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Cardiologists can perform stroke thrombectomy to fill ‘unmet need’
Cardiologists experienced in cardiac interventions can competently perform stroke thrombectomy after a short period of training, with outcomes comparable to those achieved by neuroradiology centers, a new study suggests.
“Using interventional cardiologists in this way will help address the huge unmet need for stroke thrombectomy that currently exists,” senior author Petr Widimsky, MD, said in an interview.
Although this may be a feasible way forward in Europe, there is strong opposition to such a proposal from U.S. neurointerventionalists.
The study, published in the April 12 issue of JACC: Cardiovascular Interventions, describes the establishment of a stroke thrombectomy program in University Hospital Kralovske Vinohrady, a large tertiary hospital in Prague, Czech Republic.
The hospital did not have a neurointerventional program until 2012 when a joint program was started involving an experienced team of cardiologists, angiologists, and one interventional radiologist who trained the cardiologists on the thrombectomy procedure.
The current paper reports on the outcomes of the 333 patients with large vessel occlusion stroke treated under this program between October 2012 and December 2019.
The decision to perform catheter-based thrombectomy was made by a neurologist and was based on acute stroke clinical symptoms and CT angiographic findings.
Results show that functional clinical outcomes, assessed via the Modified Rankin Scale (mRS) score at 3 months, did not vary significantly across years 2012 to 2019, with a favorable outcome (mRS 0 to 2) achieved in 47.9% of patients.
Symptomatic intracerebral hemorrhage occurred in 19 patients (5.7%) and embolization in a new vascular territory occurred in 6 patients (1.8%), outcomes similar to those of neuroradiology centers.
The desired clinical results were achieved from the onset of the program, without any signs of a learning curve effect, they reported.
“These findings support the potential role of interventional cardiac cath labs in the treatment of acute stroke in regions where this therapy is not readily available due to the lack of neurointerventionalists,” the authors concluded.
“Our main message is that our results were excellent from the beginning,” Dr. Widimsky said. “When centers prepare properly, they can achieve excellent results from the beginning with cardiologists who are experienced in interventional procedures and who have spent sufficient time learning about the brain.”
The authors noted that despite thrombectomy being an extremely beneficial treatment for severe stroke, many eligible patients remain untreated, largely because of a lack of neurointerventionalists in many regions worldwide. They estimate that about 15% of all stroke patients are eligible for thrombectomy but only around 2% of stroke patients in Europe actually receive such treatment.
Dr. Widimsky, an interventional cardiologist, first thought of the idea of using cardiologists to perform stroke thrombectomies after a good friend and colleague suffered a severe stroke in 2010.
“This made us realize that our hospital needed to be more active in the stroke field,” he said. “We decided that we needed to start doing stroke interventions.”
But the major problem was the lack of neurointerventionalists.
“There are not enough neurointerventionalists in Europe. Interventional cardiologists can perform thousands of procedures every year whereas a neurointerventionalist will at best perform hundreds a year. It is quicker and simpler to train the cardiologist to do it,” Dr. Widimsky said.
They hired one neurointerventionalist to lead the program. “He was our tutor, he taught us his skills,” Dr. Widimsky said. “The cath lab is open 24/7, but if we only have one neurointerventionalist we cannot offer a 24/7 service for stroke thrombectomy. But if we merge with cardiology then we can,” he added.
Their hospital is a very busy center for myocardial infarction, percutaneous coronary intervention, and carotid stenting, he noted. “It is not difficult to make the step from that to stroke thrombectomy. Interventional cardiologists are used to performing carotid and coronary artery stenting. Stroke thrombectomy is a similar technique. The thrombectomy procedure is different from coronary angioplasty but it is not more difficult. Actually, I think coronary angioplasty can be more difficult.”
Dr. Widimsky explained that cardiologists need to learn about the brain anatomy and physiology and learn the stroke imaging techniques. “I spent 1 month in the U.S. learning stroke interventions working with simulators,” he said. “I think interventional cardiologists can learn what they need to know in about 6 months. I would recommend they should watch about 50 procedures and perform at least 25 under supervision.”
He said this model is the way forward and hopes it will become routine. Thrombectomy is “tremendously effective” in improving outcomes in severe strokes, with a number needed to treat (NNT) of just 2.6 to prevent long-term disability in one patient, he said, while other procedures can have NNTs of 50 or more.
“But millions of patients with acute severe stroke are not getting this life-changing treatment,” he added. “We must do everything we can to make this service available to as many patients as possible.”
Dr. Widimsky acknowledges that there has been opposition to this idea from the neurointerventionalist professional bodies but this has lessened recently, at least in Europe. And a program that allows interventionalists with experience in extracranial carotid and vertebral endovascular procedures to “fast-track” technical training has now been proposed.
“There is an enormous unmet need for stroke thrombectomy in Europe, with some countries needing to increase the number of procedures done by 10 or 20 times. These include the U.K., Sweden, Italy, Spain, and Portugal. This cannot be done without cardiology,” Dr. Widimsky said.
Editorial strongly supportive
An accompanying editorial strongly endorses the idea of using interdisciplinary teams to deliver high standard stroke care.
Marius Hornung, MD, and Horst Sievert, MD, from CardioVascular Center Frankfurt (Germany), point out that many experienced cardiologists are trained in performing carotid artery interventions and are therefore experienced in accessing the supra-aortic arteries.
“To be able to guarantee optimized stroke therapy as soon as possible, disputes over competence among the individual medical societies involved must be ended,” they wrote.
They advocate for the creation of interdisciplinary teams, with diagnostics, patient selection, and follow-up care remaining the core competencies and tasks of neurology; in addition, they call for appropriately trained and experienced physicians – regardless of their specialties – performing acute stroke interventions and endovascular thrombectomy.
“Such a network must be installed as soon as possible to fulfill the mantra ‘time is brain’ ... and not losing unnecessary time to patient transfer, or continuing to offer only the second-best therapy,” they concluded.
Opposition in the United States
Dr. Widimsky explained that this proposal may not be so applicable to the United States, where the need for more clinicians capable of performing stroke thrombectomies does not appear to be as critical, possibly because vascular neurosurgeons as well as neuroradiologists are qualified to undertake these procedures.
In an interview, J. Mocco, MD, director of the cerebrovascular center, department of neurological surgery, at Mount Sinai Health System, New York, confirmed that this was the case.
“There is no legitimate data to support the claim that there is a lack of an adequate workforce to provide stroke thrombectomy, at least in the U.S.,” he said, adding that, rather, the primary limitation to patient access is a lack of adequate systems of care. “We should learn from the trauma model, which is strongly evidence based, and provide emergency stroke care in a similarly regionalized manner.”
Dr. Mocco, vice president of the Society of NeuroInterventional Surgery, was not impressed with the current study.
“This paper is a retrospective, single-center, unadjudicated, nonindependent assessor case series and therefore, as the authors acknowledge in the limitations section of their paper, it is invalid to compare these data to the results from high-quality, prospective, core-lab, and independent assessor adjudicated randomized trials,” he said. “The supposition that this trial provides evidence that the reported model should be widely considered lacks scientific rigor.”
Furthermore, “the interventional cardiology literature is replete with data regarding the importance of technical expertise and content knowledge,” he added. “Why would that community now propose that such expertise and knowledge is not necessary for the brain?”
Dr. Mocco argues that the concept that interventional cardiologists should be fast-tracked to perform stroke interventions because they use similar tools, navigate blood vessels, and are comfortable working in critical situations, does not hold up.
“Liver surgeons and brain surgeons are both familiar with tissue manipulation, are used to operating in critical situations, and use cautery, scissors, and scalpels; but no one would argue that a brain surgeon should be fast-tracked to perform liver surgery, or vice versa.”
He added: “Stroke patients do not have the luxury of choosing the physician who provides their thrombectomy. We should do everything reasonable to ensure that our systems of care are organized so that these vulnerable patients are treated by physicians who have appropriate knowledge and expertise.”
This study was supported by the Charles University Research program. The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Cardiologists experienced in cardiac interventions can competently perform stroke thrombectomy after a short period of training, with outcomes comparable to those achieved by neuroradiology centers, a new study suggests.
“Using interventional cardiologists in this way will help address the huge unmet need for stroke thrombectomy that currently exists,” senior author Petr Widimsky, MD, said in an interview.
Although this may be a feasible way forward in Europe, there is strong opposition to such a proposal from U.S. neurointerventionalists.
The study, published in the April 12 issue of JACC: Cardiovascular Interventions, describes the establishment of a stroke thrombectomy program in University Hospital Kralovske Vinohrady, a large tertiary hospital in Prague, Czech Republic.
The hospital did not have a neurointerventional program until 2012 when a joint program was started involving an experienced team of cardiologists, angiologists, and one interventional radiologist who trained the cardiologists on the thrombectomy procedure.
The current paper reports on the outcomes of the 333 patients with large vessel occlusion stroke treated under this program between October 2012 and December 2019.
The decision to perform catheter-based thrombectomy was made by a neurologist and was based on acute stroke clinical symptoms and CT angiographic findings.
Results show that functional clinical outcomes, assessed via the Modified Rankin Scale (mRS) score at 3 months, did not vary significantly across years 2012 to 2019, with a favorable outcome (mRS 0 to 2) achieved in 47.9% of patients.
Symptomatic intracerebral hemorrhage occurred in 19 patients (5.7%) and embolization in a new vascular territory occurred in 6 patients (1.8%), outcomes similar to those of neuroradiology centers.
The desired clinical results were achieved from the onset of the program, without any signs of a learning curve effect, they reported.
“These findings support the potential role of interventional cardiac cath labs in the treatment of acute stroke in regions where this therapy is not readily available due to the lack of neurointerventionalists,” the authors concluded.
“Our main message is that our results were excellent from the beginning,” Dr. Widimsky said. “When centers prepare properly, they can achieve excellent results from the beginning with cardiologists who are experienced in interventional procedures and who have spent sufficient time learning about the brain.”
The authors noted that despite thrombectomy being an extremely beneficial treatment for severe stroke, many eligible patients remain untreated, largely because of a lack of neurointerventionalists in many regions worldwide. They estimate that about 15% of all stroke patients are eligible for thrombectomy but only around 2% of stroke patients in Europe actually receive such treatment.
Dr. Widimsky, an interventional cardiologist, first thought of the idea of using cardiologists to perform stroke thrombectomies after a good friend and colleague suffered a severe stroke in 2010.
“This made us realize that our hospital needed to be more active in the stroke field,” he said. “We decided that we needed to start doing stroke interventions.”
But the major problem was the lack of neurointerventionalists.
“There are not enough neurointerventionalists in Europe. Interventional cardiologists can perform thousands of procedures every year whereas a neurointerventionalist will at best perform hundreds a year. It is quicker and simpler to train the cardiologist to do it,” Dr. Widimsky said.
They hired one neurointerventionalist to lead the program. “He was our tutor, he taught us his skills,” Dr. Widimsky said. “The cath lab is open 24/7, but if we only have one neurointerventionalist we cannot offer a 24/7 service for stroke thrombectomy. But if we merge with cardiology then we can,” he added.
Their hospital is a very busy center for myocardial infarction, percutaneous coronary intervention, and carotid stenting, he noted. “It is not difficult to make the step from that to stroke thrombectomy. Interventional cardiologists are used to performing carotid and coronary artery stenting. Stroke thrombectomy is a similar technique. The thrombectomy procedure is different from coronary angioplasty but it is not more difficult. Actually, I think coronary angioplasty can be more difficult.”
Dr. Widimsky explained that cardiologists need to learn about the brain anatomy and physiology and learn the stroke imaging techniques. “I spent 1 month in the U.S. learning stroke interventions working with simulators,” he said. “I think interventional cardiologists can learn what they need to know in about 6 months. I would recommend they should watch about 50 procedures and perform at least 25 under supervision.”
He said this model is the way forward and hopes it will become routine. Thrombectomy is “tremendously effective” in improving outcomes in severe strokes, with a number needed to treat (NNT) of just 2.6 to prevent long-term disability in one patient, he said, while other procedures can have NNTs of 50 or more.
“But millions of patients with acute severe stroke are not getting this life-changing treatment,” he added. “We must do everything we can to make this service available to as many patients as possible.”
Dr. Widimsky acknowledges that there has been opposition to this idea from the neurointerventionalist professional bodies but this has lessened recently, at least in Europe. And a program that allows interventionalists with experience in extracranial carotid and vertebral endovascular procedures to “fast-track” technical training has now been proposed.
“There is an enormous unmet need for stroke thrombectomy in Europe, with some countries needing to increase the number of procedures done by 10 or 20 times. These include the U.K., Sweden, Italy, Spain, and Portugal. This cannot be done without cardiology,” Dr. Widimsky said.
Editorial strongly supportive
An accompanying editorial strongly endorses the idea of using interdisciplinary teams to deliver high standard stroke care.
Marius Hornung, MD, and Horst Sievert, MD, from CardioVascular Center Frankfurt (Germany), point out that many experienced cardiologists are trained in performing carotid artery interventions and are therefore experienced in accessing the supra-aortic arteries.
“To be able to guarantee optimized stroke therapy as soon as possible, disputes over competence among the individual medical societies involved must be ended,” they wrote.
They advocate for the creation of interdisciplinary teams, with diagnostics, patient selection, and follow-up care remaining the core competencies and tasks of neurology; in addition, they call for appropriately trained and experienced physicians – regardless of their specialties – performing acute stroke interventions and endovascular thrombectomy.
“Such a network must be installed as soon as possible to fulfill the mantra ‘time is brain’ ... and not losing unnecessary time to patient transfer, or continuing to offer only the second-best therapy,” they concluded.
Opposition in the United States
Dr. Widimsky explained that this proposal may not be so applicable to the United States, where the need for more clinicians capable of performing stroke thrombectomies does not appear to be as critical, possibly because vascular neurosurgeons as well as neuroradiologists are qualified to undertake these procedures.
In an interview, J. Mocco, MD, director of the cerebrovascular center, department of neurological surgery, at Mount Sinai Health System, New York, confirmed that this was the case.
“There is no legitimate data to support the claim that there is a lack of an adequate workforce to provide stroke thrombectomy, at least in the U.S.,” he said, adding that, rather, the primary limitation to patient access is a lack of adequate systems of care. “We should learn from the trauma model, which is strongly evidence based, and provide emergency stroke care in a similarly regionalized manner.”
Dr. Mocco, vice president of the Society of NeuroInterventional Surgery, was not impressed with the current study.
“This paper is a retrospective, single-center, unadjudicated, nonindependent assessor case series and therefore, as the authors acknowledge in the limitations section of their paper, it is invalid to compare these data to the results from high-quality, prospective, core-lab, and independent assessor adjudicated randomized trials,” he said. “The supposition that this trial provides evidence that the reported model should be widely considered lacks scientific rigor.”
Furthermore, “the interventional cardiology literature is replete with data regarding the importance of technical expertise and content knowledge,” he added. “Why would that community now propose that such expertise and knowledge is not necessary for the brain?”
Dr. Mocco argues that the concept that interventional cardiologists should be fast-tracked to perform stroke interventions because they use similar tools, navigate blood vessels, and are comfortable working in critical situations, does not hold up.
“Liver surgeons and brain surgeons are both familiar with tissue manipulation, are used to operating in critical situations, and use cautery, scissors, and scalpels; but no one would argue that a brain surgeon should be fast-tracked to perform liver surgery, or vice versa.”
He added: “Stroke patients do not have the luxury of choosing the physician who provides their thrombectomy. We should do everything reasonable to ensure that our systems of care are organized so that these vulnerable patients are treated by physicians who have appropriate knowledge and expertise.”
This study was supported by the Charles University Research program. The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Cardiologists experienced in cardiac interventions can competently perform stroke thrombectomy after a short period of training, with outcomes comparable to those achieved by neuroradiology centers, a new study suggests.
“Using interventional cardiologists in this way will help address the huge unmet need for stroke thrombectomy that currently exists,” senior author Petr Widimsky, MD, said in an interview.
Although this may be a feasible way forward in Europe, there is strong opposition to such a proposal from U.S. neurointerventionalists.
The study, published in the April 12 issue of JACC: Cardiovascular Interventions, describes the establishment of a stroke thrombectomy program in University Hospital Kralovske Vinohrady, a large tertiary hospital in Prague, Czech Republic.
The hospital did not have a neurointerventional program until 2012 when a joint program was started involving an experienced team of cardiologists, angiologists, and one interventional radiologist who trained the cardiologists on the thrombectomy procedure.
The current paper reports on the outcomes of the 333 patients with large vessel occlusion stroke treated under this program between October 2012 and December 2019.
The decision to perform catheter-based thrombectomy was made by a neurologist and was based on acute stroke clinical symptoms and CT angiographic findings.
Results show that functional clinical outcomes, assessed via the Modified Rankin Scale (mRS) score at 3 months, did not vary significantly across years 2012 to 2019, with a favorable outcome (mRS 0 to 2) achieved in 47.9% of patients.
Symptomatic intracerebral hemorrhage occurred in 19 patients (5.7%) and embolization in a new vascular territory occurred in 6 patients (1.8%), outcomes similar to those of neuroradiology centers.
The desired clinical results were achieved from the onset of the program, without any signs of a learning curve effect, they reported.
“These findings support the potential role of interventional cardiac cath labs in the treatment of acute stroke in regions where this therapy is not readily available due to the lack of neurointerventionalists,” the authors concluded.
“Our main message is that our results were excellent from the beginning,” Dr. Widimsky said. “When centers prepare properly, they can achieve excellent results from the beginning with cardiologists who are experienced in interventional procedures and who have spent sufficient time learning about the brain.”
The authors noted that despite thrombectomy being an extremely beneficial treatment for severe stroke, many eligible patients remain untreated, largely because of a lack of neurointerventionalists in many regions worldwide. They estimate that about 15% of all stroke patients are eligible for thrombectomy but only around 2% of stroke patients in Europe actually receive such treatment.
Dr. Widimsky, an interventional cardiologist, first thought of the idea of using cardiologists to perform stroke thrombectomies after a good friend and colleague suffered a severe stroke in 2010.
“This made us realize that our hospital needed to be more active in the stroke field,” he said. “We decided that we needed to start doing stroke interventions.”
But the major problem was the lack of neurointerventionalists.
“There are not enough neurointerventionalists in Europe. Interventional cardiologists can perform thousands of procedures every year whereas a neurointerventionalist will at best perform hundreds a year. It is quicker and simpler to train the cardiologist to do it,” Dr. Widimsky said.
They hired one neurointerventionalist to lead the program. “He was our tutor, he taught us his skills,” Dr. Widimsky said. “The cath lab is open 24/7, but if we only have one neurointerventionalist we cannot offer a 24/7 service for stroke thrombectomy. But if we merge with cardiology then we can,” he added.
Their hospital is a very busy center for myocardial infarction, percutaneous coronary intervention, and carotid stenting, he noted. “It is not difficult to make the step from that to stroke thrombectomy. Interventional cardiologists are used to performing carotid and coronary artery stenting. Stroke thrombectomy is a similar technique. The thrombectomy procedure is different from coronary angioplasty but it is not more difficult. Actually, I think coronary angioplasty can be more difficult.”
Dr. Widimsky explained that cardiologists need to learn about the brain anatomy and physiology and learn the stroke imaging techniques. “I spent 1 month in the U.S. learning stroke interventions working with simulators,” he said. “I think interventional cardiologists can learn what they need to know in about 6 months. I would recommend they should watch about 50 procedures and perform at least 25 under supervision.”
He said this model is the way forward and hopes it will become routine. Thrombectomy is “tremendously effective” in improving outcomes in severe strokes, with a number needed to treat (NNT) of just 2.6 to prevent long-term disability in one patient, he said, while other procedures can have NNTs of 50 or more.
“But millions of patients with acute severe stroke are not getting this life-changing treatment,” he added. “We must do everything we can to make this service available to as many patients as possible.”
Dr. Widimsky acknowledges that there has been opposition to this idea from the neurointerventionalist professional bodies but this has lessened recently, at least in Europe. And a program that allows interventionalists with experience in extracranial carotid and vertebral endovascular procedures to “fast-track” technical training has now been proposed.
“There is an enormous unmet need for stroke thrombectomy in Europe, with some countries needing to increase the number of procedures done by 10 or 20 times. These include the U.K., Sweden, Italy, Spain, and Portugal. This cannot be done without cardiology,” Dr. Widimsky said.
Editorial strongly supportive
An accompanying editorial strongly endorses the idea of using interdisciplinary teams to deliver high standard stroke care.
Marius Hornung, MD, and Horst Sievert, MD, from CardioVascular Center Frankfurt (Germany), point out that many experienced cardiologists are trained in performing carotid artery interventions and are therefore experienced in accessing the supra-aortic arteries.
“To be able to guarantee optimized stroke therapy as soon as possible, disputes over competence among the individual medical societies involved must be ended,” they wrote.
They advocate for the creation of interdisciplinary teams, with diagnostics, patient selection, and follow-up care remaining the core competencies and tasks of neurology; in addition, they call for appropriately trained and experienced physicians – regardless of their specialties – performing acute stroke interventions and endovascular thrombectomy.
“Such a network must be installed as soon as possible to fulfill the mantra ‘time is brain’ ... and not losing unnecessary time to patient transfer, or continuing to offer only the second-best therapy,” they concluded.
Opposition in the United States
Dr. Widimsky explained that this proposal may not be so applicable to the United States, where the need for more clinicians capable of performing stroke thrombectomies does not appear to be as critical, possibly because vascular neurosurgeons as well as neuroradiologists are qualified to undertake these procedures.
In an interview, J. Mocco, MD, director of the cerebrovascular center, department of neurological surgery, at Mount Sinai Health System, New York, confirmed that this was the case.
“There is no legitimate data to support the claim that there is a lack of an adequate workforce to provide stroke thrombectomy, at least in the U.S.,” he said, adding that, rather, the primary limitation to patient access is a lack of adequate systems of care. “We should learn from the trauma model, which is strongly evidence based, and provide emergency stroke care in a similarly regionalized manner.”
Dr. Mocco, vice president of the Society of NeuroInterventional Surgery, was not impressed with the current study.
“This paper is a retrospective, single-center, unadjudicated, nonindependent assessor case series and therefore, as the authors acknowledge in the limitations section of their paper, it is invalid to compare these data to the results from high-quality, prospective, core-lab, and independent assessor adjudicated randomized trials,” he said. “The supposition that this trial provides evidence that the reported model should be widely considered lacks scientific rigor.”
Furthermore, “the interventional cardiology literature is replete with data regarding the importance of technical expertise and content knowledge,” he added. “Why would that community now propose that such expertise and knowledge is not necessary for the brain?”
Dr. Mocco argues that the concept that interventional cardiologists should be fast-tracked to perform stroke interventions because they use similar tools, navigate blood vessels, and are comfortable working in critical situations, does not hold up.
“Liver surgeons and brain surgeons are both familiar with tissue manipulation, are used to operating in critical situations, and use cautery, scissors, and scalpels; but no one would argue that a brain surgeon should be fast-tracked to perform liver surgery, or vice versa.”
He added: “Stroke patients do not have the luxury of choosing the physician who provides their thrombectomy. We should do everything reasonable to ensure that our systems of care are organized so that these vulnerable patients are treated by physicians who have appropriate knowledge and expertise.”
This study was supported by the Charles University Research program. The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
COVID vaccine ‘side effect’ or functional neurologic disorder?
The development of unusual movements after COVID-19 vaccination may be a result of functional neurologic disorder rather than being a direct adverse effect of the vaccine, it has been suggested.
Writing in an article published online in JAMA Neurology on April 9, 2021, two neurologists and a psychiatrist report the recent circulation of videos on social media about major neurologic adverse events, including continuous movements of the trunk and limbs or walking difficulties after administration of the COVID-19 vaccine. Some of these videos have been viewed millions of times by the public, they noted.
While these videos may be unsubstantiated, and it is not definitively known if the COVID-19 vaccine was administered in these cases, it was reported in the news that at least one patient was told by their physician that the diagnosis was conversion disorder, also known as functional neurological disorder (FND), the authors noted.
In addition, the Functional Neurological Disorder Society released a statement in January 2021 pointing out that the conditions described in these videos are seemingly consistent with FND, they added.
“We thought it would be useful to explain more about what functional neurological disorder is, as many people are not familiar with it,” lead author David Kim, MD, said in an interview. “We wanted to provide some contextual information about the condition, as these reports may not necessarily mean the vaccine is unsafe.”
Dr. Kim, who is part of the division of cognitive behavioral neurology at Massachusetts General Hospital, Boston, explained that, in FND, physical symptoms can be brought about after events such as head injury, surgery, vaccination, other medical procedures, or life events such as loss of employment.
“Many different factors can bring these symptoms on, and while there are definitely cases associated with stressful events, it is not necessarily stress induced,” he said. “However, the event itself does not cause the condition, rather it is the reaction of the patient to the event.”
FND is now viewed as a true brain-based disorder, Dr. Kim noted. “While in the past it has been described as psychosomatic, we are now moving away from that terminology, toward the idea of a neurological disorder that affects function. It is a neuropsychiatric disorder on the borderline between neurology and psychiatry.”
The authors believed that some of these cases of unusual movements reported after COVID vaccination are likely to be FND.
“In these cases, it is not the substance in the vaccine that is causing the condition, but the common side effects that can occur after vaccination such as aches and chills bring the attention of the patient to their bodily functions and this reaction can become maladaptive, triggering FND,” Dr. Kim said.
“We believe that health care professionals should be more aware of FND at the current time. They need to know that the general public are aware that some people are experiencing movement disorders after COVID vaccination, and that this conversation is happening on social media,” he commented. “If they see patients with these symptoms, they could consider FND to be one possibility.”
The authors emphasized that, because they have not seen the individual patients, they cannot comment on any specific cases.
“But as some of these videos circulating can be consistent with the condition being FND, and especially with news reports indicating that at least one patient was given that diagnosis, we wanted to raise awareness of this condition among health professionals,” Dr. Kim added.
He explained that, in the past, FND has been a diagnosis of exclusion but now it is diagnosed with a clinical history and physical examination, looking for appropriate rule-in signs. Ancillary testing such as neuroimaging, electrophysiological studies, and blood tests are often used to rule out other conditions.
“Neurologists have a lot of training in this condition, as it is the second most common reason for a patient to visit a neurologist after headache,” Dr. Kim noted.
It is managed with education, counseling, physical rehabilitation and cognitive behavioral therapy. “A key part of the therapeutic process is working with the patient to explain the diagnosis. If they understand the condition, they do better. Patients can learn distraction techniques to allow more fluid movements,” he reported.
“As neurologists, and health care professionals more broadly, we must explain transparently and nonjudgmentally the nature of FND, including that these symptoms are real but not the direct result of toxic vaccine effects,” the authors wrote.
“Transparency and effective communication are needed in our society more than ever, and a condition as prevalent and potentially debilitating as FND can no longer remain marginalized and in the shadows. Effective communication will help educate the public and reduce fears so that patients can make informed decisions for themselves on receiving the vaccine to reduce the risk of COVID-19,” they concluded.
A version of this article first appeared on Medscape.com.
The development of unusual movements after COVID-19 vaccination may be a result of functional neurologic disorder rather than being a direct adverse effect of the vaccine, it has been suggested.
Writing in an article published online in JAMA Neurology on April 9, 2021, two neurologists and a psychiatrist report the recent circulation of videos on social media about major neurologic adverse events, including continuous movements of the trunk and limbs or walking difficulties after administration of the COVID-19 vaccine. Some of these videos have been viewed millions of times by the public, they noted.
While these videos may be unsubstantiated, and it is not definitively known if the COVID-19 vaccine was administered in these cases, it was reported in the news that at least one patient was told by their physician that the diagnosis was conversion disorder, also known as functional neurological disorder (FND), the authors noted.
In addition, the Functional Neurological Disorder Society released a statement in January 2021 pointing out that the conditions described in these videos are seemingly consistent with FND, they added.
“We thought it would be useful to explain more about what functional neurological disorder is, as many people are not familiar with it,” lead author David Kim, MD, said in an interview. “We wanted to provide some contextual information about the condition, as these reports may not necessarily mean the vaccine is unsafe.”
Dr. Kim, who is part of the division of cognitive behavioral neurology at Massachusetts General Hospital, Boston, explained that, in FND, physical symptoms can be brought about after events such as head injury, surgery, vaccination, other medical procedures, or life events such as loss of employment.
“Many different factors can bring these symptoms on, and while there are definitely cases associated with stressful events, it is not necessarily stress induced,” he said. “However, the event itself does not cause the condition, rather it is the reaction of the patient to the event.”
FND is now viewed as a true brain-based disorder, Dr. Kim noted. “While in the past it has been described as psychosomatic, we are now moving away from that terminology, toward the idea of a neurological disorder that affects function. It is a neuropsychiatric disorder on the borderline between neurology and psychiatry.”
The authors believed that some of these cases of unusual movements reported after COVID vaccination are likely to be FND.
“In these cases, it is not the substance in the vaccine that is causing the condition, but the common side effects that can occur after vaccination such as aches and chills bring the attention of the patient to their bodily functions and this reaction can become maladaptive, triggering FND,” Dr. Kim said.
“We believe that health care professionals should be more aware of FND at the current time. They need to know that the general public are aware that some people are experiencing movement disorders after COVID vaccination, and that this conversation is happening on social media,” he commented. “If they see patients with these symptoms, they could consider FND to be one possibility.”
The authors emphasized that, because they have not seen the individual patients, they cannot comment on any specific cases.
“But as some of these videos circulating can be consistent with the condition being FND, and especially with news reports indicating that at least one patient was given that diagnosis, we wanted to raise awareness of this condition among health professionals,” Dr. Kim added.
He explained that, in the past, FND has been a diagnosis of exclusion but now it is diagnosed with a clinical history and physical examination, looking for appropriate rule-in signs. Ancillary testing such as neuroimaging, electrophysiological studies, and blood tests are often used to rule out other conditions.
“Neurologists have a lot of training in this condition, as it is the second most common reason for a patient to visit a neurologist after headache,” Dr. Kim noted.
It is managed with education, counseling, physical rehabilitation and cognitive behavioral therapy. “A key part of the therapeutic process is working with the patient to explain the diagnosis. If they understand the condition, they do better. Patients can learn distraction techniques to allow more fluid movements,” he reported.
“As neurologists, and health care professionals more broadly, we must explain transparently and nonjudgmentally the nature of FND, including that these symptoms are real but not the direct result of toxic vaccine effects,” the authors wrote.
“Transparency and effective communication are needed in our society more than ever, and a condition as prevalent and potentially debilitating as FND can no longer remain marginalized and in the shadows. Effective communication will help educate the public and reduce fears so that patients can make informed decisions for themselves on receiving the vaccine to reduce the risk of COVID-19,” they concluded.
A version of this article first appeared on Medscape.com.
The development of unusual movements after COVID-19 vaccination may be a result of functional neurologic disorder rather than being a direct adverse effect of the vaccine, it has been suggested.
Writing in an article published online in JAMA Neurology on April 9, 2021, two neurologists and a psychiatrist report the recent circulation of videos on social media about major neurologic adverse events, including continuous movements of the trunk and limbs or walking difficulties after administration of the COVID-19 vaccine. Some of these videos have been viewed millions of times by the public, they noted.
While these videos may be unsubstantiated, and it is not definitively known if the COVID-19 vaccine was administered in these cases, it was reported in the news that at least one patient was told by their physician that the diagnosis was conversion disorder, also known as functional neurological disorder (FND), the authors noted.
In addition, the Functional Neurological Disorder Society released a statement in January 2021 pointing out that the conditions described in these videos are seemingly consistent with FND, they added.
“We thought it would be useful to explain more about what functional neurological disorder is, as many people are not familiar with it,” lead author David Kim, MD, said in an interview. “We wanted to provide some contextual information about the condition, as these reports may not necessarily mean the vaccine is unsafe.”
Dr. Kim, who is part of the division of cognitive behavioral neurology at Massachusetts General Hospital, Boston, explained that, in FND, physical symptoms can be brought about after events such as head injury, surgery, vaccination, other medical procedures, or life events such as loss of employment.
“Many different factors can bring these symptoms on, and while there are definitely cases associated with stressful events, it is not necessarily stress induced,” he said. “However, the event itself does not cause the condition, rather it is the reaction of the patient to the event.”
FND is now viewed as a true brain-based disorder, Dr. Kim noted. “While in the past it has been described as psychosomatic, we are now moving away from that terminology, toward the idea of a neurological disorder that affects function. It is a neuropsychiatric disorder on the borderline between neurology and psychiatry.”
The authors believed that some of these cases of unusual movements reported after COVID vaccination are likely to be FND.
“In these cases, it is not the substance in the vaccine that is causing the condition, but the common side effects that can occur after vaccination such as aches and chills bring the attention of the patient to their bodily functions and this reaction can become maladaptive, triggering FND,” Dr. Kim said.
“We believe that health care professionals should be more aware of FND at the current time. They need to know that the general public are aware that some people are experiencing movement disorders after COVID vaccination, and that this conversation is happening on social media,” he commented. “If they see patients with these symptoms, they could consider FND to be one possibility.”
The authors emphasized that, because they have not seen the individual patients, they cannot comment on any specific cases.
“But as some of these videos circulating can be consistent with the condition being FND, and especially with news reports indicating that at least one patient was given that diagnosis, we wanted to raise awareness of this condition among health professionals,” Dr. Kim added.
He explained that, in the past, FND has been a diagnosis of exclusion but now it is diagnosed with a clinical history and physical examination, looking for appropriate rule-in signs. Ancillary testing such as neuroimaging, electrophysiological studies, and blood tests are often used to rule out other conditions.
“Neurologists have a lot of training in this condition, as it is the second most common reason for a patient to visit a neurologist after headache,” Dr. Kim noted.
It is managed with education, counseling, physical rehabilitation and cognitive behavioral therapy. “A key part of the therapeutic process is working with the patient to explain the diagnosis. If they understand the condition, they do better. Patients can learn distraction techniques to allow more fluid movements,” he reported.
“As neurologists, and health care professionals more broadly, we must explain transparently and nonjudgmentally the nature of FND, including that these symptoms are real but not the direct result of toxic vaccine effects,” the authors wrote.
“Transparency and effective communication are needed in our society more than ever, and a condition as prevalent and potentially debilitating as FND can no longer remain marginalized and in the shadows. Effective communication will help educate the public and reduce fears so that patients can make informed decisions for themselves on receiving the vaccine to reduce the risk of COVID-19,” they concluded.
A version of this article first appeared on Medscape.com.
Novel antiplatelet drug: Hope for efficacy without bleeding?
A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.
A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.
Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.
The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.
“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.
Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.
“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.
“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.
In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.
“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.
The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.
In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.
“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.
In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.
The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.
For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.
The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.
Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.
The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.
Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.
Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.
“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.
The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.
In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.
He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”
The researchers are now planning a larger phase 3 study in that group.
“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.
The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.
A version of this article first appeared on Medscape.com.
A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.
A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.
Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.
The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.
“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.
Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.
“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.
“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.
In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.
“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.
The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.
In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.
“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.
In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.
The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.
For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.
The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.
Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.
The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.
Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.
Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.
“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.
The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.
In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.
He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”
The researchers are now planning a larger phase 3 study in that group.
“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.
The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.
A version of this article first appeared on Medscape.com.
A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.
A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.
Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.
The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.
“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.
Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.
“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.
“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.
In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.
“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.
The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.
In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.
“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.
In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.
The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.
For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.
The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.
Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.
The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.
Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.
Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.
“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.
The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.
In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.
He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”
The researchers are now planning a larger phase 3 study in that group.
“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.
The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.
A version of this article first appeared on Medscape.com.
Is there a need for tPA before thrombectomy in patients with stroke?
In a new randomized trial that investigated the question of whether thrombolysis can be omitted for patients with stroke who are undergoing endovascular thrombectomy for a large-vessel occlusion, results were similar for both approaches.
and functional outcomes were not significantly different. In addition, hemorrhage rates with or without intravenous alteplase administration before endovascular treatment were similar.
“From the MR CLEAN NO IV results, we cannot change standard practice, as we failed to show superiority of the direct endovascular approach, and we also didn’t meet the noninferiority criteria. So, the standard practice of giving tPA to those eligible still holds,” said co–lead investigator Yvo Roos, MD.
“But I think we can say that these results suggest that there may also not be such a need for tPA in patients who can go straight for endovascular therapy,” said Dr. Roos, who is professor of neurology at Amsterdam Medical Center.
“If we are not sure whether a patient is suitable for tPA because they have a higher bleeding risk, I think we can be reassured about missing the tPA out and going straight to endovascular treatment. So, if in doubt, leave it out,” he added.
Results of the MR CLEAN NO IV trial were presented at the International Stroke Conference sponsored by the American Heart Association.
“If in doubt, leave it out”
Dr. Roos noted that three trials have investigated the question regarding dropping thrombolysis for patients who can receive thrombectomy quickly. These are the DIRECT MT, SKIP, and DEVT studies. All of these trials were conducted in Asian countries, and none found differences in functional outcomes between the two approaches.
The largest of these studies – the DIRECT-MT trial, from China, which was a sister study to MR CLEAN NO IV – did show noninferiority of the direct endovascular approach to tPA plus endovascular treatment.
But because of differences in health care logistics and trial populations, the benefits and risks of dropping thrombolysis in Western countries are not known, explained Charles Majoie, MD, who is co–lead investigator of the current trial and is chair of neuroradiology at Amsterdam Medical Center.
The MR CLEAN NO IV trial was designed to show superiority of the direct endovascular approach with noninferiority for hemorrhage. It enrolled 540 European patients who were eligible for both thrombolysis and thrombectomy and who presented to a thrombectomy-capable center. They were randomly assigned to receive thrombolysis plus endovascular therapy or direct endovascular therapy alone.
The mean time from stroke onset to groin puncture (the start of endovascular therapy) was very fast in both groups – 130 minutes in the direct group, and 135 minutes in the tPA group.
The primary outcome was a shift analysis of the Modified Rankin Scale (mRS). On that outcome, the trial failed to show significant superiority of the direct approach (odds ratio, 0.88; 95% confidence interval, 0.65-1.19).
A good functional outcome (mRS, 0-2) was achieved in 49% of the direct thrombectomy group and in 51% of the tPA group (OR, 0.95; 95% CI, 0.65-1.40).
Safety results showed no difference in any of the hemorrhage endpoints between the two groups. The rate of symptomatic intracranial hemorrhage was actually numerically higher in the direct thrombectomy group (5.9% vs. 5.3%).
“One of the most intriguing results of this study is that there was no increase in hemorrhage in the tPA group,” Dr. Roos commented. “This is very surprising, as we have always thought thrombolysis causes an increased bleeding risk. But after these results, we may have to rethink that idea – perhaps it is not the tPA itself that causes bleeding risk but rather the opening up of the vessel.”
On the failure to show noninferiority of the direct approach, Dr. Roos suggested that the trial may have been underpowered in this respect.
“Our sister trial, DIRECT-MT, was a noninferiority study. They had 650 patients, and they just reached noninferiority,” he said. “In MR CLEAN NO IV, we were aiming for superiority, and we had fewer patients – 540. We didn’t show superiority, and we didn’t have quite enough patients to show noninferiority.”
He added that, considering all the four studies together, the results look very similar and suggest no difference between the two approaches.
Individualized approach probable
Dr. Majoie suggested that different patients may be suitable for the different approaches.
“I think we are heading for individualized treatment. If we have a young patient and the angiography suite is ready, we could probably skip tPA, but it would be for the neurologist/neuroradiologist to make individualized decisions on this,” he said. “We need to look at subgroups for more information.”
Another large trial that investigated this issue, SWIFT-DIRECT, is expected to be presented later this year. An Australian trial, DIRECT-SAFE, is ongoing and is at an early stage of recruitment.
Dr. Roos said that the data from all the trials will be combined for a more comprehensive analysis of the benefits and risks of the two approaches in various subgroups.
Commenting on the study was cochair of the ISC session at which it was presented, Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, N.J.
“Putting these results together with the previous Asian studies, I think we can say that direct thrombectomy without tPA is clearly not superior to the combined approach of tPA plus thrombectomy,” he said.
Dr. Jovin explained that, in theory, direct thrombectomy could be faster than the combined approach and that the risk for symptomatic intracerebral hemorrhage could be lower. But neither of these two possible benefits were seen in this study.
He agreed with Dr. Roos that MR CLEAN NO IV could have failed to show noninferiority of the direct strategy because the sample was not large enough.
“The results of the two approaches are very similar in this study and in the Asian studies, so it doesn’t appear that tPA adds very much, and it is associated with a significant increase in costs,” he said.
“The answer will probably be that there is not a ‘one-size-fits-all’ strategy, and we may end up using different approaches for different patient groups,” Dr. Jovin added. “Information on this will come from subgroups analyses from these trials.”
MR CLEAN NO-IV trial was part of the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative (an initiative of the Dutch Heart Foundation), the Brain Foundation Netherlands, Medtronic, Health-Holland, and Top Sector Life Sciences. The study received additional unrestricted funding from Stryker European Operations. Dr. Roos and Dr. Majoie are shareholders of Nico Lab.
A version of this article first appeared on Medscape.com.
In a new randomized trial that investigated the question of whether thrombolysis can be omitted for patients with stroke who are undergoing endovascular thrombectomy for a large-vessel occlusion, results were similar for both approaches.
and functional outcomes were not significantly different. In addition, hemorrhage rates with or without intravenous alteplase administration before endovascular treatment were similar.
“From the MR CLEAN NO IV results, we cannot change standard practice, as we failed to show superiority of the direct endovascular approach, and we also didn’t meet the noninferiority criteria. So, the standard practice of giving tPA to those eligible still holds,” said co–lead investigator Yvo Roos, MD.
“But I think we can say that these results suggest that there may also not be such a need for tPA in patients who can go straight for endovascular therapy,” said Dr. Roos, who is professor of neurology at Amsterdam Medical Center.
“If we are not sure whether a patient is suitable for tPA because they have a higher bleeding risk, I think we can be reassured about missing the tPA out and going straight to endovascular treatment. So, if in doubt, leave it out,” he added.
Results of the MR CLEAN NO IV trial were presented at the International Stroke Conference sponsored by the American Heart Association.
“If in doubt, leave it out”
Dr. Roos noted that three trials have investigated the question regarding dropping thrombolysis for patients who can receive thrombectomy quickly. These are the DIRECT MT, SKIP, and DEVT studies. All of these trials were conducted in Asian countries, and none found differences in functional outcomes between the two approaches.
The largest of these studies – the DIRECT-MT trial, from China, which was a sister study to MR CLEAN NO IV – did show noninferiority of the direct endovascular approach to tPA plus endovascular treatment.
But because of differences in health care logistics and trial populations, the benefits and risks of dropping thrombolysis in Western countries are not known, explained Charles Majoie, MD, who is co–lead investigator of the current trial and is chair of neuroradiology at Amsterdam Medical Center.
The MR CLEAN NO IV trial was designed to show superiority of the direct endovascular approach with noninferiority for hemorrhage. It enrolled 540 European patients who were eligible for both thrombolysis and thrombectomy and who presented to a thrombectomy-capable center. They were randomly assigned to receive thrombolysis plus endovascular therapy or direct endovascular therapy alone.
The mean time from stroke onset to groin puncture (the start of endovascular therapy) was very fast in both groups – 130 minutes in the direct group, and 135 minutes in the tPA group.
The primary outcome was a shift analysis of the Modified Rankin Scale (mRS). On that outcome, the trial failed to show significant superiority of the direct approach (odds ratio, 0.88; 95% confidence interval, 0.65-1.19).
A good functional outcome (mRS, 0-2) was achieved in 49% of the direct thrombectomy group and in 51% of the tPA group (OR, 0.95; 95% CI, 0.65-1.40).
Safety results showed no difference in any of the hemorrhage endpoints between the two groups. The rate of symptomatic intracranial hemorrhage was actually numerically higher in the direct thrombectomy group (5.9% vs. 5.3%).
“One of the most intriguing results of this study is that there was no increase in hemorrhage in the tPA group,” Dr. Roos commented. “This is very surprising, as we have always thought thrombolysis causes an increased bleeding risk. But after these results, we may have to rethink that idea – perhaps it is not the tPA itself that causes bleeding risk but rather the opening up of the vessel.”
On the failure to show noninferiority of the direct approach, Dr. Roos suggested that the trial may have been underpowered in this respect.
“Our sister trial, DIRECT-MT, was a noninferiority study. They had 650 patients, and they just reached noninferiority,” he said. “In MR CLEAN NO IV, we were aiming for superiority, and we had fewer patients – 540. We didn’t show superiority, and we didn’t have quite enough patients to show noninferiority.”
He added that, considering all the four studies together, the results look very similar and suggest no difference between the two approaches.
Individualized approach probable
Dr. Majoie suggested that different patients may be suitable for the different approaches.
“I think we are heading for individualized treatment. If we have a young patient and the angiography suite is ready, we could probably skip tPA, but it would be for the neurologist/neuroradiologist to make individualized decisions on this,” he said. “We need to look at subgroups for more information.”
Another large trial that investigated this issue, SWIFT-DIRECT, is expected to be presented later this year. An Australian trial, DIRECT-SAFE, is ongoing and is at an early stage of recruitment.
Dr. Roos said that the data from all the trials will be combined for a more comprehensive analysis of the benefits and risks of the two approaches in various subgroups.
Commenting on the study was cochair of the ISC session at which it was presented, Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, N.J.
“Putting these results together with the previous Asian studies, I think we can say that direct thrombectomy without tPA is clearly not superior to the combined approach of tPA plus thrombectomy,” he said.
Dr. Jovin explained that, in theory, direct thrombectomy could be faster than the combined approach and that the risk for symptomatic intracerebral hemorrhage could be lower. But neither of these two possible benefits were seen in this study.
He agreed with Dr. Roos that MR CLEAN NO IV could have failed to show noninferiority of the direct strategy because the sample was not large enough.
“The results of the two approaches are very similar in this study and in the Asian studies, so it doesn’t appear that tPA adds very much, and it is associated with a significant increase in costs,” he said.
“The answer will probably be that there is not a ‘one-size-fits-all’ strategy, and we may end up using different approaches for different patient groups,” Dr. Jovin added. “Information on this will come from subgroups analyses from these trials.”
MR CLEAN NO-IV trial was part of the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative (an initiative of the Dutch Heart Foundation), the Brain Foundation Netherlands, Medtronic, Health-Holland, and Top Sector Life Sciences. The study received additional unrestricted funding from Stryker European Operations. Dr. Roos and Dr. Majoie are shareholders of Nico Lab.
A version of this article first appeared on Medscape.com.
In a new randomized trial that investigated the question of whether thrombolysis can be omitted for patients with stroke who are undergoing endovascular thrombectomy for a large-vessel occlusion, results were similar for both approaches.
and functional outcomes were not significantly different. In addition, hemorrhage rates with or without intravenous alteplase administration before endovascular treatment were similar.
“From the MR CLEAN NO IV results, we cannot change standard practice, as we failed to show superiority of the direct endovascular approach, and we also didn’t meet the noninferiority criteria. So, the standard practice of giving tPA to those eligible still holds,” said co–lead investigator Yvo Roos, MD.
“But I think we can say that these results suggest that there may also not be such a need for tPA in patients who can go straight for endovascular therapy,” said Dr. Roos, who is professor of neurology at Amsterdam Medical Center.
“If we are not sure whether a patient is suitable for tPA because they have a higher bleeding risk, I think we can be reassured about missing the tPA out and going straight to endovascular treatment. So, if in doubt, leave it out,” he added.
Results of the MR CLEAN NO IV trial were presented at the International Stroke Conference sponsored by the American Heart Association.
“If in doubt, leave it out”
Dr. Roos noted that three trials have investigated the question regarding dropping thrombolysis for patients who can receive thrombectomy quickly. These are the DIRECT MT, SKIP, and DEVT studies. All of these trials were conducted in Asian countries, and none found differences in functional outcomes between the two approaches.
The largest of these studies – the DIRECT-MT trial, from China, which was a sister study to MR CLEAN NO IV – did show noninferiority of the direct endovascular approach to tPA plus endovascular treatment.
But because of differences in health care logistics and trial populations, the benefits and risks of dropping thrombolysis in Western countries are not known, explained Charles Majoie, MD, who is co–lead investigator of the current trial and is chair of neuroradiology at Amsterdam Medical Center.
The MR CLEAN NO IV trial was designed to show superiority of the direct endovascular approach with noninferiority for hemorrhage. It enrolled 540 European patients who were eligible for both thrombolysis and thrombectomy and who presented to a thrombectomy-capable center. They were randomly assigned to receive thrombolysis plus endovascular therapy or direct endovascular therapy alone.
The mean time from stroke onset to groin puncture (the start of endovascular therapy) was very fast in both groups – 130 minutes in the direct group, and 135 minutes in the tPA group.
The primary outcome was a shift analysis of the Modified Rankin Scale (mRS). On that outcome, the trial failed to show significant superiority of the direct approach (odds ratio, 0.88; 95% confidence interval, 0.65-1.19).
A good functional outcome (mRS, 0-2) was achieved in 49% of the direct thrombectomy group and in 51% of the tPA group (OR, 0.95; 95% CI, 0.65-1.40).
Safety results showed no difference in any of the hemorrhage endpoints between the two groups. The rate of symptomatic intracranial hemorrhage was actually numerically higher in the direct thrombectomy group (5.9% vs. 5.3%).
“One of the most intriguing results of this study is that there was no increase in hemorrhage in the tPA group,” Dr. Roos commented. “This is very surprising, as we have always thought thrombolysis causes an increased bleeding risk. But after these results, we may have to rethink that idea – perhaps it is not the tPA itself that causes bleeding risk but rather the opening up of the vessel.”
On the failure to show noninferiority of the direct approach, Dr. Roos suggested that the trial may have been underpowered in this respect.
“Our sister trial, DIRECT-MT, was a noninferiority study. They had 650 patients, and they just reached noninferiority,” he said. “In MR CLEAN NO IV, we were aiming for superiority, and we had fewer patients – 540. We didn’t show superiority, and we didn’t have quite enough patients to show noninferiority.”
He added that, considering all the four studies together, the results look very similar and suggest no difference between the two approaches.
Individualized approach probable
Dr. Majoie suggested that different patients may be suitable for the different approaches.
“I think we are heading for individualized treatment. If we have a young patient and the angiography suite is ready, we could probably skip tPA, but it would be for the neurologist/neuroradiologist to make individualized decisions on this,” he said. “We need to look at subgroups for more information.”
Another large trial that investigated this issue, SWIFT-DIRECT, is expected to be presented later this year. An Australian trial, DIRECT-SAFE, is ongoing and is at an early stage of recruitment.
Dr. Roos said that the data from all the trials will be combined for a more comprehensive analysis of the benefits and risks of the two approaches in various subgroups.
Commenting on the study was cochair of the ISC session at which it was presented, Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, N.J.
“Putting these results together with the previous Asian studies, I think we can say that direct thrombectomy without tPA is clearly not superior to the combined approach of tPA plus thrombectomy,” he said.
Dr. Jovin explained that, in theory, direct thrombectomy could be faster than the combined approach and that the risk for symptomatic intracerebral hemorrhage could be lower. But neither of these two possible benefits were seen in this study.
He agreed with Dr. Roos that MR CLEAN NO IV could have failed to show noninferiority of the direct strategy because the sample was not large enough.
“The results of the two approaches are very similar in this study and in the Asian studies, so it doesn’t appear that tPA adds very much, and it is associated with a significant increase in costs,” he said.
“The answer will probably be that there is not a ‘one-size-fits-all’ strategy, and we may end up using different approaches for different patient groups,” Dr. Jovin added. “Information on this will come from subgroups analyses from these trials.”
MR CLEAN NO-IV trial was part of the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative (an initiative of the Dutch Heart Foundation), the Brain Foundation Netherlands, Medtronic, Health-Holland, and Top Sector Life Sciences. The study received additional unrestricted funding from Stryker European Operations. Dr. Roos and Dr. Majoie are shareholders of Nico Lab.
A version of this article first appeared on Medscape.com.
FROM ISC 2021
AstraZeneca COVID vaccine: Clotting disorder mechanism revealed?
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
Meta-analysis supports late thrombectomy in selected stroke patients
of data from six clinical trials.
Results of the AURORA analysis showed that for every 100 patients treated with thrombectomy, 33 patients will have less disability, and 27 patients will achieve an independent level of functioning compared with patients who receive only standard medical care.
The benefit of mechanical removal of the clot for selected patients who may have salvageable brain tissue, as identified through the use of various imaging modalities, was maintained whether the patient had a “wake-up stroke” or the onset of symptoms was witnessed, regardless of the point in time within the late window. In fact, the benefit of intervention was greater for patients who presented in the latter part of the late time window.
Never too late for urgent medical care
“While the findings of this analysis do not contradict the mantra that the earlier treatment is instituted, the higher the chance of a good outcome, they highlight the fact that it is never too late to seek urgent medical care,” said lead investigator Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey.
“The implications of the findings from AURORA are that they could lead to a change in guidelines from endorsement of thrombectomy as level 1a recommendation in eligible patients presenting in the 6- to 16-hour time window to a 6- to 24-hour time window,” said Dr. Jovin.
“Furthermore, there are strong signals of benefit of thrombectomy in patients who are not selected based on volumetric analysis of baseline infarct (core) or extent of tissue at risk (penumbra), such that when those imaging modalities are not available or contraindicated, selection based on noncontrast CT and clinical information only may be acceptable,” he added. “Finally, the possibility of benefit from thrombectomy performed beyond 24 hours from last seen well is real and should be explored in future studies.”
The AURORA findings were presented at the virtual International Stroke Conference (ISC) 2021.
The objective of the study was to provide a more precise estimate of the benefit of thrombectomy for patients with stroke when performed within 6-24 hours after the patient was last seen well, Dr. Jovin explained.
He said the 6-hour cutoff was chosen somewhat arbitrarily, but added, “It is highly consequential, as it marks the point of demarcation between the early and late time window, and virtually all guidelines recommend different approaches, dependent on whether patients present before or after 6 hours from symptom onset.”
The 6+ hour window
Dr. Jovin pointed out that for patients who present beyond 6 hours, treatment options are more restricted, because the data on thrombectomy in this later period come mainly from two North American trials (DEFUSE 3 and DAWN) that had very stringent imaging criteria for enrollment.
“We wanted to create a heterogeneous dataset with regard to geography and selection criteria by forming the AURORA collaboration,” he commented. Their study involved an individual-level pooled analysis of all patients who underwent randomization after 6 hours from the time that they were last seen well. Patients were randomly assigned to receive either best medical therapy alone or best medical therapy plus thrombectomy (either with stent retrievers or aspiration) for anterior circulation proximal large-vessel occlusion stroke.
The data came from six trials: DAWN (which enrolled patients 6-24 hours from stroke onset), DEFUSE 3 (6-16 hours), ESCAPE (0-12 hours), REVASCAT (0-8 hours), RESILIENT (0-8 hours), and POSITIVE (0-12 hours). In total, 505 patients were included in the meta-analysis, 266 in the intervention group, and 239 in the control group.
“By pooling data on patients presenting after 6 hours from all these trails, we achieve greater precision for treatment effect estimation and increased the power for subgroup analysis,” Dr. Jovin noted.
Although the majority of the patients were in the DAWN and DIFFUSE 3 trials (n = 388), “there are still a good number from the other four trials (n = 117),” Dr. Jovin reported.
Most of the trials used Modified Rankin Scale (mRS) ordinal or shift analysis as their primary endpoint, which was the also the endpoint chosen for this meta-analysis.
Imaging selection criteria ranged from fully automated software-generated quantitative volumetric analysis of baseline infarct (core) or tissue at risk to CT perfusion and plain CT/CTA. The minimum ASPECTS score was 5 or 6.
There were no imbalances in baseline characteristics. The median NIH Stroke Scale score was 16, and the median ASPECTS score was 8. The median time to randomization was 10.5 hours.
With regard to safety, there was no significant difference in rates of symptomatic intracerebral hemorrhage (5.3% in the intervention group vs. 3.3% in the control group; P = .23) or in mortality at 90 days (16.5% vs. 19.3%; P = .87). Jovin noted that these results are very similar to those from the HERMES meta-analysis of patients treated in the early time window.
The primary outcome – ordinal analysis of the mRS distribution – showed an adjusted odds ratio of 2.54 (P < .0001) for benefit in the intervention group. The number needed to treat to reduce disability was 3. “This is again very similar to the HERMES meta-analysis of patients in the early window,” Dr. Jovin said.
The P value for heterogeneity of treatment effect across the six studies was nonsignificant.
Secondary outcome analysis showed an “almost 27%” difference in good functional outcome (MRS, 0-2) between the two groups (45.9% in the intervention group vs. 19.3% in the control group), which translates into a number needed to treat of 3.8, Dr. Jovin reported.
Subgroup analysis showed a treatment effect favoring intervention across all prespecified subgroup factors, including age, sex, occlusion location, mode of presentation (wake-up vs. witnessed), and ASPECTS score, with the caveat that most of the patients were enrolled with ASPECTS scores of 7 or greater.
Early versus late
Surprisingly, although thrombectomy was found to be beneficial in both the 6- to 12-hour and 12- to 24-hour time window, the magnitude of benefit was significantly higher in the later rather than the earlier time window. The odds ratio of a better outcome with thrombectomy on the mRS shift analysis in those presenting in the 6- to 12-hour period was 1.78, compared with 5.86 in the 12- to 24-hour time window.
“This should not be interpreted as a higher chance of a good outcome if treated late. In fact, the rate of good outcomes were numerically higher in the earlier treated patients, but the difference comes from the control group, which did much worse in patients randomized in the later time period,” Dr. Jovin said.
“Aurora was the goddess of dawn [in ancient Roman mythology], so this is a very fitting name, as it reminds us that we are in the dawn of a new era where patients are selected based on physiological data rather than on time, and we certainly hope that this work has brought us closer to this reality,” Dr. Jovin concluded.
Commenting on the study, Michael Hill, MD, University of Calgary (Alta.), said: “The work provides pooled empiric data to support the concept that time to treatment is no longer the sole threshold variable to be used in treatment decision-making. Instead, time is now simply another variable to consider in the context of clinical and imaging factors.”
Dr. Hill, who headed up the ESCAPE trial and was also involved in the current meta-analysis, added: “This meta-analysis supports the concept of patient selection using the ‘good scan’ model, rather than using a time-based concept of patient eligibility for endovascular therapy. It will further push changes in care, because the implication is that all patients with more severe acute stroke presentations need emergency neurovascular imaging to decide if they are eligible for treatment.”
The AURORA meta-analysis was funded by Stryker Neurovascular. Dr. Jovin reports stock holdings in Anaconda, Route 92, VizAi, FreeOx, Blockade Medical, Methinks, and Corindus; personal fees from Cerenovus and Contego Medical; travel support from Fundacio Ictus; and grant support from Medtronic and Stryker Neurovascular.
A version of this article first appeared on Medscape.com.
of data from six clinical trials.
Results of the AURORA analysis showed that for every 100 patients treated with thrombectomy, 33 patients will have less disability, and 27 patients will achieve an independent level of functioning compared with patients who receive only standard medical care.
The benefit of mechanical removal of the clot for selected patients who may have salvageable brain tissue, as identified through the use of various imaging modalities, was maintained whether the patient had a “wake-up stroke” or the onset of symptoms was witnessed, regardless of the point in time within the late window. In fact, the benefit of intervention was greater for patients who presented in the latter part of the late time window.
Never too late for urgent medical care
“While the findings of this analysis do not contradict the mantra that the earlier treatment is instituted, the higher the chance of a good outcome, they highlight the fact that it is never too late to seek urgent medical care,” said lead investigator Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey.
“The implications of the findings from AURORA are that they could lead to a change in guidelines from endorsement of thrombectomy as level 1a recommendation in eligible patients presenting in the 6- to 16-hour time window to a 6- to 24-hour time window,” said Dr. Jovin.
“Furthermore, there are strong signals of benefit of thrombectomy in patients who are not selected based on volumetric analysis of baseline infarct (core) or extent of tissue at risk (penumbra), such that when those imaging modalities are not available or contraindicated, selection based on noncontrast CT and clinical information only may be acceptable,” he added. “Finally, the possibility of benefit from thrombectomy performed beyond 24 hours from last seen well is real and should be explored in future studies.”
The AURORA findings were presented at the virtual International Stroke Conference (ISC) 2021.
The objective of the study was to provide a more precise estimate of the benefit of thrombectomy for patients with stroke when performed within 6-24 hours after the patient was last seen well, Dr. Jovin explained.
He said the 6-hour cutoff was chosen somewhat arbitrarily, but added, “It is highly consequential, as it marks the point of demarcation between the early and late time window, and virtually all guidelines recommend different approaches, dependent on whether patients present before or after 6 hours from symptom onset.”
The 6+ hour window
Dr. Jovin pointed out that for patients who present beyond 6 hours, treatment options are more restricted, because the data on thrombectomy in this later period come mainly from two North American trials (DEFUSE 3 and DAWN) that had very stringent imaging criteria for enrollment.
“We wanted to create a heterogeneous dataset with regard to geography and selection criteria by forming the AURORA collaboration,” he commented. Their study involved an individual-level pooled analysis of all patients who underwent randomization after 6 hours from the time that they were last seen well. Patients were randomly assigned to receive either best medical therapy alone or best medical therapy plus thrombectomy (either with stent retrievers or aspiration) for anterior circulation proximal large-vessel occlusion stroke.
The data came from six trials: DAWN (which enrolled patients 6-24 hours from stroke onset), DEFUSE 3 (6-16 hours), ESCAPE (0-12 hours), REVASCAT (0-8 hours), RESILIENT (0-8 hours), and POSITIVE (0-12 hours). In total, 505 patients were included in the meta-analysis, 266 in the intervention group, and 239 in the control group.
“By pooling data on patients presenting after 6 hours from all these trails, we achieve greater precision for treatment effect estimation and increased the power for subgroup analysis,” Dr. Jovin noted.
Although the majority of the patients were in the DAWN and DIFFUSE 3 trials (n = 388), “there are still a good number from the other four trials (n = 117),” Dr. Jovin reported.
Most of the trials used Modified Rankin Scale (mRS) ordinal or shift analysis as their primary endpoint, which was the also the endpoint chosen for this meta-analysis.
Imaging selection criteria ranged from fully automated software-generated quantitative volumetric analysis of baseline infarct (core) or tissue at risk to CT perfusion and plain CT/CTA. The minimum ASPECTS score was 5 or 6.
There were no imbalances in baseline characteristics. The median NIH Stroke Scale score was 16, and the median ASPECTS score was 8. The median time to randomization was 10.5 hours.
With regard to safety, there was no significant difference in rates of symptomatic intracerebral hemorrhage (5.3% in the intervention group vs. 3.3% in the control group; P = .23) or in mortality at 90 days (16.5% vs. 19.3%; P = .87). Jovin noted that these results are very similar to those from the HERMES meta-analysis of patients treated in the early time window.
The primary outcome – ordinal analysis of the mRS distribution – showed an adjusted odds ratio of 2.54 (P < .0001) for benefit in the intervention group. The number needed to treat to reduce disability was 3. “This is again very similar to the HERMES meta-analysis of patients in the early window,” Dr. Jovin said.
The P value for heterogeneity of treatment effect across the six studies was nonsignificant.
Secondary outcome analysis showed an “almost 27%” difference in good functional outcome (MRS, 0-2) between the two groups (45.9% in the intervention group vs. 19.3% in the control group), which translates into a number needed to treat of 3.8, Dr. Jovin reported.
Subgroup analysis showed a treatment effect favoring intervention across all prespecified subgroup factors, including age, sex, occlusion location, mode of presentation (wake-up vs. witnessed), and ASPECTS score, with the caveat that most of the patients were enrolled with ASPECTS scores of 7 or greater.
Early versus late
Surprisingly, although thrombectomy was found to be beneficial in both the 6- to 12-hour and 12- to 24-hour time window, the magnitude of benefit was significantly higher in the later rather than the earlier time window. The odds ratio of a better outcome with thrombectomy on the mRS shift analysis in those presenting in the 6- to 12-hour period was 1.78, compared with 5.86 in the 12- to 24-hour time window.
“This should not be interpreted as a higher chance of a good outcome if treated late. In fact, the rate of good outcomes were numerically higher in the earlier treated patients, but the difference comes from the control group, which did much worse in patients randomized in the later time period,” Dr. Jovin said.
“Aurora was the goddess of dawn [in ancient Roman mythology], so this is a very fitting name, as it reminds us that we are in the dawn of a new era where patients are selected based on physiological data rather than on time, and we certainly hope that this work has brought us closer to this reality,” Dr. Jovin concluded.
Commenting on the study, Michael Hill, MD, University of Calgary (Alta.), said: “The work provides pooled empiric data to support the concept that time to treatment is no longer the sole threshold variable to be used in treatment decision-making. Instead, time is now simply another variable to consider in the context of clinical and imaging factors.”
Dr. Hill, who headed up the ESCAPE trial and was also involved in the current meta-analysis, added: “This meta-analysis supports the concept of patient selection using the ‘good scan’ model, rather than using a time-based concept of patient eligibility for endovascular therapy. It will further push changes in care, because the implication is that all patients with more severe acute stroke presentations need emergency neurovascular imaging to decide if they are eligible for treatment.”
The AURORA meta-analysis was funded by Stryker Neurovascular. Dr. Jovin reports stock holdings in Anaconda, Route 92, VizAi, FreeOx, Blockade Medical, Methinks, and Corindus; personal fees from Cerenovus and Contego Medical; travel support from Fundacio Ictus; and grant support from Medtronic and Stryker Neurovascular.
A version of this article first appeared on Medscape.com.
of data from six clinical trials.
Results of the AURORA analysis showed that for every 100 patients treated with thrombectomy, 33 patients will have less disability, and 27 patients will achieve an independent level of functioning compared with patients who receive only standard medical care.
The benefit of mechanical removal of the clot for selected patients who may have salvageable brain tissue, as identified through the use of various imaging modalities, was maintained whether the patient had a “wake-up stroke” or the onset of symptoms was witnessed, regardless of the point in time within the late window. In fact, the benefit of intervention was greater for patients who presented in the latter part of the late time window.
Never too late for urgent medical care
“While the findings of this analysis do not contradict the mantra that the earlier treatment is instituted, the higher the chance of a good outcome, they highlight the fact that it is never too late to seek urgent medical care,” said lead investigator Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey.
“The implications of the findings from AURORA are that they could lead to a change in guidelines from endorsement of thrombectomy as level 1a recommendation in eligible patients presenting in the 6- to 16-hour time window to a 6- to 24-hour time window,” said Dr. Jovin.
“Furthermore, there are strong signals of benefit of thrombectomy in patients who are not selected based on volumetric analysis of baseline infarct (core) or extent of tissue at risk (penumbra), such that when those imaging modalities are not available or contraindicated, selection based on noncontrast CT and clinical information only may be acceptable,” he added. “Finally, the possibility of benefit from thrombectomy performed beyond 24 hours from last seen well is real and should be explored in future studies.”
The AURORA findings were presented at the virtual International Stroke Conference (ISC) 2021.
The objective of the study was to provide a more precise estimate of the benefit of thrombectomy for patients with stroke when performed within 6-24 hours after the patient was last seen well, Dr. Jovin explained.
He said the 6-hour cutoff was chosen somewhat arbitrarily, but added, “It is highly consequential, as it marks the point of demarcation between the early and late time window, and virtually all guidelines recommend different approaches, dependent on whether patients present before or after 6 hours from symptom onset.”
The 6+ hour window
Dr. Jovin pointed out that for patients who present beyond 6 hours, treatment options are more restricted, because the data on thrombectomy in this later period come mainly from two North American trials (DEFUSE 3 and DAWN) that had very stringent imaging criteria for enrollment.
“We wanted to create a heterogeneous dataset with regard to geography and selection criteria by forming the AURORA collaboration,” he commented. Their study involved an individual-level pooled analysis of all patients who underwent randomization after 6 hours from the time that they were last seen well. Patients were randomly assigned to receive either best medical therapy alone or best medical therapy plus thrombectomy (either with stent retrievers or aspiration) for anterior circulation proximal large-vessel occlusion stroke.
The data came from six trials: DAWN (which enrolled patients 6-24 hours from stroke onset), DEFUSE 3 (6-16 hours), ESCAPE (0-12 hours), REVASCAT (0-8 hours), RESILIENT (0-8 hours), and POSITIVE (0-12 hours). In total, 505 patients were included in the meta-analysis, 266 in the intervention group, and 239 in the control group.
“By pooling data on patients presenting after 6 hours from all these trails, we achieve greater precision for treatment effect estimation and increased the power for subgroup analysis,” Dr. Jovin noted.
Although the majority of the patients were in the DAWN and DIFFUSE 3 trials (n = 388), “there are still a good number from the other four trials (n = 117),” Dr. Jovin reported.
Most of the trials used Modified Rankin Scale (mRS) ordinal or shift analysis as their primary endpoint, which was the also the endpoint chosen for this meta-analysis.
Imaging selection criteria ranged from fully automated software-generated quantitative volumetric analysis of baseline infarct (core) or tissue at risk to CT perfusion and plain CT/CTA. The minimum ASPECTS score was 5 or 6.
There were no imbalances in baseline characteristics. The median NIH Stroke Scale score was 16, and the median ASPECTS score was 8. The median time to randomization was 10.5 hours.
With regard to safety, there was no significant difference in rates of symptomatic intracerebral hemorrhage (5.3% in the intervention group vs. 3.3% in the control group; P = .23) or in mortality at 90 days (16.5% vs. 19.3%; P = .87). Jovin noted that these results are very similar to those from the HERMES meta-analysis of patients treated in the early time window.
The primary outcome – ordinal analysis of the mRS distribution – showed an adjusted odds ratio of 2.54 (P < .0001) for benefit in the intervention group. The number needed to treat to reduce disability was 3. “This is again very similar to the HERMES meta-analysis of patients in the early window,” Dr. Jovin said.
The P value for heterogeneity of treatment effect across the six studies was nonsignificant.
Secondary outcome analysis showed an “almost 27%” difference in good functional outcome (MRS, 0-2) between the two groups (45.9% in the intervention group vs. 19.3% in the control group), which translates into a number needed to treat of 3.8, Dr. Jovin reported.
Subgroup analysis showed a treatment effect favoring intervention across all prespecified subgroup factors, including age, sex, occlusion location, mode of presentation (wake-up vs. witnessed), and ASPECTS score, with the caveat that most of the patients were enrolled with ASPECTS scores of 7 or greater.
Early versus late
Surprisingly, although thrombectomy was found to be beneficial in both the 6- to 12-hour and 12- to 24-hour time window, the magnitude of benefit was significantly higher in the later rather than the earlier time window. The odds ratio of a better outcome with thrombectomy on the mRS shift analysis in those presenting in the 6- to 12-hour period was 1.78, compared with 5.86 in the 12- to 24-hour time window.
“This should not be interpreted as a higher chance of a good outcome if treated late. In fact, the rate of good outcomes were numerically higher in the earlier treated patients, but the difference comes from the control group, which did much worse in patients randomized in the later time period,” Dr. Jovin said.
“Aurora was the goddess of dawn [in ancient Roman mythology], so this is a very fitting name, as it reminds us that we are in the dawn of a new era where patients are selected based on physiological data rather than on time, and we certainly hope that this work has brought us closer to this reality,” Dr. Jovin concluded.
Commenting on the study, Michael Hill, MD, University of Calgary (Alta.), said: “The work provides pooled empiric data to support the concept that time to treatment is no longer the sole threshold variable to be used in treatment decision-making. Instead, time is now simply another variable to consider in the context of clinical and imaging factors.”
Dr. Hill, who headed up the ESCAPE trial and was also involved in the current meta-analysis, added: “This meta-analysis supports the concept of patient selection using the ‘good scan’ model, rather than using a time-based concept of patient eligibility for endovascular therapy. It will further push changes in care, because the implication is that all patients with more severe acute stroke presentations need emergency neurovascular imaging to decide if they are eligible for treatment.”
The AURORA meta-analysis was funded by Stryker Neurovascular. Dr. Jovin reports stock holdings in Anaconda, Route 92, VizAi, FreeOx, Blockade Medical, Methinks, and Corindus; personal fees from Cerenovus and Contego Medical; travel support from Fundacio Ictus; and grant support from Medtronic and Stryker Neurovascular.
A version of this article first appeared on Medscape.com.
FROM ISC 2021
Direct transfer to angiography improves outcome in large-vessel stroke
in a new study.
Results of the ANGIO-CAT trial were presented at the International Stroke Conference sponsored by the American Heart Association.
The study involved patients suspected of having a large-vessel occlusion, as assessed in the prehospital setting by paramedics using the Rapid Arterial Occlusion Evaluation (RACE) score.
In his presentation, Manuel Requena, PhD, a neurologist and neurointerventionalist fellow at Vall d’Hebron Hospital, Barcelona, explained that, if patients were within 6 hours of symptom onset with a RACE scale score greater than 4, paramedics called ahead to a stroke neurologist, who met the patient directly at the hospital.
If on clinical examination the National Institutes of Health Stroke Scale (NIHSS) score was greater than 10, patients could be enrolled into the study. Upon enrollment, they were randomly assigned either to be taken directly to the angiography suite or to receive standard care.
Bypassing the emergency department
Dr. Requena noted that, at his center, patients who receive standard care are transferred to the CT imaging suite, where they are evaluated with noncontrast CT and CT angiography. CT perfusion is also performed if the treating physician deems it necessary.
If a large-vessel occlusion is confirmed, patients are then transferred to the angiography suite for endovascular treatment. He added that in many centers, patients are evaluated in the ED before undergoing CT scanning.
Patients in the direct angiography group received a “flat-panel” noncontrast CT in the angiography suite to rule out intracranial hemorrhage or a large, established infarct. The large-vessel occlusion would be confirmed by arteriography before the endovascular procedure was performed.
After CT scanning, patients received thrombolysis as recommended in the guidelines.
The current interim analysis includes the 174 patients who have been enrolled so far in the study. The median RACE score for these patients was 7, and the median NIHSS score was 17. Large-vessel occlusion was confirmed in 84% of patients, and 8% had an intracerebral hemorrhage.
Results showed that of the 147 patients who received endovascular therapy, puncture time was shorter for those who were taken directly to angiography (median, 18 min vs. 42 min), as was time to reperfusion (median, 57 min vs. 84 min).
The primary outcome was a shift analysis of the Modified Rankin Scale functional outcome scale at 90 days (odds of 1-point improvement or more). In the direct angiography group, the adjusted odds ratio for an improved functional outcome was 2.2 (95% confidence interval, 1.2-.1).
There were no significant differences in safety endpoints. There was a trend toward more procedural complications in those receiving endovascular therapy in the direct angiography group (8.1% vs. 2.7%; P = .6), but there was also a trend toward lower 90-day mortality in this group (20.2% vs. 32.9%; P = .07)
Dr. Requena reported no significant difference in safety outcomes among those with a hemorrhagic stroke.
“Our study is the first clinical trial that shows the superiority of direct transfer to an angiography suite,” said Dr. Requena. “Our findings were close to what we expected, and we were surprised that they occurred so early in the study. We trust that they will be confirmed in ongoing, multicenter, international trials.”
Stroke patients who were transferred directly to an angiography suite were also less likely to be dependent on assistance with daily activities than were those who received the current standard of care, Dr. Requena said. “More frequent and more rapid treatment can help improve outcomes for our stroke patients.”
A limitation of this study is that the hospital had extensive experience with immediate angiography, so findings may differ at hospitals or care centers with less angiography expertise or experience, Dr. Requena said.
He added that retrospective studies conducted in hospitals in the United States, Germany, and Switzerland show that this kind of protocol can be developed in any high-volume stroke center, although multicenter, international trials are needed.
The cost of speed
Commenting on the ANGIO-CAT study, Michael Hill, MD, a professor at the University of Calgary (Alta.), said the 27-minute improvement in door-to-reperfusion time achieved in the study was meaningful and correlates with the degree of improved outcomes observed. “So, the improvement in speed of treatment resulting in better outcomes makes sense,” he added.
He cautioned that this strategy would only be feasible in certain centers with selected patients and that cost will be a fundamental issue.
“If you identify patients at angiography, you risk having some patients with no target large-vessel occlusion,” Dr. Hill added. “The real question is, how many of these patients without a large-vessel occlusion can the system tolerate before it becomes uneconomical and not fruitful or harmful, given that groin puncture is not totally harmless?”
The moderator of the ISC news conference on the study, Mitchell Elkind, MD, professor of neurology at Columbia University, New York, who is also president of the American Stroke Association, said the study reflects the growing recognition of the importance of speed when treating stroke. “If we can shorten time to treatment using rapid evaluation and imaging protocols, this will help save brain,” he said.
Also commenting on the study, Louisa McCullough, MD, PhD, chief of neurology at Memorial Hermann Hospital–Texas Medical Center, Houston, who is the ISC meeting chair, said she thought the study would be relevant to the United States. “Speed is really of the essence. Whenever we can reduce delays, that will make a big difference to patients.”
Referring to this study on improving hospital systems, as well as a second study that was presented at the meeting that showed benefits from delivery of prehospital thrombolysis via a mobile stroke unit, Dr. McCullough added that “we need to set up models so we can get the best of both these worlds. These studies are really leading the way on how we can change the stroke systems of care.”
The study was funded by Vall d’Hebron Research Institute. Dr. Requena disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in a new study.
Results of the ANGIO-CAT trial were presented at the International Stroke Conference sponsored by the American Heart Association.
The study involved patients suspected of having a large-vessel occlusion, as assessed in the prehospital setting by paramedics using the Rapid Arterial Occlusion Evaluation (RACE) score.
In his presentation, Manuel Requena, PhD, a neurologist and neurointerventionalist fellow at Vall d’Hebron Hospital, Barcelona, explained that, if patients were within 6 hours of symptom onset with a RACE scale score greater than 4, paramedics called ahead to a stroke neurologist, who met the patient directly at the hospital.
If on clinical examination the National Institutes of Health Stroke Scale (NIHSS) score was greater than 10, patients could be enrolled into the study. Upon enrollment, they were randomly assigned either to be taken directly to the angiography suite or to receive standard care.
Bypassing the emergency department
Dr. Requena noted that, at his center, patients who receive standard care are transferred to the CT imaging suite, where they are evaluated with noncontrast CT and CT angiography. CT perfusion is also performed if the treating physician deems it necessary.
If a large-vessel occlusion is confirmed, patients are then transferred to the angiography suite for endovascular treatment. He added that in many centers, patients are evaluated in the ED before undergoing CT scanning.
Patients in the direct angiography group received a “flat-panel” noncontrast CT in the angiography suite to rule out intracranial hemorrhage or a large, established infarct. The large-vessel occlusion would be confirmed by arteriography before the endovascular procedure was performed.
After CT scanning, patients received thrombolysis as recommended in the guidelines.
The current interim analysis includes the 174 patients who have been enrolled so far in the study. The median RACE score for these patients was 7, and the median NIHSS score was 17. Large-vessel occlusion was confirmed in 84% of patients, and 8% had an intracerebral hemorrhage.
Results showed that of the 147 patients who received endovascular therapy, puncture time was shorter for those who were taken directly to angiography (median, 18 min vs. 42 min), as was time to reperfusion (median, 57 min vs. 84 min).
The primary outcome was a shift analysis of the Modified Rankin Scale functional outcome scale at 90 days (odds of 1-point improvement or more). In the direct angiography group, the adjusted odds ratio for an improved functional outcome was 2.2 (95% confidence interval, 1.2-.1).
There were no significant differences in safety endpoints. There was a trend toward more procedural complications in those receiving endovascular therapy in the direct angiography group (8.1% vs. 2.7%; P = .6), but there was also a trend toward lower 90-day mortality in this group (20.2% vs. 32.9%; P = .07)
Dr. Requena reported no significant difference in safety outcomes among those with a hemorrhagic stroke.
“Our study is the first clinical trial that shows the superiority of direct transfer to an angiography suite,” said Dr. Requena. “Our findings were close to what we expected, and we were surprised that they occurred so early in the study. We trust that they will be confirmed in ongoing, multicenter, international trials.”
Stroke patients who were transferred directly to an angiography suite were also less likely to be dependent on assistance with daily activities than were those who received the current standard of care, Dr. Requena said. “More frequent and more rapid treatment can help improve outcomes for our stroke patients.”
A limitation of this study is that the hospital had extensive experience with immediate angiography, so findings may differ at hospitals or care centers with less angiography expertise or experience, Dr. Requena said.
He added that retrospective studies conducted in hospitals in the United States, Germany, and Switzerland show that this kind of protocol can be developed in any high-volume stroke center, although multicenter, international trials are needed.
The cost of speed
Commenting on the ANGIO-CAT study, Michael Hill, MD, a professor at the University of Calgary (Alta.), said the 27-minute improvement in door-to-reperfusion time achieved in the study was meaningful and correlates with the degree of improved outcomes observed. “So, the improvement in speed of treatment resulting in better outcomes makes sense,” he added.
He cautioned that this strategy would only be feasible in certain centers with selected patients and that cost will be a fundamental issue.
“If you identify patients at angiography, you risk having some patients with no target large-vessel occlusion,” Dr. Hill added. “The real question is, how many of these patients without a large-vessel occlusion can the system tolerate before it becomes uneconomical and not fruitful or harmful, given that groin puncture is not totally harmless?”
The moderator of the ISC news conference on the study, Mitchell Elkind, MD, professor of neurology at Columbia University, New York, who is also president of the American Stroke Association, said the study reflects the growing recognition of the importance of speed when treating stroke. “If we can shorten time to treatment using rapid evaluation and imaging protocols, this will help save brain,” he said.
Also commenting on the study, Louisa McCullough, MD, PhD, chief of neurology at Memorial Hermann Hospital–Texas Medical Center, Houston, who is the ISC meeting chair, said she thought the study would be relevant to the United States. “Speed is really of the essence. Whenever we can reduce delays, that will make a big difference to patients.”
Referring to this study on improving hospital systems, as well as a second study that was presented at the meeting that showed benefits from delivery of prehospital thrombolysis via a mobile stroke unit, Dr. McCullough added that “we need to set up models so we can get the best of both these worlds. These studies are really leading the way on how we can change the stroke systems of care.”
The study was funded by Vall d’Hebron Research Institute. Dr. Requena disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in a new study.
Results of the ANGIO-CAT trial were presented at the International Stroke Conference sponsored by the American Heart Association.
The study involved patients suspected of having a large-vessel occlusion, as assessed in the prehospital setting by paramedics using the Rapid Arterial Occlusion Evaluation (RACE) score.
In his presentation, Manuel Requena, PhD, a neurologist and neurointerventionalist fellow at Vall d’Hebron Hospital, Barcelona, explained that, if patients were within 6 hours of symptom onset with a RACE scale score greater than 4, paramedics called ahead to a stroke neurologist, who met the patient directly at the hospital.
If on clinical examination the National Institutes of Health Stroke Scale (NIHSS) score was greater than 10, patients could be enrolled into the study. Upon enrollment, they were randomly assigned either to be taken directly to the angiography suite or to receive standard care.
Bypassing the emergency department
Dr. Requena noted that, at his center, patients who receive standard care are transferred to the CT imaging suite, where they are evaluated with noncontrast CT and CT angiography. CT perfusion is also performed if the treating physician deems it necessary.
If a large-vessel occlusion is confirmed, patients are then transferred to the angiography suite for endovascular treatment. He added that in many centers, patients are evaluated in the ED before undergoing CT scanning.
Patients in the direct angiography group received a “flat-panel” noncontrast CT in the angiography suite to rule out intracranial hemorrhage or a large, established infarct. The large-vessel occlusion would be confirmed by arteriography before the endovascular procedure was performed.
After CT scanning, patients received thrombolysis as recommended in the guidelines.
The current interim analysis includes the 174 patients who have been enrolled so far in the study. The median RACE score for these patients was 7, and the median NIHSS score was 17. Large-vessel occlusion was confirmed in 84% of patients, and 8% had an intracerebral hemorrhage.
Results showed that of the 147 patients who received endovascular therapy, puncture time was shorter for those who were taken directly to angiography (median, 18 min vs. 42 min), as was time to reperfusion (median, 57 min vs. 84 min).
The primary outcome was a shift analysis of the Modified Rankin Scale functional outcome scale at 90 days (odds of 1-point improvement or more). In the direct angiography group, the adjusted odds ratio for an improved functional outcome was 2.2 (95% confidence interval, 1.2-.1).
There were no significant differences in safety endpoints. There was a trend toward more procedural complications in those receiving endovascular therapy in the direct angiography group (8.1% vs. 2.7%; P = .6), but there was also a trend toward lower 90-day mortality in this group (20.2% vs. 32.9%; P = .07)
Dr. Requena reported no significant difference in safety outcomes among those with a hemorrhagic stroke.
“Our study is the first clinical trial that shows the superiority of direct transfer to an angiography suite,” said Dr. Requena. “Our findings were close to what we expected, and we were surprised that they occurred so early in the study. We trust that they will be confirmed in ongoing, multicenter, international trials.”
Stroke patients who were transferred directly to an angiography suite were also less likely to be dependent on assistance with daily activities than were those who received the current standard of care, Dr. Requena said. “More frequent and more rapid treatment can help improve outcomes for our stroke patients.”
A limitation of this study is that the hospital had extensive experience with immediate angiography, so findings may differ at hospitals or care centers with less angiography expertise or experience, Dr. Requena said.
He added that retrospective studies conducted in hospitals in the United States, Germany, and Switzerland show that this kind of protocol can be developed in any high-volume stroke center, although multicenter, international trials are needed.
The cost of speed
Commenting on the ANGIO-CAT study, Michael Hill, MD, a professor at the University of Calgary (Alta.), said the 27-minute improvement in door-to-reperfusion time achieved in the study was meaningful and correlates with the degree of improved outcomes observed. “So, the improvement in speed of treatment resulting in better outcomes makes sense,” he added.
He cautioned that this strategy would only be feasible in certain centers with selected patients and that cost will be a fundamental issue.
“If you identify patients at angiography, you risk having some patients with no target large-vessel occlusion,” Dr. Hill added. “The real question is, how many of these patients without a large-vessel occlusion can the system tolerate before it becomes uneconomical and not fruitful or harmful, given that groin puncture is not totally harmless?”
The moderator of the ISC news conference on the study, Mitchell Elkind, MD, professor of neurology at Columbia University, New York, who is also president of the American Stroke Association, said the study reflects the growing recognition of the importance of speed when treating stroke. “If we can shorten time to treatment using rapid evaluation and imaging protocols, this will help save brain,” he said.
Also commenting on the study, Louisa McCullough, MD, PhD, chief of neurology at Memorial Hermann Hospital–Texas Medical Center, Houston, who is the ISC meeting chair, said she thought the study would be relevant to the United States. “Speed is really of the essence. Whenever we can reduce delays, that will make a big difference to patients.”
Referring to this study on improving hospital systems, as well as a second study that was presented at the meeting that showed benefits from delivery of prehospital thrombolysis via a mobile stroke unit, Dr. McCullough added that “we need to set up models so we can get the best of both these worlds. These studies are really leading the way on how we can change the stroke systems of care.”
The study was funded by Vall d’Hebron Research Institute. Dr. Requena disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2021
Dose-related AFib risk with omega-3 fatty acids?
There may be a dose-related risk for atrial fibrillation (AFib) with omega-3 fatty acid intake, data from four randomized clinical trials suggest.
The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AFib.
The trial, first reported at last year’s American Heart Association meeting, was published online March 16 in the Journal of the American Medical Association.
Together with three other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AFib, an accompanying “Editor’s Note” suggests.
The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, four randomized clinical trials have provided data on the risk of AFib with omega-3 fatty acid intake.
In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AFib in the omega-3 groups vs. controls in both trials.
In the OMEMI trial in elderly patients with a recent myocardial infarction, an intermediate dose (1.8 g/day) of omega-3 fatty acids also showed an increase in AFib risk (hazard ratio, 1.84) but this was not significant. And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AFib in a primary prevention population.
“Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF [AFib] and followed up for the possible development of this common and potentially hazardous arrhythmia,” Dr. Curfman concludes.
The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, Calif., explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D3 have higher risks of incident AFib, but data on dietary or supplemental intake of these nutrients on AFib risk were mixed.
“To our knowledge, this study is the first randomized, placebo-controlled trial to prospectively test the effect of any intervention on incident AF and is the only trial to test alternative upstream preventive agents for AF in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks,” they write.
The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2 x 2 factorial design to evaluate daily supplementation with 2,000 IU of vitamin D3 and/or 840 mg of marine omega-3 fatty acids (460 mg EPA and 380 mg DHA), in the primary prevention of cardiovascular disease and cancer in 25,871 men and women age 50 and older in the United States.
Results showed that over a median 5.3 years of treatment and follow-up, the primary endpoint of incident AFib occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AFib events occurred in 3.7% of patients taking EPA/DHA vs. 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P = .19).
For the vitamin D3 vs. placebo comparison, results were very similar, with incident AFib events occurring in 3.7% vs. 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P = .19). There was no evidence for interaction between the two study agents.
“Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D3 for the primary prevention of AFib and provide reassurance regarding lack of a major risk of AFib incidence associated with these commonly used supplements at these doses,” the authors conclude.
Noting that significant increases in AFib have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: “Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.”
The researchers say that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D3 supplementation on AFib risk and results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.
They point out that, while there were no significant differences in incident AFib for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AFib associated with randomized treatment was observed in selected subgroups.
For omega-3 fatty acids, AFib risk was modestly increased in taller individuals, and for vitamin D3, elevations in AFib risk were observed in younger individuals and participants who drank less alcohol.
“Although the hazard ratios and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating,” they warn.
The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr. Curfman reports no relevant disclosures.
A version of this article first appeared on Medscape.com.
There may be a dose-related risk for atrial fibrillation (AFib) with omega-3 fatty acid intake, data from four randomized clinical trials suggest.
The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AFib.
The trial, first reported at last year’s American Heart Association meeting, was published online March 16 in the Journal of the American Medical Association.
Together with three other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AFib, an accompanying “Editor’s Note” suggests.
The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, four randomized clinical trials have provided data on the risk of AFib with omega-3 fatty acid intake.
In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AFib in the omega-3 groups vs. controls in both trials.
In the OMEMI trial in elderly patients with a recent myocardial infarction, an intermediate dose (1.8 g/day) of omega-3 fatty acids also showed an increase in AFib risk (hazard ratio, 1.84) but this was not significant. And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AFib in a primary prevention population.
“Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF [AFib] and followed up for the possible development of this common and potentially hazardous arrhythmia,” Dr. Curfman concludes.
The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, Calif., explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D3 have higher risks of incident AFib, but data on dietary or supplemental intake of these nutrients on AFib risk were mixed.
“To our knowledge, this study is the first randomized, placebo-controlled trial to prospectively test the effect of any intervention on incident AF and is the only trial to test alternative upstream preventive agents for AF in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks,” they write.
The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2 x 2 factorial design to evaluate daily supplementation with 2,000 IU of vitamin D3 and/or 840 mg of marine omega-3 fatty acids (460 mg EPA and 380 mg DHA), in the primary prevention of cardiovascular disease and cancer in 25,871 men and women age 50 and older in the United States.
Results showed that over a median 5.3 years of treatment and follow-up, the primary endpoint of incident AFib occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AFib events occurred in 3.7% of patients taking EPA/DHA vs. 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P = .19).
For the vitamin D3 vs. placebo comparison, results were very similar, with incident AFib events occurring in 3.7% vs. 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P = .19). There was no evidence for interaction between the two study agents.
“Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D3 for the primary prevention of AFib and provide reassurance regarding lack of a major risk of AFib incidence associated with these commonly used supplements at these doses,” the authors conclude.
Noting that significant increases in AFib have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: “Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.”
The researchers say that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D3 supplementation on AFib risk and results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.
They point out that, while there were no significant differences in incident AFib for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AFib associated with randomized treatment was observed in selected subgroups.
For omega-3 fatty acids, AFib risk was modestly increased in taller individuals, and for vitamin D3, elevations in AFib risk were observed in younger individuals and participants who drank less alcohol.
“Although the hazard ratios and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating,” they warn.
The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr. Curfman reports no relevant disclosures.
A version of this article first appeared on Medscape.com.
There may be a dose-related risk for atrial fibrillation (AFib) with omega-3 fatty acid intake, data from four randomized clinical trials suggest.
The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AFib.
The trial, first reported at last year’s American Heart Association meeting, was published online March 16 in the Journal of the American Medical Association.
Together with three other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AFib, an accompanying “Editor’s Note” suggests.
The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, four randomized clinical trials have provided data on the risk of AFib with omega-3 fatty acid intake.
In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AFib in the omega-3 groups vs. controls in both trials.
In the OMEMI trial in elderly patients with a recent myocardial infarction, an intermediate dose (1.8 g/day) of omega-3 fatty acids also showed an increase in AFib risk (hazard ratio, 1.84) but this was not significant. And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AFib in a primary prevention population.
“Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF [AFib] and followed up for the possible development of this common and potentially hazardous arrhythmia,” Dr. Curfman concludes.
The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, Calif., explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D3 have higher risks of incident AFib, but data on dietary or supplemental intake of these nutrients on AFib risk were mixed.
“To our knowledge, this study is the first randomized, placebo-controlled trial to prospectively test the effect of any intervention on incident AF and is the only trial to test alternative upstream preventive agents for AF in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks,” they write.
The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2 x 2 factorial design to evaluate daily supplementation with 2,000 IU of vitamin D3 and/or 840 mg of marine omega-3 fatty acids (460 mg EPA and 380 mg DHA), in the primary prevention of cardiovascular disease and cancer in 25,871 men and women age 50 and older in the United States.
Results showed that over a median 5.3 years of treatment and follow-up, the primary endpoint of incident AFib occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AFib events occurred in 3.7% of patients taking EPA/DHA vs. 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P = .19).
For the vitamin D3 vs. placebo comparison, results were very similar, with incident AFib events occurring in 3.7% vs. 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P = .19). There was no evidence for interaction between the two study agents.
“Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D3 for the primary prevention of AFib and provide reassurance regarding lack of a major risk of AFib incidence associated with these commonly used supplements at these doses,” the authors conclude.
Noting that significant increases in AFib have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: “Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.”
The researchers say that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D3 supplementation on AFib risk and results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.
They point out that, while there were no significant differences in incident AFib for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AFib associated with randomized treatment was observed in selected subgroups.
For omega-3 fatty acids, AFib risk was modestly increased in taller individuals, and for vitamin D3, elevations in AFib risk were observed in younger individuals and participants who drank less alcohol.
“Although the hazard ratios and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating,” they warn.
The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr. Curfman reports no relevant disclosures.
A version of this article first appeared on Medscape.com.
Type 2 diabetes linked to increased risk for Parkinson’s
New analyses of both observational and genetic data have provided “convincing evidence” that type 2 diabetes is associated with an increased risk for Parkinson’s disease.
“The fact that we see the same effects in both types of analysis separately makes it more likely that these results are real – that type 2 diabetes really is a driver of Parkinson’s disease risk,” Alastair Noyce, PhD, senior author of the new studies, said in an interview.
The two analyses are reported in one paper published online March 8 in the journal Movement Disorders.
Dr. Noyce, clinical senior lecturer in the preventive neurology unit at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, explained that his group is interested in risk factors for Parkinson’s disease, particularly those relevant at the population level and which might be modifiable.
“Several studies have looked at diabetes as a risk factor for Parkinson’s but very few have focused on type 2 diabetes, and, as this is such a growing health issue, we wanted to look at that in more detail,” he said.
The researchers performed two different analyses: a meta-analysis of observational studies investigating an association between type 2 diabetes and Parkinson’s; and a separate Mendelian randomization analysis of genetic data on the two conditions.
They found similar results in both studies, with the observational data suggesting type 2 diabetes was associated with a 21% increased risk for Parkinson’s disease and the genetic data suggesting an 8% increased risk. There were also hints that type 2 diabetes might also be associated with faster progression of Parkinson’s symptoms.
“I don’t think type 2 diabetes is a major cause of Parkinson’s, but it probably makes some contribution and may increase the risk of a more aggressive form of the condition,” Dr. Noyce said.
“I would say the increased risk of Parkinson’s disease attributable to type 2 diabetes may be similar to that of head injury or pesticide exposure, but it is important, as type 2 diabetes is very prevalent and is increasing,” he added. “As we see the growth in type 2 diabetes, this could lead to a later increase in Parkinson’s, which is already one of the fastest-growing diseases worldwide.”
For the meta-analysis of observational data, the researchers included nine studies that investigated preceding type 2 diabetes specifically and its effect on the risk for Parkinson’s disease and progression.
The pooled effect estimates showed that type 2 diabetes was associated with an increased risk for Parkinson’s disease (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), and there was some evidence that type 2 diabetes was associated with faster progression of motor symptoms (standardized mean difference [SMD], 0.55) and cognitive decline (SMD, −0.92).
The observational meta-analysis included seven cohort studies and two case-control studies, and these different types of studies showed different results in regard to the association between diabetes and Parkinson’s. While the cohort studies showed a detrimental effect of diabetes on Parkinson’s risk (OR, 1.29), the case-control studies suggested protective effect (OR, 0.51).
Addressing this, Dr. Noyce noted that the case-control studies may be less reliable as they suffered more from survivor bias. “Diabetes may cause deaths in mid-life before people go on to develop Parkinson’s, and this would cause a protective effect to be seen, but we believe this to be a spurious result. Cohort studies are generally more reliable and are less susceptible to survivor bias,” he said.
For the genetic analysis, the researchers combined results from two large publicly available genome-wide association studies – one for type 2 diabetes and one for Parkinson’s disease to assess whether individuals with a genetic tendency to type 2 diabetes had a higher risk of developing Parkinson’s.
Results showed an increased risk for Parkinson’s in those individuals with genetic variants associated with type 2 diabetes, with an odds ratio of 1.08 (P = .010). There was also some evidence of an effect on motor progression (OR, 1.10; P = .032) but not on cognitive progression.
On the possible mechanism behind this observation, Dr. Noyce noted type 2 diabetes and Parkinson’s have some similarities in biology, including abnormal protein aggregation.
In the study, the authors also suggest that circulating insulin may have a neuroprotective role, whereas systemic and local insulin resistance can influence pathways known to be important in Parkinson’s pathogenesis, including those that relate to mitochondrial dysfunction, neuroinflammation, synaptic plasticity, and mitochondrial dysfunction.
Dr. Noyce further pointed out that several drugs used for the treatment of type 2 diabetes have been repurposed as possible treatments for Parkinson’s disease and are now being tested for this new indication. “Our results support that approach and raise the idea that some of these drugs may even prevent Parkinson’s in people at risk,” he said.
Most people who have type 2 diabetes won’t get Parkinson’s disease, he added. Other outcomes such as heart disease, kidney disease, and microvascular complications are far more likely, and the main aim of preventing and treating type 2 diabetes is to prevent these far more common outcomes. “But our data suggests that this could also have a possible benefit in reducing future Parkinson’s risk,” he said.
Not on the horizon at present is the possibility of screening patients with type 2 diabetes for signs of early Parkinson’s, Dr. Noyce said.
“There isn’t a test for identifying presymptomatic neurodegenerative diseases such as Parkinson’s yet, but perhaps in the future there will be, and type 2 diabetes may be one risk factor to take into account when considering such screening,” he added.
This work was financially supported by grants from The Michael J. Fox Foundation; the Canadian Consortium on Neurodegeneration in Aging (CCNA); the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative; and Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.
Dr. Noyce reports grants from the Barts Charity, Parkinson’s UK, Aligning Science Across Parkinson’s and Michael J. Fox Foundation, and the Virginia Keiley Benefaction; and personal fees/honoraria from Britannia, BIAL, AbbVie, Global Kinetics Corporation, Profile, Biogen, Roche, and UCB outside of the submitted work.
A version of this article first appeared on Medscape.com.
New analyses of both observational and genetic data have provided “convincing evidence” that type 2 diabetes is associated with an increased risk for Parkinson’s disease.
“The fact that we see the same effects in both types of analysis separately makes it more likely that these results are real – that type 2 diabetes really is a driver of Parkinson’s disease risk,” Alastair Noyce, PhD, senior author of the new studies, said in an interview.
The two analyses are reported in one paper published online March 8 in the journal Movement Disorders.
Dr. Noyce, clinical senior lecturer in the preventive neurology unit at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, explained that his group is interested in risk factors for Parkinson’s disease, particularly those relevant at the population level and which might be modifiable.
“Several studies have looked at diabetes as a risk factor for Parkinson’s but very few have focused on type 2 diabetes, and, as this is such a growing health issue, we wanted to look at that in more detail,” he said.
The researchers performed two different analyses: a meta-analysis of observational studies investigating an association between type 2 diabetes and Parkinson’s; and a separate Mendelian randomization analysis of genetic data on the two conditions.
They found similar results in both studies, with the observational data suggesting type 2 diabetes was associated with a 21% increased risk for Parkinson’s disease and the genetic data suggesting an 8% increased risk. There were also hints that type 2 diabetes might also be associated with faster progression of Parkinson’s symptoms.
“I don’t think type 2 diabetes is a major cause of Parkinson’s, but it probably makes some contribution and may increase the risk of a more aggressive form of the condition,” Dr. Noyce said.
“I would say the increased risk of Parkinson’s disease attributable to type 2 diabetes may be similar to that of head injury or pesticide exposure, but it is important, as type 2 diabetes is very prevalent and is increasing,” he added. “As we see the growth in type 2 diabetes, this could lead to a later increase in Parkinson’s, which is already one of the fastest-growing diseases worldwide.”
For the meta-analysis of observational data, the researchers included nine studies that investigated preceding type 2 diabetes specifically and its effect on the risk for Parkinson’s disease and progression.
The pooled effect estimates showed that type 2 diabetes was associated with an increased risk for Parkinson’s disease (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), and there was some evidence that type 2 diabetes was associated with faster progression of motor symptoms (standardized mean difference [SMD], 0.55) and cognitive decline (SMD, −0.92).
The observational meta-analysis included seven cohort studies and two case-control studies, and these different types of studies showed different results in regard to the association between diabetes and Parkinson’s. While the cohort studies showed a detrimental effect of diabetes on Parkinson’s risk (OR, 1.29), the case-control studies suggested protective effect (OR, 0.51).
Addressing this, Dr. Noyce noted that the case-control studies may be less reliable as they suffered more from survivor bias. “Diabetes may cause deaths in mid-life before people go on to develop Parkinson’s, and this would cause a protective effect to be seen, but we believe this to be a spurious result. Cohort studies are generally more reliable and are less susceptible to survivor bias,” he said.
For the genetic analysis, the researchers combined results from two large publicly available genome-wide association studies – one for type 2 diabetes and one for Parkinson’s disease to assess whether individuals with a genetic tendency to type 2 diabetes had a higher risk of developing Parkinson’s.
Results showed an increased risk for Parkinson’s in those individuals with genetic variants associated with type 2 diabetes, with an odds ratio of 1.08 (P = .010). There was also some evidence of an effect on motor progression (OR, 1.10; P = .032) but not on cognitive progression.
On the possible mechanism behind this observation, Dr. Noyce noted type 2 diabetes and Parkinson’s have some similarities in biology, including abnormal protein aggregation.
In the study, the authors also suggest that circulating insulin may have a neuroprotective role, whereas systemic and local insulin resistance can influence pathways known to be important in Parkinson’s pathogenesis, including those that relate to mitochondrial dysfunction, neuroinflammation, synaptic plasticity, and mitochondrial dysfunction.
Dr. Noyce further pointed out that several drugs used for the treatment of type 2 diabetes have been repurposed as possible treatments for Parkinson’s disease and are now being tested for this new indication. “Our results support that approach and raise the idea that some of these drugs may even prevent Parkinson’s in people at risk,” he said.
Most people who have type 2 diabetes won’t get Parkinson’s disease, he added. Other outcomes such as heart disease, kidney disease, and microvascular complications are far more likely, and the main aim of preventing and treating type 2 diabetes is to prevent these far more common outcomes. “But our data suggests that this could also have a possible benefit in reducing future Parkinson’s risk,” he said.
Not on the horizon at present is the possibility of screening patients with type 2 diabetes for signs of early Parkinson’s, Dr. Noyce said.
“There isn’t a test for identifying presymptomatic neurodegenerative diseases such as Parkinson’s yet, but perhaps in the future there will be, and type 2 diabetes may be one risk factor to take into account when considering such screening,” he added.
This work was financially supported by grants from The Michael J. Fox Foundation; the Canadian Consortium on Neurodegeneration in Aging (CCNA); the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative; and Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.
Dr. Noyce reports grants from the Barts Charity, Parkinson’s UK, Aligning Science Across Parkinson’s and Michael J. Fox Foundation, and the Virginia Keiley Benefaction; and personal fees/honoraria from Britannia, BIAL, AbbVie, Global Kinetics Corporation, Profile, Biogen, Roche, and UCB outside of the submitted work.
A version of this article first appeared on Medscape.com.
New analyses of both observational and genetic data have provided “convincing evidence” that type 2 diabetes is associated with an increased risk for Parkinson’s disease.
“The fact that we see the same effects in both types of analysis separately makes it more likely that these results are real – that type 2 diabetes really is a driver of Parkinson’s disease risk,” Alastair Noyce, PhD, senior author of the new studies, said in an interview.
The two analyses are reported in one paper published online March 8 in the journal Movement Disorders.
Dr. Noyce, clinical senior lecturer in the preventive neurology unit at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, explained that his group is interested in risk factors for Parkinson’s disease, particularly those relevant at the population level and which might be modifiable.
“Several studies have looked at diabetes as a risk factor for Parkinson’s but very few have focused on type 2 diabetes, and, as this is such a growing health issue, we wanted to look at that in more detail,” he said.
The researchers performed two different analyses: a meta-analysis of observational studies investigating an association between type 2 diabetes and Parkinson’s; and a separate Mendelian randomization analysis of genetic data on the two conditions.
They found similar results in both studies, with the observational data suggesting type 2 diabetes was associated with a 21% increased risk for Parkinson’s disease and the genetic data suggesting an 8% increased risk. There were also hints that type 2 diabetes might also be associated with faster progression of Parkinson’s symptoms.
“I don’t think type 2 diabetes is a major cause of Parkinson’s, but it probably makes some contribution and may increase the risk of a more aggressive form of the condition,” Dr. Noyce said.
“I would say the increased risk of Parkinson’s disease attributable to type 2 diabetes may be similar to that of head injury or pesticide exposure, but it is important, as type 2 diabetes is very prevalent and is increasing,” he added. “As we see the growth in type 2 diabetes, this could lead to a later increase in Parkinson’s, which is already one of the fastest-growing diseases worldwide.”
For the meta-analysis of observational data, the researchers included nine studies that investigated preceding type 2 diabetes specifically and its effect on the risk for Parkinson’s disease and progression.
The pooled effect estimates showed that type 2 diabetes was associated with an increased risk for Parkinson’s disease (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), and there was some evidence that type 2 diabetes was associated with faster progression of motor symptoms (standardized mean difference [SMD], 0.55) and cognitive decline (SMD, −0.92).
The observational meta-analysis included seven cohort studies and two case-control studies, and these different types of studies showed different results in regard to the association between diabetes and Parkinson’s. While the cohort studies showed a detrimental effect of diabetes on Parkinson’s risk (OR, 1.29), the case-control studies suggested protective effect (OR, 0.51).
Addressing this, Dr. Noyce noted that the case-control studies may be less reliable as they suffered more from survivor bias. “Diabetes may cause deaths in mid-life before people go on to develop Parkinson’s, and this would cause a protective effect to be seen, but we believe this to be a spurious result. Cohort studies are generally more reliable and are less susceptible to survivor bias,” he said.
For the genetic analysis, the researchers combined results from two large publicly available genome-wide association studies – one for type 2 diabetes and one for Parkinson’s disease to assess whether individuals with a genetic tendency to type 2 diabetes had a higher risk of developing Parkinson’s.
Results showed an increased risk for Parkinson’s in those individuals with genetic variants associated with type 2 diabetes, with an odds ratio of 1.08 (P = .010). There was also some evidence of an effect on motor progression (OR, 1.10; P = .032) but not on cognitive progression.
On the possible mechanism behind this observation, Dr. Noyce noted type 2 diabetes and Parkinson’s have some similarities in biology, including abnormal protein aggregation.
In the study, the authors also suggest that circulating insulin may have a neuroprotective role, whereas systemic and local insulin resistance can influence pathways known to be important in Parkinson’s pathogenesis, including those that relate to mitochondrial dysfunction, neuroinflammation, synaptic plasticity, and mitochondrial dysfunction.
Dr. Noyce further pointed out that several drugs used for the treatment of type 2 diabetes have been repurposed as possible treatments for Parkinson’s disease and are now being tested for this new indication. “Our results support that approach and raise the idea that some of these drugs may even prevent Parkinson’s in people at risk,” he said.
Most people who have type 2 diabetes won’t get Parkinson’s disease, he added. Other outcomes such as heart disease, kidney disease, and microvascular complications are far more likely, and the main aim of preventing and treating type 2 diabetes is to prevent these far more common outcomes. “But our data suggests that this could also have a possible benefit in reducing future Parkinson’s risk,” he said.
Not on the horizon at present is the possibility of screening patients with type 2 diabetes for signs of early Parkinson’s, Dr. Noyce said.
“There isn’t a test for identifying presymptomatic neurodegenerative diseases such as Parkinson’s yet, but perhaps in the future there will be, and type 2 diabetes may be one risk factor to take into account when considering such screening,” he added.
This work was financially supported by grants from The Michael J. Fox Foundation; the Canadian Consortium on Neurodegeneration in Aging (CCNA); the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative; and Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.
Dr. Noyce reports grants from the Barts Charity, Parkinson’s UK, Aligning Science Across Parkinson’s and Michael J. Fox Foundation, and the Virginia Keiley Benefaction; and personal fees/honoraria from Britannia, BIAL, AbbVie, Global Kinetics Corporation, Profile, Biogen, Roche, and UCB outside of the submitted work.
A version of this article first appeared on Medscape.com.
Late-window stroke thrombolysis not linked to clot migration
In patients with acute ischemic stroke, the use of thrombolysis in the late window of 4.5-9 hours after symptom onset was not associated with an increase in clot migration that would cause reduced clot accessibility to endovascular therapy, a new analysis from the EXTEND trial shows.
“There was no significant difference in the incidence of clot migration leading to clot inaccessibility in patients who received placebo or (intravenous) thrombolysis,” the authors report.
“Our results found no convincing evidence against the use of bridging thrombolysis before endovascular therapy in patients with acute ischemic stroke who present outside the 4.5-hour window,” they conclude.
“This information is important because it provides some comfort for neurointerventionists that IV thrombolysis does not unduly increase the risk of clot migration,” senior author, Bernard Yan, DMedSci, FRACP, told this news organization.
The study was published online in Stroke on Feb. 16.
The Australian researchers explain that endovascular thrombectomy is the standard of care in patients presenting with acute ischemic stroke caused by large-vessel occlusion, and current treatment guidelines recommend bridging thrombolysis for all patients receiving thrombectomy within the 4.5-hour time window.
While thrombectomy is also recommended in selected patients up to 24 hours after onset of symptoms, it remains unclear whether thrombolysis pretreatment should be administered in this setting.
One of the issues that might affect use of thrombolysis is distal clot migration. As proximal clot location is a crucial factor determining suitability for endovascular clot retrieval, distal migration may prevent successful thrombectomy, they note.
“Clot migration can happen any time and makes life more difficult for the neurointerventionist who performs the endovascular clot retrieval,” added Dr. Yan, who is a neurologist and neurointerventionist at the Royal Melbourne Hospital, Australia.
In the current paper, the researchers report a retrospective analysis of data from the EXTEND trial of late thrombolysis, defined as 4.5-9 hours after symptom onset, to investigate the association between thrombolysis and clot migration leading to clot irretrievability.
The analysis included a total of 220 patients (109 patients in the placebo group and 111 in the thrombolysis group).
Results showed that retrievable clot was seen on baseline imaging in 69% of patients in the placebo group and 61% in the thrombolysis group. Clot resolution occurred in 28% of patients in the placebo group and 50% in the thrombolysis group.
No significant difference was observed in the incidence of clot migration leading to inaccessibility between groups. Clot migration from a retrievable to nonretrievable location occurred in 19% of the placebo group and 14% of the thrombolysis group, with an odds ratio for clot migration in the thrombolysis group of 0.70 (95% confidence interval, 0.35-1.44). This outcome was consistent across subgroups.
The researchers note that, to their knowledge, this is the first randomized controlled study to assess the effect of thrombolysis on clot migration and accessibility in an extended time window.
They acknowledge that a limitation of this study is that they only assessed clot migration from a retrievable to a nonretrievable location; therefore, the true frequency of any clot migration occurring was likely to be higher, and this could explain why other reports have found higher odds ratios of clot migration.
But they point out that they chose to limit their analysis in this way specifically to guide decision-making regarding bridging thrombolysis incorporating endovascular therapy in the extended time window.
“The findings of this study are highly relevant in the current clinical environment, where there are multiple ongoing trials looking at removing thrombolysis pretreatment within the 4.5-hour time window in thrombectomy patients,” the authors write.
“We have demonstrated that thrombolysis in the 4.5- to 9-hour window is not associated with reduced clot accessibility, and this information will be useful in future trial designs incorporating this extended time window,” they add.
Commenting on the study for this news organization, Michael Hill, MD, University of Calgary (Alta.), said: “Thrombus migration does happen and is likely part of the natural history of ischemic stroke, which may be influenced by therapeutics such as thrombolysis. This paper’s top-line result is that thrombus migration occurs in both treated and untreated groups – and therefore that this is really an observation of natural history.”
Dr. Hill says that, at present, patients should be treated with thrombolysis before endovascular therapy if they are eligible, and these results do not change that recommendation.
“The results of the ongoing trials comparing direct thrombectomy with thrombolysis plus thrombectomy will help to understand the potential clinical outcome relevance of this phenomenon,” he added.
The EXTEND trial was supported by grants from the Australian National Health and Medical Research Council of Australia and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Dr. Yan reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In patients with acute ischemic stroke, the use of thrombolysis in the late window of 4.5-9 hours after symptom onset was not associated with an increase in clot migration that would cause reduced clot accessibility to endovascular therapy, a new analysis from the EXTEND trial shows.
“There was no significant difference in the incidence of clot migration leading to clot inaccessibility in patients who received placebo or (intravenous) thrombolysis,” the authors report.
“Our results found no convincing evidence against the use of bridging thrombolysis before endovascular therapy in patients with acute ischemic stroke who present outside the 4.5-hour window,” they conclude.
“This information is important because it provides some comfort for neurointerventionists that IV thrombolysis does not unduly increase the risk of clot migration,” senior author, Bernard Yan, DMedSci, FRACP, told this news organization.
The study was published online in Stroke on Feb. 16.
The Australian researchers explain that endovascular thrombectomy is the standard of care in patients presenting with acute ischemic stroke caused by large-vessel occlusion, and current treatment guidelines recommend bridging thrombolysis for all patients receiving thrombectomy within the 4.5-hour time window.
While thrombectomy is also recommended in selected patients up to 24 hours after onset of symptoms, it remains unclear whether thrombolysis pretreatment should be administered in this setting.
One of the issues that might affect use of thrombolysis is distal clot migration. As proximal clot location is a crucial factor determining suitability for endovascular clot retrieval, distal migration may prevent successful thrombectomy, they note.
“Clot migration can happen any time and makes life more difficult for the neurointerventionist who performs the endovascular clot retrieval,” added Dr. Yan, who is a neurologist and neurointerventionist at the Royal Melbourne Hospital, Australia.
In the current paper, the researchers report a retrospective analysis of data from the EXTEND trial of late thrombolysis, defined as 4.5-9 hours after symptom onset, to investigate the association between thrombolysis and clot migration leading to clot irretrievability.
The analysis included a total of 220 patients (109 patients in the placebo group and 111 in the thrombolysis group).
Results showed that retrievable clot was seen on baseline imaging in 69% of patients in the placebo group and 61% in the thrombolysis group. Clot resolution occurred in 28% of patients in the placebo group and 50% in the thrombolysis group.
No significant difference was observed in the incidence of clot migration leading to inaccessibility between groups. Clot migration from a retrievable to nonretrievable location occurred in 19% of the placebo group and 14% of the thrombolysis group, with an odds ratio for clot migration in the thrombolysis group of 0.70 (95% confidence interval, 0.35-1.44). This outcome was consistent across subgroups.
The researchers note that, to their knowledge, this is the first randomized controlled study to assess the effect of thrombolysis on clot migration and accessibility in an extended time window.
They acknowledge that a limitation of this study is that they only assessed clot migration from a retrievable to a nonretrievable location; therefore, the true frequency of any clot migration occurring was likely to be higher, and this could explain why other reports have found higher odds ratios of clot migration.
But they point out that they chose to limit their analysis in this way specifically to guide decision-making regarding bridging thrombolysis incorporating endovascular therapy in the extended time window.
“The findings of this study are highly relevant in the current clinical environment, where there are multiple ongoing trials looking at removing thrombolysis pretreatment within the 4.5-hour time window in thrombectomy patients,” the authors write.
“We have demonstrated that thrombolysis in the 4.5- to 9-hour window is not associated with reduced clot accessibility, and this information will be useful in future trial designs incorporating this extended time window,” they add.
Commenting on the study for this news organization, Michael Hill, MD, University of Calgary (Alta.), said: “Thrombus migration does happen and is likely part of the natural history of ischemic stroke, which may be influenced by therapeutics such as thrombolysis. This paper’s top-line result is that thrombus migration occurs in both treated and untreated groups – and therefore that this is really an observation of natural history.”
Dr. Hill says that, at present, patients should be treated with thrombolysis before endovascular therapy if they are eligible, and these results do not change that recommendation.
“The results of the ongoing trials comparing direct thrombectomy with thrombolysis plus thrombectomy will help to understand the potential clinical outcome relevance of this phenomenon,” he added.
The EXTEND trial was supported by grants from the Australian National Health and Medical Research Council of Australia and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Dr. Yan reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In patients with acute ischemic stroke, the use of thrombolysis in the late window of 4.5-9 hours after symptom onset was not associated with an increase in clot migration that would cause reduced clot accessibility to endovascular therapy, a new analysis from the EXTEND trial shows.
“There was no significant difference in the incidence of clot migration leading to clot inaccessibility in patients who received placebo or (intravenous) thrombolysis,” the authors report.
“Our results found no convincing evidence against the use of bridging thrombolysis before endovascular therapy in patients with acute ischemic stroke who present outside the 4.5-hour window,” they conclude.
“This information is important because it provides some comfort for neurointerventionists that IV thrombolysis does not unduly increase the risk of clot migration,” senior author, Bernard Yan, DMedSci, FRACP, told this news organization.
The study was published online in Stroke on Feb. 16.
The Australian researchers explain that endovascular thrombectomy is the standard of care in patients presenting with acute ischemic stroke caused by large-vessel occlusion, and current treatment guidelines recommend bridging thrombolysis for all patients receiving thrombectomy within the 4.5-hour time window.
While thrombectomy is also recommended in selected patients up to 24 hours after onset of symptoms, it remains unclear whether thrombolysis pretreatment should be administered in this setting.
One of the issues that might affect use of thrombolysis is distal clot migration. As proximal clot location is a crucial factor determining suitability for endovascular clot retrieval, distal migration may prevent successful thrombectomy, they note.
“Clot migration can happen any time and makes life more difficult for the neurointerventionist who performs the endovascular clot retrieval,” added Dr. Yan, who is a neurologist and neurointerventionist at the Royal Melbourne Hospital, Australia.
In the current paper, the researchers report a retrospective analysis of data from the EXTEND trial of late thrombolysis, defined as 4.5-9 hours after symptom onset, to investigate the association between thrombolysis and clot migration leading to clot irretrievability.
The analysis included a total of 220 patients (109 patients in the placebo group and 111 in the thrombolysis group).
Results showed that retrievable clot was seen on baseline imaging in 69% of patients in the placebo group and 61% in the thrombolysis group. Clot resolution occurred in 28% of patients in the placebo group and 50% in the thrombolysis group.
No significant difference was observed in the incidence of clot migration leading to inaccessibility between groups. Clot migration from a retrievable to nonretrievable location occurred in 19% of the placebo group and 14% of the thrombolysis group, with an odds ratio for clot migration in the thrombolysis group of 0.70 (95% confidence interval, 0.35-1.44). This outcome was consistent across subgroups.
The researchers note that, to their knowledge, this is the first randomized controlled study to assess the effect of thrombolysis on clot migration and accessibility in an extended time window.
They acknowledge that a limitation of this study is that they only assessed clot migration from a retrievable to a nonretrievable location; therefore, the true frequency of any clot migration occurring was likely to be higher, and this could explain why other reports have found higher odds ratios of clot migration.
But they point out that they chose to limit their analysis in this way specifically to guide decision-making regarding bridging thrombolysis incorporating endovascular therapy in the extended time window.
“The findings of this study are highly relevant in the current clinical environment, where there are multiple ongoing trials looking at removing thrombolysis pretreatment within the 4.5-hour time window in thrombectomy patients,” the authors write.
“We have demonstrated that thrombolysis in the 4.5- to 9-hour window is not associated with reduced clot accessibility, and this information will be useful in future trial designs incorporating this extended time window,” they add.
Commenting on the study for this news organization, Michael Hill, MD, University of Calgary (Alta.), said: “Thrombus migration does happen and is likely part of the natural history of ischemic stroke, which may be influenced by therapeutics such as thrombolysis. This paper’s top-line result is that thrombus migration occurs in both treated and untreated groups – and therefore that this is really an observation of natural history.”
Dr. Hill says that, at present, patients should be treated with thrombolysis before endovascular therapy if they are eligible, and these results do not change that recommendation.
“The results of the ongoing trials comparing direct thrombectomy with thrombolysis plus thrombectomy will help to understand the potential clinical outcome relevance of this phenomenon,” he added.
The EXTEND trial was supported by grants from the Australian National Health and Medical Research Council of Australia and the Commonwealth Scientific and Industrial Research Organization Flagship Program. Dr. Yan reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.