (ISET); Jan. 27-30, 2019; Hollywood, Fla.

Disclosures: Jaff reports he is a paid consultant to American Orthotics and Prosthetics Association, Medtronic Vascular, Philips/Volcano, Silk Road Medical, Vactronix, and Venarum; is an equity shareholder in Embolitech, Gemini, Janacare, MC10, Micell, PQ Bypass, Primacea, Sano V and Vascular Therapies; and is a non-compensated advisor to Abbott Vascular and Boston Scientific. Mustapha reports he has financial ties with 480 Biomedical, BD/Bard, Bioendothelium, Boston Scientific, Cagent Vascular, Cardio Flow, Cardiovascular Systems Inc., Medtronic, Micromedical Solutions, Philips, PQ Bypass, Reflow Medical and Terumo. Zeller reports he has financial ties with Abbott Vascular, Biotronik, Boston Scientific, Cook Medical, Medtronic, Philips/Spectranetics, QT Medical, Shockwave Medical, Terumo, TriReme, Veryan and W.L. Gore and Associates.

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