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Patients with epilepsy may underreport seizures, survey finds
according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.
Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.
To evaluate treatment complacency among adult patients with epilepsy, caregivers, and HCPs, Dr. Penovich and collaborators analyzed data from the STEP survey (Seize the Truth about Epilepsy Perceptions), which was conducted between February and March 2019. In all, 400 adults with epilepsy, 201 caregivers, and 258 HCPs completed the survey. The HCPs included 96 epileptologists, 112 general neurologists, and 50 nurse practitioners or physician assistants.
Patients had an average epilepsy duration of 16 years, and 58% were on at least their third antiepileptic drug (AED). In the past year, 52% of patients had 1-9 seizures, and 31% had 10 or more seizures. “Patients estimated reporting 45% of their seizures to their HCPs, and for the seizures not reported, 57% provided reasoning that they were not serious enough to mention,” reported Dr. Penovich and colleagues. “Alternatively, HCPs estimated that patients report 73% of seizures.”
Survey participants most frequently selected HCPs as the ones to initiate conversations about changing AEDs or increasing dosage. “Patient-initiated discussions were reported by 39% of patients for changing AEDs and 27% of patients for increasing AED dosage; 25% of patients reported they were likely to ask their HCP about changing treatments in the next 12 months,” the authors said. Discussion of vagus nerve stimulation was reported by 21% of HCPs, and 10% reported discussion of responsive neurostimulation. HCPs also discussed surgical options such as hemispherectomy (3%), corpus callosotomy and multiple subpial transection (4%), lobe resection (8%), and lesionectomy (11%).
Among patients with 13 or more seizures per year, 27% reported referral to an epilepsy center. Most survey participants – 61% of patients and HCPs and 68% of caregivers – “reported a desire for a treatment map that tells patients to see an epileptologist/specialist as soon as they have symptoms,” the researchers said.
“What we would like to think is that we are getting the whole scoop and the honest scoop” about seizure activity, Dr. Penovich said in an interview. “What this shows us is that that’s probably not always true. Some health care providers understand that the patients do not tell them everything,” but the degree of seizure underreporting may be surprising.
Dr. Penovich has seen this phenomenon in practice. In some cases, caregivers return to the office to explain that a patient did not report all of their seizures. Other patients may omit entire days of seizures in their diaries as an oversight. In addition, patients may not report seizures to avoid having a driver’s license revoked. In some instances, clinicians may not take the time to discuss seizure activity in detail.
Having an accurate picture of seizure activity is an “important part of working with our patients, particularly when we are trying to get them to the point of being seizure free,” said Dr. Penovich.
Failing a first or second AED indicates a greater likelihood that medication will not stop a patient’s seizures, “but it does not mean that you will not be controlled,” Dr. Penovich said. More medications, surgical options, and investigative treatments have become available. Still, AED trials should not prevent a timely referral to an epilepsy center. “You don’t need to go through 10 or 15 before you get referred” to an epilepsy center, she said.
The STEP survey was conducted by Kantar Health on behalf of SK Life Science. Dr. Penovich has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from SK Life Science, Neurelis, GW Pharmaceuticals, Engage Therapeutics, and UCB Pharma. A coauthor was employed by Kantar Health. Other coauthors disclosed compensation from SK Life Science and various pharmaceutical companies.
SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.
according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.
Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.
To evaluate treatment complacency among adult patients with epilepsy, caregivers, and HCPs, Dr. Penovich and collaborators analyzed data from the STEP survey (Seize the Truth about Epilepsy Perceptions), which was conducted between February and March 2019. In all, 400 adults with epilepsy, 201 caregivers, and 258 HCPs completed the survey. The HCPs included 96 epileptologists, 112 general neurologists, and 50 nurse practitioners or physician assistants.
Patients had an average epilepsy duration of 16 years, and 58% were on at least their third antiepileptic drug (AED). In the past year, 52% of patients had 1-9 seizures, and 31% had 10 or more seizures. “Patients estimated reporting 45% of their seizures to their HCPs, and for the seizures not reported, 57% provided reasoning that they were not serious enough to mention,” reported Dr. Penovich and colleagues. “Alternatively, HCPs estimated that patients report 73% of seizures.”
Survey participants most frequently selected HCPs as the ones to initiate conversations about changing AEDs or increasing dosage. “Patient-initiated discussions were reported by 39% of patients for changing AEDs and 27% of patients for increasing AED dosage; 25% of patients reported they were likely to ask their HCP about changing treatments in the next 12 months,” the authors said. Discussion of vagus nerve stimulation was reported by 21% of HCPs, and 10% reported discussion of responsive neurostimulation. HCPs also discussed surgical options such as hemispherectomy (3%), corpus callosotomy and multiple subpial transection (4%), lobe resection (8%), and lesionectomy (11%).
Among patients with 13 or more seizures per year, 27% reported referral to an epilepsy center. Most survey participants – 61% of patients and HCPs and 68% of caregivers – “reported a desire for a treatment map that tells patients to see an epileptologist/specialist as soon as they have symptoms,” the researchers said.
“What we would like to think is that we are getting the whole scoop and the honest scoop” about seizure activity, Dr. Penovich said in an interview. “What this shows us is that that’s probably not always true. Some health care providers understand that the patients do not tell them everything,” but the degree of seizure underreporting may be surprising.
Dr. Penovich has seen this phenomenon in practice. In some cases, caregivers return to the office to explain that a patient did not report all of their seizures. Other patients may omit entire days of seizures in their diaries as an oversight. In addition, patients may not report seizures to avoid having a driver’s license revoked. In some instances, clinicians may not take the time to discuss seizure activity in detail.
Having an accurate picture of seizure activity is an “important part of working with our patients, particularly when we are trying to get them to the point of being seizure free,” said Dr. Penovich.
Failing a first or second AED indicates a greater likelihood that medication will not stop a patient’s seizures, “but it does not mean that you will not be controlled,” Dr. Penovich said. More medications, surgical options, and investigative treatments have become available. Still, AED trials should not prevent a timely referral to an epilepsy center. “You don’t need to go through 10 or 15 before you get referred” to an epilepsy center, she said.
The STEP survey was conducted by Kantar Health on behalf of SK Life Science. Dr. Penovich has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from SK Life Science, Neurelis, GW Pharmaceuticals, Engage Therapeutics, and UCB Pharma. A coauthor was employed by Kantar Health. Other coauthors disclosed compensation from SK Life Science and various pharmaceutical companies.
SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.
according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.
Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.
To evaluate treatment complacency among adult patients with epilepsy, caregivers, and HCPs, Dr. Penovich and collaborators analyzed data from the STEP survey (Seize the Truth about Epilepsy Perceptions), which was conducted between February and March 2019. In all, 400 adults with epilepsy, 201 caregivers, and 258 HCPs completed the survey. The HCPs included 96 epileptologists, 112 general neurologists, and 50 nurse practitioners or physician assistants.
Patients had an average epilepsy duration of 16 years, and 58% were on at least their third antiepileptic drug (AED). In the past year, 52% of patients had 1-9 seizures, and 31% had 10 or more seizures. “Patients estimated reporting 45% of their seizures to their HCPs, and for the seizures not reported, 57% provided reasoning that they were not serious enough to mention,” reported Dr. Penovich and colleagues. “Alternatively, HCPs estimated that patients report 73% of seizures.”
Survey participants most frequently selected HCPs as the ones to initiate conversations about changing AEDs or increasing dosage. “Patient-initiated discussions were reported by 39% of patients for changing AEDs and 27% of patients for increasing AED dosage; 25% of patients reported they were likely to ask their HCP about changing treatments in the next 12 months,” the authors said. Discussion of vagus nerve stimulation was reported by 21% of HCPs, and 10% reported discussion of responsive neurostimulation. HCPs also discussed surgical options such as hemispherectomy (3%), corpus callosotomy and multiple subpial transection (4%), lobe resection (8%), and lesionectomy (11%).
Among patients with 13 or more seizures per year, 27% reported referral to an epilepsy center. Most survey participants – 61% of patients and HCPs and 68% of caregivers – “reported a desire for a treatment map that tells patients to see an epileptologist/specialist as soon as they have symptoms,” the researchers said.
“What we would like to think is that we are getting the whole scoop and the honest scoop” about seizure activity, Dr. Penovich said in an interview. “What this shows us is that that’s probably not always true. Some health care providers understand that the patients do not tell them everything,” but the degree of seizure underreporting may be surprising.
Dr. Penovich has seen this phenomenon in practice. In some cases, caregivers return to the office to explain that a patient did not report all of their seizures. Other patients may omit entire days of seizures in their diaries as an oversight. In addition, patients may not report seizures to avoid having a driver’s license revoked. In some instances, clinicians may not take the time to discuss seizure activity in detail.
Having an accurate picture of seizure activity is an “important part of working with our patients, particularly when we are trying to get them to the point of being seizure free,” said Dr. Penovich.
Failing a first or second AED indicates a greater likelihood that medication will not stop a patient’s seizures, “but it does not mean that you will not be controlled,” Dr. Penovich said. More medications, surgical options, and investigative treatments have become available. Still, AED trials should not prevent a timely referral to an epilepsy center. “You don’t need to go through 10 or 15 before you get referred” to an epilepsy center, she said.
The STEP survey was conducted by Kantar Health on behalf of SK Life Science. Dr. Penovich has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from SK Life Science, Neurelis, GW Pharmaceuticals, Engage Therapeutics, and UCB Pharma. A coauthor was employed by Kantar Health. Other coauthors disclosed compensation from SK Life Science and various pharmaceutical companies.
SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.
FROM AAN 2020
Statins and ICH: new meta-analysis
The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.
To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.
Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).
“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
Increased secondary ICH?
However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).
“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.
Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”
Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.
“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.
Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.
“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.
“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.
Dr. Pandhi has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.
The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.
To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.
Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).
“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
Increased secondary ICH?
However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).
“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.
Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”
Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.
“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.
Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.
“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.
“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.
Dr. Pandhi has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.
The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.
To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.
Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).
“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
Increased secondary ICH?
However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).
“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.
Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”
Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.
“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.
Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.
“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.
“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.
Dr. Pandhi has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.
AAN 2020
Initial high-efficacy MS therapy tied to less disability later
new research suggests. However, there is a trade-off: In this study of nearly 300 patients, those treated with initial HET experienced more disease activity in the first 2 years than other participants.
The HET benefit emerged between 2 and 10 years into the study. For example, the mean Expanded Disability Status Scale (EDSS) scores were significantly lower at 6 years in the early, aggressive treatment group than in the later HET group (2.4 vs 3.3, respectively).
“Treatment decisions made around the time of diagnosis will affect long-term outcomes,” said lead author Anna He, MBBS, currently with the Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and the UCL Queen Square Institute of Neurology in London.
Using the most efficacious disease-modifying therapies from the start minimizes disability, “whereas those patients escalating to high-efficacy disease-modifying therapies later do not seem to catch up to those who commenced earlier,” Dr. He said.
“Patients and clinicians should be aware of this when choosing treatment in early MS,” she added.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Patient-centered outcome
Instead of measures of brain volume, lesion count, serum neurofilament, or other biomarkers that are mainly of interest to clinicians and scientists, “the main outcome of interest to our patients is their disability,” Dr. He said. “The first question they ask at diagnosis is usually along the lines of: ‘What will my disability be in 10 years?’ ”
“This is what matters to patients and is fundamentally what motivated this study,” Dr. He added.
The investigators searched international MS registries for patients with relapsing-remitting MS starting HET, which included rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab.
They compared 117 participants who started HET within the first 2 years of clinical disease onset (the early group) with 181 participants who started HET after more than 4 years (the late group). All were followed for a median of 7.4 years (range, 6.4 to 8.6 years).
Difference in EDSS scores from baseline was the primary outcome. Both cohorts began the study with a mean EDSS score of 2.4, but between-group differences were significant at 10 years.
The secondary outcome of cumulative hazard of disability progression was higher in the early-treatment group from baseline to 2 years. Between the period of 2 and 10 years, the inverse was true.
In patients with highly active MS, “early exposure to high efficacy therapies is recommended,” Dr. He noted.
“We can already affect our patients’ lives enormously by utilizing our current toolbox in the most optimal way. It is our task to optimize this in a data-driven manner.”
Going forward, Dr. He plans to look at other outcomes, including patient-reported quality of life and health economic measures, and to take a different approach to future research.
Rather than assess MS outcomes from a disease-biology perspective, “I will be looking at MS outcomes from the perspective of its key stakeholders—the individual and society,” and the factors that influence them, Dr. He said.
Confirmatory evidence?
Commenting on the findings, Robert Gross, MD, a neurologist at the Rocky Mountain MS Center at the University of Colorado Denver in Aurora, said it is “hard to believe we are still having this debate” about earlier versus later HET.
There are now “numerous studies, including head-to-head trials and large cohort studies, showing superiority of highly efficacious agents to older disease-modifying therapies of more limited efficacy, as well as better outcomes with early versus delayed use of high-efficacy therapy,” said Dr. Gross, who was not involved with the current research.
“This study further adds to the evidence that we should be preferentially starting folks with relapsing-remitting MS right away on high-efficacy therapy, rather than waiting for relapses and disease progression to occur,” he added.
Drs. He and Gross have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
new research suggests. However, there is a trade-off: In this study of nearly 300 patients, those treated with initial HET experienced more disease activity in the first 2 years than other participants.
The HET benefit emerged between 2 and 10 years into the study. For example, the mean Expanded Disability Status Scale (EDSS) scores were significantly lower at 6 years in the early, aggressive treatment group than in the later HET group (2.4 vs 3.3, respectively).
“Treatment decisions made around the time of diagnosis will affect long-term outcomes,” said lead author Anna He, MBBS, currently with the Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and the UCL Queen Square Institute of Neurology in London.
Using the most efficacious disease-modifying therapies from the start minimizes disability, “whereas those patients escalating to high-efficacy disease-modifying therapies later do not seem to catch up to those who commenced earlier,” Dr. He said.
“Patients and clinicians should be aware of this when choosing treatment in early MS,” she added.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Patient-centered outcome
Instead of measures of brain volume, lesion count, serum neurofilament, or other biomarkers that are mainly of interest to clinicians and scientists, “the main outcome of interest to our patients is their disability,” Dr. He said. “The first question they ask at diagnosis is usually along the lines of: ‘What will my disability be in 10 years?’ ”
“This is what matters to patients and is fundamentally what motivated this study,” Dr. He added.
The investigators searched international MS registries for patients with relapsing-remitting MS starting HET, which included rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab.
They compared 117 participants who started HET within the first 2 years of clinical disease onset (the early group) with 181 participants who started HET after more than 4 years (the late group). All were followed for a median of 7.4 years (range, 6.4 to 8.6 years).
Difference in EDSS scores from baseline was the primary outcome. Both cohorts began the study with a mean EDSS score of 2.4, but between-group differences were significant at 10 years.
The secondary outcome of cumulative hazard of disability progression was higher in the early-treatment group from baseline to 2 years. Between the period of 2 and 10 years, the inverse was true.
In patients with highly active MS, “early exposure to high efficacy therapies is recommended,” Dr. He noted.
“We can already affect our patients’ lives enormously by utilizing our current toolbox in the most optimal way. It is our task to optimize this in a data-driven manner.”
Going forward, Dr. He plans to look at other outcomes, including patient-reported quality of life and health economic measures, and to take a different approach to future research.
Rather than assess MS outcomes from a disease-biology perspective, “I will be looking at MS outcomes from the perspective of its key stakeholders—the individual and society,” and the factors that influence them, Dr. He said.
Confirmatory evidence?
Commenting on the findings, Robert Gross, MD, a neurologist at the Rocky Mountain MS Center at the University of Colorado Denver in Aurora, said it is “hard to believe we are still having this debate” about earlier versus later HET.
There are now “numerous studies, including head-to-head trials and large cohort studies, showing superiority of highly efficacious agents to older disease-modifying therapies of more limited efficacy, as well as better outcomes with early versus delayed use of high-efficacy therapy,” said Dr. Gross, who was not involved with the current research.
“This study further adds to the evidence that we should be preferentially starting folks with relapsing-remitting MS right away on high-efficacy therapy, rather than waiting for relapses and disease progression to occur,” he added.
Drs. He and Gross have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
new research suggests. However, there is a trade-off: In this study of nearly 300 patients, those treated with initial HET experienced more disease activity in the first 2 years than other participants.
The HET benefit emerged between 2 and 10 years into the study. For example, the mean Expanded Disability Status Scale (EDSS) scores were significantly lower at 6 years in the early, aggressive treatment group than in the later HET group (2.4 vs 3.3, respectively).
“Treatment decisions made around the time of diagnosis will affect long-term outcomes,” said lead author Anna He, MBBS, currently with the Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and the UCL Queen Square Institute of Neurology in London.
Using the most efficacious disease-modifying therapies from the start minimizes disability, “whereas those patients escalating to high-efficacy disease-modifying therapies later do not seem to catch up to those who commenced earlier,” Dr. He said.
“Patients and clinicians should be aware of this when choosing treatment in early MS,” she added.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Patient-centered outcome
Instead of measures of brain volume, lesion count, serum neurofilament, or other biomarkers that are mainly of interest to clinicians and scientists, “the main outcome of interest to our patients is their disability,” Dr. He said. “The first question they ask at diagnosis is usually along the lines of: ‘What will my disability be in 10 years?’ ”
“This is what matters to patients and is fundamentally what motivated this study,” Dr. He added.
The investigators searched international MS registries for patients with relapsing-remitting MS starting HET, which included rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab.
They compared 117 participants who started HET within the first 2 years of clinical disease onset (the early group) with 181 participants who started HET after more than 4 years (the late group). All were followed for a median of 7.4 years (range, 6.4 to 8.6 years).
Difference in EDSS scores from baseline was the primary outcome. Both cohorts began the study with a mean EDSS score of 2.4, but between-group differences were significant at 10 years.
The secondary outcome of cumulative hazard of disability progression was higher in the early-treatment group from baseline to 2 years. Between the period of 2 and 10 years, the inverse was true.
In patients with highly active MS, “early exposure to high efficacy therapies is recommended,” Dr. He noted.
“We can already affect our patients’ lives enormously by utilizing our current toolbox in the most optimal way. It is our task to optimize this in a data-driven manner.”
Going forward, Dr. He plans to look at other outcomes, including patient-reported quality of life and health economic measures, and to take a different approach to future research.
Rather than assess MS outcomes from a disease-biology perspective, “I will be looking at MS outcomes from the perspective of its key stakeholders—the individual and society,” and the factors that influence them, Dr. He said.
Confirmatory evidence?
Commenting on the findings, Robert Gross, MD, a neurologist at the Rocky Mountain MS Center at the University of Colorado Denver in Aurora, said it is “hard to believe we are still having this debate” about earlier versus later HET.
There are now “numerous studies, including head-to-head trials and large cohort studies, showing superiority of highly efficacious agents to older disease-modifying therapies of more limited efficacy, as well as better outcomes with early versus delayed use of high-efficacy therapy,” said Dr. Gross, who was not involved with the current research.
“This study further adds to the evidence that we should be preferentially starting folks with relapsing-remitting MS right away on high-efficacy therapy, rather than waiting for relapses and disease progression to occur,” he added.
Drs. He and Gross have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Diastolic dysfunction is a common risk factor for cognitive decline
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
FOURIER: Evolocumab follow-up shows no cognitive adverse effects
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
FROM JACC
Key clinical point: A cognition survey of a large number of trial participants showed no signal of adverse effects from evolocumab treatment.
Major finding: Survey results showed cognitive compromise in 3.7% of patients on evolocumab and in 3.6% control patients on placebo.
Study details:
Disclosures: FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Guigliano has received personal fees and research support from Amgen and from several other companies.
Source: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Cautionary findings on acquired immunodeficiency from anti-CD20 MS therapy
, Brandi L. Vollmer, MPH, reported online as part of the 2020 American Academy of Neurology Science Highlights.
The hypogammaglobulinemia was preceded by an IgM of 40 mg/dL or less in 35% of cases and was accompanied by concurrent development of low IgM in another 39%, added Ms. Vollmer, a professional research assistant at the Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Denver.
She presented a retrospective study of 527 randomly selected MS patients and another 17 with neuromyelitis optica spectrum disorder who averaged 44 years of age and a 9.2-year disease duration upon commencing rituximab (Rituxan) with close laboratory monitoring. Their mean cumulative rituximab dose during a mean 30.2 months of therapy was 3,312 mg. Ninety-six MS patients eventually switched to ocrelizumab (Ocrevus), accumulating a total dose of 1,175 mg of that anti-CD20 humanized monoclonal antibody.
Absolute lymphocyte count dropped to 500 cells/mm3 or lower in 10.4% of patients at a mean of 11.3 months into anti-CD20 therapy. Low immunoglobulins came later: The mean time to onset of low IgM in affected patients was 19.7 months, and hypogammaglobulinemia, as defined by an IgG of 500 mg/dL or less, occurred at a mean of 36.1 months. Higher cumulative doses of anti-CD20 agents were associated with increased likelihood of hypogammaglobulinemia.
Asked to comment on the research findings, neurologist Nida Laurin, MD, said the Colorado study provides helpful insights into the timing of onset of acquired immunodeficiency in patients on B-cell-targeted therapy.
“This paper informs us that we should monitor our patients much closer for signs of hypogammaglobulinemia and lymphopenia starting with year 2 on therapy, and switch treatment when the threshold is reached. I do expect production of gamma globulins and lymphocytes to recover with discontinuation of anti-CD20 therapy, maybe over a period of 6-10 months. It might also recover with lower-dose therapy because the effect on B cells is dose-dependent,” observed Dr. Laurin, an MS specialist at the Banner Health–University Medicine Neuroscience Institute in Phoenix and the University of Arizona in Tucson.
Her colleague Barry Hendin, MD, noted that there is no consensus regarding the best response to all these changes.
“Some clinicians add IVIG, some change therapies, and some observe only,” said Dr. Hendin, a neurologist at Banner Health–University Medical Center, Phoenix, and clinical professor of neurology at the University of Arizona in Tucson.
However, Dr. Laurin asserted that it would be a mistake for physicians and patients to shrug off anti-CD20 therapy–induced lymphopenia in light of studies demonstrating that lymphopenia and older age are two main risk factors for progressive multifocal leukoencephalopathy in patients on disease-modifying therapies.
“More cases of PML can be expected with continuous use of anti-CD20 therapies if lymphopenia is ignored,” she cautioned.
Depressed levels of IgM and IgG have been associated with increased risk of serious infections. In light of the COVID-19 pandemic and the eventual prospect of a vaccine, it is especially important to avoid putting patients with MS in harm’s way via treatment-induced acquired immunodeficiency, Dr. Laurin said.
Ms. Vollmer reported having no financial conflicts regarding her study. Dr. Laurin reported serving as a speaker or consultant for Alexion, Allergan, Biogen, Bristol-Myers Squibb, EMD Serono, Genentech, Lundbeck, and Sanofi Genzyme. Dr. Hendin serves as a consultant to Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Bristol-Myers Squibb.
SOURCE: Vollmer BL et al. AAN 2020. Abstract S29.002.
, Brandi L. Vollmer, MPH, reported online as part of the 2020 American Academy of Neurology Science Highlights.
The hypogammaglobulinemia was preceded by an IgM of 40 mg/dL or less in 35% of cases and was accompanied by concurrent development of low IgM in another 39%, added Ms. Vollmer, a professional research assistant at the Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Denver.
She presented a retrospective study of 527 randomly selected MS patients and another 17 with neuromyelitis optica spectrum disorder who averaged 44 years of age and a 9.2-year disease duration upon commencing rituximab (Rituxan) with close laboratory monitoring. Their mean cumulative rituximab dose during a mean 30.2 months of therapy was 3,312 mg. Ninety-six MS patients eventually switched to ocrelizumab (Ocrevus), accumulating a total dose of 1,175 mg of that anti-CD20 humanized monoclonal antibody.
Absolute lymphocyte count dropped to 500 cells/mm3 or lower in 10.4% of patients at a mean of 11.3 months into anti-CD20 therapy. Low immunoglobulins came later: The mean time to onset of low IgM in affected patients was 19.7 months, and hypogammaglobulinemia, as defined by an IgG of 500 mg/dL or less, occurred at a mean of 36.1 months. Higher cumulative doses of anti-CD20 agents were associated with increased likelihood of hypogammaglobulinemia.
Asked to comment on the research findings, neurologist Nida Laurin, MD, said the Colorado study provides helpful insights into the timing of onset of acquired immunodeficiency in patients on B-cell-targeted therapy.
“This paper informs us that we should monitor our patients much closer for signs of hypogammaglobulinemia and lymphopenia starting with year 2 on therapy, and switch treatment when the threshold is reached. I do expect production of gamma globulins and lymphocytes to recover with discontinuation of anti-CD20 therapy, maybe over a period of 6-10 months. It might also recover with lower-dose therapy because the effect on B cells is dose-dependent,” observed Dr. Laurin, an MS specialist at the Banner Health–University Medicine Neuroscience Institute in Phoenix and the University of Arizona in Tucson.
Her colleague Barry Hendin, MD, noted that there is no consensus regarding the best response to all these changes.
“Some clinicians add IVIG, some change therapies, and some observe only,” said Dr. Hendin, a neurologist at Banner Health–University Medical Center, Phoenix, and clinical professor of neurology at the University of Arizona in Tucson.
However, Dr. Laurin asserted that it would be a mistake for physicians and patients to shrug off anti-CD20 therapy–induced lymphopenia in light of studies demonstrating that lymphopenia and older age are two main risk factors for progressive multifocal leukoencephalopathy in patients on disease-modifying therapies.
“More cases of PML can be expected with continuous use of anti-CD20 therapies if lymphopenia is ignored,” she cautioned.
Depressed levels of IgM and IgG have been associated with increased risk of serious infections. In light of the COVID-19 pandemic and the eventual prospect of a vaccine, it is especially important to avoid putting patients with MS in harm’s way via treatment-induced acquired immunodeficiency, Dr. Laurin said.
Ms. Vollmer reported having no financial conflicts regarding her study. Dr. Laurin reported serving as a speaker or consultant for Alexion, Allergan, Biogen, Bristol-Myers Squibb, EMD Serono, Genentech, Lundbeck, and Sanofi Genzyme. Dr. Hendin serves as a consultant to Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Bristol-Myers Squibb.
SOURCE: Vollmer BL et al. AAN 2020. Abstract S29.002.
, Brandi L. Vollmer, MPH, reported online as part of the 2020 American Academy of Neurology Science Highlights.
The hypogammaglobulinemia was preceded by an IgM of 40 mg/dL or less in 35% of cases and was accompanied by concurrent development of low IgM in another 39%, added Ms. Vollmer, a professional research assistant at the Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Denver.
She presented a retrospective study of 527 randomly selected MS patients and another 17 with neuromyelitis optica spectrum disorder who averaged 44 years of age and a 9.2-year disease duration upon commencing rituximab (Rituxan) with close laboratory monitoring. Their mean cumulative rituximab dose during a mean 30.2 months of therapy was 3,312 mg. Ninety-six MS patients eventually switched to ocrelizumab (Ocrevus), accumulating a total dose of 1,175 mg of that anti-CD20 humanized monoclonal antibody.
Absolute lymphocyte count dropped to 500 cells/mm3 or lower in 10.4% of patients at a mean of 11.3 months into anti-CD20 therapy. Low immunoglobulins came later: The mean time to onset of low IgM in affected patients was 19.7 months, and hypogammaglobulinemia, as defined by an IgG of 500 mg/dL or less, occurred at a mean of 36.1 months. Higher cumulative doses of anti-CD20 agents were associated with increased likelihood of hypogammaglobulinemia.
Asked to comment on the research findings, neurologist Nida Laurin, MD, said the Colorado study provides helpful insights into the timing of onset of acquired immunodeficiency in patients on B-cell-targeted therapy.
“This paper informs us that we should monitor our patients much closer for signs of hypogammaglobulinemia and lymphopenia starting with year 2 on therapy, and switch treatment when the threshold is reached. I do expect production of gamma globulins and lymphocytes to recover with discontinuation of anti-CD20 therapy, maybe over a period of 6-10 months. It might also recover with lower-dose therapy because the effect on B cells is dose-dependent,” observed Dr. Laurin, an MS specialist at the Banner Health–University Medicine Neuroscience Institute in Phoenix and the University of Arizona in Tucson.
Her colleague Barry Hendin, MD, noted that there is no consensus regarding the best response to all these changes.
“Some clinicians add IVIG, some change therapies, and some observe only,” said Dr. Hendin, a neurologist at Banner Health–University Medical Center, Phoenix, and clinical professor of neurology at the University of Arizona in Tucson.
However, Dr. Laurin asserted that it would be a mistake for physicians and patients to shrug off anti-CD20 therapy–induced lymphopenia in light of studies demonstrating that lymphopenia and older age are two main risk factors for progressive multifocal leukoencephalopathy in patients on disease-modifying therapies.
“More cases of PML can be expected with continuous use of anti-CD20 therapies if lymphopenia is ignored,” she cautioned.
Depressed levels of IgM and IgG have been associated with increased risk of serious infections. In light of the COVID-19 pandemic and the eventual prospect of a vaccine, it is especially important to avoid putting patients with MS in harm’s way via treatment-induced acquired immunodeficiency, Dr. Laurin said.
Ms. Vollmer reported having no financial conflicts regarding her study. Dr. Laurin reported serving as a speaker or consultant for Alexion, Allergan, Biogen, Bristol-Myers Squibb, EMD Serono, Genentech, Lundbeck, and Sanofi Genzyme. Dr. Hendin serves as a consultant to Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Bristol-Myers Squibb.
SOURCE: Vollmer BL et al. AAN 2020. Abstract S29.002.
REPORTING FROM AAN 2020
Five-year siponimod data support early MS treatment
Among and had a lower annualized relapse rate up to 5 years later, compared with patients who initially received placebo and switched to siponimod. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Benefits of siponimod gained during the controlled period were “sustained for up to 5 years, suggesting a continuous effect of siponimod and underlining the advantages of early treatment initiation with siponimod,” the researchers said. Incidence rates of adverse events during the extension study were consistent with those during the controlled treatment period.
The results “highlight the critical importance of early treatment intervention ... to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” study investigator Bruce Cree, MD, PhD, said in a news release.
“It’s never too early to stay ahead of progression in MS, since the early identification of physical and cognitive changes – even subtle ones – can indicate MS disease progression and therefore allow for timely intervention.” said Dr. Cree, who is clinical research director and George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco.
Siponimod, marketed as Mayzent, is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors. The oral drug was approved by the Food and Drug Administration in 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease in adults.
To assess the long-term efficacy and safety of siponimod in patients with secondary progressive MS, Dr. Cree and colleagues analyzed data from patients in the controlled and extension parts of the EXPAND trial. Patients could have had been in the study for as long as 5 years at the data cutoff in April 2019. Efficacy analyses included time to 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), time to 6-month confirmed disability progression, time to 6-month confirmed worsening of 4 or more points on the Symbol Digit Modalities Test (SDMT), and annualized relapse rate. In EXPAND, the researchers defined confirmed disability progression as a 1-point increase in EDSS if the baseline score was 3.0-5.0, or a 0.5-point increase if the baseline score was 5.5-6.5.
“Of the 1,224 (74% of 1,651 randomized) patients entering the extension, 878 (72%) were ongoing,” the researchers reported. Patients who received siponimod continuously were less likely to experience 3-month confirmed disability progression and 6-month confirmed disability progression, relative to patients who switched from placebo. In addition, patients who received continuous siponimod treatment had a prolonged time to 6-month confirmed disability progression, compared with patients who switched from placebo. For the 25th percentile of patients, continuous siponimod treatment corresponded to a delay of 54% (21 months vs. 13.6 months). Risk of worsening on the SDMT was reduced by 23% in the continuous siponimod–treatment group. For the 25th percentile of patients, this reduced risk corresponded to a delay of 62% (29.6 months vs. 18.3 months). ARR was 0.054 in the continuous-siponimod group, compared with 0.097 in the group that switched to siponimod from placebo, a reduction of 52%.
Dr. Cree has received personal compensation from Novartis, which markets siponimod, as well as Akili, Alexion, Atara, Biogen, EMD Serono, and TG Therapeutics. His coauthors reported receiving research support and personal compensation from Novartis and other pharmaceutical companies. Several coauthors were Novartis employees.
SOURCE: Kappos L et al. AAN 2020, Abstract S40.003.
Among and had a lower annualized relapse rate up to 5 years later, compared with patients who initially received placebo and switched to siponimod. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Benefits of siponimod gained during the controlled period were “sustained for up to 5 years, suggesting a continuous effect of siponimod and underlining the advantages of early treatment initiation with siponimod,” the researchers said. Incidence rates of adverse events during the extension study were consistent with those during the controlled treatment period.
The results “highlight the critical importance of early treatment intervention ... to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” study investigator Bruce Cree, MD, PhD, said in a news release.
“It’s never too early to stay ahead of progression in MS, since the early identification of physical and cognitive changes – even subtle ones – can indicate MS disease progression and therefore allow for timely intervention.” said Dr. Cree, who is clinical research director and George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco.
Siponimod, marketed as Mayzent, is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors. The oral drug was approved by the Food and Drug Administration in 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease in adults.
To assess the long-term efficacy and safety of siponimod in patients with secondary progressive MS, Dr. Cree and colleagues analyzed data from patients in the controlled and extension parts of the EXPAND trial. Patients could have had been in the study for as long as 5 years at the data cutoff in April 2019. Efficacy analyses included time to 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), time to 6-month confirmed disability progression, time to 6-month confirmed worsening of 4 or more points on the Symbol Digit Modalities Test (SDMT), and annualized relapse rate. In EXPAND, the researchers defined confirmed disability progression as a 1-point increase in EDSS if the baseline score was 3.0-5.0, or a 0.5-point increase if the baseline score was 5.5-6.5.
“Of the 1,224 (74% of 1,651 randomized) patients entering the extension, 878 (72%) were ongoing,” the researchers reported. Patients who received siponimod continuously were less likely to experience 3-month confirmed disability progression and 6-month confirmed disability progression, relative to patients who switched from placebo. In addition, patients who received continuous siponimod treatment had a prolonged time to 6-month confirmed disability progression, compared with patients who switched from placebo. For the 25th percentile of patients, continuous siponimod treatment corresponded to a delay of 54% (21 months vs. 13.6 months). Risk of worsening on the SDMT was reduced by 23% in the continuous siponimod–treatment group. For the 25th percentile of patients, this reduced risk corresponded to a delay of 62% (29.6 months vs. 18.3 months). ARR was 0.054 in the continuous-siponimod group, compared with 0.097 in the group that switched to siponimod from placebo, a reduction of 52%.
Dr. Cree has received personal compensation from Novartis, which markets siponimod, as well as Akili, Alexion, Atara, Biogen, EMD Serono, and TG Therapeutics. His coauthors reported receiving research support and personal compensation from Novartis and other pharmaceutical companies. Several coauthors were Novartis employees.
SOURCE: Kappos L et al. AAN 2020, Abstract S40.003.
Among and had a lower annualized relapse rate up to 5 years later, compared with patients who initially received placebo and switched to siponimod. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Benefits of siponimod gained during the controlled period were “sustained for up to 5 years, suggesting a continuous effect of siponimod and underlining the advantages of early treatment initiation with siponimod,” the researchers said. Incidence rates of adverse events during the extension study were consistent with those during the controlled treatment period.
The results “highlight the critical importance of early treatment intervention ... to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” study investigator Bruce Cree, MD, PhD, said in a news release.
“It’s never too early to stay ahead of progression in MS, since the early identification of physical and cognitive changes – even subtle ones – can indicate MS disease progression and therefore allow for timely intervention.” said Dr. Cree, who is clinical research director and George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco.
Siponimod, marketed as Mayzent, is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors. The oral drug was approved by the Food and Drug Administration in 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease in adults.
To assess the long-term efficacy and safety of siponimod in patients with secondary progressive MS, Dr. Cree and colleagues analyzed data from patients in the controlled and extension parts of the EXPAND trial. Patients could have had been in the study for as long as 5 years at the data cutoff in April 2019. Efficacy analyses included time to 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), time to 6-month confirmed disability progression, time to 6-month confirmed worsening of 4 or more points on the Symbol Digit Modalities Test (SDMT), and annualized relapse rate. In EXPAND, the researchers defined confirmed disability progression as a 1-point increase in EDSS if the baseline score was 3.0-5.0, or a 0.5-point increase if the baseline score was 5.5-6.5.
“Of the 1,224 (74% of 1,651 randomized) patients entering the extension, 878 (72%) were ongoing,” the researchers reported. Patients who received siponimod continuously were less likely to experience 3-month confirmed disability progression and 6-month confirmed disability progression, relative to patients who switched from placebo. In addition, patients who received continuous siponimod treatment had a prolonged time to 6-month confirmed disability progression, compared with patients who switched from placebo. For the 25th percentile of patients, continuous siponimod treatment corresponded to a delay of 54% (21 months vs. 13.6 months). Risk of worsening on the SDMT was reduced by 23% in the continuous siponimod–treatment group. For the 25th percentile of patients, this reduced risk corresponded to a delay of 62% (29.6 months vs. 18.3 months). ARR was 0.054 in the continuous-siponimod group, compared with 0.097 in the group that switched to siponimod from placebo, a reduction of 52%.
Dr. Cree has received personal compensation from Novartis, which markets siponimod, as well as Akili, Alexion, Atara, Biogen, EMD Serono, and TG Therapeutics. His coauthors reported receiving research support and personal compensation from Novartis and other pharmaceutical companies. Several coauthors were Novartis employees.
SOURCE: Kappos L et al. AAN 2020, Abstract S40.003.
FROM AAN 2020
Economic burden of migraine increases with the number of treatment failures
, researchers wrote. Utilization of health care resources and associated costs are greater among patients with three or more treatment failures, compared with patients with fewer treatment failures. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Migraine entails a significant economic burden, including direct costs (e.g., medical costs) and indirect costs (e.g., lost productivity). Information about the burden associated with failed preventive treatments among migraineurs is limited, however. Lawrence C. Newman, MD, director of the division of headache at NYU Langone Health in New York, and colleagues conducted a study to characterize health care resource utilization (HCRU) and its associated costs among migraineurs, stratified by the number of preventive treatment failures.
About one quarter of patients had two treatment failures
Using data from the IBM MarketScan Commercial and Medicare Supplemental database, Dr. Newman and colleagues identified patients who received a new diagnosis of migraine between Jan. 1, 2011, and June 30, 2015. Next, they identified the number of treatment failures during the 2 years following the initial migraine diagnosis. They assessed HCRU and associated costs during the 12 months following an index event. The index was the date of initiation of the second preventive treatment for patients with one treatment failure, the date of initiation of the third treatment for patients with two treatment failures, and the date of initiation of the fourth treatment for patients with three or more treatment failures.
Dr. Newman’s group identified 44,181 patients with incident migraine who had failed preventive treatments. Of this population, 27,112 patients (61.4%) had one treatment failure, 10,583 (24%) had two treatment failures, and 6,486 (14.7%) had three or more treatment failures.
The total medical cost per patient, including emergency room (ER), inpatient (IP), and outpatient (OP) care, increased with increasing number of treatment failures ($10,329 for one, $13,774 for two, and $35,392 for three or more). When the investigators added prescription drug costs, the total health care costs also increased with number of treatment failures ($13,946 for one, $18,685 for two, and $41,864 for three or more).
Similarly, the per-patient annual health care provider visits increased with increasing numbers of treatment failures. The number of ER visits per year was 0.54, 0.69, and 1.02 for patients with one, two, and three or more treatment failures, respectively. The annual number of IP visits was 0.46, 0.59, and 0.97, for patients with one, two, and three or more treatment failures, respectively. OP visits showed a similar trend. The annual number of office visits was 9.47 for patients with one, 11.24 for patients with two, and 14.26 for patients with three or more treatment failures. The annual number of other visits was 13.15 for patients with one, 15.73 for patients with two, and 19.96 for patients with three or more treatment failures.
Guidelines could enable appropriate treatment
Reasons for treatment failure include misdiagnosis of the headache disorder, failure to identify and account for comorbidities, overlooking concurrent acute medication overuse, and inappropriate dose or formulation, said Dr. Newman. “Common pitfalls in prevention that lead to treatment failure include not using evidence-based treatments, starting at too low of a dose and not increasing, starting too high or increasing the dose too quickly, discontinuing the medication before an effect can be seen (before 8 weeks), patient nonadherence, and not establishing realistic expectations.”
Available resources could help clinicians treat migraine effectively. “The American Headache Society (AHS)/AAN preventive guidelines have been retired, yet they offered several levels of effectiveness of pharmacologic treatments that were evidence-based,” said Dr. Newman. “Furthermore, in 2019, the AHS published a consensus statement on integrating new migraine treatments into clinical practice. This statement offered advice about the new anti-CGRP agents, onabotulinum toxin, and neuromodulation devices. I think this is a good starting point for neurologists to be familiar with to choose appropriate therapeutic options for people living with migraine.”
Earlier treatment may reduce patients’ economic burden
The study’s weaknesses included its observational design and its reliance on diagnostic codes, which raised the possibility that comorbidities were inadequately recognized, said Dr. Newman. The reasons that patients changed medications are unknown, and the results are not generalizable to patients aged 65 years or older, he added.
Major strengths of Dr. Newman’s study are its large sample size and wealth of available data, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. “The multiple subcategories suggest that this was a carefully organized and implemented study,” he added. If any diagnoses of migraine were provided by general practitioners with little knowledge of migraine, this would weaken the study, said Dr. Rapoport, editor-in-chief of Neurology Reviews.
“We can ease the economic burden of migraineurs by improving acute care therapy with better selection and earlier starting of effective preventive therapy,” he continued. “Going for migraine-specific acute care therapy is better than pain medications or other nonspecific therapies. If you do not stop a migraine attack with effective therapy, you increase the odds that the patient will go on to chronic migraine. It is always important to effectively teach doctors and nurses to improve their diagnostic skills and use the optimal acute and preventive therapy.” For their next trial, maximizing an accurate diagnosis and performing a prospective study measuring treatment outcomes will be particularly valuable, Dr. Rapoport concluded.
Dr. Newman’s study was supported by Novartis Pharma in Basel, Switzerland. Together with Amgen, Novartis developed erenumab. Dr. Newman has received compensation from Allergan, Alder, Amgen, Biohaven, Novartis, Teva, Supernus, and Theranica for consulting, serving on a scientific advisory board, speaking, or other activities. He has received compensation from Springer Scientific for editorial services.
SOURCE: Newman L et al. AAN 2020, Abstract S47.009.
, researchers wrote. Utilization of health care resources and associated costs are greater among patients with three or more treatment failures, compared with patients with fewer treatment failures. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Migraine entails a significant economic burden, including direct costs (e.g., medical costs) and indirect costs (e.g., lost productivity). Information about the burden associated with failed preventive treatments among migraineurs is limited, however. Lawrence C. Newman, MD, director of the division of headache at NYU Langone Health in New York, and colleagues conducted a study to characterize health care resource utilization (HCRU) and its associated costs among migraineurs, stratified by the number of preventive treatment failures.
About one quarter of patients had two treatment failures
Using data from the IBM MarketScan Commercial and Medicare Supplemental database, Dr. Newman and colleagues identified patients who received a new diagnosis of migraine between Jan. 1, 2011, and June 30, 2015. Next, they identified the number of treatment failures during the 2 years following the initial migraine diagnosis. They assessed HCRU and associated costs during the 12 months following an index event. The index was the date of initiation of the second preventive treatment for patients with one treatment failure, the date of initiation of the third treatment for patients with two treatment failures, and the date of initiation of the fourth treatment for patients with three or more treatment failures.
Dr. Newman’s group identified 44,181 patients with incident migraine who had failed preventive treatments. Of this population, 27,112 patients (61.4%) had one treatment failure, 10,583 (24%) had two treatment failures, and 6,486 (14.7%) had three or more treatment failures.
The total medical cost per patient, including emergency room (ER), inpatient (IP), and outpatient (OP) care, increased with increasing number of treatment failures ($10,329 for one, $13,774 for two, and $35,392 for three or more). When the investigators added prescription drug costs, the total health care costs also increased with number of treatment failures ($13,946 for one, $18,685 for two, and $41,864 for three or more).
Similarly, the per-patient annual health care provider visits increased with increasing numbers of treatment failures. The number of ER visits per year was 0.54, 0.69, and 1.02 for patients with one, two, and three or more treatment failures, respectively. The annual number of IP visits was 0.46, 0.59, and 0.97, for patients with one, two, and three or more treatment failures, respectively. OP visits showed a similar trend. The annual number of office visits was 9.47 for patients with one, 11.24 for patients with two, and 14.26 for patients with three or more treatment failures. The annual number of other visits was 13.15 for patients with one, 15.73 for patients with two, and 19.96 for patients with three or more treatment failures.
Guidelines could enable appropriate treatment
Reasons for treatment failure include misdiagnosis of the headache disorder, failure to identify and account for comorbidities, overlooking concurrent acute medication overuse, and inappropriate dose or formulation, said Dr. Newman. “Common pitfalls in prevention that lead to treatment failure include not using evidence-based treatments, starting at too low of a dose and not increasing, starting too high or increasing the dose too quickly, discontinuing the medication before an effect can be seen (before 8 weeks), patient nonadherence, and not establishing realistic expectations.”
Available resources could help clinicians treat migraine effectively. “The American Headache Society (AHS)/AAN preventive guidelines have been retired, yet they offered several levels of effectiveness of pharmacologic treatments that were evidence-based,” said Dr. Newman. “Furthermore, in 2019, the AHS published a consensus statement on integrating new migraine treatments into clinical practice. This statement offered advice about the new anti-CGRP agents, onabotulinum toxin, and neuromodulation devices. I think this is a good starting point for neurologists to be familiar with to choose appropriate therapeutic options for people living with migraine.”
Earlier treatment may reduce patients’ economic burden
The study’s weaknesses included its observational design and its reliance on diagnostic codes, which raised the possibility that comorbidities were inadequately recognized, said Dr. Newman. The reasons that patients changed medications are unknown, and the results are not generalizable to patients aged 65 years or older, he added.
Major strengths of Dr. Newman’s study are its large sample size and wealth of available data, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. “The multiple subcategories suggest that this was a carefully organized and implemented study,” he added. If any diagnoses of migraine were provided by general practitioners with little knowledge of migraine, this would weaken the study, said Dr. Rapoport, editor-in-chief of Neurology Reviews.
“We can ease the economic burden of migraineurs by improving acute care therapy with better selection and earlier starting of effective preventive therapy,” he continued. “Going for migraine-specific acute care therapy is better than pain medications or other nonspecific therapies. If you do not stop a migraine attack with effective therapy, you increase the odds that the patient will go on to chronic migraine. It is always important to effectively teach doctors and nurses to improve their diagnostic skills and use the optimal acute and preventive therapy.” For their next trial, maximizing an accurate diagnosis and performing a prospective study measuring treatment outcomes will be particularly valuable, Dr. Rapoport concluded.
Dr. Newman’s study was supported by Novartis Pharma in Basel, Switzerland. Together with Amgen, Novartis developed erenumab. Dr. Newman has received compensation from Allergan, Alder, Amgen, Biohaven, Novartis, Teva, Supernus, and Theranica for consulting, serving on a scientific advisory board, speaking, or other activities. He has received compensation from Springer Scientific for editorial services.
SOURCE: Newman L et al. AAN 2020, Abstract S47.009.
, researchers wrote. Utilization of health care resources and associated costs are greater among patients with three or more treatment failures, compared with patients with fewer treatment failures. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Migraine entails a significant economic burden, including direct costs (e.g., medical costs) and indirect costs (e.g., lost productivity). Information about the burden associated with failed preventive treatments among migraineurs is limited, however. Lawrence C. Newman, MD, director of the division of headache at NYU Langone Health in New York, and colleagues conducted a study to characterize health care resource utilization (HCRU) and its associated costs among migraineurs, stratified by the number of preventive treatment failures.
About one quarter of patients had two treatment failures
Using data from the IBM MarketScan Commercial and Medicare Supplemental database, Dr. Newman and colleagues identified patients who received a new diagnosis of migraine between Jan. 1, 2011, and June 30, 2015. Next, they identified the number of treatment failures during the 2 years following the initial migraine diagnosis. They assessed HCRU and associated costs during the 12 months following an index event. The index was the date of initiation of the second preventive treatment for patients with one treatment failure, the date of initiation of the third treatment for patients with two treatment failures, and the date of initiation of the fourth treatment for patients with three or more treatment failures.
Dr. Newman’s group identified 44,181 patients with incident migraine who had failed preventive treatments. Of this population, 27,112 patients (61.4%) had one treatment failure, 10,583 (24%) had two treatment failures, and 6,486 (14.7%) had three or more treatment failures.
The total medical cost per patient, including emergency room (ER), inpatient (IP), and outpatient (OP) care, increased with increasing number of treatment failures ($10,329 for one, $13,774 for two, and $35,392 for three or more). When the investigators added prescription drug costs, the total health care costs also increased with number of treatment failures ($13,946 for one, $18,685 for two, and $41,864 for three or more).
Similarly, the per-patient annual health care provider visits increased with increasing numbers of treatment failures. The number of ER visits per year was 0.54, 0.69, and 1.02 for patients with one, two, and three or more treatment failures, respectively. The annual number of IP visits was 0.46, 0.59, and 0.97, for patients with one, two, and three or more treatment failures, respectively. OP visits showed a similar trend. The annual number of office visits was 9.47 for patients with one, 11.24 for patients with two, and 14.26 for patients with three or more treatment failures. The annual number of other visits was 13.15 for patients with one, 15.73 for patients with two, and 19.96 for patients with three or more treatment failures.
Guidelines could enable appropriate treatment
Reasons for treatment failure include misdiagnosis of the headache disorder, failure to identify and account for comorbidities, overlooking concurrent acute medication overuse, and inappropriate dose or formulation, said Dr. Newman. “Common pitfalls in prevention that lead to treatment failure include not using evidence-based treatments, starting at too low of a dose and not increasing, starting too high or increasing the dose too quickly, discontinuing the medication before an effect can be seen (before 8 weeks), patient nonadherence, and not establishing realistic expectations.”
Available resources could help clinicians treat migraine effectively. “The American Headache Society (AHS)/AAN preventive guidelines have been retired, yet they offered several levels of effectiveness of pharmacologic treatments that were evidence-based,” said Dr. Newman. “Furthermore, in 2019, the AHS published a consensus statement on integrating new migraine treatments into clinical practice. This statement offered advice about the new anti-CGRP agents, onabotulinum toxin, and neuromodulation devices. I think this is a good starting point for neurologists to be familiar with to choose appropriate therapeutic options for people living with migraine.”
Earlier treatment may reduce patients’ economic burden
The study’s weaknesses included its observational design and its reliance on diagnostic codes, which raised the possibility that comorbidities were inadequately recognized, said Dr. Newman. The reasons that patients changed medications are unknown, and the results are not generalizable to patients aged 65 years or older, he added.
Major strengths of Dr. Newman’s study are its large sample size and wealth of available data, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. “The multiple subcategories suggest that this was a carefully organized and implemented study,” he added. If any diagnoses of migraine were provided by general practitioners with little knowledge of migraine, this would weaken the study, said Dr. Rapoport, editor-in-chief of Neurology Reviews.
“We can ease the economic burden of migraineurs by improving acute care therapy with better selection and earlier starting of effective preventive therapy,” he continued. “Going for migraine-specific acute care therapy is better than pain medications or other nonspecific therapies. If you do not stop a migraine attack with effective therapy, you increase the odds that the patient will go on to chronic migraine. It is always important to effectively teach doctors and nurses to improve their diagnostic skills and use the optimal acute and preventive therapy.” For their next trial, maximizing an accurate diagnosis and performing a prospective study measuring treatment outcomes will be particularly valuable, Dr. Rapoport concluded.
Dr. Newman’s study was supported by Novartis Pharma in Basel, Switzerland. Together with Amgen, Novartis developed erenumab. Dr. Newman has received compensation from Allergan, Alder, Amgen, Biohaven, Novartis, Teva, Supernus, and Theranica for consulting, serving on a scientific advisory board, speaking, or other activities. He has received compensation from Springer Scientific for editorial services.
SOURCE: Newman L et al. AAN 2020, Abstract S47.009.
From AAN 2020
Predictors of ICH after thrombectomy identified
(ICH), new research suggests. In a study of nearly 600 patients undergoing thrombectomy, investigators combined a modified Thrombolysis in Cerebral Ischemia (TICI) score, an Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and glucose levels (the “TAG score”) to predict risk. Results showed that each unit increase in the combination score was associated with a significant, nearly twofold greater likelihood of symptomatic ICH.
“It is very easy” to calculate the new score in a clinical setting, lead author Mayra Johana Montalvo Perero, MD, Department of Neurology, Brown University and Rhode Island Hospital, Providence, said. “You just need three variables.”
The findings were presented online as part of the 2020 American Academy of Neurology Science Highlights.
Limited data
High TAG scores are associated with symptomatic ICH in patients receiving mechanical thrombectomy, Dr. Montalvo Perero and colleagues said.
Although clinical predictors of symptomatic ICH are well established, “there is limited data in patients who underwent mechanical thrombectomy,” the researchers noted.
To learn more, they assessed 578 patients (52% women; mean age, 73 years) who had mechanical thrombectomy for acute ischemic stroke at a comprehensive stroke center. Within this cohort, 19 patients (3.3%) developed symptomatic ICH.
The investigators compared clinical and radiographic findings between patients who experienced symptomatic ICH and those who did not.
The TICI score emerged as a predictor when each unit decrease in this score was associated with greater risk for symptomatic ICH (odds ratio, 5.13; 95% confidence interval, 1.84-14.29; P = .002).
Each one-point decrease in the ASPECTS score also predicted increased risk (OR, 1.52; 95% CI, 1.1-2.0; P = .003).
“The main driver is the size of the stroke core, which is correlated with the ASPECTS score,” Dr. Montalvo Perero said.
Each 10 mg/dL increase in glucose level also correlated with increased risk (OR, 1.07; 95% CI, 1.01-1.13; P = .018).
Twice the risk
The investigators then combined these three independent variables into a weighted TAG score based on a multivariate analysis. Each unit increase in this composite score was associated with increased risk of symptomatic ICH (OR, 1.98; 95% CI, 1.48-2.66; P < .001).
There was no association between patients who received tissue plasminogen activator (tPA) and risk of symptomatic ICH, which Dr. Montalvo Perero said was surprising.
However, “that may be due to a small number” of patients with symptomatic ICH included in the study, she said. “Therefore, that would be an interesting question to ask in future studies with bigger cohorts.”
Larger studies are also needed to validate this scoring system and to test strategies to reduce risk of symptomatic ICH and make thrombectomy safer in patients with elevated TAG scores, Dr. Montalvo Perero said.
A step in the right direction?
Commenting on the study, Jeremy Payne, MD, PhD, director of the Stroke Center at Banner Health’s University Medicine Neuroscience Institute in Phoenix, Arizona, noted the importance of predicting which patients might have secondary bleeding after interventional treatment of a large vessel occlusion stroke
“In aggregate, the role of endovascular thrombectomy is quite clear, but we still struggle to predict at the individual patient level who will benefit,” said Dr. Payne, who was not involved with the research.
Transfer and treatment of these patients also carries an economic cost. “Just getting patients to our center, where about 80% of the complex stroke patients come by helicopter, costs upwards of $30,000,” Dr. Payne said. “The financial argument isn’t one we like to talk much about, but we’re committing to spending probably $100,000-$200,000 on each person’s care.”
This study “attempts to address an important issue,” he said.
Predicting who is more likely to benefit leads to the assumption that if that were to happen, “we could skip all the rigamarole of helicopters and procedures, avoid the extra expense and particularly not make things worse than they already are,” explained Dr. Payne.
Potential limitations include that this is a single-center study and is based on an analysis of 19 patients out of 578. As a result, it is not clear that these findings will necessarily be generalizable to other centers, said Dr. Payne.
The TICI and ASPECTS “are pretty obvious markers of risk,” he noted. “The glucose levels, however, are more subtly interesting.”
He also pointed out that an association between diabetes and worse stroke outcomes is well established.
“The mechanisms are poorly understood, but the role of glucose keeps popping up as a potential marker of risk, and so it’s interesting that it bubbles up in their work too,” Dr. Payne said.
Furthermore, unlike TICI and ASPECTS, glucose levels are modifiable.
“Overall, then, we will continue to study this,” Dr. Payne said. “It’s very important to refine our ability to predict which patients may receive benefit versus harm from such procedures, and this is a step in the right direction.”
Some findings were also published December 2019 in the Journal of Neurology, Neurosurgery & Psychiatry.
Montalvo Perero and Payne have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Motalvo Perero MJ et al. AAN 2020, Abstract S20.001.
(ICH), new research suggests. In a study of nearly 600 patients undergoing thrombectomy, investigators combined a modified Thrombolysis in Cerebral Ischemia (TICI) score, an Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and glucose levels (the “TAG score”) to predict risk. Results showed that each unit increase in the combination score was associated with a significant, nearly twofold greater likelihood of symptomatic ICH.
“It is very easy” to calculate the new score in a clinical setting, lead author Mayra Johana Montalvo Perero, MD, Department of Neurology, Brown University and Rhode Island Hospital, Providence, said. “You just need three variables.”
The findings were presented online as part of the 2020 American Academy of Neurology Science Highlights.
Limited data
High TAG scores are associated with symptomatic ICH in patients receiving mechanical thrombectomy, Dr. Montalvo Perero and colleagues said.
Although clinical predictors of symptomatic ICH are well established, “there is limited data in patients who underwent mechanical thrombectomy,” the researchers noted.
To learn more, they assessed 578 patients (52% women; mean age, 73 years) who had mechanical thrombectomy for acute ischemic stroke at a comprehensive stroke center. Within this cohort, 19 patients (3.3%) developed symptomatic ICH.
The investigators compared clinical and radiographic findings between patients who experienced symptomatic ICH and those who did not.
The TICI score emerged as a predictor when each unit decrease in this score was associated with greater risk for symptomatic ICH (odds ratio, 5.13; 95% confidence interval, 1.84-14.29; P = .002).
Each one-point decrease in the ASPECTS score also predicted increased risk (OR, 1.52; 95% CI, 1.1-2.0; P = .003).
“The main driver is the size of the stroke core, which is correlated with the ASPECTS score,” Dr. Montalvo Perero said.
Each 10 mg/dL increase in glucose level also correlated with increased risk (OR, 1.07; 95% CI, 1.01-1.13; P = .018).
Twice the risk
The investigators then combined these three independent variables into a weighted TAG score based on a multivariate analysis. Each unit increase in this composite score was associated with increased risk of symptomatic ICH (OR, 1.98; 95% CI, 1.48-2.66; P < .001).
There was no association between patients who received tissue plasminogen activator (tPA) and risk of symptomatic ICH, which Dr. Montalvo Perero said was surprising.
However, “that may be due to a small number” of patients with symptomatic ICH included in the study, she said. “Therefore, that would be an interesting question to ask in future studies with bigger cohorts.”
Larger studies are also needed to validate this scoring system and to test strategies to reduce risk of symptomatic ICH and make thrombectomy safer in patients with elevated TAG scores, Dr. Montalvo Perero said.
A step in the right direction?
Commenting on the study, Jeremy Payne, MD, PhD, director of the Stroke Center at Banner Health’s University Medicine Neuroscience Institute in Phoenix, Arizona, noted the importance of predicting which patients might have secondary bleeding after interventional treatment of a large vessel occlusion stroke
“In aggregate, the role of endovascular thrombectomy is quite clear, but we still struggle to predict at the individual patient level who will benefit,” said Dr. Payne, who was not involved with the research.
Transfer and treatment of these patients also carries an economic cost. “Just getting patients to our center, where about 80% of the complex stroke patients come by helicopter, costs upwards of $30,000,” Dr. Payne said. “The financial argument isn’t one we like to talk much about, but we’re committing to spending probably $100,000-$200,000 on each person’s care.”
This study “attempts to address an important issue,” he said.
Predicting who is more likely to benefit leads to the assumption that if that were to happen, “we could skip all the rigamarole of helicopters and procedures, avoid the extra expense and particularly not make things worse than they already are,” explained Dr. Payne.
Potential limitations include that this is a single-center study and is based on an analysis of 19 patients out of 578. As a result, it is not clear that these findings will necessarily be generalizable to other centers, said Dr. Payne.
The TICI and ASPECTS “are pretty obvious markers of risk,” he noted. “The glucose levels, however, are more subtly interesting.”
He also pointed out that an association between diabetes and worse stroke outcomes is well established.
“The mechanisms are poorly understood, but the role of glucose keeps popping up as a potential marker of risk, and so it’s interesting that it bubbles up in their work too,” Dr. Payne said.
Furthermore, unlike TICI and ASPECTS, glucose levels are modifiable.
“Overall, then, we will continue to study this,” Dr. Payne said. “It’s very important to refine our ability to predict which patients may receive benefit versus harm from such procedures, and this is a step in the right direction.”
Some findings were also published December 2019 in the Journal of Neurology, Neurosurgery & Psychiatry.
Montalvo Perero and Payne have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Motalvo Perero MJ et al. AAN 2020, Abstract S20.001.
(ICH), new research suggests. In a study of nearly 600 patients undergoing thrombectomy, investigators combined a modified Thrombolysis in Cerebral Ischemia (TICI) score, an Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and glucose levels (the “TAG score”) to predict risk. Results showed that each unit increase in the combination score was associated with a significant, nearly twofold greater likelihood of symptomatic ICH.
“It is very easy” to calculate the new score in a clinical setting, lead author Mayra Johana Montalvo Perero, MD, Department of Neurology, Brown University and Rhode Island Hospital, Providence, said. “You just need three variables.”
The findings were presented online as part of the 2020 American Academy of Neurology Science Highlights.
Limited data
High TAG scores are associated with symptomatic ICH in patients receiving mechanical thrombectomy, Dr. Montalvo Perero and colleagues said.
Although clinical predictors of symptomatic ICH are well established, “there is limited data in patients who underwent mechanical thrombectomy,” the researchers noted.
To learn more, they assessed 578 patients (52% women; mean age, 73 years) who had mechanical thrombectomy for acute ischemic stroke at a comprehensive stroke center. Within this cohort, 19 patients (3.3%) developed symptomatic ICH.
The investigators compared clinical and radiographic findings between patients who experienced symptomatic ICH and those who did not.
The TICI score emerged as a predictor when each unit decrease in this score was associated with greater risk for symptomatic ICH (odds ratio, 5.13; 95% confidence interval, 1.84-14.29; P = .002).
Each one-point decrease in the ASPECTS score also predicted increased risk (OR, 1.52; 95% CI, 1.1-2.0; P = .003).
“The main driver is the size of the stroke core, which is correlated with the ASPECTS score,” Dr. Montalvo Perero said.
Each 10 mg/dL increase in glucose level also correlated with increased risk (OR, 1.07; 95% CI, 1.01-1.13; P = .018).
Twice the risk
The investigators then combined these three independent variables into a weighted TAG score based on a multivariate analysis. Each unit increase in this composite score was associated with increased risk of symptomatic ICH (OR, 1.98; 95% CI, 1.48-2.66; P < .001).
There was no association between patients who received tissue plasminogen activator (tPA) and risk of symptomatic ICH, which Dr. Montalvo Perero said was surprising.
However, “that may be due to a small number” of patients with symptomatic ICH included in the study, she said. “Therefore, that would be an interesting question to ask in future studies with bigger cohorts.”
Larger studies are also needed to validate this scoring system and to test strategies to reduce risk of symptomatic ICH and make thrombectomy safer in patients with elevated TAG scores, Dr. Montalvo Perero said.
A step in the right direction?
Commenting on the study, Jeremy Payne, MD, PhD, director of the Stroke Center at Banner Health’s University Medicine Neuroscience Institute in Phoenix, Arizona, noted the importance of predicting which patients might have secondary bleeding after interventional treatment of a large vessel occlusion stroke
“In aggregate, the role of endovascular thrombectomy is quite clear, but we still struggle to predict at the individual patient level who will benefit,” said Dr. Payne, who was not involved with the research.
Transfer and treatment of these patients also carries an economic cost. “Just getting patients to our center, where about 80% of the complex stroke patients come by helicopter, costs upwards of $30,000,” Dr. Payne said. “The financial argument isn’t one we like to talk much about, but we’re committing to spending probably $100,000-$200,000 on each person’s care.”
This study “attempts to address an important issue,” he said.
Predicting who is more likely to benefit leads to the assumption that if that were to happen, “we could skip all the rigamarole of helicopters and procedures, avoid the extra expense and particularly not make things worse than they already are,” explained Dr. Payne.
Potential limitations include that this is a single-center study and is based on an analysis of 19 patients out of 578. As a result, it is not clear that these findings will necessarily be generalizable to other centers, said Dr. Payne.
The TICI and ASPECTS “are pretty obvious markers of risk,” he noted. “The glucose levels, however, are more subtly interesting.”
He also pointed out that an association between diabetes and worse stroke outcomes is well established.
“The mechanisms are poorly understood, but the role of glucose keeps popping up as a potential marker of risk, and so it’s interesting that it bubbles up in their work too,” Dr. Payne said.
Furthermore, unlike TICI and ASPECTS, glucose levels are modifiable.
“Overall, then, we will continue to study this,” Dr. Payne said. “It’s very important to refine our ability to predict which patients may receive benefit versus harm from such procedures, and this is a step in the right direction.”
Some findings were also published December 2019 in the Journal of Neurology, Neurosurgery & Psychiatry.
Montalvo Perero and Payne have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Motalvo Perero MJ et al. AAN 2020, Abstract S20.001.
AAN 2020
CGRP inhibitors receive reassuring real-world safety report
Stephen D. Silberstein, MD, reported online as part of the 2020 American Academy of Neurology Science Highlights.
He presented a retrospective analysis of spontaneous postmarketing reports to the Food and Drug Administration Adverse Events Reporting System (FAERS) for Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), and Emgality (galcanezumab-gnlm).
The top-10 lists of adverse events for all three monoclonal antibodies targeting CGRP were skewed heavily towards injection-site reactions, such as injection-site pain, itching, swelling, and erythema. The rates were relatively low. For example, injection-site pain was reported at a rate of 2.94 cases per 1,000 patients exposed to erenumab, 0.8/1,000 for fremanezumab, and 4.9/1,000 for galcanezumab, according to Dr. Silberstein, professor of neurology and director of the headache center at Sidney Kimmel Medical College, Philadelphia.
Migraine, headache, and drug ineffectiveness were in the top 10 for all three medications, as is typical in FAERS reports, since no drug is effective in everyone. These events were reported at rates of 1-5/1,000 exposed patients. Constipation was reported in association with the use of erenumab at a rate of 4.9 cases/1,000 patients, but did not reach the top-10 lists for the other two CGRP antagonists.
Notably, cardiovascular events were not among the top-10 adverse events reported for any of the novel preventive agents.
“These results will be practice changing, since some physicians have been holding back from prescribing these drugs pending the results of this sort of longer-term safety data,” Dr. Silberstein predicted in an interview.
Asked to comment on the FAERS study, neurologist Holly Yancy, DO, said that she found the findings unsurprising because the adverse effects were essentially as expected based upon the earlier favorable clinical trials experience.
“These medications are living up to the expectations for good tolerability that were in place when they were initially approved by the FDA just under 2 years ago,” said Dr. Yancy, a headache specialist at the Banner–University Medicine Neuroscience Institute in Phoenix.
“Injection-site reactions were anticipated. Clinically, I’ve found that if the medications reduce migraine days and severity, patients find the risk of temporary pain, redness, or itching at the injection site is an easy trade off,” she added.
CGRP is a vasoactive peptide. There has been a theoretic concern that its pharmacologic inhibition for prevention of migraine could lead to an increased risk of adverse cardiovascular events, especially in individuals with coronary disease or a history of stroke. The absence of any such signal during the first 6 months of widespread clinical use of the CGRP inhibitors is highly encouraging, although this is an issue that warrants longer-term study, Dr. Yancy continued.
These drugs, which were expressly designed for migraine prevention, are a considerable advance over what was previously available in her view. They’re equally or more effective and considerably better tolerated than the preventive medications physicians had long been using off label, including antidepressants, antiepileptics, and cardiac drugs.
Dr. Silberstein reported financial relationships with close to two dozen pharmaceutical companies. Dr. Yancy reported serving on speakers’ bureaus for Amgen and Novartis.
SOURCE: Silverstein SD et al. AAN 2020, Abstract S58.008.
Stephen D. Silberstein, MD, reported online as part of the 2020 American Academy of Neurology Science Highlights.
He presented a retrospective analysis of spontaneous postmarketing reports to the Food and Drug Administration Adverse Events Reporting System (FAERS) for Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), and Emgality (galcanezumab-gnlm).
The top-10 lists of adverse events for all three monoclonal antibodies targeting CGRP were skewed heavily towards injection-site reactions, such as injection-site pain, itching, swelling, and erythema. The rates were relatively low. For example, injection-site pain was reported at a rate of 2.94 cases per 1,000 patients exposed to erenumab, 0.8/1,000 for fremanezumab, and 4.9/1,000 for galcanezumab, according to Dr. Silberstein, professor of neurology and director of the headache center at Sidney Kimmel Medical College, Philadelphia.
Migraine, headache, and drug ineffectiveness were in the top 10 for all three medications, as is typical in FAERS reports, since no drug is effective in everyone. These events were reported at rates of 1-5/1,000 exposed patients. Constipation was reported in association with the use of erenumab at a rate of 4.9 cases/1,000 patients, but did not reach the top-10 lists for the other two CGRP antagonists.
Notably, cardiovascular events were not among the top-10 adverse events reported for any of the novel preventive agents.
“These results will be practice changing, since some physicians have been holding back from prescribing these drugs pending the results of this sort of longer-term safety data,” Dr. Silberstein predicted in an interview.
Asked to comment on the FAERS study, neurologist Holly Yancy, DO, said that she found the findings unsurprising because the adverse effects were essentially as expected based upon the earlier favorable clinical trials experience.
“These medications are living up to the expectations for good tolerability that were in place when they were initially approved by the FDA just under 2 years ago,” said Dr. Yancy, a headache specialist at the Banner–University Medicine Neuroscience Institute in Phoenix.
“Injection-site reactions were anticipated. Clinically, I’ve found that if the medications reduce migraine days and severity, patients find the risk of temporary pain, redness, or itching at the injection site is an easy trade off,” she added.
CGRP is a vasoactive peptide. There has been a theoretic concern that its pharmacologic inhibition for prevention of migraine could lead to an increased risk of adverse cardiovascular events, especially in individuals with coronary disease or a history of stroke. The absence of any such signal during the first 6 months of widespread clinical use of the CGRP inhibitors is highly encouraging, although this is an issue that warrants longer-term study, Dr. Yancy continued.
These drugs, which were expressly designed for migraine prevention, are a considerable advance over what was previously available in her view. They’re equally or more effective and considerably better tolerated than the preventive medications physicians had long been using off label, including antidepressants, antiepileptics, and cardiac drugs.
Dr. Silberstein reported financial relationships with close to two dozen pharmaceutical companies. Dr. Yancy reported serving on speakers’ bureaus for Amgen and Novartis.
SOURCE: Silverstein SD et al. AAN 2020, Abstract S58.008.
Stephen D. Silberstein, MD, reported online as part of the 2020 American Academy of Neurology Science Highlights.
He presented a retrospective analysis of spontaneous postmarketing reports to the Food and Drug Administration Adverse Events Reporting System (FAERS) for Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), and Emgality (galcanezumab-gnlm).
The top-10 lists of adverse events for all three monoclonal antibodies targeting CGRP were skewed heavily towards injection-site reactions, such as injection-site pain, itching, swelling, and erythema. The rates were relatively low. For example, injection-site pain was reported at a rate of 2.94 cases per 1,000 patients exposed to erenumab, 0.8/1,000 for fremanezumab, and 4.9/1,000 for galcanezumab, according to Dr. Silberstein, professor of neurology and director of the headache center at Sidney Kimmel Medical College, Philadelphia.
Migraine, headache, and drug ineffectiveness were in the top 10 for all three medications, as is typical in FAERS reports, since no drug is effective in everyone. These events were reported at rates of 1-5/1,000 exposed patients. Constipation was reported in association with the use of erenumab at a rate of 4.9 cases/1,000 patients, but did not reach the top-10 lists for the other two CGRP antagonists.
Notably, cardiovascular events were not among the top-10 adverse events reported for any of the novel preventive agents.
“These results will be practice changing, since some physicians have been holding back from prescribing these drugs pending the results of this sort of longer-term safety data,” Dr. Silberstein predicted in an interview.
Asked to comment on the FAERS study, neurologist Holly Yancy, DO, said that she found the findings unsurprising because the adverse effects were essentially as expected based upon the earlier favorable clinical trials experience.
“These medications are living up to the expectations for good tolerability that were in place when they were initially approved by the FDA just under 2 years ago,” said Dr. Yancy, a headache specialist at the Banner–University Medicine Neuroscience Institute in Phoenix.
“Injection-site reactions were anticipated. Clinically, I’ve found that if the medications reduce migraine days and severity, patients find the risk of temporary pain, redness, or itching at the injection site is an easy trade off,” she added.
CGRP is a vasoactive peptide. There has been a theoretic concern that its pharmacologic inhibition for prevention of migraine could lead to an increased risk of adverse cardiovascular events, especially in individuals with coronary disease or a history of stroke. The absence of any such signal during the first 6 months of widespread clinical use of the CGRP inhibitors is highly encouraging, although this is an issue that warrants longer-term study, Dr. Yancy continued.
These drugs, which were expressly designed for migraine prevention, are a considerable advance over what was previously available in her view. They’re equally or more effective and considerably better tolerated than the preventive medications physicians had long been using off label, including antidepressants, antiepileptics, and cardiac drugs.
Dr. Silberstein reported financial relationships with close to two dozen pharmaceutical companies. Dr. Yancy reported serving on speakers’ bureaus for Amgen and Novartis.
SOURCE: Silverstein SD et al. AAN 2020, Abstract S58.008.
FROM AAN 2020