Ted Bosworth

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

In response to a randomized trial that associated elective revascularization for ischemia with an increase in noncardiac mortality versus medical therapy alone, a meta-analysis with a far larger dataset challenges this assertion, suggesting the initial conclusion is due to a type 1 error. 

With data from nearly 17,000 patients in 18 randomized trials, the meta-analysis showed no signal for increased noncardiac mortality in the revascularization group overall or across several sensitivity analyses, reports William Wijns, MD, PhD, professor of interventional cardiology, National University of Ireland, Galway.

The larger pool of data from the meta-analysis was considered compelling by several experts at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, where it was presented.

“I think these data will close once and forever this controversy,” said Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy). 

Evidence for an unexpected increased risk of noncardiac mortality was drawn from the ISCHEMIA-EXTEND study, which was published earlier this year. Numerous prior studies comparing percutaneous intervention (PCI) to medical therapy for relief of ischemia had shown no such safety signal. 

The ISCHEMIA-EXTEND study provided long-term follow up of patients enrolled in ISCHEMIA, a study that randomized patients with stable coronary disease and moderate or severe ischemia to PCI or a conservative approach. After 3.2 years of follow up, there was no reduction in risk of cardiovascular events or all-cause death. While this lack of benefit was a disappointing result from the perspective of interventional cardiology, there was also no increase in these risks. 

In ISCHEMIA-EXTEND, the more than 5,000 patients originally randomized were followed for an additional 2.5 years (total 5.7 years). During this extended period, the estimated 7-year risk of cardiovascular mortality was 22% lower in the group randomized to PCI (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96) but the noncardiac mortality was increased by 44% (HR, 1.44; 95% CI, 1.08-1.91). Because of the counterbalancing effects on survival, all-cause mortality was similar in the two groups.

The newly completed meta-analysis was undertaken to address this surprising result not least because the increased rates of noncardiac death did not have a plausible explanation, according to Dr. Wijns. 

When the patients from the 18 randomized trials were compared, noncardiac death occurred in 4.68% of the 8,665 patients assigned to elective revascularization and in 4.17% of the 8,243 patients assigned to medical therapy alone at an average follow up of 5.7 years. 

This difference was not significant overall (HR, 1.09; 95% CI, 0.94-1.26; P = .26) or after sensitivity analyses. For example, there was no difference (P = .52) between an invasive or conservative approach after controlling for length of follow up. 

There was also no heterogeneity (I2 = 0%) among the studies when ISCHEMIA-EXTEND was excluded.
 

Absence of negative effect ‘is confirmed’

On the basis of a Bayesian meta-analysis designed to account for residual uncertainty (relative risk, 1.08, 95% CI, 0.90-1.30) and the consistency of results among all studies with the exception of ISCHEMIA-EXTEND (RR, 1.0; 95% CI, 0.84-1;18; P = .7), “the absence of a negative effect of revascularization on noncardiac death was confirmed,” Dr. Wijns reported. 

Based on the preponderance of evidence assembled in this meta-analysis, the “noncardiac mortality excess risk observed following revascularization relative to medical therapy was confined to a single large trial and is likely due to a type 1 error,” Dr. Wijns reported. He noted that this study is “the first large-scale meta-analysis study designed to systematically evaluate potential differences in noncardiac mortality between treatment strategies for chronic coronary syndromes.” 

Eliano P. Navarese, MD, PhD, an associate professor of interventional cardiology at Nicolaus Copernicus University, Bydgoszcz, Poland, was the lead author of this study and Dr. Wijns was a coinvestigator. The study was published simultaneously in the Journal of the American College of Cardiology at the time of the EuroPCR meeting.

In the late-breaking session where these data were presented, there was a general consensus among invited panelists that the data are convincing. For example, Michael Joner, MD, PhD, director of early clinical trials, German Heart Centre, Munich, agreed that these data “resolve the issue.” 

Bernard de Bruyne, MD, PhD, an interventional cardiologist associated with the Cardiovascular Center Aalst, Kraainem, Belgium, also agreed that these data argue convincingly against the concern raised by publication of ISCHEMIA-EXTEND, but he added that this controversy has raised an important issue.

“We should always be reporting all-cause mortality, not just cardiovascular mortality, in our clinical trials,” he said, emphasizing that extending all-cause survival, not just preventing cardiovascular-related events, should be recognized as the goal of invasive strategies.

In an editorial accompanying the publication, Dr. Harvey D. White, MD, Te Whatu Ora-Health New Zealand, Auckland, writes similarly that the current findings, “alert us to the importance of adjudicating causes of death in clinical trials. 

“The current trial-level meta-analysis may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death,” Dr. White notes. He feels the signal of increased noncardiac or noncardiovascular death in ISCHEMIA EXTEND and the REVIVED trials is something “that we should pay attention to and explore the possibility that increased radiation doses with PCI may cause increased rates of cancer.” 

Further study, including longer follow-up, other datasets, and quality of life data including cognitive function and “patient-focused outcomes such as day alive out of hospital,” is needed, he concludes. 

Dr. Navarese has received research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron. Dr. Wijns reports financial relationships with Argonauts, Corrib Core Laboratory, and Rede Optimus Research. Dr. Capodanno reports financial relationships with Amgen, Daiichi Sankyo, and Sanofi. Dr. de Bruyne and Dr. Joner report financial relationships with multiple pharmaceutical and device manufacturers. Prof. White, as the John Neutze scholar, is supported by the Green Lane Research and Educational Fund. Prof. White has received grant support paid to the institution and fees for serving on steering committees of multiple trials sponsored by various companies.
 

In response to a randomized trial that associated elective revascularization for ischemia with an increase in noncardiac mortality versus medical therapy alone, a meta-analysis with a far larger dataset challenges this assertion, suggesting the initial conclusion is due to a type 1 error. 

With data from nearly 17,000 patients in 18 randomized trials, the meta-analysis showed no signal for increased noncardiac mortality in the revascularization group overall or across several sensitivity analyses, reports William Wijns, MD, PhD, professor of interventional cardiology, National University of Ireland, Galway.

The larger pool of data from the meta-analysis was considered compelling by several experts at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, where it was presented.

“I think these data will close once and forever this controversy,” said Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy). 

Evidence for an unexpected increased risk of noncardiac mortality was drawn from the ISCHEMIA-EXTEND study, which was published earlier this year. Numerous prior studies comparing percutaneous intervention (PCI) to medical therapy for relief of ischemia had shown no such safety signal. 

The ISCHEMIA-EXTEND study provided long-term follow up of patients enrolled in ISCHEMIA, a study that randomized patients with stable coronary disease and moderate or severe ischemia to PCI or a conservative approach. After 3.2 years of follow up, there was no reduction in risk of cardiovascular events or all-cause death. While this lack of benefit was a disappointing result from the perspective of interventional cardiology, there was also no increase in these risks. 

In ISCHEMIA-EXTEND, the more than 5,000 patients originally randomized were followed for an additional 2.5 years (total 5.7 years). During this extended period, the estimated 7-year risk of cardiovascular mortality was 22% lower in the group randomized to PCI (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96) but the noncardiac mortality was increased by 44% (HR, 1.44; 95% CI, 1.08-1.91). Because of the counterbalancing effects on survival, all-cause mortality was similar in the two groups.

The newly completed meta-analysis was undertaken to address this surprising result not least because the increased rates of noncardiac death did not have a plausible explanation, according to Dr. Wijns. 

When the patients from the 18 randomized trials were compared, noncardiac death occurred in 4.68% of the 8,665 patients assigned to elective revascularization and in 4.17% of the 8,243 patients assigned to medical therapy alone at an average follow up of 5.7 years. 

This difference was not significant overall (HR, 1.09; 95% CI, 0.94-1.26; P = .26) or after sensitivity analyses. For example, there was no difference (P = .52) between an invasive or conservative approach after controlling for length of follow up. 

There was also no heterogeneity (I2 = 0%) among the studies when ISCHEMIA-EXTEND was excluded.
 

Absence of negative effect ‘is confirmed’

On the basis of a Bayesian meta-analysis designed to account for residual uncertainty (relative risk, 1.08, 95% CI, 0.90-1.30) and the consistency of results among all studies with the exception of ISCHEMIA-EXTEND (RR, 1.0; 95% CI, 0.84-1;18; P = .7), “the absence of a negative effect of revascularization on noncardiac death was confirmed,” Dr. Wijns reported. 

Based on the preponderance of evidence assembled in this meta-analysis, the “noncardiac mortality excess risk observed following revascularization relative to medical therapy was confined to a single large trial and is likely due to a type 1 error,” Dr. Wijns reported. He noted that this study is “the first large-scale meta-analysis study designed to systematically evaluate potential differences in noncardiac mortality between treatment strategies for chronic coronary syndromes.” 

Eliano P. Navarese, MD, PhD, an associate professor of interventional cardiology at Nicolaus Copernicus University, Bydgoszcz, Poland, was the lead author of this study and Dr. Wijns was a coinvestigator. The study was published simultaneously in the Journal of the American College of Cardiology at the time of the EuroPCR meeting.

In the late-breaking session where these data were presented, there was a general consensus among invited panelists that the data are convincing. For example, Michael Joner, MD, PhD, director of early clinical trials, German Heart Centre, Munich, agreed that these data “resolve the issue.” 

Bernard de Bruyne, MD, PhD, an interventional cardiologist associated with the Cardiovascular Center Aalst, Kraainem, Belgium, also agreed that these data argue convincingly against the concern raised by publication of ISCHEMIA-EXTEND, but he added that this controversy has raised an important issue.

“We should always be reporting all-cause mortality, not just cardiovascular mortality, in our clinical trials,” he said, emphasizing that extending all-cause survival, not just preventing cardiovascular-related events, should be recognized as the goal of invasive strategies.

In an editorial accompanying the publication, Dr. Harvey D. White, MD, Te Whatu Ora-Health New Zealand, Auckland, writes similarly that the current findings, “alert us to the importance of adjudicating causes of death in clinical trials. 

“The current trial-level meta-analysis may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death,” Dr. White notes. He feels the signal of increased noncardiac or noncardiovascular death in ISCHEMIA EXTEND and the REVIVED trials is something “that we should pay attention to and explore the possibility that increased radiation doses with PCI may cause increased rates of cancer.” 

Further study, including longer follow-up, other datasets, and quality of life data including cognitive function and “patient-focused outcomes such as day alive out of hospital,” is needed, he concludes. 

Dr. Navarese has received research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron. Dr. Wijns reports financial relationships with Argonauts, Corrib Core Laboratory, and Rede Optimus Research. Dr. Capodanno reports financial relationships with Amgen, Daiichi Sankyo, and Sanofi. Dr. de Bruyne and Dr. Joner report financial relationships with multiple pharmaceutical and device manufacturers. Prof. White, as the John Neutze scholar, is supported by the Green Lane Research and Educational Fund. Prof. White has received grant support paid to the institution and fees for serving on steering committees of multiple trials sponsored by various companies.
 

In response to a randomized trial that associated elective revascularization for ischemia with an increase in noncardiac mortality versus medical therapy alone, a meta-analysis with a far larger dataset challenges this assertion, suggesting the initial conclusion is due to a type 1 error. 

With data from nearly 17,000 patients in 18 randomized trials, the meta-analysis showed no signal for increased noncardiac mortality in the revascularization group overall or across several sensitivity analyses, reports William Wijns, MD, PhD, professor of interventional cardiology, National University of Ireland, Galway.

The larger pool of data from the meta-analysis was considered compelling by several experts at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, where it was presented.

“I think these data will close once and forever this controversy,” said Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy). 

Evidence for an unexpected increased risk of noncardiac mortality was drawn from the ISCHEMIA-EXTEND study, which was published earlier this year. Numerous prior studies comparing percutaneous intervention (PCI) to medical therapy for relief of ischemia had shown no such safety signal. 

The ISCHEMIA-EXTEND study provided long-term follow up of patients enrolled in ISCHEMIA, a study that randomized patients with stable coronary disease and moderate or severe ischemia to PCI or a conservative approach. After 3.2 years of follow up, there was no reduction in risk of cardiovascular events or all-cause death. While this lack of benefit was a disappointing result from the perspective of interventional cardiology, there was also no increase in these risks. 

In ISCHEMIA-EXTEND, the more than 5,000 patients originally randomized were followed for an additional 2.5 years (total 5.7 years). During this extended period, the estimated 7-year risk of cardiovascular mortality was 22% lower in the group randomized to PCI (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96) but the noncardiac mortality was increased by 44% (HR, 1.44; 95% CI, 1.08-1.91). Because of the counterbalancing effects on survival, all-cause mortality was similar in the two groups.

The newly completed meta-analysis was undertaken to address this surprising result not least because the increased rates of noncardiac death did not have a plausible explanation, according to Dr. Wijns. 

When the patients from the 18 randomized trials were compared, noncardiac death occurred in 4.68% of the 8,665 patients assigned to elective revascularization and in 4.17% of the 8,243 patients assigned to medical therapy alone at an average follow up of 5.7 years. 

This difference was not significant overall (HR, 1.09; 95% CI, 0.94-1.26; P = .26) or after sensitivity analyses. For example, there was no difference (P = .52) between an invasive or conservative approach after controlling for length of follow up. 

There was also no heterogeneity (I2 = 0%) among the studies when ISCHEMIA-EXTEND was excluded.
 

Absence of negative effect ‘is confirmed’

On the basis of a Bayesian meta-analysis designed to account for residual uncertainty (relative risk, 1.08, 95% CI, 0.90-1.30) and the consistency of results among all studies with the exception of ISCHEMIA-EXTEND (RR, 1.0; 95% CI, 0.84-1;18; P = .7), “the absence of a negative effect of revascularization on noncardiac death was confirmed,” Dr. Wijns reported. 

Based on the preponderance of evidence assembled in this meta-analysis, the “noncardiac mortality excess risk observed following revascularization relative to medical therapy was confined to a single large trial and is likely due to a type 1 error,” Dr. Wijns reported. He noted that this study is “the first large-scale meta-analysis study designed to systematically evaluate potential differences in noncardiac mortality between treatment strategies for chronic coronary syndromes.” 

Eliano P. Navarese, MD, PhD, an associate professor of interventional cardiology at Nicolaus Copernicus University, Bydgoszcz, Poland, was the lead author of this study and Dr. Wijns was a coinvestigator. The study was published simultaneously in the Journal of the American College of Cardiology at the time of the EuroPCR meeting.

In the late-breaking session where these data were presented, there was a general consensus among invited panelists that the data are convincing. For example, Michael Joner, MD, PhD, director of early clinical trials, German Heart Centre, Munich, agreed that these data “resolve the issue.” 

Bernard de Bruyne, MD, PhD, an interventional cardiologist associated with the Cardiovascular Center Aalst, Kraainem, Belgium, also agreed that these data argue convincingly against the concern raised by publication of ISCHEMIA-EXTEND, but he added that this controversy has raised an important issue.

“We should always be reporting all-cause mortality, not just cardiovascular mortality, in our clinical trials,” he said, emphasizing that extending all-cause survival, not just preventing cardiovascular-related events, should be recognized as the goal of invasive strategies.

In an editorial accompanying the publication, Dr. Harvey D. White, MD, Te Whatu Ora-Health New Zealand, Auckland, writes similarly that the current findings, “alert us to the importance of adjudicating causes of death in clinical trials. 

“The current trial-level meta-analysis may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death,” Dr. White notes. He feels the signal of increased noncardiac or noncardiovascular death in ISCHEMIA EXTEND and the REVIVED trials is something “that we should pay attention to and explore the possibility that increased radiation doses with PCI may cause increased rates of cancer.” 

Further study, including longer follow-up, other datasets, and quality of life data including cognitive function and “patient-focused outcomes such as day alive out of hospital,” is needed, he concludes. 

Dr. Navarese has received research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron. Dr. Wijns reports financial relationships with Argonauts, Corrib Core Laboratory, and Rede Optimus Research. Dr. Capodanno reports financial relationships with Amgen, Daiichi Sankyo, and Sanofi. Dr. de Bruyne and Dr. Joner report financial relationships with multiple pharmaceutical and device manufacturers. Prof. White, as the John Neutze scholar, is supported by the Green Lane Research and Educational Fund. Prof. White has received grant support paid to the institution and fees for serving on steering committees of multiple trials sponsored by various companies.
 

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

Moving in a very different direction from past coronary stent designs, a new device that is being characterized as bioadaptable, as opposed to bioabsorbable, was noninferior to a widely used drug-eluting stent, and associated with several unique vessel functional improvements at 12 months in a randomized controlled trial.

“The device restored vessel motion, which we think is the reason that we saw plaque stabilization and regression,” reported Shigero Saito, MD, director of the catheterization laboratory at Shonan Kamakura (Japan) General Hospital.

The principal features of the bioadaptable design are cobalt-chromium metal helical strands to provide indefinite scaffolding support coupled with a biodegradable sirolimus-containing poly(D,L-lacti-co-glycolic acid) (PLGA) topcoat and a biodegradable poly-L-lactic acid (PLLA) bottom coat to “uncage” the vessel once these materials are resorbed, said Dr. Saito.

Twelve-month data from the randomized BIOADAPTOR trial, presented as a late breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, provide the first evidence that this uncaging of the vessel is an advantage.

Compared head-to-head in a contemporary drug-eluting stent (DES) in a randomized trial, the bioadaptable stent, as predicted in prior studies, “improved hemodynamics and supported plaque stabilization and positive remodeling,” said Dr. Saito.

In BIOADAPTOR, 445 patients in Japan, Germany, Belgium, and New Zealand were randomized to the novel stent, called DynamX, or to the Resolute Onyx. The trial has a planned follow-up of 5 years.

While the primary endpoint at 12 months was noninferiority for target lesion failure (TLF), it was a series of secondary imaging endpoints that suggest an important impact of uncaging the vessel. This includes better vessel function potentially relevant to resistance to restenosis.

As a result of numerically lower TLF in the DynamX group (1.8% vs. 2.8%), the new device easily demonstrated noninferiority at a high level of significance (P < .001). A numerical advantage for most events, including cardiovascular death (0% vs. 0.9%) and target-vessel myocardial infarction (1.4% vs. 1.9%), favored the novel device, but event rates were low in both arms and none of these differences were statistically significant.

However, the secondary imaging analyses at 12 months suggested major differences between the two devices from “uncaging” the vessel.

These differences included a highly significant improvement at 12 months in vessel pulsatility (P < .001) within the DynamX stent relative to the Onyx stent in all measured segments (proximal, mid, and distal).

In addition, compliance remained suppressed relative to both the proximal (P < .001) and distal (P < .001) vessels of patients fitted with Onyx device. Conversely, there was no significant relative difference in this measure among those fitted with the DynamX device.

At 12 months, the plaque volume change behind the stent of noncalcified lesions increased 9% in the Onyx group but was reduced 4% in the DynamX group (P = .028).

While there was a 13% gain overall in percent diameter stenosis within the stent of patients receiving the DynamX device, it was consistently lower than that observed in the Onyx group. This difference was only a trend overall (12.7% vs. 17.3%; P = .051), but the advantage reached significance, favoring DynamX, for the left anterior descending (LAD) artery (12.1% vs. 19.0%; P = .006), small vessels (13.0% vs. 18.3%; P = .045), and long lesions (13.0% vs. 22.9%; P = .008).

The same relative advantage for DynamX was seen on late lumen loss at 6 months. In this case, the overall advantage of DynamX (0.09 vs. 0.25; P = .038) did reach significance, and there was an advantage for the LAD (–0.02 vs. 0.24; P = .007) and long lesions (–0.06 vs. 0.38; P = .016). The difference did not reach significance for small vessels (0.08 vs. 0.26; P = .121).

All of these advantages on the secondary endpoints can be directly attributed to the effect of uncaging the vessel, according to Dr. Saito, who said this new design “addresses the shortcomings” of both previous drug-eluting and biodegradable stents.

Pointing out that the nonplateauing of late events has persisted regardless of stent design after “more than 20 years of innovation in design and materials,” Dr. Saito said all current stents have weaknesses. While biodegradable stents have not improved long-term outcomes relative to DES “as a result of loss of long-term vessel dynamic support,” DES are flawed due to “permanent caging of the vessel and loss of vessel motion and function.”

This novel hybrid design, employing both metal and biodegradable components, “is a completely different concept,” said Ron Waksman, MD, associate director, division of cardiology, Medstar Hospital Center, Washington. He was particularly impressed by the improvements in pulsatility and compliance in target vessels along with the favorable effects on plaque volume.

“The reduction in plaque volume is something we have not seen before. Usually we see the opposite,” Dr. Waksman said.

“Clearly, the Bioadaptor device is not a me-too stent,” he said. He was not surprised that there was no difference in hard outcomes given both the small sample size and the fact that the advantages of uncaging the vessel are likely to accrue over time.

“We need to look at what happens after 1 year. We still have not seen the potential of this device,” he said, adding he was “impressed” by the features of this novel concept. However, he suggested the advantages remain theoretical from the clinical standpoint, advising Dr. Saito that “you still need to demonstrate the clinical benefits.”

Dr. Saito reports a financial relationship with Elixir Medical, which funded the BIOADAPTOR trial. Dr. Waksman reports financial relationships with 19 pharmaceutical companies including those that manufacture cardiovascular stents.

Moving in a very different direction from past coronary stent designs, a new device that is being characterized as bioadaptable, as opposed to bioabsorbable, was noninferior to a widely used drug-eluting stent, and associated with several unique vessel functional improvements at 12 months in a randomized controlled trial.

“The device restored vessel motion, which we think is the reason that we saw plaque stabilization and regression,” reported Shigero Saito, MD, director of the catheterization laboratory at Shonan Kamakura (Japan) General Hospital.

The principal features of the bioadaptable design are cobalt-chromium metal helical strands to provide indefinite scaffolding support coupled with a biodegradable sirolimus-containing poly(D,L-lacti-co-glycolic acid) (PLGA) topcoat and a biodegradable poly-L-lactic acid (PLLA) bottom coat to “uncage” the vessel once these materials are resorbed, said Dr. Saito.

Twelve-month data from the randomized BIOADAPTOR trial, presented as a late breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, provide the first evidence that this uncaging of the vessel is an advantage.

Compared head-to-head in a contemporary drug-eluting stent (DES) in a randomized trial, the bioadaptable stent, as predicted in prior studies, “improved hemodynamics and supported plaque stabilization and positive remodeling,” said Dr. Saito.

In BIOADAPTOR, 445 patients in Japan, Germany, Belgium, and New Zealand were randomized to the novel stent, called DynamX, or to the Resolute Onyx. The trial has a planned follow-up of 5 years.

While the primary endpoint at 12 months was noninferiority for target lesion failure (TLF), it was a series of secondary imaging endpoints that suggest an important impact of uncaging the vessel. This includes better vessel function potentially relevant to resistance to restenosis.

As a result of numerically lower TLF in the DynamX group (1.8% vs. 2.8%), the new device easily demonstrated noninferiority at a high level of significance (P < .001). A numerical advantage for most events, including cardiovascular death (0% vs. 0.9%) and target-vessel myocardial infarction (1.4% vs. 1.9%), favored the novel device, but event rates were low in both arms and none of these differences were statistically significant.

However, the secondary imaging analyses at 12 months suggested major differences between the two devices from “uncaging” the vessel.

These differences included a highly significant improvement at 12 months in vessel pulsatility (P < .001) within the DynamX stent relative to the Onyx stent in all measured segments (proximal, mid, and distal).

In addition, compliance remained suppressed relative to both the proximal (P < .001) and distal (P < .001) vessels of patients fitted with Onyx device. Conversely, there was no significant relative difference in this measure among those fitted with the DynamX device.

At 12 months, the plaque volume change behind the stent of noncalcified lesions increased 9% in the Onyx group but was reduced 4% in the DynamX group (P = .028).

While there was a 13% gain overall in percent diameter stenosis within the stent of patients receiving the DynamX device, it was consistently lower than that observed in the Onyx group. This difference was only a trend overall (12.7% vs. 17.3%; P = .051), but the advantage reached significance, favoring DynamX, for the left anterior descending (LAD) artery (12.1% vs. 19.0%; P = .006), small vessels (13.0% vs. 18.3%; P = .045), and long lesions (13.0% vs. 22.9%; P = .008).

The same relative advantage for DynamX was seen on late lumen loss at 6 months. In this case, the overall advantage of DynamX (0.09 vs. 0.25; P = .038) did reach significance, and there was an advantage for the LAD (–0.02 vs. 0.24; P = .007) and long lesions (–0.06 vs. 0.38; P = .016). The difference did not reach significance for small vessels (0.08 vs. 0.26; P = .121).

All of these advantages on the secondary endpoints can be directly attributed to the effect of uncaging the vessel, according to Dr. Saito, who said this new design “addresses the shortcomings” of both previous drug-eluting and biodegradable stents.

Pointing out that the nonplateauing of late events has persisted regardless of stent design after “more than 20 years of innovation in design and materials,” Dr. Saito said all current stents have weaknesses. While biodegradable stents have not improved long-term outcomes relative to DES “as a result of loss of long-term vessel dynamic support,” DES are flawed due to “permanent caging of the vessel and loss of vessel motion and function.”

This novel hybrid design, employing both metal and biodegradable components, “is a completely different concept,” said Ron Waksman, MD, associate director, division of cardiology, Medstar Hospital Center, Washington. He was particularly impressed by the improvements in pulsatility and compliance in target vessels along with the favorable effects on plaque volume.

“The reduction in plaque volume is something we have not seen before. Usually we see the opposite,” Dr. Waksman said.

“Clearly, the Bioadaptor device is not a me-too stent,” he said. He was not surprised that there was no difference in hard outcomes given both the small sample size and the fact that the advantages of uncaging the vessel are likely to accrue over time.

“We need to look at what happens after 1 year. We still have not seen the potential of this device,” he said, adding he was “impressed” by the features of this novel concept. However, he suggested the advantages remain theoretical from the clinical standpoint, advising Dr. Saito that “you still need to demonstrate the clinical benefits.”

Dr. Saito reports a financial relationship with Elixir Medical, which funded the BIOADAPTOR trial. Dr. Waksman reports financial relationships with 19 pharmaceutical companies including those that manufacture cardiovascular stents.

Moving in a very different direction from past coronary stent designs, a new device that is being characterized as bioadaptable, as opposed to bioabsorbable, was noninferior to a widely used drug-eluting stent, and associated with several unique vessel functional improvements at 12 months in a randomized controlled trial.

“The device restored vessel motion, which we think is the reason that we saw plaque stabilization and regression,” reported Shigero Saito, MD, director of the catheterization laboratory at Shonan Kamakura (Japan) General Hospital.

The principal features of the bioadaptable design are cobalt-chromium metal helical strands to provide indefinite scaffolding support coupled with a biodegradable sirolimus-containing poly(D,L-lacti-co-glycolic acid) (PLGA) topcoat and a biodegradable poly-L-lactic acid (PLLA) bottom coat to “uncage” the vessel once these materials are resorbed, said Dr. Saito.

Twelve-month data from the randomized BIOADAPTOR trial, presented as a late breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, provide the first evidence that this uncaging of the vessel is an advantage.

Compared head-to-head in a contemporary drug-eluting stent (DES) in a randomized trial, the bioadaptable stent, as predicted in prior studies, “improved hemodynamics and supported plaque stabilization and positive remodeling,” said Dr. Saito.

In BIOADAPTOR, 445 patients in Japan, Germany, Belgium, and New Zealand were randomized to the novel stent, called DynamX, or to the Resolute Onyx. The trial has a planned follow-up of 5 years.

While the primary endpoint at 12 months was noninferiority for target lesion failure (TLF), it was a series of secondary imaging endpoints that suggest an important impact of uncaging the vessel. This includes better vessel function potentially relevant to resistance to restenosis.

As a result of numerically lower TLF in the DynamX group (1.8% vs. 2.8%), the new device easily demonstrated noninferiority at a high level of significance (P < .001). A numerical advantage for most events, including cardiovascular death (0% vs. 0.9%) and target-vessel myocardial infarction (1.4% vs. 1.9%), favored the novel device, but event rates were low in both arms and none of these differences were statistically significant.

However, the secondary imaging analyses at 12 months suggested major differences between the two devices from “uncaging” the vessel.

These differences included a highly significant improvement at 12 months in vessel pulsatility (P < .001) within the DynamX stent relative to the Onyx stent in all measured segments (proximal, mid, and distal).

In addition, compliance remained suppressed relative to both the proximal (P < .001) and distal (P < .001) vessels of patients fitted with Onyx device. Conversely, there was no significant relative difference in this measure among those fitted with the DynamX device.

At 12 months, the plaque volume change behind the stent of noncalcified lesions increased 9% in the Onyx group but was reduced 4% in the DynamX group (P = .028).

While there was a 13% gain overall in percent diameter stenosis within the stent of patients receiving the DynamX device, it was consistently lower than that observed in the Onyx group. This difference was only a trend overall (12.7% vs. 17.3%; P = .051), but the advantage reached significance, favoring DynamX, for the left anterior descending (LAD) artery (12.1% vs. 19.0%; P = .006), small vessels (13.0% vs. 18.3%; P = .045), and long lesions (13.0% vs. 22.9%; P = .008).

The same relative advantage for DynamX was seen on late lumen loss at 6 months. In this case, the overall advantage of DynamX (0.09 vs. 0.25; P = .038) did reach significance, and there was an advantage for the LAD (–0.02 vs. 0.24; P = .007) and long lesions (–0.06 vs. 0.38; P = .016). The difference did not reach significance for small vessels (0.08 vs. 0.26; P = .121).

All of these advantages on the secondary endpoints can be directly attributed to the effect of uncaging the vessel, according to Dr. Saito, who said this new design “addresses the shortcomings” of both previous drug-eluting and biodegradable stents.

Pointing out that the nonplateauing of late events has persisted regardless of stent design after “more than 20 years of innovation in design and materials,” Dr. Saito said all current stents have weaknesses. While biodegradable stents have not improved long-term outcomes relative to DES “as a result of loss of long-term vessel dynamic support,” DES are flawed due to “permanent caging of the vessel and loss of vessel motion and function.”

This novel hybrid design, employing both metal and biodegradable components, “is a completely different concept,” said Ron Waksman, MD, associate director, division of cardiology, Medstar Hospital Center, Washington. He was particularly impressed by the improvements in pulsatility and compliance in target vessels along with the favorable effects on plaque volume.

“The reduction in plaque volume is something we have not seen before. Usually we see the opposite,” Dr. Waksman said.

“Clearly, the Bioadaptor device is not a me-too stent,” he said. He was not surprised that there was no difference in hard outcomes given both the small sample size and the fact that the advantages of uncaging the vessel are likely to accrue over time.

“We need to look at what happens after 1 year. We still have not seen the potential of this device,” he said, adding he was “impressed” by the features of this novel concept. However, he suggested the advantages remain theoretical from the clinical standpoint, advising Dr. Saito that “you still need to demonstrate the clinical benefits.”

Dr. Saito reports a financial relationship with Elixir Medical, which funded the BIOADAPTOR trial. Dr. Waksman reports financial relationships with 19 pharmaceutical companies including those that manufacture cardiovascular stents.

Real-world data accumulated in Europe outside of a clinical trial support both the safety and the benefit of two transcatheter edge-to-edge (TEER) devices designed specifically for the treatment of tricuspid regurgitation (TR).

For the TriClip system (Abbott), the data were drawn from a prospective postmarketing registry, and for the EVOQUE system (Edwards Lifesciences), data were generated by a compassionate use program.

The TriClip system is approved and available in Europe, but neither system has regulatory approval in the United States.

The two sets of data, each presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, are consistent with controlled trials. Each system was associated with high rates of procedural success, low rates of adverse events, and sustained improvements in quality of life.
 

Real-world backup for TRILUMINATE

Presented just days before the pivotal multinational TRILUMINATE trial was published in the New England Journal of Medicine, the bRIGHT postmarketing study of the TriClip device demonstrated a procedural rate of success and a subsequent reduction in TR that was at least as good but in a substantially sicker patient population.

“To appreciate these results, you have to put into perspective the baseline TR in our population,” reported Philipp Lurz, MD, PhD, of the Heart Center Leipzig, University of Leipzig, Germany. Whereas only 70% of those randomized in TRILUMINATE had grade 4 (massive) or 5 (torrential) TR, the proportion was 90% in bRIGHT.

The proportion with TR of moderate or less severity was 77% when assessed at 30 days in bRIGHT versus 72%, however, when assessed at 1 year in TRILUMINATE. In addition, procedural success was 99% in both studies even though patients in bRIGHT were on average older and had more comorbidities. At baseline, 80% of bRIGHT patients were in New York Heart Association (NYHA) class III or IV heart failure versus 59% of those in TRILUMINATE.

TRILUMINATE data, presented prior to publication at the annual meeting of the American College of Cardiology earlier this year, did not associate the transcatheter TR repair with a reduction in mortality or a reduction in hospitalization for heart failure, which were the first two of three hierarchical endpoints, but it did show benefit on the third, which was quality of life. As measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), patients in the transcatheter repair group gained 12.3 points versus 0.6 points (P < .001) on medical therapy.

In the bRIGHT registry, patients gained 19 points in the KCCQ score after treatment. By 30 days, the proportion of patients in NHYA class III/IV had fallen from 80% to 20%. The major adverse event rate of 2.5% at 30 days was only modestly higher than the 1.7% rate at 30 days in TRILUMINATE.

“The safety profile remained strong despite the sicker population treated in the registry,” reported Dr. Lurz, whose results were simultaneously published in the Journal of the American College of Cardiology (JACC).

The bRIGHT registry analysis was based on 511 patients treated at 26 sites in Europe. Dr. Lurz characterized it as “the first prospective, single-arm, open-label, multicenter, postmarket registry to evaluate the safety and performance of any transcatheter tricuspid valve repair system.”

In a panel discussion following the presentation, Nicole Karam, MD, PhD, codirector of the heart valve unit, Hospital Georges Pompidou, Paris, praised a study of TEER tricuspid valve device in the real world, but she pointed out that the question of who to treat remains unanswered. Although symptom relief has value for a condition that can impose large deficits in quality of life, she called for more data to identify optimal candidates, particularly in the persistent absence of a major effect on hard endpoints.

Dr. Lurz agreed. In bRIGHT, predictors of a moderate or less TR at discharge included a smaller tethering distance, a smaller right ventricular end diastolic dimension, a smaller right atrial volume, and a smaller tricuspid annular diameter.

Each of these predictors argues for earlier treatment, he said, even if later treatment in a clinical trial provides a greater likelihood of eventually demonstrating benefits on hard endpoints.

‘Remarkable reduction’

The data from the much smaller compassionate use evaluation of the EVOQUE system generated similar evidence of safety and benefit while also making the point that earlier intervention offers a greater opportunity for preventing irreversible progression. With much longer follow up, the compassionate-use analysis, which involved patients even sicker than those included in bRIGHT, suggested these repairs are durable.

In this retrospective analysis of 38 patients treated at eight centers in Europe, the United States, and Canada, the mortality climbed steadily over 2 years of follow-up, reaching 29% at 2 years despite the fact that TR was reduced to < 1% after the procedure and remained durably suppressed at a median follow-up of 520 days.

The tricuspid valve repair with the EVOQUE system “was associated with a remarkable reduction in heart failure symptoms and significant improvement in NYHA functional class up to a maximum of 1,074 days after the intervention,” reported Lukas Stolz, MD, an interventional cardiologist at Ludwig-Maximilians-University, Munich.

In the data he presented at EuroPCR, which was published simultaneously as a letter in JACC, he said that favorable reverse remodeling of the right ventricle, which was observed as early as 30 days after the procedure, was maintained at long-term follow up.

The uncontrolled data from the compassionate analysis, like the bRIGHT registry, could not confirm that tricuspid valve repair changes the trajectory of progressive heart disease, but the favorable effects Dr. Stolz reported on cardiovascular function, not just symptoms, support this idea.

Dr. Lutz has financial relationships with Edwards Lifesciences, ReCor, and Abbott, which funded the bRIGHT registry. Dr. Karam reports financial relationships with Abbott, Edwards Lifesciences, and Medtronic. Dr. Stolz reports no potential conflicts of interest, but other coinvestigators of the retrospective analysis have financial relationships with Edwards Lifesciences, which is developing the EVOQUE system.

Real-world data accumulated in Europe outside of a clinical trial support both the safety and the benefit of two transcatheter edge-to-edge (TEER) devices designed specifically for the treatment of tricuspid regurgitation (TR).

For the TriClip system (Abbott), the data were drawn from a prospective postmarketing registry, and for the EVOQUE system (Edwards Lifesciences), data were generated by a compassionate use program.

The TriClip system is approved and available in Europe, but neither system has regulatory approval in the United States.

The two sets of data, each presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, are consistent with controlled trials. Each system was associated with high rates of procedural success, low rates of adverse events, and sustained improvements in quality of life.
 

Real-world backup for TRILUMINATE

Presented just days before the pivotal multinational TRILUMINATE trial was published in the New England Journal of Medicine, the bRIGHT postmarketing study of the TriClip device demonstrated a procedural rate of success and a subsequent reduction in TR that was at least as good but in a substantially sicker patient population.

“To appreciate these results, you have to put into perspective the baseline TR in our population,” reported Philipp Lurz, MD, PhD, of the Heart Center Leipzig, University of Leipzig, Germany. Whereas only 70% of those randomized in TRILUMINATE had grade 4 (massive) or 5 (torrential) TR, the proportion was 90% in bRIGHT.

The proportion with TR of moderate or less severity was 77% when assessed at 30 days in bRIGHT versus 72%, however, when assessed at 1 year in TRILUMINATE. In addition, procedural success was 99% in both studies even though patients in bRIGHT were on average older and had more comorbidities. At baseline, 80% of bRIGHT patients were in New York Heart Association (NYHA) class III or IV heart failure versus 59% of those in TRILUMINATE.

TRILUMINATE data, presented prior to publication at the annual meeting of the American College of Cardiology earlier this year, did not associate the transcatheter TR repair with a reduction in mortality or a reduction in hospitalization for heart failure, which were the first two of three hierarchical endpoints, but it did show benefit on the third, which was quality of life. As measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), patients in the transcatheter repair group gained 12.3 points versus 0.6 points (P < .001) on medical therapy.

In the bRIGHT registry, patients gained 19 points in the KCCQ score after treatment. By 30 days, the proportion of patients in NHYA class III/IV had fallen from 80% to 20%. The major adverse event rate of 2.5% at 30 days was only modestly higher than the 1.7% rate at 30 days in TRILUMINATE.

“The safety profile remained strong despite the sicker population treated in the registry,” reported Dr. Lurz, whose results were simultaneously published in the Journal of the American College of Cardiology (JACC).

The bRIGHT registry analysis was based on 511 patients treated at 26 sites in Europe. Dr. Lurz characterized it as “the first prospective, single-arm, open-label, multicenter, postmarket registry to evaluate the safety and performance of any transcatheter tricuspid valve repair system.”

In a panel discussion following the presentation, Nicole Karam, MD, PhD, codirector of the heart valve unit, Hospital Georges Pompidou, Paris, praised a study of TEER tricuspid valve device in the real world, but she pointed out that the question of who to treat remains unanswered. Although symptom relief has value for a condition that can impose large deficits in quality of life, she called for more data to identify optimal candidates, particularly in the persistent absence of a major effect on hard endpoints.

Dr. Lurz agreed. In bRIGHT, predictors of a moderate or less TR at discharge included a smaller tethering distance, a smaller right ventricular end diastolic dimension, a smaller right atrial volume, and a smaller tricuspid annular diameter.

Each of these predictors argues for earlier treatment, he said, even if later treatment in a clinical trial provides a greater likelihood of eventually demonstrating benefits on hard endpoints.

‘Remarkable reduction’

The data from the much smaller compassionate use evaluation of the EVOQUE system generated similar evidence of safety and benefit while also making the point that earlier intervention offers a greater opportunity for preventing irreversible progression. With much longer follow up, the compassionate-use analysis, which involved patients even sicker than those included in bRIGHT, suggested these repairs are durable.

In this retrospective analysis of 38 patients treated at eight centers in Europe, the United States, and Canada, the mortality climbed steadily over 2 years of follow-up, reaching 29% at 2 years despite the fact that TR was reduced to < 1% after the procedure and remained durably suppressed at a median follow-up of 520 days.

The tricuspid valve repair with the EVOQUE system “was associated with a remarkable reduction in heart failure symptoms and significant improvement in NYHA functional class up to a maximum of 1,074 days after the intervention,” reported Lukas Stolz, MD, an interventional cardiologist at Ludwig-Maximilians-University, Munich.

In the data he presented at EuroPCR, which was published simultaneously as a letter in JACC, he said that favorable reverse remodeling of the right ventricle, which was observed as early as 30 days after the procedure, was maintained at long-term follow up.

The uncontrolled data from the compassionate analysis, like the bRIGHT registry, could not confirm that tricuspid valve repair changes the trajectory of progressive heart disease, but the favorable effects Dr. Stolz reported on cardiovascular function, not just symptoms, support this idea.

Dr. Lutz has financial relationships with Edwards Lifesciences, ReCor, and Abbott, which funded the bRIGHT registry. Dr. Karam reports financial relationships with Abbott, Edwards Lifesciences, and Medtronic. Dr. Stolz reports no potential conflicts of interest, but other coinvestigators of the retrospective analysis have financial relationships with Edwards Lifesciences, which is developing the EVOQUE system.

Real-world data accumulated in Europe outside of a clinical trial support both the safety and the benefit of two transcatheter edge-to-edge (TEER) devices designed specifically for the treatment of tricuspid regurgitation (TR).

For the TriClip system (Abbott), the data were drawn from a prospective postmarketing registry, and for the EVOQUE system (Edwards Lifesciences), data were generated by a compassionate use program.

The TriClip system is approved and available in Europe, but neither system has regulatory approval in the United States.

The two sets of data, each presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, are consistent with controlled trials. Each system was associated with high rates of procedural success, low rates of adverse events, and sustained improvements in quality of life.
 

Real-world backup for TRILUMINATE

Presented just days before the pivotal multinational TRILUMINATE trial was published in the New England Journal of Medicine, the bRIGHT postmarketing study of the TriClip device demonstrated a procedural rate of success and a subsequent reduction in TR that was at least as good but in a substantially sicker patient population.

“To appreciate these results, you have to put into perspective the baseline TR in our population,” reported Philipp Lurz, MD, PhD, of the Heart Center Leipzig, University of Leipzig, Germany. Whereas only 70% of those randomized in TRILUMINATE had grade 4 (massive) or 5 (torrential) TR, the proportion was 90% in bRIGHT.

The proportion with TR of moderate or less severity was 77% when assessed at 30 days in bRIGHT versus 72%, however, when assessed at 1 year in TRILUMINATE. In addition, procedural success was 99% in both studies even though patients in bRIGHT were on average older and had more comorbidities. At baseline, 80% of bRIGHT patients were in New York Heart Association (NYHA) class III or IV heart failure versus 59% of those in TRILUMINATE.

TRILUMINATE data, presented prior to publication at the annual meeting of the American College of Cardiology earlier this year, did not associate the transcatheter TR repair with a reduction in mortality or a reduction in hospitalization for heart failure, which were the first two of three hierarchical endpoints, but it did show benefit on the third, which was quality of life. As measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), patients in the transcatheter repair group gained 12.3 points versus 0.6 points (P < .001) on medical therapy.

In the bRIGHT registry, patients gained 19 points in the KCCQ score after treatment. By 30 days, the proportion of patients in NHYA class III/IV had fallen from 80% to 20%. The major adverse event rate of 2.5% at 30 days was only modestly higher than the 1.7% rate at 30 days in TRILUMINATE.

“The safety profile remained strong despite the sicker population treated in the registry,” reported Dr. Lurz, whose results were simultaneously published in the Journal of the American College of Cardiology (JACC).

The bRIGHT registry analysis was based on 511 patients treated at 26 sites in Europe. Dr. Lurz characterized it as “the first prospective, single-arm, open-label, multicenter, postmarket registry to evaluate the safety and performance of any transcatheter tricuspid valve repair system.”

In a panel discussion following the presentation, Nicole Karam, MD, PhD, codirector of the heart valve unit, Hospital Georges Pompidou, Paris, praised a study of TEER tricuspid valve device in the real world, but she pointed out that the question of who to treat remains unanswered. Although symptom relief has value for a condition that can impose large deficits in quality of life, she called for more data to identify optimal candidates, particularly in the persistent absence of a major effect on hard endpoints.

Dr. Lurz agreed. In bRIGHT, predictors of a moderate or less TR at discharge included a smaller tethering distance, a smaller right ventricular end diastolic dimension, a smaller right atrial volume, and a smaller tricuspid annular diameter.

Each of these predictors argues for earlier treatment, he said, even if later treatment in a clinical trial provides a greater likelihood of eventually demonstrating benefits on hard endpoints.

‘Remarkable reduction’

The data from the much smaller compassionate use evaluation of the EVOQUE system generated similar evidence of safety and benefit while also making the point that earlier intervention offers a greater opportunity for preventing irreversible progression. With much longer follow up, the compassionate-use analysis, which involved patients even sicker than those included in bRIGHT, suggested these repairs are durable.

In this retrospective analysis of 38 patients treated at eight centers in Europe, the United States, and Canada, the mortality climbed steadily over 2 years of follow-up, reaching 29% at 2 years despite the fact that TR was reduced to < 1% after the procedure and remained durably suppressed at a median follow-up of 520 days.

The tricuspid valve repair with the EVOQUE system “was associated with a remarkable reduction in heart failure symptoms and significant improvement in NYHA functional class up to a maximum of 1,074 days after the intervention,” reported Lukas Stolz, MD, an interventional cardiologist at Ludwig-Maximilians-University, Munich.

In the data he presented at EuroPCR, which was published simultaneously as a letter in JACC, he said that favorable reverse remodeling of the right ventricle, which was observed as early as 30 days after the procedure, was maintained at long-term follow up.

The uncontrolled data from the compassionate analysis, like the bRIGHT registry, could not confirm that tricuspid valve repair changes the trajectory of progressive heart disease, but the favorable effects Dr. Stolz reported on cardiovascular function, not just symptoms, support this idea.

Dr. Lutz has financial relationships with Edwards Lifesciences, ReCor, and Abbott, which funded the bRIGHT registry. Dr. Karam reports financial relationships with Abbott, Edwards Lifesciences, and Medtronic. Dr. Stolz reports no potential conflicts of interest, but other coinvestigators of the retrospective analysis have financial relationships with Edwards Lifesciences, which is developing the EVOQUE system.

For patients undergoing transcatheter aortic valve replacement (TAVR), adverse outcomes are more common in those who are in cardiogenic shock than those who are not, but the greater risks appear to be completely concentrated in the early period of recovery, suggests a propensity-matched study.

“The landmark analysis we conducted at 4 weeks suggest patients do remarkably well – as good as patients without cardiogenic shock – if they survive through the initial recovery period,” reported Abhijeet Dhoble, MD, associate professor and an interventional cardiologist at McGovern Medical School, University of Texas Health Science Center, Houston.

Their results were presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

The study, which drew data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Replacement (STS/ACC TVR) Registry, looked only at patients who underwent TAVR with the Sapien3 or Sapience3 Ultra device. Patients with CS were propensity matched to Sapien device-treated patients in the registry without CS.

Taken from a pool of 9,348 patients with CS and 299,600 patients without, the matching included a large array of clinically relevant covariates, including age, gender, prior cardiovascular events, left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class.

After matching, there were 4,952 patients in each arm. The baseline Society of Thoracic Surgeons (STS) risk score was approximately 10.0 in both arms. About half had atrial fibrillation and 90% were in NYHA class III or IV. The median LVEF in both groups was 39.9%.
 

Mortality more than twofold higher in CS patients

At 30 days, outcomes were worse in patients with CS, including the proportion who died (12.9% vs. 4.9%; P < .0001) and the proportion with stroke (3.3% vs. 1.9%; P < .0001).

The only major study endpoint not significantly different, although higher in the CS group, was the rate of readmission (12.0% vs. 11.0%; P = .25).

At 1 year, the differences in the rates of mortality (29.7% vs. 22.6%; P < .0001) and stroke (4.3% vs. 3.1%; P = .0004) had narrowed modestly but remained highly significant. A closer analysis indicated that almost all of the difference in the rate of events occurred prior to hospital discharge.

In fact, mortality (9.9% vs. 2.7%; P < .0001), stroke (2.9% vs. 1.5%; P < .0001), major vascular complications (2.3% vs. 1.9%; P = .0002), life-threatening bleeding (2.5% vs. 0.7%; P < .0001), new dialysis (3.5% vs. 1.1%; P < .0001) and new onset atrial fibrillation (3.8% vs. 1.6%; P < .0001) were all significantly higher in the CS group in this very early time period. By hazard ratio (HR), the risk of a major event prior to leaving the hospital was nearly threefold higher (HR 2.3; P < .0001) in the CS group.

Yet, there was no significant difference in the accumulation of adverse events after discharge. When compared for major events in the landmark analysis, the event curves were essentially superimposable from 30 days to 1 year. During this period, event rates were 19.3% versus 18.5% for CS and non-CS patients (HR 1.07; P = .2640).

The higher rate of events was unrelated to procedural complications, which were very low in both groups and did not differ significantly. Transition to open surgery, annular disruption, aortic dissection, coronary occlusion, and device embolization occurred in < 1% of patients in both groups.
 

Predictors of a poor outcome identified

On multivariate analysis, the predictors of events in the CS patients were comorbidities. Despite propensity matching, being on dialysis, having a permanent pacemaker, or having a mechanical assist device were all independent predictors of mortality risk specific to the CS group.

Age and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) score were not predictors.

These risk factors deserve consideration when evaluating CS candidates for TAVR, but Dr. Dhoble said that none are absolute contraindications. Rather, he advised that they should be considered in the context of the entire clinical picture, including the expected benefit from TAVR. Indeed, the benefit-to-risk ratio generally favors TAVR in CS patients, particularly those with obstructive CS caused by aortic stenosis, according to Dr. Dhoble.

“Efforts should be made not only to avoid delaying TAVR in such patients but also to prevent CS by early definitive treatment of patients with aortic stenosis,” he said.

These data are useful and important, said Jonathan Schwartz, MD, medical director, interventional cardiology, Atrium Health, Charlotte, N.C.

CS candidates for TAVR “are some of the sickest patients we treat. It is nice to finally have some data for this group,” he said. He agreed that CS patients can derive major benefit from TAVR if appropriately selected.

While many CS patients are already considered for TAVR, one source of hesitation has been the exclusion of CS patients from major TAVR trials, said Dr. Dhoble. He hopes these data will provide a framework for clinical decisions.

Ironically, the first TAVR patient and half of the initial series of 38 TAVR patients had CS, noted Alain G. Cribier, MD, director of cardiology, Charles Nicolle Hospital, University of Rouen, France. As the primary investigator of that initial TAVR study, conducted more than 20 years ago, he said he was not surprised by the favorable results of the propensity analysis.

“There is an almost miraculous clinical improvement to be achieved when you succeed with the procedure,” said Dr. Cribier, recounting his own experience. Improvements in LVEF of up to 30% can be achieved “within a day or two or even the first day,” he said.

Dr. Dhoble reports financial relationships with Abbott Vascular and Edwards Lifesciences. Dr. Schwartz reports that he has financial relationships with Abbott Vascular, Boston Scientific, Cordis, Edwards Lifesciences and Medtronic. Dr. Cribier reports a financial relationship with Edwards Lifesciences.

For patients undergoing transcatheter aortic valve replacement (TAVR), adverse outcomes are more common in those who are in cardiogenic shock than those who are not, but the greater risks appear to be completely concentrated in the early period of recovery, suggests a propensity-matched study.

“The landmark analysis we conducted at 4 weeks suggest patients do remarkably well – as good as patients without cardiogenic shock – if they survive through the initial recovery period,” reported Abhijeet Dhoble, MD, associate professor and an interventional cardiologist at McGovern Medical School, University of Texas Health Science Center, Houston.

Their results were presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

The study, which drew data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Replacement (STS/ACC TVR) Registry, looked only at patients who underwent TAVR with the Sapien3 or Sapience3 Ultra device. Patients with CS were propensity matched to Sapien device-treated patients in the registry without CS.

Taken from a pool of 9,348 patients with CS and 299,600 patients without, the matching included a large array of clinically relevant covariates, including age, gender, prior cardiovascular events, left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class.

After matching, there were 4,952 patients in each arm. The baseline Society of Thoracic Surgeons (STS) risk score was approximately 10.0 in both arms. About half had atrial fibrillation and 90% were in NYHA class III or IV. The median LVEF in both groups was 39.9%.
 

Mortality more than twofold higher in CS patients

At 30 days, outcomes were worse in patients with CS, including the proportion who died (12.9% vs. 4.9%; P < .0001) and the proportion with stroke (3.3% vs. 1.9%; P < .0001).

The only major study endpoint not significantly different, although higher in the CS group, was the rate of readmission (12.0% vs. 11.0%; P = .25).

At 1 year, the differences in the rates of mortality (29.7% vs. 22.6%; P < .0001) and stroke (4.3% vs. 3.1%; P = .0004) had narrowed modestly but remained highly significant. A closer analysis indicated that almost all of the difference in the rate of events occurred prior to hospital discharge.

In fact, mortality (9.9% vs. 2.7%; P < .0001), stroke (2.9% vs. 1.5%; P < .0001), major vascular complications (2.3% vs. 1.9%; P = .0002), life-threatening bleeding (2.5% vs. 0.7%; P < .0001), new dialysis (3.5% vs. 1.1%; P < .0001) and new onset atrial fibrillation (3.8% vs. 1.6%; P < .0001) were all significantly higher in the CS group in this very early time period. By hazard ratio (HR), the risk of a major event prior to leaving the hospital was nearly threefold higher (HR 2.3; P < .0001) in the CS group.

Yet, there was no significant difference in the accumulation of adverse events after discharge. When compared for major events in the landmark analysis, the event curves were essentially superimposable from 30 days to 1 year. During this period, event rates were 19.3% versus 18.5% for CS and non-CS patients (HR 1.07; P = .2640).

The higher rate of events was unrelated to procedural complications, which were very low in both groups and did not differ significantly. Transition to open surgery, annular disruption, aortic dissection, coronary occlusion, and device embolization occurred in < 1% of patients in both groups.
 

Predictors of a poor outcome identified

On multivariate analysis, the predictors of events in the CS patients were comorbidities. Despite propensity matching, being on dialysis, having a permanent pacemaker, or having a mechanical assist device were all independent predictors of mortality risk specific to the CS group.

Age and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) score were not predictors.

These risk factors deserve consideration when evaluating CS candidates for TAVR, but Dr. Dhoble said that none are absolute contraindications. Rather, he advised that they should be considered in the context of the entire clinical picture, including the expected benefit from TAVR. Indeed, the benefit-to-risk ratio generally favors TAVR in CS patients, particularly those with obstructive CS caused by aortic stenosis, according to Dr. Dhoble.

“Efforts should be made not only to avoid delaying TAVR in such patients but also to prevent CS by early definitive treatment of patients with aortic stenosis,” he said.

These data are useful and important, said Jonathan Schwartz, MD, medical director, interventional cardiology, Atrium Health, Charlotte, N.C.

CS candidates for TAVR “are some of the sickest patients we treat. It is nice to finally have some data for this group,” he said. He agreed that CS patients can derive major benefit from TAVR if appropriately selected.

While many CS patients are already considered for TAVR, one source of hesitation has been the exclusion of CS patients from major TAVR trials, said Dr. Dhoble. He hopes these data will provide a framework for clinical decisions.

Ironically, the first TAVR patient and half of the initial series of 38 TAVR patients had CS, noted Alain G. Cribier, MD, director of cardiology, Charles Nicolle Hospital, University of Rouen, France. As the primary investigator of that initial TAVR study, conducted more than 20 years ago, he said he was not surprised by the favorable results of the propensity analysis.

“There is an almost miraculous clinical improvement to be achieved when you succeed with the procedure,” said Dr. Cribier, recounting his own experience. Improvements in LVEF of up to 30% can be achieved “within a day or two or even the first day,” he said.

Dr. Dhoble reports financial relationships with Abbott Vascular and Edwards Lifesciences. Dr. Schwartz reports that he has financial relationships with Abbott Vascular, Boston Scientific, Cordis, Edwards Lifesciences and Medtronic. Dr. Cribier reports a financial relationship with Edwards Lifesciences.

For patients undergoing transcatheter aortic valve replacement (TAVR), adverse outcomes are more common in those who are in cardiogenic shock than those who are not, but the greater risks appear to be completely concentrated in the early period of recovery, suggests a propensity-matched study.

“The landmark analysis we conducted at 4 weeks suggest patients do remarkably well – as good as patients without cardiogenic shock – if they survive through the initial recovery period,” reported Abhijeet Dhoble, MD, associate professor and an interventional cardiologist at McGovern Medical School, University of Texas Health Science Center, Houston.

Their results were presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

The study, which drew data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Replacement (STS/ACC TVR) Registry, looked only at patients who underwent TAVR with the Sapien3 or Sapience3 Ultra device. Patients with CS were propensity matched to Sapien device-treated patients in the registry without CS.

Taken from a pool of 9,348 patients with CS and 299,600 patients without, the matching included a large array of clinically relevant covariates, including age, gender, prior cardiovascular events, left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class.

After matching, there were 4,952 patients in each arm. The baseline Society of Thoracic Surgeons (STS) risk score was approximately 10.0 in both arms. About half had atrial fibrillation and 90% were in NYHA class III or IV. The median LVEF in both groups was 39.9%.
 

Mortality more than twofold higher in CS patients

At 30 days, outcomes were worse in patients with CS, including the proportion who died (12.9% vs. 4.9%; P < .0001) and the proportion with stroke (3.3% vs. 1.9%; P < .0001).

The only major study endpoint not significantly different, although higher in the CS group, was the rate of readmission (12.0% vs. 11.0%; P = .25).

At 1 year, the differences in the rates of mortality (29.7% vs. 22.6%; P < .0001) and stroke (4.3% vs. 3.1%; P = .0004) had narrowed modestly but remained highly significant. A closer analysis indicated that almost all of the difference in the rate of events occurred prior to hospital discharge.

In fact, mortality (9.9% vs. 2.7%; P < .0001), stroke (2.9% vs. 1.5%; P < .0001), major vascular complications (2.3% vs. 1.9%; P = .0002), life-threatening bleeding (2.5% vs. 0.7%; P < .0001), new dialysis (3.5% vs. 1.1%; P < .0001) and new onset atrial fibrillation (3.8% vs. 1.6%; P < .0001) were all significantly higher in the CS group in this very early time period. By hazard ratio (HR), the risk of a major event prior to leaving the hospital was nearly threefold higher (HR 2.3; P < .0001) in the CS group.

Yet, there was no significant difference in the accumulation of adverse events after discharge. When compared for major events in the landmark analysis, the event curves were essentially superimposable from 30 days to 1 year. During this period, event rates were 19.3% versus 18.5% for CS and non-CS patients (HR 1.07; P = .2640).

The higher rate of events was unrelated to procedural complications, which were very low in both groups and did not differ significantly. Transition to open surgery, annular disruption, aortic dissection, coronary occlusion, and device embolization occurred in < 1% of patients in both groups.
 

Predictors of a poor outcome identified

On multivariate analysis, the predictors of events in the CS patients were comorbidities. Despite propensity matching, being on dialysis, having a permanent pacemaker, or having a mechanical assist device were all independent predictors of mortality risk specific to the CS group.

Age and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) score were not predictors.

These risk factors deserve consideration when evaluating CS candidates for TAVR, but Dr. Dhoble said that none are absolute contraindications. Rather, he advised that they should be considered in the context of the entire clinical picture, including the expected benefit from TAVR. Indeed, the benefit-to-risk ratio generally favors TAVR in CS patients, particularly those with obstructive CS caused by aortic stenosis, according to Dr. Dhoble.

“Efforts should be made not only to avoid delaying TAVR in such patients but also to prevent CS by early definitive treatment of patients with aortic stenosis,” he said.

These data are useful and important, said Jonathan Schwartz, MD, medical director, interventional cardiology, Atrium Health, Charlotte, N.C.

CS candidates for TAVR “are some of the sickest patients we treat. It is nice to finally have some data for this group,” he said. He agreed that CS patients can derive major benefit from TAVR if appropriately selected.

While many CS patients are already considered for TAVR, one source of hesitation has been the exclusion of CS patients from major TAVR trials, said Dr. Dhoble. He hopes these data will provide a framework for clinical decisions.

Ironically, the first TAVR patient and half of the initial series of 38 TAVR patients had CS, noted Alain G. Cribier, MD, director of cardiology, Charles Nicolle Hospital, University of Rouen, France. As the primary investigator of that initial TAVR study, conducted more than 20 years ago, he said he was not surprised by the favorable results of the propensity analysis.

“There is an almost miraculous clinical improvement to be achieved when you succeed with the procedure,” said Dr. Cribier, recounting his own experience. Improvements in LVEF of up to 30% can be achieved “within a day or two or even the first day,” he said.

Dr. Dhoble reports financial relationships with Abbott Vascular and Edwards Lifesciences. Dr. Schwartz reports that he has financial relationships with Abbott Vascular, Boston Scientific, Cordis, Edwards Lifesciences and Medtronic. Dr. Cribier reports a financial relationship with Edwards Lifesciences.

Even after 3 years of follow-up, redo transcatheter aortic valve replacement (TAVR) performs about as well as the first procedure, whether compared for hard endpoints, such as death and stroke, or for softer endpoints, such as function and quality of life, new registry data suggest.

The findings generally support redo-TAVR with balloon-expandable devices as “a reasonable treatment option for failed transcatheter heart valves,” reported Rajendra Makkar, MD, associate director, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles.

The results were presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

Data for this analysis were drawn from 348,338 TAVR procedures with the Edwards balloon-expandable valves in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Replacement Registry.

Of these, 1,216 were redo procedures. In 475 of the cases, the redo was performed in a patient whose first procedure was with an Edwards device. In the remaining 741 cases, the Edwards device replaced a different prosthetic heart valve. The median time to the redo from the first procedure was 26 months.

For the analysis, the redo-TAVRs were compared with native TAVR patients through 1:1 propensity matching employing 35 covariates, such as age, body mass index (BMI), baseline comorbidities, prior cardiovascular procedures, valve size, and Society of Thoracic Surgeons risk score.
 

Low death and stroke rates following TAVR redos

The rates of all-cause death or stroke within hospital (4.7% vs. 3.9%; P = .32) and at 30 days (6.1% vs. 5.9%; P = .77) were numerically but not statistically higher in the redo group.

At 1 year, the rates of death (17.3% vs. 17.7%; P = .961) and stroke (3.3% vs. 3.5%; P = .982) were numerically but not significantly lower among those who underwent a redo procedure.

The secondary endpoints told the same story. The one exception was the higher aortic valve reintervention rate (0.61% vs. 0.09%; P = .03) at 30 days in the redo group. This did reach statistical significance, but Dr. Makkar pointed out rates were very low regardless. The rates climbed in both groups by 1 year (1.09% vs. 0.21%; P = .01).

No other secondary endpoints differed significantly at 30 days or at 1 year. Even though some were numerically higher after redo at 1 year, such as major vascular complications (1.25 vs. 1.60; P = .51), others were lower, such as new-start dialysis (1.62 vs. 0.98; P = .26). All-cause readmission rates at 1 year were nearly identical (32.56% vs. 32.23%; P = .82).

Consistent with the comparable outcomes on the hard endpoints, major and similar improvements were seen in both the redo and the propensity-matched native TAVR patients on the Kansas City Cardiomyopathy Questionnaire Overall Summary. The slight advantage for the redo group was not significant at 30 days, but the degree of improvement was greater after the redo than after native TAVR at 1 year (15% vs. 10%; P = .03).

“You bring good news,” said Alain G. Cribier, MD, director of cardiology, Charles Nicolle Hospital, University of Rouen, France. Widely regarded as the father of TAVR for his first-in-human series in 2002, Dr. Cribier said that there are several reassuring take-home messages from this study.

“First, these data tell us that the redo rate is extremely low,” he said, noting that the registry data suggests a risk well below 1%. “Second, we are seeing from this data that there are no more complications [than TAVR in a native valve] if you need to do this.”
 

Redo patients are generally sicker

The propensity matching was designed to eliminate baseline differences for the outcome comparisons, but Dr. Makkar did point out that redo-TAVR patients were sicker than the native TAVR patients. For example, when compared prior to propensity matching, the STS score was higher (8.3 vs. 5.2; P < .01), more patients had atrial fibrillation (47.9% vs. 36.2%; P < .01), and more patients had a prior stroke (15.0% vs. 10.7%; P < .01).

The registry only has follow-up out to 1 year, but participating patients were matched to a claims database to capture outcomes out to 3 years. Mortality rates at long-term follow-up were not significantly different for redo vs. native TAVR (42.2% vs. 40.3% respectively; P = .98); for the entire dataset or when compared in subgroups defined by Edwards valve redo of an Edwards valve (P = .909) or an Edwards valve redo of a non-Edwards device (P = .871).

Whether an early redo, defined as 12 months after the index TAVR procedure, or a late redo, the rate of mortality ranged from approximately 16% to 18% with no significant difference between redo and native TAVR.

A moderator for the late-breaking trials session where these data were presented, Darren Mylotte, MD, a consultant in cardiology for the Galway University Hospitals, Ireland, challenged Dr. Makkar about the potential for selection bias. He said redo patients might be the ones that interventionalists feel confident about helping, making this comparison unrepresentative.

“I think that the selection bias is likely to cut both ways,” Dr. Makkar replied. For many patients with a failed TAVR, he explained that clinicians might think, “There is nothing to be done for this patient except to try a redo.”

Dr. Makkar reports financial relationships with Abbott, Cordis, Edwards Lifesciences, and Medtronic. Dr. Cribier reports a financial relationship with Edwards Lifesciences. Dr. Mylotte reports no potential conflicts of interest.

Even after 3 years of follow-up, redo transcatheter aortic valve replacement (TAVR) performs about as well as the first procedure, whether compared for hard endpoints, such as death and stroke, or for softer endpoints, such as function and quality of life, new registry data suggest.

The findings generally support redo-TAVR with balloon-expandable devices as “a reasonable treatment option for failed transcatheter heart valves,” reported Rajendra Makkar, MD, associate director, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles.

The results were presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

Data for this analysis were drawn from 348,338 TAVR procedures with the Edwards balloon-expandable valves in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Replacement Registry.

Of these, 1,216 were redo procedures. In 475 of the cases, the redo was performed in a patient whose first procedure was with an Edwards device. In the remaining 741 cases, the Edwards device replaced a different prosthetic heart valve. The median time to the redo from the first procedure was 26 months.

For the analysis, the redo-TAVRs were compared with native TAVR patients through 1:1 propensity matching employing 35 covariates, such as age, body mass index (BMI), baseline comorbidities, prior cardiovascular procedures, valve size, and Society of Thoracic Surgeons risk score.
 

Low death and stroke rates following TAVR redos

The rates of all-cause death or stroke within hospital (4.7% vs. 3.9%; P = .32) and at 30 days (6.1% vs. 5.9%; P = .77) were numerically but not statistically higher in the redo group.

At 1 year, the rates of death (17.3% vs. 17.7%; P = .961) and stroke (3.3% vs. 3.5%; P = .982) were numerically but not significantly lower among those who underwent a redo procedure.

The secondary endpoints told the same story. The one exception was the higher aortic valve reintervention rate (0.61% vs. 0.09%; P = .03) at 30 days in the redo group. This did reach statistical significance, but Dr. Makkar pointed out rates were very low regardless. The rates climbed in both groups by 1 year (1.09% vs. 0.21%; P = .01).

No other secondary endpoints differed significantly at 30 days or at 1 year. Even though some were numerically higher after redo at 1 year, such as major vascular complications (1.25 vs. 1.60; P = .51), others were lower, such as new-start dialysis (1.62 vs. 0.98; P = .26). All-cause readmission rates at 1 year were nearly identical (32.56% vs. 32.23%; P = .82).

Consistent with the comparable outcomes on the hard endpoints, major and similar improvements were seen in both the redo and the propensity-matched native TAVR patients on the Kansas City Cardiomyopathy Questionnaire Overall Summary. The slight advantage for the redo group was not significant at 30 days, but the degree of improvement was greater after the redo than after native TAVR at 1 year (15% vs. 10%; P = .03).

“You bring good news,” said Alain G. Cribier, MD, director of cardiology, Charles Nicolle Hospital, University of Rouen, France. Widely regarded as the father of TAVR for his first-in-human series in 2002, Dr. Cribier said that there are several reassuring take-home messages from this study.

“First, these data tell us that the redo rate is extremely low,” he said, noting that the registry data suggests a risk well below 1%. “Second, we are seeing from this data that there are no more complications [than TAVR in a native valve] if you need to do this.”
 

Redo patients are generally sicker

The propensity matching was designed to eliminate baseline differences for the outcome comparisons, but Dr. Makkar did point out that redo-TAVR patients were sicker than the native TAVR patients. For example, when compared prior to propensity matching, the STS score was higher (8.3 vs. 5.2; P < .01), more patients had atrial fibrillation (47.9% vs. 36.2%; P < .01), and more patients had a prior stroke (15.0% vs. 10.7%; P < .01).

The registry only has follow-up out to 1 year, but participating patients were matched to a claims database to capture outcomes out to 3 years. Mortality rates at long-term follow-up were not significantly different for redo vs. native TAVR (42.2% vs. 40.3% respectively; P = .98); for the entire dataset or when compared in subgroups defined by Edwards valve redo of an Edwards valve (P = .909) or an Edwards valve redo of a non-Edwards device (P = .871).

Whether an early redo, defined as 12 months after the index TAVR procedure, or a late redo, the rate of mortality ranged from approximately 16% to 18% with no significant difference between redo and native TAVR.

A moderator for the late-breaking trials session where these data were presented, Darren Mylotte, MD, a consultant in cardiology for the Galway University Hospitals, Ireland, challenged Dr. Makkar about the potential for selection bias. He said redo patients might be the ones that interventionalists feel confident about helping, making this comparison unrepresentative.

“I think that the selection bias is likely to cut both ways,” Dr. Makkar replied. For many patients with a failed TAVR, he explained that clinicians might think, “There is nothing to be done for this patient except to try a redo.”

Dr. Makkar reports financial relationships with Abbott, Cordis, Edwards Lifesciences, and Medtronic. Dr. Cribier reports a financial relationship with Edwards Lifesciences. Dr. Mylotte reports no potential conflicts of interest.

Even after 3 years of follow-up, redo transcatheter aortic valve replacement (TAVR) performs about as well as the first procedure, whether compared for hard endpoints, such as death and stroke, or for softer endpoints, such as function and quality of life, new registry data suggest.

The findings generally support redo-TAVR with balloon-expandable devices as “a reasonable treatment option for failed transcatheter heart valves,” reported Rajendra Makkar, MD, associate director, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles.

The results were presented at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

Data for this analysis were drawn from 348,338 TAVR procedures with the Edwards balloon-expandable valves in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Replacement Registry.

Of these, 1,216 were redo procedures. In 475 of the cases, the redo was performed in a patient whose first procedure was with an Edwards device. In the remaining 741 cases, the Edwards device replaced a different prosthetic heart valve. The median time to the redo from the first procedure was 26 months.

For the analysis, the redo-TAVRs were compared with native TAVR patients through 1:1 propensity matching employing 35 covariates, such as age, body mass index (BMI), baseline comorbidities, prior cardiovascular procedures, valve size, and Society of Thoracic Surgeons risk score.
 

Low death and stroke rates following TAVR redos

The rates of all-cause death or stroke within hospital (4.7% vs. 3.9%; P = .32) and at 30 days (6.1% vs. 5.9%; P = .77) were numerically but not statistically higher in the redo group.

At 1 year, the rates of death (17.3% vs. 17.7%; P = .961) and stroke (3.3% vs. 3.5%; P = .982) were numerically but not significantly lower among those who underwent a redo procedure.

The secondary endpoints told the same story. The one exception was the higher aortic valve reintervention rate (0.61% vs. 0.09%; P = .03) at 30 days in the redo group. This did reach statistical significance, but Dr. Makkar pointed out rates were very low regardless. The rates climbed in both groups by 1 year (1.09% vs. 0.21%; P = .01).

No other secondary endpoints differed significantly at 30 days or at 1 year. Even though some were numerically higher after redo at 1 year, such as major vascular complications (1.25 vs. 1.60; P = .51), others were lower, such as new-start dialysis (1.62 vs. 0.98; P = .26). All-cause readmission rates at 1 year were nearly identical (32.56% vs. 32.23%; P = .82).

Consistent with the comparable outcomes on the hard endpoints, major and similar improvements were seen in both the redo and the propensity-matched native TAVR patients on the Kansas City Cardiomyopathy Questionnaire Overall Summary. The slight advantage for the redo group was not significant at 30 days, but the degree of improvement was greater after the redo than after native TAVR at 1 year (15% vs. 10%; P = .03).

“You bring good news,” said Alain G. Cribier, MD, director of cardiology, Charles Nicolle Hospital, University of Rouen, France. Widely regarded as the father of TAVR for his first-in-human series in 2002, Dr. Cribier said that there are several reassuring take-home messages from this study.

“First, these data tell us that the redo rate is extremely low,” he said, noting that the registry data suggests a risk well below 1%. “Second, we are seeing from this data that there are no more complications [than TAVR in a native valve] if you need to do this.”
 

Redo patients are generally sicker

The propensity matching was designed to eliminate baseline differences for the outcome comparisons, but Dr. Makkar did point out that redo-TAVR patients were sicker than the native TAVR patients. For example, when compared prior to propensity matching, the STS score was higher (8.3 vs. 5.2; P < .01), more patients had atrial fibrillation (47.9% vs. 36.2%; P < .01), and more patients had a prior stroke (15.0% vs. 10.7%; P < .01).

The registry only has follow-up out to 1 year, but participating patients were matched to a claims database to capture outcomes out to 3 years. Mortality rates at long-term follow-up were not significantly different for redo vs. native TAVR (42.2% vs. 40.3% respectively; P = .98); for the entire dataset or when compared in subgroups defined by Edwards valve redo of an Edwards valve (P = .909) or an Edwards valve redo of a non-Edwards device (P = .871).

Whether an early redo, defined as 12 months after the index TAVR procedure, or a late redo, the rate of mortality ranged from approximately 16% to 18% with no significant difference between redo and native TAVR.

A moderator for the late-breaking trials session where these data were presented, Darren Mylotte, MD, a consultant in cardiology for the Galway University Hospitals, Ireland, challenged Dr. Makkar about the potential for selection bias. He said redo patients might be the ones that interventionalists feel confident about helping, making this comparison unrepresentative.

“I think that the selection bias is likely to cut both ways,” Dr. Makkar replied. For many patients with a failed TAVR, he explained that clinicians might think, “There is nothing to be done for this patient except to try a redo.”

Dr. Makkar reports financial relationships with Abbott, Cordis, Edwards Lifesciences, and Medtronic. Dr. Cribier reports a financial relationship with Edwards Lifesciences. Dr. Mylotte reports no potential conflicts of interest.

BOSTON – In emergency department stroke consultations, the National Institute of Health Stroke Scale (NIHSS) alone does not appear to be a reliable guide for ordering diagnostic tests for a large vessel occlusion (LVO), according to large body of data presented at the 2023 annual meeting of the American Academy of Neurology.

If the goal is not to miss any LVOs, there is no NIHSS score below which these do not occur, according to Theresa Sevilis, DO, regional medical director, TeleSpecialists, Fort Myers, Fla.

For example, her evaluation of a large and nationally representative dataset shows that more than 10% of the LVOs eventually identified and accepted for intervention would be missed with a cutoff of NIHSS score of 6 or higher. Moving the cutoff NIHSS score to 4 or greater, 6% of LVOs among the 23,166 strokes evaluated would have gone undetected.

“The current guidelines do not address low NIHSS score largely due to a paucity of data,” according to Dr. Sevilis, who showed data indicating that there is great variation among institutions in regard to ordering computed tomography angiography (CTA). She indicated that CTA is the current imaging standard for detecting LVO.
 

Large prospective dataset

The data for this study were derived from the TeleCare database, which captures acute stroke consultations in the emergency departments in 227 facilities in 27 states. Stroke consultations over a 6-month period from July through December 2021 were evaluated. The prospectively collected data were subjected to a multivariate analysis to determine the odds ratio for a CTA performed and LVO found at each NIHSS score of 0 to 5. Scores 6 or above served as the reference.

“Only consults performed within 24 hours [of presentation] were included,” Dr. Sevilis said.

After excluding cases in which no NIHSS score was captured, which represented less than 1% of cases, more than 10,500 cases underwent CTA, providing a rate of 45.5%. The rate of CTA for the whole dataset was 45.5%. Of the study population, 24.6% had a NIHSS score of 6 or above.

“When you are discussing when to perform CTA in patients with a low NIHSS score, you are discussing the majority of patients,” Dr. Sevilis said.

Of those with a NIHSS stroke of 6 or below, 28.2% had a score of 0. Not surprisingly, these were the least likely to have a CTA performed on the basis of an odds ratio of 0.14 and the least likely to have a LVO detected (OR, 0.1). With the exception of a NIHSS stroke score of 1, the likelihood of CTA and LVO climbed incrementally with higher stroke scores. These odds ratios were, respectively, 0.16 and 0.09 for a score of 1; 0.27 and 0.16 for a score of 2; 0.33 and 0.14 for a score of 3; 0.49 and 0.24 for a score of 4; and 0.71 and 0.27 for a score of 5.

In the group with NIHSS score of 6 or above, 24.1% were found to have an LVO. Of these, the proportion accepted for a mechanical thrombectomy was less than half. The intervention acceptance rate for mechanical intervention among LVOs in patients with lower NIHSS scores again fell incrementally by score. The acceptance rate was about 35% among LVO patients with a NIHSS score of 3 or 4 and 25% for those with a score of 0-2.

The interpretation of these data “depends on goals,” Dr. Sevilis said. “If the goal is to not miss a single LVO, then it is important to consider the balance between benefits and risks.”
 

No consistent cutoff

In participating facilities, the protocol for considering CTA to detect and treat LVOs ranges from neurologist choice to cutoffs of NIHSS scores of 2, 4, and 6, according to Dr. Sevilis. Where the data suggest that a cutoff of 4 or above might be reasonable, she said that NIHSS scoring is not a useful tool for those “who do not want to miss any LVOs.”

These data are based on emergency room stroke consultations and not on confirmed strokes,” Dr. Sevilis emphasized. Indeed, she noted that the final discharge diagnosis was not available. Recognizing that the analysis was not performed on a population with confirmed strokes is particularly important for understanding the limited rate of CTAs performed even in those with relatively high NIHSS scores. She noted this could be explained by many different reasons, including suspicion of hemorrhage or clinical features that took the workup in a different direction.
 

Reconsidering protocols

Based on the large sample size, Dr. Sevilis contended that it is likely that these data are representative, but she considers this study a first step toward considering protocols and developing guidelines for addressing stroke alerts in the emergency department.

A more important step will be ongoing trials designed specifically to generate data to answer this question. Pascal Jabbour, MD, chief of the division of neurovascular and endovascular neurosurgery, Thomas Jefferson University Hospitals, Philadelphia, is participating in one of these trials. He agreed with the premise that better evidence-based criteria are needed when evaluating acute stroke patients with a potential LVO.

The trial in which he is a coinvestigator, called ENDOLOW, is testing the hypothesis that outcomes will be better if acute stroke patients with a LVO and a low baseline NIHSS score (< 5) are treated with immediate thrombectomy rather than medical management. If this hypothesis is confirmed in the randomized ENDOLOW, it will provide an evidence basis for an approach already being practiced at some centers.

“There should be a very low threshold for CTA,” said Dr. Jabbour in an interview. This imaging “takes less than 2 minutes and it can provide the basis for a life-saving endovascular thrombectomy if a LVO is found.”

It is already well known that LVO is not restricted only to patients with an elevated NIHSS score, he said.

For determining whether to order a CTA, “I do not agree with NIHSS score of 6 or above. There is no absolute number below which risk of missing a LVO is eliminated,” Dr. Jabbour said. He also argued against relying on NIHSS score without considering other clinical features, particularly cortical signs, which should raise suspicion of a LVO regardless of NIHSS score.

One problem is that NIHSS scores are not static. Decompensation can be rapid with the NIHSS score quickly climbing. When this happens, the delay in treatment might lead to a preventable adverse outcome.

“There is a change in the paradigm now that we have more evidence of a benefit from aggressive treatment in the right candidates,” according to Dr. Jabbour, referring to the recently published SELECT2 trial. In that trial, on which Dr. Jabbour served as a coauthor, patients with LVO and large territory infarct were randomized to thrombectomy or medical care within 24 hours of a stroke. It was stopped early for efficacy because of the increased functional independence (20% vs. 7%) in the surgical intervention group.

If the ongoing trials establish better criteria for ruling in or out the presence of LVO in patients with acute stroke, Dr. Jabbour predicted that guidelines will be written to standardize practice.

Dr. Sevilis reports no potential conflicts of interest. Dr. Jabbour has financial relationships with Cerenovus, Medtronic, and Microvention.
 

BOSTON – In emergency department stroke consultations, the National Institute of Health Stroke Scale (NIHSS) alone does not appear to be a reliable guide for ordering diagnostic tests for a large vessel occlusion (LVO), according to large body of data presented at the 2023 annual meeting of the American Academy of Neurology.

If the goal is not to miss any LVOs, there is no NIHSS score below which these do not occur, according to Theresa Sevilis, DO, regional medical director, TeleSpecialists, Fort Myers, Fla.

For example, her evaluation of a large and nationally representative dataset shows that more than 10% of the LVOs eventually identified and accepted for intervention would be missed with a cutoff of NIHSS score of 6 or higher. Moving the cutoff NIHSS score to 4 or greater, 6% of LVOs among the 23,166 strokes evaluated would have gone undetected.

“The current guidelines do not address low NIHSS score largely due to a paucity of data,” according to Dr. Sevilis, who showed data indicating that there is great variation among institutions in regard to ordering computed tomography angiography (CTA). She indicated that CTA is the current imaging standard for detecting LVO.
 

Large prospective dataset

The data for this study were derived from the TeleCare database, which captures acute stroke consultations in the emergency departments in 227 facilities in 27 states. Stroke consultations over a 6-month period from July through December 2021 were evaluated. The prospectively collected data were subjected to a multivariate analysis to determine the odds ratio for a CTA performed and LVO found at each NIHSS score of 0 to 5. Scores 6 or above served as the reference.

“Only consults performed within 24 hours [of presentation] were included,” Dr. Sevilis said.

After excluding cases in which no NIHSS score was captured, which represented less than 1% of cases, more than 10,500 cases underwent CTA, providing a rate of 45.5%. The rate of CTA for the whole dataset was 45.5%. Of the study population, 24.6% had a NIHSS score of 6 or above.

“When you are discussing when to perform CTA in patients with a low NIHSS score, you are discussing the majority of patients,” Dr. Sevilis said.

Of those with a NIHSS stroke of 6 or below, 28.2% had a score of 0. Not surprisingly, these were the least likely to have a CTA performed on the basis of an odds ratio of 0.14 and the least likely to have a LVO detected (OR, 0.1). With the exception of a NIHSS stroke score of 1, the likelihood of CTA and LVO climbed incrementally with higher stroke scores. These odds ratios were, respectively, 0.16 and 0.09 for a score of 1; 0.27 and 0.16 for a score of 2; 0.33 and 0.14 for a score of 3; 0.49 and 0.24 for a score of 4; and 0.71 and 0.27 for a score of 5.

In the group with NIHSS score of 6 or above, 24.1% were found to have an LVO. Of these, the proportion accepted for a mechanical thrombectomy was less than half. The intervention acceptance rate for mechanical intervention among LVOs in patients with lower NIHSS scores again fell incrementally by score. The acceptance rate was about 35% among LVO patients with a NIHSS score of 3 or 4 and 25% for those with a score of 0-2.

The interpretation of these data “depends on goals,” Dr. Sevilis said. “If the goal is to not miss a single LVO, then it is important to consider the balance between benefits and risks.”
 

No consistent cutoff

In participating facilities, the protocol for considering CTA to detect and treat LVOs ranges from neurologist choice to cutoffs of NIHSS scores of 2, 4, and 6, according to Dr. Sevilis. Where the data suggest that a cutoff of 4 or above might be reasonable, she said that NIHSS scoring is not a useful tool for those “who do not want to miss any LVOs.”

These data are based on emergency room stroke consultations and not on confirmed strokes,” Dr. Sevilis emphasized. Indeed, she noted that the final discharge diagnosis was not available. Recognizing that the analysis was not performed on a population with confirmed strokes is particularly important for understanding the limited rate of CTAs performed even in those with relatively high NIHSS scores. She noted this could be explained by many different reasons, including suspicion of hemorrhage or clinical features that took the workup in a different direction.
 

Reconsidering protocols

Based on the large sample size, Dr. Sevilis contended that it is likely that these data are representative, but she considers this study a first step toward considering protocols and developing guidelines for addressing stroke alerts in the emergency department.

A more important step will be ongoing trials designed specifically to generate data to answer this question. Pascal Jabbour, MD, chief of the division of neurovascular and endovascular neurosurgery, Thomas Jefferson University Hospitals, Philadelphia, is participating in one of these trials. He agreed with the premise that better evidence-based criteria are needed when evaluating acute stroke patients with a potential LVO.

The trial in which he is a coinvestigator, called ENDOLOW, is testing the hypothesis that outcomes will be better if acute stroke patients with a LVO and a low baseline NIHSS score (< 5) are treated with immediate thrombectomy rather than medical management. If this hypothesis is confirmed in the randomized ENDOLOW, it will provide an evidence basis for an approach already being practiced at some centers.

“There should be a very low threshold for CTA,” said Dr. Jabbour in an interview. This imaging “takes less than 2 minutes and it can provide the basis for a life-saving endovascular thrombectomy if a LVO is found.”

It is already well known that LVO is not restricted only to patients with an elevated NIHSS score, he said.

For determining whether to order a CTA, “I do not agree with NIHSS score of 6 or above. There is no absolute number below which risk of missing a LVO is eliminated,” Dr. Jabbour said. He also argued against relying on NIHSS score without considering other clinical features, particularly cortical signs, which should raise suspicion of a LVO regardless of NIHSS score.

One problem is that NIHSS scores are not static. Decompensation can be rapid with the NIHSS score quickly climbing. When this happens, the delay in treatment might lead to a preventable adverse outcome.

“There is a change in the paradigm now that we have more evidence of a benefit from aggressive treatment in the right candidates,” according to Dr. Jabbour, referring to the recently published SELECT2 trial. In that trial, on which Dr. Jabbour served as a coauthor, patients with LVO and large territory infarct were randomized to thrombectomy or medical care within 24 hours of a stroke. It was stopped early for efficacy because of the increased functional independence (20% vs. 7%) in the surgical intervention group.

If the ongoing trials establish better criteria for ruling in or out the presence of LVO in patients with acute stroke, Dr. Jabbour predicted that guidelines will be written to standardize practice.

Dr. Sevilis reports no potential conflicts of interest. Dr. Jabbour has financial relationships with Cerenovus, Medtronic, and Microvention.
 

BOSTON – In emergency department stroke consultations, the National Institute of Health Stroke Scale (NIHSS) alone does not appear to be a reliable guide for ordering diagnostic tests for a large vessel occlusion (LVO), according to large body of data presented at the 2023 annual meeting of the American Academy of Neurology.

If the goal is not to miss any LVOs, there is no NIHSS score below which these do not occur, according to Theresa Sevilis, DO, regional medical director, TeleSpecialists, Fort Myers, Fla.

For example, her evaluation of a large and nationally representative dataset shows that more than 10% of the LVOs eventually identified and accepted for intervention would be missed with a cutoff of NIHSS score of 6 or higher. Moving the cutoff NIHSS score to 4 or greater, 6% of LVOs among the 23,166 strokes evaluated would have gone undetected.

“The current guidelines do not address low NIHSS score largely due to a paucity of data,” according to Dr. Sevilis, who showed data indicating that there is great variation among institutions in regard to ordering computed tomography angiography (CTA). She indicated that CTA is the current imaging standard for detecting LVO.
 

Large prospective dataset

The data for this study were derived from the TeleCare database, which captures acute stroke consultations in the emergency departments in 227 facilities in 27 states. Stroke consultations over a 6-month period from July through December 2021 were evaluated. The prospectively collected data were subjected to a multivariate analysis to determine the odds ratio for a CTA performed and LVO found at each NIHSS score of 0 to 5. Scores 6 or above served as the reference.

“Only consults performed within 24 hours [of presentation] were included,” Dr. Sevilis said.

After excluding cases in which no NIHSS score was captured, which represented less than 1% of cases, more than 10,500 cases underwent CTA, providing a rate of 45.5%. The rate of CTA for the whole dataset was 45.5%. Of the study population, 24.6% had a NIHSS score of 6 or above.

“When you are discussing when to perform CTA in patients with a low NIHSS score, you are discussing the majority of patients,” Dr. Sevilis said.

Of those with a NIHSS stroke of 6 or below, 28.2% had a score of 0. Not surprisingly, these were the least likely to have a CTA performed on the basis of an odds ratio of 0.14 and the least likely to have a LVO detected (OR, 0.1). With the exception of a NIHSS stroke score of 1, the likelihood of CTA and LVO climbed incrementally with higher stroke scores. These odds ratios were, respectively, 0.16 and 0.09 for a score of 1; 0.27 and 0.16 for a score of 2; 0.33 and 0.14 for a score of 3; 0.49 and 0.24 for a score of 4; and 0.71 and 0.27 for a score of 5.

In the group with NIHSS score of 6 or above, 24.1% were found to have an LVO. Of these, the proportion accepted for a mechanical thrombectomy was less than half. The intervention acceptance rate for mechanical intervention among LVOs in patients with lower NIHSS scores again fell incrementally by score. The acceptance rate was about 35% among LVO patients with a NIHSS score of 3 or 4 and 25% for those with a score of 0-2.

The interpretation of these data “depends on goals,” Dr. Sevilis said. “If the goal is to not miss a single LVO, then it is important to consider the balance between benefits and risks.”
 

No consistent cutoff

In participating facilities, the protocol for considering CTA to detect and treat LVOs ranges from neurologist choice to cutoffs of NIHSS scores of 2, 4, and 6, according to Dr. Sevilis. Where the data suggest that a cutoff of 4 or above might be reasonable, she said that NIHSS scoring is not a useful tool for those “who do not want to miss any LVOs.”

These data are based on emergency room stroke consultations and not on confirmed strokes,” Dr. Sevilis emphasized. Indeed, she noted that the final discharge diagnosis was not available. Recognizing that the analysis was not performed on a population with confirmed strokes is particularly important for understanding the limited rate of CTAs performed even in those with relatively high NIHSS scores. She noted this could be explained by many different reasons, including suspicion of hemorrhage or clinical features that took the workup in a different direction.
 

Reconsidering protocols

Based on the large sample size, Dr. Sevilis contended that it is likely that these data are representative, but she considers this study a first step toward considering protocols and developing guidelines for addressing stroke alerts in the emergency department.

A more important step will be ongoing trials designed specifically to generate data to answer this question. Pascal Jabbour, MD, chief of the division of neurovascular and endovascular neurosurgery, Thomas Jefferson University Hospitals, Philadelphia, is participating in one of these trials. He agreed with the premise that better evidence-based criteria are needed when evaluating acute stroke patients with a potential LVO.

The trial in which he is a coinvestigator, called ENDOLOW, is testing the hypothesis that outcomes will be better if acute stroke patients with a LVO and a low baseline NIHSS score (< 5) are treated with immediate thrombectomy rather than medical management. If this hypothesis is confirmed in the randomized ENDOLOW, it will provide an evidence basis for an approach already being practiced at some centers.

“There should be a very low threshold for CTA,” said Dr. Jabbour in an interview. This imaging “takes less than 2 minutes and it can provide the basis for a life-saving endovascular thrombectomy if a LVO is found.”

It is already well known that LVO is not restricted only to patients with an elevated NIHSS score, he said.

For determining whether to order a CTA, “I do not agree with NIHSS score of 6 or above. There is no absolute number below which risk of missing a LVO is eliminated,” Dr. Jabbour said. He also argued against relying on NIHSS score without considering other clinical features, particularly cortical signs, which should raise suspicion of a LVO regardless of NIHSS score.

One problem is that NIHSS scores are not static. Decompensation can be rapid with the NIHSS score quickly climbing. When this happens, the delay in treatment might lead to a preventable adverse outcome.

“There is a change in the paradigm now that we have more evidence of a benefit from aggressive treatment in the right candidates,” according to Dr. Jabbour, referring to the recently published SELECT2 trial. In that trial, on which Dr. Jabbour served as a coauthor, patients with LVO and large territory infarct were randomized to thrombectomy or medical care within 24 hours of a stroke. It was stopped early for efficacy because of the increased functional independence (20% vs. 7%) in the surgical intervention group.

If the ongoing trials establish better criteria for ruling in or out the presence of LVO in patients with acute stroke, Dr. Jabbour predicted that guidelines will be written to standardize practice.

Dr. Sevilis reports no potential conflicts of interest. Dr. Jabbour has financial relationships with Cerenovus, Medtronic, and Microvention.
 

BOSTON – In patients with radiologically isolated syndrome (RIS) predictive of multiple sclerosis (MS), teriflunomide reduced the risk of a demyelinating event by more than 60% over a 2-year period, according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.

Bruce Jancin/MDedge News

“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
 

TERIS trial data

In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.

During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.

Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.

“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
 

Caution warranted when interpreting the findings

The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.

“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.

“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.

Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
 

Challenging the traditional definition of MS

The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.

“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”

“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.

“Gaining a more refined sense of who we should treat will require more work,” he said.

These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.

“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”

Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.

BOSTON – In patients with radiologically isolated syndrome (RIS) predictive of multiple sclerosis (MS), teriflunomide reduced the risk of a demyelinating event by more than 60% over a 2-year period, according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.

Bruce Jancin/MDedge News

“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
 

TERIS trial data

In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.

During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.

Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.

“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
 

Caution warranted when interpreting the findings

The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.

“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.

“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.

Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
 

Challenging the traditional definition of MS

The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.

“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”

“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.

“Gaining a more refined sense of who we should treat will require more work,” he said.

These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.

“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”

Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.

BOSTON – In patients with radiologically isolated syndrome (RIS) predictive of multiple sclerosis (MS), teriflunomide reduced the risk of a demyelinating event by more than 60% over a 2-year period, according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.

Bruce Jancin/MDedge News

“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
 

TERIS trial data

In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.

During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.

Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.

“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
 

Caution warranted when interpreting the findings

The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.

“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.

“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.

Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
 

Challenging the traditional definition of MS

The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.

“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”

“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.

“Gaining a more refined sense of who we should treat will require more work,” he said.

These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.

“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”

Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.

BOSTON – A novel levodopa/carbidopa delivery system fitted to a retainer worn in the mouth appears to achieve the advantages of continuous drug delivery without the need for surgery or external pumps, according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.

Icahn School of Medicine

On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
 

A novel strategy

Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.

“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.

Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
 

Encouraging trial results

In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.

When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.

Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.

“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.

There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.

“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.

Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.

“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.
 

More delivery strategies are needed

This device is in an early phase of development, but several specialists in Parkinson’s disease agreed that there is a need for more strategies to provide continuous levodopa in patients with advancing symptoms. Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Fla., is among them.

“Novel delivery devices that can provide more continuous levodopa delivery would be an important therapeutic advance,” Dr. Isaacson said. He called levodopa “the cornerstone of treatment through the course of Parkinson’s disease,” but more physiologic dosing in advancing disease has been a challenge.

“While there are many therapies currently available to manage OFF time, many people living with Parkinson’s disease continue to spend only half of their waking day with good ON time,” he added.

The currently approved method of delivering continuous levodopa through a surgically placed catheter into the gastrointestinal system is effective, but has limitations, according to Aaron L. Ellenbogen, MD, a neurologist at Beaumont Hospital, Farmington Hills, Mich.

“One of the challenges with the current treatment landscape of Parkinson’s disease is that medication can be absorbed variably through the gastrointestinal system,” he said. “As the disease progresses, this often becomes more troublesome.” Although this new device is likely to share this issue, Dr. Ellenbogen said that several devices might be useful to match patients with the one that works best for them.

Dr. Olanow is the founder and CEO of Clintrex Research Corporation, through which he also serves as chief medical officer of SynAgile, the company developing DopaFuse. Dr. Isaacson has financial relationships with more than 30 companies, including those that produce levodopa and levodopa delivery systems. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva.

BOSTON – A novel levodopa/carbidopa delivery system fitted to a retainer worn in the mouth appears to achieve the advantages of continuous drug delivery without the need for surgery or external pumps, according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.

Icahn School of Medicine

On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
 

A novel strategy

Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.

“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.

Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
 

Encouraging trial results

In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.

When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.

Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.

“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.

There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.

“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.

Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.

“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.
 

More delivery strategies are needed

This device is in an early phase of development, but several specialists in Parkinson’s disease agreed that there is a need for more strategies to provide continuous levodopa in patients with advancing symptoms. Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Fla., is among them.

“Novel delivery devices that can provide more continuous levodopa delivery would be an important therapeutic advance,” Dr. Isaacson said. He called levodopa “the cornerstone of treatment through the course of Parkinson’s disease,” but more physiologic dosing in advancing disease has been a challenge.

“While there are many therapies currently available to manage OFF time, many people living with Parkinson’s disease continue to spend only half of their waking day with good ON time,” he added.

The currently approved method of delivering continuous levodopa through a surgically placed catheter into the gastrointestinal system is effective, but has limitations, according to Aaron L. Ellenbogen, MD, a neurologist at Beaumont Hospital, Farmington Hills, Mich.

“One of the challenges with the current treatment landscape of Parkinson’s disease is that medication can be absorbed variably through the gastrointestinal system,” he said. “As the disease progresses, this often becomes more troublesome.” Although this new device is likely to share this issue, Dr. Ellenbogen said that several devices might be useful to match patients with the one that works best for them.

Dr. Olanow is the founder and CEO of Clintrex Research Corporation, through which he also serves as chief medical officer of SynAgile, the company developing DopaFuse. Dr. Isaacson has financial relationships with more than 30 companies, including those that produce levodopa and levodopa delivery systems. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva.

BOSTON – A novel levodopa/carbidopa delivery system fitted to a retainer worn in the mouth appears to achieve the advantages of continuous drug delivery without the need for surgery or external pumps, according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.

Icahn School of Medicine

On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
 

A novel strategy

Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.

“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.

Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
 

Encouraging trial results

In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.

When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.

Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.

“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.

There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.

“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.

Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.

“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.
 

More delivery strategies are needed

This device is in an early phase of development, but several specialists in Parkinson’s disease agreed that there is a need for more strategies to provide continuous levodopa in patients with advancing symptoms. Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Fla., is among them.

“Novel delivery devices that can provide more continuous levodopa delivery would be an important therapeutic advance,” Dr. Isaacson said. He called levodopa “the cornerstone of treatment through the course of Parkinson’s disease,” but more physiologic dosing in advancing disease has been a challenge.

“While there are many therapies currently available to manage OFF time, many people living with Parkinson’s disease continue to spend only half of their waking day with good ON time,” he added.

The currently approved method of delivering continuous levodopa through a surgically placed catheter into the gastrointestinal system is effective, but has limitations, according to Aaron L. Ellenbogen, MD, a neurologist at Beaumont Hospital, Farmington Hills, Mich.

“One of the challenges with the current treatment landscape of Parkinson’s disease is that medication can be absorbed variably through the gastrointestinal system,” he said. “As the disease progresses, this often becomes more troublesome.” Although this new device is likely to share this issue, Dr. Ellenbogen said that several devices might be useful to match patients with the one that works best for them.

Dr. Olanow is the founder and CEO of Clintrex Research Corporation, through which he also serves as chief medical officer of SynAgile, the company developing DopaFuse. Dr. Isaacson has financial relationships with more than 30 companies, including those that produce levodopa and levodopa delivery systems. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva.