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Risk stratification of syncope patients can help determine duration of telemetry monitoring
Background: About half of ED patients with syncope of unknown etiology are admitted for telemetry monitoring. No consensus exists regarding the optimal duration of telemetry monitoring in these patients to detect underlying arrhythmia.
Study design: Prospective cohort study.
Setting: Six EDs in Canada during September 2010–March 2015.
Synopsis: Using the Canadian Syncope Risk Score, 5,581 adults who presented to the ED within 24 hours of a syncopal event were risk stratified as low, medium, or high risk for serious adverse events (arrhythmic vs. nonarrhythmic) and then followed for 30 days. Approximately half of arrhythmias were identified among low-risk patients within 2 hours of telemetry monitoring and within 6 hours of monitoring among medium- and high-risk patients. In the low-risk group, none experienced death or ventricular arrhythmia within 30 days. In the medium- and high-risk group, 91.7% of underlying arrhythmias were identified within 15 days. The study was limited by the lack of standardized approach in the use of outpatient cardiac rhythm monitoring, which may have resulted in arrhythmia underdetection.
Bottom line: Among ED patients with syncope of unknown etiology, approximately 47% of arrhythmias were detected after 2-6 hours of telemetry monitoring. Among medium- and high-risk patients, the majority of serious arrhythmias were identified within 15 days. Based on these results, the authors recommend the use of 15-day outpatient cardiac monitoring for medium- and high-risk patients.
Citation: Thiruganasambandamoorthy V et al. Duration of electrocardiographic monitoring of emergency department patients with syncope. Circulation. 2019 Mar 12;139(11):1396-406.
Dr. Roy is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.
Background: About half of ED patients with syncope of unknown etiology are admitted for telemetry monitoring. No consensus exists regarding the optimal duration of telemetry monitoring in these patients to detect underlying arrhythmia.
Study design: Prospective cohort study.
Setting: Six EDs in Canada during September 2010–March 2015.
Synopsis: Using the Canadian Syncope Risk Score, 5,581 adults who presented to the ED within 24 hours of a syncopal event were risk stratified as low, medium, or high risk for serious adverse events (arrhythmic vs. nonarrhythmic) and then followed for 30 days. Approximately half of arrhythmias were identified among low-risk patients within 2 hours of telemetry monitoring and within 6 hours of monitoring among medium- and high-risk patients. In the low-risk group, none experienced death or ventricular arrhythmia within 30 days. In the medium- and high-risk group, 91.7% of underlying arrhythmias were identified within 15 days. The study was limited by the lack of standardized approach in the use of outpatient cardiac rhythm monitoring, which may have resulted in arrhythmia underdetection.
Bottom line: Among ED patients with syncope of unknown etiology, approximately 47% of arrhythmias were detected after 2-6 hours of telemetry monitoring. Among medium- and high-risk patients, the majority of serious arrhythmias were identified within 15 days. Based on these results, the authors recommend the use of 15-day outpatient cardiac monitoring for medium- and high-risk patients.
Citation: Thiruganasambandamoorthy V et al. Duration of electrocardiographic monitoring of emergency department patients with syncope. Circulation. 2019 Mar 12;139(11):1396-406.
Dr. Roy is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.
Background: About half of ED patients with syncope of unknown etiology are admitted for telemetry monitoring. No consensus exists regarding the optimal duration of telemetry monitoring in these patients to detect underlying arrhythmia.
Study design: Prospective cohort study.
Setting: Six EDs in Canada during September 2010–March 2015.
Synopsis: Using the Canadian Syncope Risk Score, 5,581 adults who presented to the ED within 24 hours of a syncopal event were risk stratified as low, medium, or high risk for serious adverse events (arrhythmic vs. nonarrhythmic) and then followed for 30 days. Approximately half of arrhythmias were identified among low-risk patients within 2 hours of telemetry monitoring and within 6 hours of monitoring among medium- and high-risk patients. In the low-risk group, none experienced death or ventricular arrhythmia within 30 days. In the medium- and high-risk group, 91.7% of underlying arrhythmias were identified within 15 days. The study was limited by the lack of standardized approach in the use of outpatient cardiac rhythm monitoring, which may have resulted in arrhythmia underdetection.
Bottom line: Among ED patients with syncope of unknown etiology, approximately 47% of arrhythmias were detected after 2-6 hours of telemetry monitoring. Among medium- and high-risk patients, the majority of serious arrhythmias were identified within 15 days. Based on these results, the authors recommend the use of 15-day outpatient cardiac monitoring for medium- and high-risk patients.
Citation: Thiruganasambandamoorthy V et al. Duration of electrocardiographic monitoring of emergency department patients with syncope. Circulation. 2019 Mar 12;139(11):1396-406.
Dr. Roy is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.
Direct-acting antiviral treatment linked to lower mortality in patients with HCC history
BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.
The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.
Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.
“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.
While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.
Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.
In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.
Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.
The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.
While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.
Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.
BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.
The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.
Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.
“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.
While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.
Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.
In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.
Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.
The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.
While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.
Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.
BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.
The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.
Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.
“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.
While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.
Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.
In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.
Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.
The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.
While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.
Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.
REPORTING FROM THE LIVER MEETING 2019
Kratom: Botanical with opiate-like effects increasingly blamed for liver injury
BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.
Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.
“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.
Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.
Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.
The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.
Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.
Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.
“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.
The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.
SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.
BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.
Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.
“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.
Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.
Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.
The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.
Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.
Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.
“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.
The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.
SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.
BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.
Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.
“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.
Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.
Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.
The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.
Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.
Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.
“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.
The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.
SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.
REPORTING FROM THE LIVER MEETING 2019
Fentanyl-related deaths show strong regional pattern
Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.
Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.
Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.
A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.
The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.
The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.
Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.
Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.
Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.
A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.
The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.
The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.
Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.
Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.
Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.
A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.
The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.
The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.
MS-related disability may be decreasing
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
EXPERT ANALYSIS FROM ECTRIMS 2019
Integrating lay navigation programs into cancer care is a challenge
The implementation of a lay navigation program as part of the delivery of cancer care presents a number of challenges, particularly because of the complexities of treating cancer, a new study has found.
Researchers looked at a lay navigator program, which uses nonclinical members to help provide information to cancer patients about their treatments, at the University of Alabama, and how the program was doing a year after its implementation.
“Integrating lay navigators into a complex clinical environment needs careful consideration at an organizational level, because this experience demonstrates that the integration process is not straightforward for clinical teams, patients, or navigators,” wrote Laura M. Holdsworth, PhD, Stanford (Calif.) University, and colleague. Their report is in the Journal of Oncology Practice.
A key difficulty discovered through the course of the research is that approximately two-thirds of concerns brought by patients to the lay navigators were clinical in nature, though only about a third (30%) required clinical follow-up and an additional 7% required social work follow-up.
“This seeming misalignment of nonclinical staff handling clinical issues is likely explained by the fact that clinical issues were often a request to repeat information previously delivered by a clinician,” the authors wrote. “The high proportion of clinical concerns brought to navigators is likely a consequence of navigators proactively contacting patients and thus being perceived as an accessible extension of the clinical team with whom to raise concern.”
Researchers found that clinical members did find navigators useful to the care team “specifically because they brought clinical issues to the attention of the clinical team that might otherwise have been missed.”
But on the other hand, some clinicians believed that “clinical concerns being raised with navigators were a source of concern and felt to be inappropriate, suggesting a lack of compatibility of a lay service layered onto complex clinical care,” Dr. Holdsworth and colleagues stated, adding that nurses “with a negative view of lay navigation seemed to lack knowledge and information about the navigator role, which created trust issues.”
Another potential issue is staff turnover within the navigator program and an ever-changing environment of patient education and support programs. Navigators can be very beneficial connecting patients to things such as support groups or helping to connect patients to insurers, but it requires a significant effort on the part of navigators to know, understand, and keep up to date with all the nonclinical opportunities that patients have, and high turnover can be an issue here.
Overall, though, the researchers note that the key finding “was that it was difficult to implement a lay navigation program outside of the clinical team for the purposes of cancer care coordination. The navigators were not integrated into the clinical teams and as such, the navigator role was treated with some suspicion by clinical team members; there was a sense of mistrust among some clinicians, and mismatched expectations around what navigators could or should be doing.”
SOURCE: Holdsworth L et al. J Oncol Pract, 2019 Nov. 6. doi: 10.1200/JOP.19.00339.
The implementation of a lay navigation program as part of the delivery of cancer care presents a number of challenges, particularly because of the complexities of treating cancer, a new study has found.
Researchers looked at a lay navigator program, which uses nonclinical members to help provide information to cancer patients about their treatments, at the University of Alabama, and how the program was doing a year after its implementation.
“Integrating lay navigators into a complex clinical environment needs careful consideration at an organizational level, because this experience demonstrates that the integration process is not straightforward for clinical teams, patients, or navigators,” wrote Laura M. Holdsworth, PhD, Stanford (Calif.) University, and colleague. Their report is in the Journal of Oncology Practice.
A key difficulty discovered through the course of the research is that approximately two-thirds of concerns brought by patients to the lay navigators were clinical in nature, though only about a third (30%) required clinical follow-up and an additional 7% required social work follow-up.
“This seeming misalignment of nonclinical staff handling clinical issues is likely explained by the fact that clinical issues were often a request to repeat information previously delivered by a clinician,” the authors wrote. “The high proportion of clinical concerns brought to navigators is likely a consequence of navigators proactively contacting patients and thus being perceived as an accessible extension of the clinical team with whom to raise concern.”
Researchers found that clinical members did find navigators useful to the care team “specifically because they brought clinical issues to the attention of the clinical team that might otherwise have been missed.”
But on the other hand, some clinicians believed that “clinical concerns being raised with navigators were a source of concern and felt to be inappropriate, suggesting a lack of compatibility of a lay service layered onto complex clinical care,” Dr. Holdsworth and colleagues stated, adding that nurses “with a negative view of lay navigation seemed to lack knowledge and information about the navigator role, which created trust issues.”
Another potential issue is staff turnover within the navigator program and an ever-changing environment of patient education and support programs. Navigators can be very beneficial connecting patients to things such as support groups or helping to connect patients to insurers, but it requires a significant effort on the part of navigators to know, understand, and keep up to date with all the nonclinical opportunities that patients have, and high turnover can be an issue here.
Overall, though, the researchers note that the key finding “was that it was difficult to implement a lay navigation program outside of the clinical team for the purposes of cancer care coordination. The navigators were not integrated into the clinical teams and as such, the navigator role was treated with some suspicion by clinical team members; there was a sense of mistrust among some clinicians, and mismatched expectations around what navigators could or should be doing.”
SOURCE: Holdsworth L et al. J Oncol Pract, 2019 Nov. 6. doi: 10.1200/JOP.19.00339.
The implementation of a lay navigation program as part of the delivery of cancer care presents a number of challenges, particularly because of the complexities of treating cancer, a new study has found.
Researchers looked at a lay navigator program, which uses nonclinical members to help provide information to cancer patients about their treatments, at the University of Alabama, and how the program was doing a year after its implementation.
“Integrating lay navigators into a complex clinical environment needs careful consideration at an organizational level, because this experience demonstrates that the integration process is not straightforward for clinical teams, patients, or navigators,” wrote Laura M. Holdsworth, PhD, Stanford (Calif.) University, and colleague. Their report is in the Journal of Oncology Practice.
A key difficulty discovered through the course of the research is that approximately two-thirds of concerns brought by patients to the lay navigators were clinical in nature, though only about a third (30%) required clinical follow-up and an additional 7% required social work follow-up.
“This seeming misalignment of nonclinical staff handling clinical issues is likely explained by the fact that clinical issues were often a request to repeat information previously delivered by a clinician,” the authors wrote. “The high proportion of clinical concerns brought to navigators is likely a consequence of navigators proactively contacting patients and thus being perceived as an accessible extension of the clinical team with whom to raise concern.”
Researchers found that clinical members did find navigators useful to the care team “specifically because they brought clinical issues to the attention of the clinical team that might otherwise have been missed.”
But on the other hand, some clinicians believed that “clinical concerns being raised with navigators were a source of concern and felt to be inappropriate, suggesting a lack of compatibility of a lay service layered onto complex clinical care,” Dr. Holdsworth and colleagues stated, adding that nurses “with a negative view of lay navigation seemed to lack knowledge and information about the navigator role, which created trust issues.”
Another potential issue is staff turnover within the navigator program and an ever-changing environment of patient education and support programs. Navigators can be very beneficial connecting patients to things such as support groups or helping to connect patients to insurers, but it requires a significant effort on the part of navigators to know, understand, and keep up to date with all the nonclinical opportunities that patients have, and high turnover can be an issue here.
Overall, though, the researchers note that the key finding “was that it was difficult to implement a lay navigation program outside of the clinical team for the purposes of cancer care coordination. The navigators were not integrated into the clinical teams and as such, the navigator role was treated with some suspicion by clinical team members; there was a sense of mistrust among some clinicians, and mismatched expectations around what navigators could or should be doing.”
SOURCE: Holdsworth L et al. J Oncol Pract, 2019 Nov. 6. doi: 10.1200/JOP.19.00339.
FROM JOURNAL OF ONCOLOGY PRACTICE
Armored CAR T cells elicit responses in NHL patients
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
REPORTING FROM SITC 2019
Combo shows promise for checkpoint inhibitor-refractory urothelial carcinoma
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
REPORTING FROM SITC 2019
Short-course DAA therapy may prevent hepatitis transmission in transplant patients
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
REPORTING FROM THE LIVER MEETING 2019
Dextromethorphan/bupropion combo is remarkably fast-acting antidepressant
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
REPORTING FROM ECNP 2019