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Cardiac arrhythmia heightens mortality risk during epilepsy hospitalizations
BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.
“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.
Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.
To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.
Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.
“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.
In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).
The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”
Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.
The researchers had no disclosures and reported receiving no outside funding for their work.
SOURCE: Patel UK et al. AES 2019, Abstract 2.140.
BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.
“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.
Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.
To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.
Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.
“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.
In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).
The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”
Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.
The researchers had no disclosures and reported receiving no outside funding for their work.
SOURCE: Patel UK et al. AES 2019, Abstract 2.140.
BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.
“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.
Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.
To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.
Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.
“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.
In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).
The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”
Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.
The researchers had no disclosures and reported receiving no outside funding for their work.
SOURCE: Patel UK et al. AES 2019, Abstract 2.140.
REPORTING FROM AES 2019
Study delineates spectrum of Dravet syndrome phenotypes
BALTIMORE – , researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.
“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”
Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.
Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”
To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).
In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.
In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.
Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.
Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.
The researchers had no disclosures.
SOURCE: Li W et al. AES 2019. Abstract 2.116.
BALTIMORE – , researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.
“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”
Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.
Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”
To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).
In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.
In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.
Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.
Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.
The researchers had no disclosures.
SOURCE: Li W et al. AES 2019. Abstract 2.116.
BALTIMORE – , researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.
“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”
Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.
Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”
To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).
In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.
In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.
Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.
Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.
The researchers had no disclosures.
SOURCE: Li W et al. AES 2019. Abstract 2.116.
REPORTING FROM AES 2019
Moderate coffee intake associated with few seizures in drug-refractory patients with epilepsy
BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.
In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.
To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.
For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.
The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.
The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.
Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.
Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).
“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”
While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.
The study was funded by the French Ministry of Health. The researchers had no disclosures.
SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.
BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.
In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.
To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.
For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.
The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.
The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.
Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.
Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).
“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”
While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.
The study was funded by the French Ministry of Health. The researchers had no disclosures.
SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.
BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.
In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.
To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.
For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.
The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.
The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.
Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.
Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).
“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”
While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.
The study was funded by the French Ministry of Health. The researchers had no disclosures.
SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.
REPORTING FROM AES 2019
Researchers mine free-text diary entries for seizure cluster insights
BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.
To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.
“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.
Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.
An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.
“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.
Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:
- Massive ongoing cluster with about 20% apneic events.
- My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
- Started feeling like I was having an aura and pulled over.
- Thought about suicide for the first time in a while.
Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.
UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.
SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.
BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.
To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.
“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.
Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.
An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.
“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.
Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:
- Massive ongoing cluster with about 20% apneic events.
- My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
- Started feeling like I was having an aura and pulled over.
- Thought about suicide for the first time in a while.
Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.
UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.
SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.
BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.
To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.
“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.
Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.
An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.
“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.
Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:
- Massive ongoing cluster with about 20% apneic events.
- My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
- Started feeling like I was having an aura and pulled over.
- Thought about suicide for the first time in a while.
Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.
UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.
SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.
REPORTING FROM AES 2019
More phase 3 ubrogepant data published as FDA decision nears
published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.
Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.
Assessing a gepant for acute migraine treatment
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.
To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.
In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.
The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.
The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”
“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”
The CGRP therapeutic landscape
“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.
Ubrogepant stands to join other treatments targeting CGRP.
“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”
Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.
Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.
Assessing a gepant for acute migraine treatment
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.
To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.
In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.
The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.
The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”
“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”
The CGRP therapeutic landscape
“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.
Ubrogepant stands to join other treatments targeting CGRP.
“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”
Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.
Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.
Assessing a gepant for acute migraine treatment
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.
To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.
In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.
The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.
The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”
“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”
The CGRP therapeutic landscape
“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.
Ubrogepant stands to join other treatments targeting CGRP.
“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”
Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Compared with placebo, ubrogepant tablets result in higher rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours following treatment.
Major finding: About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo.
Study details: A randomized trial that enrolled 1,672 adults with migraine with or without aura. Participants treated a single migraine attack.
Disclosures: Allergan funded the trial, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
Source: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
Trial finds three drugs equally effective for established status epilepticus
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
FROM NEJM
Key clinical point: Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients.
Major finding: Absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
Study details: The Established Status Epilepticus Treatment Trial (ESETT) was a blinded, comparative-effectiveness trial that enrolled 384 patients at 57 hospital EDs in the United States.
Disclosures: The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Source: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
‘Remarkable’ seizure-free rates seen with adjunctive cenobamate
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
FROM LANCET NEUROLOGY
Ubrogepant may relieve migraine pain at 2 hours
Ubrogepant, an oral calcitonin gene–related peptide (CGRP)–receptor antagonist, may relieve patients’ migraine pain and their most bothersome associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours after acute treatment, according to phase 3 trial results published Nov. 19 in JAMA.
“Among adults with migraine, acute treatment with ubrogepant, compared with placebo, led to significantly greater rates of pain freedom at 2 hours with the 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose,” wrote first author Richard B. Lipton, MD, director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, and his colleagues. “Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.”
A researcher who commented on the results said that the drug appears “modestly better than placebo” and called for a trial comparing ubrogepant, aspirin, and oral sumatriptan.
The Food and Drug Administration is reviewing an application for ubrogepant. Allergan, the company developing the drug, has said it expects a regulatory decision in December.
ACHIEVE II
To evaluate the efficacy and tolerability of ubrogepant versus placebo for the acute treatment of a migraine attack, investigators conducted ACHIEVE II, a randomized, double-blind, placebo-controlled, single-attack clinical trial. The study was conducted at 99 primary care and research clinics during 2016-2018.
The trial included adults with migraine with or without aura who experienced two to eight migraine attacks per month. Participants had a mean age of 41.5 years, and 90% were female. The safety analysis included data from 1,465 participants, and the efficacy analysis included data from 1,355 participants. The primary efficacy outcomes were pain freedom and the absence of participants’ most bothersome migraine-associated symptom at 2 hours after taking the medication. Patients received ubrogepant 50 mg, ubrogepant 25 mg, or placebo to treat a migraine attack of moderate or severe pain intensity.
At 2 hours, pain freedom was reported by 101 of 464 participants in the ubrogepant 50-mg group (21.8%), 90 of 435 in the ubrogepant 25-mg group (20.7%), and 65 of 456 in the placebo group (14.3%). Absence of the most bothersome symptom was reported by 180 of 463 participants in the ubrogepant 50-mg group (38.9%), 148 of 434 in the ubrogepant 25-mg group (34.1%), and 125 of 456 in the placebo group (27.4%).
The most common adverse events within 48 hours were nausea and dizziness. Nausea occurred in 2.0% of the 50-mg group, 2.5% of the 25-mg group, and 2.0% of the placebo group. Dizziness occurred in 1.4% of the 50-mg group, 2.1% of the 25-mg group, and 1.6% of the placebo group.
At conferences, researchers have presented results from the phase 3 ACHIEVE I trial as well as an analysis that suggests ubrogepant may be effective in patients for whom triptans have been ineffective. In addition, studies have supported the safety of “gepants” after earlier concerns about potential liver toxicity. Physicians have called the safety data reassuring.
The ACHIEVE II trial was sponsored by Allergan. Several authors are Allergan employees. Dr. Lipton is a consultant, advisory board member, or has received honoraria from Allergan and other companies.
Number needed to treat
“The study was large, appears to have been well conducted, is clearly reported, and used appropriate outcome measures,” said Elizabeth Loder, MD, commenting on the trial.
A year ago, Dr. Loder, chief of the division of headache at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School in Boston, coauthored a paper with Peer Tfelt-Hansen, MD, DMSc, of the University of Copenhagen, that said the phase 3 trials of gepants so far have found the drugs to have small effect sizes and low efficacy (Headache. 2019 Jan;59[1]:113-7. doi: 10.1111/head.13444).
Their publication included preliminary figures from ACHIEVE II, which are consistent with those published in JAMA. “The effect size for both doses of ubrogepant is small and of debatable clinical significance,” Dr. Loder said. “The therapeutic gain over placebo is 7.5% for the 50-mg dose and 6.4% for the 25-mg dose for the outcome of pain freedom at 2 hours. That corresponds to a number needed to treat of 13 and 15.6 people, respectively, in order to have one person achieve pain freedom at 2 hours that is attributable to the active treatment.”
For a secondary outcome of pain relief at 2 hours, defined as reduction of headache pain severity from moderate or severe to mild or none, the therapeutic gain versus placebo is 14.5% for the 50-mg dose and 12.3% for the 25-mg dose. “That corresponds to a number needed to treat of 6.8 and 8.1 people, respectively, to have one person achieve pain relief at 2 hours attributable to the drug,” Dr. Loder said.
“Although there are no head to head studies comparing ubrogepant to triptans, for reference the [number needed to treat] for a 100-mg oral dose of sumatriptan is on the order of 3.5 for pain relief at 2 hours, meaning that one needs to treat just 3.5 people with sumatriptan in order to have one person achieve pain relief at 2 hours attributable to the drug,” she said (Cochrane Database Syst Rev. 2014;5:CD009108. doi: 10.1002/14651858.CD009108.pub2).
“The bottom line is that in the ACHIEVE II study, ubrogepant appears, on average, to be modestly better than placebo to treat migraine. It does not appear to be in the same league as sumatriptan. Instead, as Dr. Tfelt-Hansen and I said in our article, the results look comparable to those likely to be achieved with inexpensive nonprescription medications such as NSAIDs.”
Dr. Loder called for a trial comparing ubrogepant and other therapies. “I challenge the authors and the company to conduct a large, placebo-controlled trial comparing ubrogepant to 100 mg of oral sumatriptan and to 650 mg of aspirin,” Dr. Loder said.
Dr. Loder has no financial connections with any pharmaceutical or device companies and is paid for her work as the head of research for the British Medical Journal.
SOURCE: Lipton RB et al. JAMA. 2019;322(19):1887-98. doi: 10.1001/jama.2019.16711.
Ubrogepant, an oral calcitonin gene–related peptide (CGRP)–receptor antagonist, may relieve patients’ migraine pain and their most bothersome associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours after acute treatment, according to phase 3 trial results published Nov. 19 in JAMA.
“Among adults with migraine, acute treatment with ubrogepant, compared with placebo, led to significantly greater rates of pain freedom at 2 hours with the 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose,” wrote first author Richard B. Lipton, MD, director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, and his colleagues. “Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.”
A researcher who commented on the results said that the drug appears “modestly better than placebo” and called for a trial comparing ubrogepant, aspirin, and oral sumatriptan.
The Food and Drug Administration is reviewing an application for ubrogepant. Allergan, the company developing the drug, has said it expects a regulatory decision in December.
ACHIEVE II
To evaluate the efficacy and tolerability of ubrogepant versus placebo for the acute treatment of a migraine attack, investigators conducted ACHIEVE II, a randomized, double-blind, placebo-controlled, single-attack clinical trial. The study was conducted at 99 primary care and research clinics during 2016-2018.
The trial included adults with migraine with or without aura who experienced two to eight migraine attacks per month. Participants had a mean age of 41.5 years, and 90% were female. The safety analysis included data from 1,465 participants, and the efficacy analysis included data from 1,355 participants. The primary efficacy outcomes were pain freedom and the absence of participants’ most bothersome migraine-associated symptom at 2 hours after taking the medication. Patients received ubrogepant 50 mg, ubrogepant 25 mg, or placebo to treat a migraine attack of moderate or severe pain intensity.
At 2 hours, pain freedom was reported by 101 of 464 participants in the ubrogepant 50-mg group (21.8%), 90 of 435 in the ubrogepant 25-mg group (20.7%), and 65 of 456 in the placebo group (14.3%). Absence of the most bothersome symptom was reported by 180 of 463 participants in the ubrogepant 50-mg group (38.9%), 148 of 434 in the ubrogepant 25-mg group (34.1%), and 125 of 456 in the placebo group (27.4%).
The most common adverse events within 48 hours were nausea and dizziness. Nausea occurred in 2.0% of the 50-mg group, 2.5% of the 25-mg group, and 2.0% of the placebo group. Dizziness occurred in 1.4% of the 50-mg group, 2.1% of the 25-mg group, and 1.6% of the placebo group.
At conferences, researchers have presented results from the phase 3 ACHIEVE I trial as well as an analysis that suggests ubrogepant may be effective in patients for whom triptans have been ineffective. In addition, studies have supported the safety of “gepants” after earlier concerns about potential liver toxicity. Physicians have called the safety data reassuring.
The ACHIEVE II trial was sponsored by Allergan. Several authors are Allergan employees. Dr. Lipton is a consultant, advisory board member, or has received honoraria from Allergan and other companies.
Number needed to treat
“The study was large, appears to have been well conducted, is clearly reported, and used appropriate outcome measures,” said Elizabeth Loder, MD, commenting on the trial.
A year ago, Dr. Loder, chief of the division of headache at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School in Boston, coauthored a paper with Peer Tfelt-Hansen, MD, DMSc, of the University of Copenhagen, that said the phase 3 trials of gepants so far have found the drugs to have small effect sizes and low efficacy (Headache. 2019 Jan;59[1]:113-7. doi: 10.1111/head.13444).
Their publication included preliminary figures from ACHIEVE II, which are consistent with those published in JAMA. “The effect size for both doses of ubrogepant is small and of debatable clinical significance,” Dr. Loder said. “The therapeutic gain over placebo is 7.5% for the 50-mg dose and 6.4% for the 25-mg dose for the outcome of pain freedom at 2 hours. That corresponds to a number needed to treat of 13 and 15.6 people, respectively, in order to have one person achieve pain freedom at 2 hours that is attributable to the active treatment.”
For a secondary outcome of pain relief at 2 hours, defined as reduction of headache pain severity from moderate or severe to mild or none, the therapeutic gain versus placebo is 14.5% for the 50-mg dose and 12.3% for the 25-mg dose. “That corresponds to a number needed to treat of 6.8 and 8.1 people, respectively, to have one person achieve pain relief at 2 hours attributable to the drug,” Dr. Loder said.
“Although there are no head to head studies comparing ubrogepant to triptans, for reference the [number needed to treat] for a 100-mg oral dose of sumatriptan is on the order of 3.5 for pain relief at 2 hours, meaning that one needs to treat just 3.5 people with sumatriptan in order to have one person achieve pain relief at 2 hours attributable to the drug,” she said (Cochrane Database Syst Rev. 2014;5:CD009108. doi: 10.1002/14651858.CD009108.pub2).
“The bottom line is that in the ACHIEVE II study, ubrogepant appears, on average, to be modestly better than placebo to treat migraine. It does not appear to be in the same league as sumatriptan. Instead, as Dr. Tfelt-Hansen and I said in our article, the results look comparable to those likely to be achieved with inexpensive nonprescription medications such as NSAIDs.”
Dr. Loder called for a trial comparing ubrogepant and other therapies. “I challenge the authors and the company to conduct a large, placebo-controlled trial comparing ubrogepant to 100 mg of oral sumatriptan and to 650 mg of aspirin,” Dr. Loder said.
Dr. Loder has no financial connections with any pharmaceutical or device companies and is paid for her work as the head of research for the British Medical Journal.
SOURCE: Lipton RB et al. JAMA. 2019;322(19):1887-98. doi: 10.1001/jama.2019.16711.
Ubrogepant, an oral calcitonin gene–related peptide (CGRP)–receptor antagonist, may relieve patients’ migraine pain and their most bothersome associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours after acute treatment, according to phase 3 trial results published Nov. 19 in JAMA.
“Among adults with migraine, acute treatment with ubrogepant, compared with placebo, led to significantly greater rates of pain freedom at 2 hours with the 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose,” wrote first author Richard B. Lipton, MD, director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, and his colleagues. “Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.”
A researcher who commented on the results said that the drug appears “modestly better than placebo” and called for a trial comparing ubrogepant, aspirin, and oral sumatriptan.
The Food and Drug Administration is reviewing an application for ubrogepant. Allergan, the company developing the drug, has said it expects a regulatory decision in December.
ACHIEVE II
To evaluate the efficacy and tolerability of ubrogepant versus placebo for the acute treatment of a migraine attack, investigators conducted ACHIEVE II, a randomized, double-blind, placebo-controlled, single-attack clinical trial. The study was conducted at 99 primary care and research clinics during 2016-2018.
The trial included adults with migraine with or without aura who experienced two to eight migraine attacks per month. Participants had a mean age of 41.5 years, and 90% were female. The safety analysis included data from 1,465 participants, and the efficacy analysis included data from 1,355 participants. The primary efficacy outcomes were pain freedom and the absence of participants’ most bothersome migraine-associated symptom at 2 hours after taking the medication. Patients received ubrogepant 50 mg, ubrogepant 25 mg, or placebo to treat a migraine attack of moderate or severe pain intensity.
At 2 hours, pain freedom was reported by 101 of 464 participants in the ubrogepant 50-mg group (21.8%), 90 of 435 in the ubrogepant 25-mg group (20.7%), and 65 of 456 in the placebo group (14.3%). Absence of the most bothersome symptom was reported by 180 of 463 participants in the ubrogepant 50-mg group (38.9%), 148 of 434 in the ubrogepant 25-mg group (34.1%), and 125 of 456 in the placebo group (27.4%).
The most common adverse events within 48 hours were nausea and dizziness. Nausea occurred in 2.0% of the 50-mg group, 2.5% of the 25-mg group, and 2.0% of the placebo group. Dizziness occurred in 1.4% of the 50-mg group, 2.1% of the 25-mg group, and 1.6% of the placebo group.
At conferences, researchers have presented results from the phase 3 ACHIEVE I trial as well as an analysis that suggests ubrogepant may be effective in patients for whom triptans have been ineffective. In addition, studies have supported the safety of “gepants” after earlier concerns about potential liver toxicity. Physicians have called the safety data reassuring.
The ACHIEVE II trial was sponsored by Allergan. Several authors are Allergan employees. Dr. Lipton is a consultant, advisory board member, or has received honoraria from Allergan and other companies.
Number needed to treat
“The study was large, appears to have been well conducted, is clearly reported, and used appropriate outcome measures,” said Elizabeth Loder, MD, commenting on the trial.
A year ago, Dr. Loder, chief of the division of headache at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School in Boston, coauthored a paper with Peer Tfelt-Hansen, MD, DMSc, of the University of Copenhagen, that said the phase 3 trials of gepants so far have found the drugs to have small effect sizes and low efficacy (Headache. 2019 Jan;59[1]:113-7. doi: 10.1111/head.13444).
Their publication included preliminary figures from ACHIEVE II, which are consistent with those published in JAMA. “The effect size for both doses of ubrogepant is small and of debatable clinical significance,” Dr. Loder said. “The therapeutic gain over placebo is 7.5% for the 50-mg dose and 6.4% for the 25-mg dose for the outcome of pain freedom at 2 hours. That corresponds to a number needed to treat of 13 and 15.6 people, respectively, in order to have one person achieve pain freedom at 2 hours that is attributable to the active treatment.”
For a secondary outcome of pain relief at 2 hours, defined as reduction of headache pain severity from moderate or severe to mild or none, the therapeutic gain versus placebo is 14.5% for the 50-mg dose and 12.3% for the 25-mg dose. “That corresponds to a number needed to treat of 6.8 and 8.1 people, respectively, to have one person achieve pain relief at 2 hours attributable to the drug,” Dr. Loder said.
“Although there are no head to head studies comparing ubrogepant to triptans, for reference the [number needed to treat] for a 100-mg oral dose of sumatriptan is on the order of 3.5 for pain relief at 2 hours, meaning that one needs to treat just 3.5 people with sumatriptan in order to have one person achieve pain relief at 2 hours attributable to the drug,” she said (Cochrane Database Syst Rev. 2014;5:CD009108. doi: 10.1002/14651858.CD009108.pub2).
“The bottom line is that in the ACHIEVE II study, ubrogepant appears, on average, to be modestly better than placebo to treat migraine. It does not appear to be in the same league as sumatriptan. Instead, as Dr. Tfelt-Hansen and I said in our article, the results look comparable to those likely to be achieved with inexpensive nonprescription medications such as NSAIDs.”
Dr. Loder called for a trial comparing ubrogepant and other therapies. “I challenge the authors and the company to conduct a large, placebo-controlled trial comparing ubrogepant to 100 mg of oral sumatriptan and to 650 mg of aspirin,” Dr. Loder said.
Dr. Loder has no financial connections with any pharmaceutical or device companies and is paid for her work as the head of research for the British Medical Journal.
SOURCE: Lipton RB et al. JAMA. 2019;322(19):1887-98. doi: 10.1001/jama.2019.16711.
FROM JAMA
Insomnia symptoms increase likelihood of stroke and heart disease
, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.
“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.
To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.
For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.
The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.
More than 16% had any insomnia symptom
Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.
After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.
In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”
Opportunity for intervention
Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”
The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.
The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.
This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.
“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.
To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.
For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.
The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.
More than 16% had any insomnia symptom
Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.
After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.
In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”
Opportunity for intervention
Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”
The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.
The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.
This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.
“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.
To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.
For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.
The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.
More than 16% had any insomnia symptom
Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.
After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.
In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”
Opportunity for intervention
Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”
The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.
The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.
This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
FROM NEUROLOGY
Key clinical point: The presence of insomnia symptoms increases the likelihood of cardiovascular or cerebrovascular disease during approximately 10 years of follow-up.
Major finding: After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13.
Study details: An analysis of data from 487,200 adults in China aged 30-79 years who completed a baseline survey during 2004-2008 and were followed through 2016.
Disclosures: This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
Source: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
Serum urate level governs management of difficult-to-treat gout
LAS VEGAS – Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.
“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”
The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.
Addressing intolerance and undertreatment
Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.
“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”
Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.
Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.
Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.
If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.
Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.
Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.
The FAST trial
The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).
“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.
Allopurinol hypersensitivity and chronic kidney disease
Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.
One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.
Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.
Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.
“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”
The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.
Addressing intolerance and undertreatment
Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.
“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”
Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.
Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.
Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.
If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.
Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.
Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.
The FAST trial
The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).
“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.
Allopurinol hypersensitivity and chronic kidney disease
Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.
One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.
Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.
Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.
“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”
The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.
Addressing intolerance and undertreatment
Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.
“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”
Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.
Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.
Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.
If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.
Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.
Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.
The FAST trial
The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).
“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.
Allopurinol hypersensitivity and chronic kidney disease
Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.
One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.
Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.
Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019