Neurology

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

[email protected]

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

[email protected]

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

[email protected]

DALLAS – A multicenter, prospective study is underway to determine if the central vein sign can be incorporated into existing multiple sclerosis diagnostic criteria.

At the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, Daniel Ontaneda, MD, said that up to 20% of individuals referred for a diagnosis of multiple sclerosis (MS) are incorrectly diagnosed with the disease, and about two-thirds of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with disease-modifying therapies. “MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for MS,” said Dr. Ontaneda, a neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “However, there are problems with its implementation. Approximately half of individuals referred to an MS clinic present with atypical symptoms [fatigue, cognitive disturbance, pain] and not typical syndromes [unilateral optic neuritis, brain stem syndromes, partial myelitis]. Increasing diagnostic sensitivity may have come at the price of decreased specificity. MRI criteria have a specificity of 32% for dissemination in space and 42% for dissemination in time.”

While misdiagnosis appears to be mainly caused by overinterpretation of abnormal MRI findings, the central vein sign (CVS) is an effective method to overcome such challenges. Recent studies have demonstrated that CVS may help to identify MS, as 85% of white matter lesions in MS have a central vein, compared with only 8% of small vessel ischemic disease, 34% of migraine, and 14% of other inflammatory or autoimmune diseases.

“We think there is a significant and unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS,” Dr. Ontaneda said. “We propose a prospective evaluation of the central vein sign, which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision making.”


With funding from the Race to Erase MS Foundation, he and his associates have designed CAVS-MS (Central Vein Sign in MS), a multicenter, prospective, observational trial being conducted at 10 sites. The first phase of the study is a cross-sectional pilot at the 10 sites. The primary objective is to establish the contrast-to-noise ratio of lesion to normal-appearing white matter and central vein to lesion across the 10 sites using 3-tesla FLAIR imaging in subjects with a clinical or radiologic suspicion of MS. The secondary objectives are to investigate the difference in contrast-to-noise ratio identified in the primary objective between pre- and postcontrast FLAIR imaging to identify whether gadolinium injection improves central vein detection, to determine the reproducibility of different methods for detection of positive CVS across sites, and to determine the sensitivity and specificity of the different methods for the diagnosis of MS, compared with the McDonald 2010 MS criteria.

The study population will consist of 100 individuals referred to an MS center based on clinical or radiologic suspicion of MS; 30 participants are currently enrolled. The 10 sites include the Cleveland Clinic; Johns Hopkins University, Baltimore; the University of California, San Francisco; the University of Texas, Houston; the University of Toronto; the University of Vermont, Burlington; the University of Southern California, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; Yale University, New Haven, Conn.; and the University of Pennsylvania, Philadelphia.

CAVS-MS includes development of a software platform for rating of central veins through an imaging software partner, QMENTA. “We are going to have the individual clinicians at each site rate the lesions, so we will have information from 10 different raters,” Dr. Ontaneda said. The study will be coordinated at the Cleveland Clinic, central image analysis will be conducted at the National Institutes of Health, and statistical analysis will be performed at the University of Pennsylvania.

The researchers also hope to perform a prospective study with three objectives. The first is to determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. The second objective “is to determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes,” Dr. Ontaneda said. “The third aim is to look at central vein volume as a predictor of clinical/MRI disease activity associated with disability in MS.”

He concluded his remarks by describing the CVS as “a tool that offers promise both for increasing specificity and perhaps enabling earlier diagnosis of MS. Studies will determine if the central vein sign can be incorporated into the diagnostic criteria. The NIH is working with MRI manufacturers to make sequences available for disseminated clinical use.”

Dr. Ontaneda reported that he has received grant support from the National Institutes of Health, the Race to Erase MS Foundation, the Patient-Centered Outcomes Research Institute, the National Multiple Sclerosis Society, Genentech, Genzyme, and Novartis. He has also received consulting fees from Biogen, Genentech, and Novartis.

[email protected]

DALLAS – A multicenter, prospective study is underway to determine if the central vein sign can be incorporated into existing multiple sclerosis diagnostic criteria.

At the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, Daniel Ontaneda, MD, said that up to 20% of individuals referred for a diagnosis of multiple sclerosis (MS) are incorrectly diagnosed with the disease, and about two-thirds of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with disease-modifying therapies. “MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for MS,” said Dr. Ontaneda, a neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “However, there are problems with its implementation. Approximately half of individuals referred to an MS clinic present with atypical symptoms [fatigue, cognitive disturbance, pain] and not typical syndromes [unilateral optic neuritis, brain stem syndromes, partial myelitis]. Increasing diagnostic sensitivity may have come at the price of decreased specificity. MRI criteria have a specificity of 32% for dissemination in space and 42% for dissemination in time.”

While misdiagnosis appears to be mainly caused by overinterpretation of abnormal MRI findings, the central vein sign (CVS) is an effective method to overcome such challenges. Recent studies have demonstrated that CVS may help to identify MS, as 85% of white matter lesions in MS have a central vein, compared with only 8% of small vessel ischemic disease, 34% of migraine, and 14% of other inflammatory or autoimmune diseases.

“We think there is a significant and unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS,” Dr. Ontaneda said. “We propose a prospective evaluation of the central vein sign, which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision making.”


With funding from the Race to Erase MS Foundation, he and his associates have designed CAVS-MS (Central Vein Sign in MS), a multicenter, prospective, observational trial being conducted at 10 sites. The first phase of the study is a cross-sectional pilot at the 10 sites. The primary objective is to establish the contrast-to-noise ratio of lesion to normal-appearing white matter and central vein to lesion across the 10 sites using 3-tesla FLAIR imaging in subjects with a clinical or radiologic suspicion of MS. The secondary objectives are to investigate the difference in contrast-to-noise ratio identified in the primary objective between pre- and postcontrast FLAIR imaging to identify whether gadolinium injection improves central vein detection, to determine the reproducibility of different methods for detection of positive CVS across sites, and to determine the sensitivity and specificity of the different methods for the diagnosis of MS, compared with the McDonald 2010 MS criteria.

The study population will consist of 100 individuals referred to an MS center based on clinical or radiologic suspicion of MS; 30 participants are currently enrolled. The 10 sites include the Cleveland Clinic; Johns Hopkins University, Baltimore; the University of California, San Francisco; the University of Texas, Houston; the University of Toronto; the University of Vermont, Burlington; the University of Southern California, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; Yale University, New Haven, Conn.; and the University of Pennsylvania, Philadelphia.

CAVS-MS includes development of a software platform for rating of central veins through an imaging software partner, QMENTA. “We are going to have the individual clinicians at each site rate the lesions, so we will have information from 10 different raters,” Dr. Ontaneda said. The study will be coordinated at the Cleveland Clinic, central image analysis will be conducted at the National Institutes of Health, and statistical analysis will be performed at the University of Pennsylvania.

The researchers also hope to perform a prospective study with three objectives. The first is to determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. The second objective “is to determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes,” Dr. Ontaneda said. “The third aim is to look at central vein volume as a predictor of clinical/MRI disease activity associated with disability in MS.”

He concluded his remarks by describing the CVS as “a tool that offers promise both for increasing specificity and perhaps enabling earlier diagnosis of MS. Studies will determine if the central vein sign can be incorporated into the diagnostic criteria. The NIH is working with MRI manufacturers to make sequences available for disseminated clinical use.”

Dr. Ontaneda reported that he has received grant support from the National Institutes of Health, the Race to Erase MS Foundation, the Patient-Centered Outcomes Research Institute, the National Multiple Sclerosis Society, Genentech, Genzyme, and Novartis. He has also received consulting fees from Biogen, Genentech, and Novartis.

[email protected]

DALLAS – A multicenter, prospective study is underway to determine if the central vein sign can be incorporated into existing multiple sclerosis diagnostic criteria.

At the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, Daniel Ontaneda, MD, said that up to 20% of individuals referred for a diagnosis of multiple sclerosis (MS) are incorrectly diagnosed with the disease, and about two-thirds of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with disease-modifying therapies. “MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for MS,” said Dr. Ontaneda, a neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “However, there are problems with its implementation. Approximately half of individuals referred to an MS clinic present with atypical symptoms [fatigue, cognitive disturbance, pain] and not typical syndromes [unilateral optic neuritis, brain stem syndromes, partial myelitis]. Increasing diagnostic sensitivity may have come at the price of decreased specificity. MRI criteria have a specificity of 32% for dissemination in space and 42% for dissemination in time.”

While misdiagnosis appears to be mainly caused by overinterpretation of abnormal MRI findings, the central vein sign (CVS) is an effective method to overcome such challenges. Recent studies have demonstrated that CVS may help to identify MS, as 85% of white matter lesions in MS have a central vein, compared with only 8% of small vessel ischemic disease, 34% of migraine, and 14% of other inflammatory or autoimmune diseases.

“We think there is a significant and unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS,” Dr. Ontaneda said. “We propose a prospective evaluation of the central vein sign, which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision making.”


With funding from the Race to Erase MS Foundation, he and his associates have designed CAVS-MS (Central Vein Sign in MS), a multicenter, prospective, observational trial being conducted at 10 sites. The first phase of the study is a cross-sectional pilot at the 10 sites. The primary objective is to establish the contrast-to-noise ratio of lesion to normal-appearing white matter and central vein to lesion across the 10 sites using 3-tesla FLAIR imaging in subjects with a clinical or radiologic suspicion of MS. The secondary objectives are to investigate the difference in contrast-to-noise ratio identified in the primary objective between pre- and postcontrast FLAIR imaging to identify whether gadolinium injection improves central vein detection, to determine the reproducibility of different methods for detection of positive CVS across sites, and to determine the sensitivity and specificity of the different methods for the diagnosis of MS, compared with the McDonald 2010 MS criteria.

The study population will consist of 100 individuals referred to an MS center based on clinical or radiologic suspicion of MS; 30 participants are currently enrolled. The 10 sites include the Cleveland Clinic; Johns Hopkins University, Baltimore; the University of California, San Francisco; the University of Texas, Houston; the University of Toronto; the University of Vermont, Burlington; the University of Southern California, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; Yale University, New Haven, Conn.; and the University of Pennsylvania, Philadelphia.

CAVS-MS includes development of a software platform for rating of central veins through an imaging software partner, QMENTA. “We are going to have the individual clinicians at each site rate the lesions, so we will have information from 10 different raters,” Dr. Ontaneda said. The study will be coordinated at the Cleveland Clinic, central image analysis will be conducted at the National Institutes of Health, and statistical analysis will be performed at the University of Pennsylvania.

The researchers also hope to perform a prospective study with three objectives. The first is to determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. The second objective “is to determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes,” Dr. Ontaneda said. “The third aim is to look at central vein volume as a predictor of clinical/MRI disease activity associated with disability in MS.”

He concluded his remarks by describing the CVS as “a tool that offers promise both for increasing specificity and perhaps enabling earlier diagnosis of MS. Studies will determine if the central vein sign can be incorporated into the diagnostic criteria. The NIH is working with MRI manufacturers to make sequences available for disseminated clinical use.”

Dr. Ontaneda reported that he has received grant support from the National Institutes of Health, the Race to Erase MS Foundation, the Patient-Centered Outcomes Research Institute, the National Multiple Sclerosis Society, Genentech, Genzyme, and Novartis. He has also received consulting fees from Biogen, Genentech, and Novartis.

[email protected]

Most people who could benefit from FDA-approved medications for opioid use disorder do not receive them, and access to those treatments is not equitable, according to a new consensus study report from the National Academies of Sciences, Engineering, and Medicine.

“Methadone, buprenorphine, and extended-release naltrexone are safe and highly effective medications that are already approved by the U.S. Food and Drug Administration to treat OUD,” the report said. “These medications save lives, but the majority of people with OUD in the United States receive no treatment at all.”

The report, called “Medications for Opioid Use Disorder Save Lives,” said a critical factor in addressing the crisis is “confronting the major barriers” to using those medications. It also said additional research will be needed to address opioid use disorder among subpopulations in the United States, such as adolescents, older adults, people with comorbidities, racial and ethnic groups, and people with low socioeconomic status. The National Academies’ report was sponsored by NIDA and SAMHSA.

A few weeks before the release of National Academies report, the National Academy of Medicine (NAM) held a webinar providing details on its Action Collaborative on Countering the U.S. Opioid Epidemic. The collaborative, a partnership of public and private stakeholders, aims to address the opioid crisis through a multidisciplinary, cross-sector effort.

The collaborative is represented by federal agencies, state and local governments, health care systems, provider groups, nonprofits, payers, industry, academia, patient organizations, and communities across about 55 organizations, according to Victor J. Dzau, MD, chair of the Action Collaborative and current NAM president. Over a 2-year period, the collaborative’s goal is to accelerate progress in overcoming the opioid crisis by recognizing the challenges, research gaps, and needs of organizations involved in the crisis and “elevate and accelerate evidence-based, multisectoral, and interprofessional solutions,” he said.

“This is not a problem that can be solved by a single sector. It is truly a whole of society problem,” said Adm. Brett P. Giroir, MD, assistant secretary for health at the U.S. Department of Health and Human Services, said during the webinar. “And the only way that we are going to be able to begin making inroads to reverse the trends of this crisis is if we work together.” Dr. Giroir also serves as cochair of the steering committee for the collaborative.

In its overview of the collaborative, the NAM outlined four working groups developed through a series of surveys and planning meetings that would identify the resources that currently exist to combat the opioid epidemic and determine which resources still need to be developed. In the Health Professional Education and Training Working Group, for example, the objective is to examine what is being taught to health professionals about acute and chronic pain management at an accreditation, certification, and regulatory level to develop educational tools based around knowledge gaps in those areas and analyze how the new resources are affecting health professions after they have been adopted, said Steve Singer, PhD, vice president of education and outreach at the Accreditation Council for Graduate Medical Education and colead of the working group.“Our goal is really to provide guidance and resources across the continuum of health professions and education with an interprofessional – and patient-informed view,” he said.

The Opioid Prescribing Guidelines and Evidence Standards Working Group plans to address the disparities in prescribing and tapering guidelines for acute and chronic pain as well as identify where pain management guidelines in different specialties “cannot be justified,” based on available evidence.

“Further, we think it’s really important to not just have guidelines that will sit on a shelf, but we also want to think about how we can support implementation of these guidelines into practice ... ” said Helen Burstin, MD, MPH, executive vice president and CEO for the Council of Medical Specialty Societies and colead of the working group.

Alonzo L. Plough, PhD, MPH, vice president of research-evaluation-learning at the Robert Wood Johnson Foundation and colead of the Prevention, Treatment, and Recovery Services Working Group, explained that the goal of his group is to identify the “essential elements and components” and best practices of prevention, treatment, and recovery for OUD. He noted that, although the working group will not be able to reach all patient populations affected by OUD, it has discussed targeting vulnerable high-risk populations, such as those involved in the criminal justice system, homeless veterans, mothers, and children.

“This is an ecosystem that requires great concentration and effort to make sure that there are integrated approaches throughout the continuum that work for patients and clients from different walks of life, and I think that our overall guidance is how we can recognize and use evidence to find those approaches and build on them for guidance,” he said.

The Research, Data, and Metrics Needs Working Group is tasked with collaborating with the other groups to obtain currently available information and identify what barriers exist to greater transparency, sharing and interoperability of data as well as what gaps in research currently exist that would further the collaborative’s mission, said Kelly J. Clark, MD, MBA, of the ASAM. “It is simply critical for us to utilize the data that’s out there, to pool it into more actionable information – and then to act on it,” Dr. Clark said.

The NAM is seeking new organizations interested in joining the collaborative as a network organization, which would receive updates and provide input on the collaborative but would not be a part of the working groups.

The first public meeting of the Action Collaborative on Countering the U.S. Opioid Epidemic will take place on April 30, 2019, in Washington.

Most people who could benefit from FDA-approved medications for opioid use disorder do not receive them, and access to those treatments is not equitable, according to a new consensus study report from the National Academies of Sciences, Engineering, and Medicine.

“Methadone, buprenorphine, and extended-release naltrexone are safe and highly effective medications that are already approved by the U.S. Food and Drug Administration to treat OUD,” the report said. “These medications save lives, but the majority of people with OUD in the United States receive no treatment at all.”

The report, called “Medications for Opioid Use Disorder Save Lives,” said a critical factor in addressing the crisis is “confronting the major barriers” to using those medications. It also said additional research will be needed to address opioid use disorder among subpopulations in the United States, such as adolescents, older adults, people with comorbidities, racial and ethnic groups, and people with low socioeconomic status. The National Academies’ report was sponsored by NIDA and SAMHSA.

A few weeks before the release of National Academies report, the National Academy of Medicine (NAM) held a webinar providing details on its Action Collaborative on Countering the U.S. Opioid Epidemic. The collaborative, a partnership of public and private stakeholders, aims to address the opioid crisis through a multidisciplinary, cross-sector effort.

The collaborative is represented by federal agencies, state and local governments, health care systems, provider groups, nonprofits, payers, industry, academia, patient organizations, and communities across about 55 organizations, according to Victor J. Dzau, MD, chair of the Action Collaborative and current NAM president. Over a 2-year period, the collaborative’s goal is to accelerate progress in overcoming the opioid crisis by recognizing the challenges, research gaps, and needs of organizations involved in the crisis and “elevate and accelerate evidence-based, multisectoral, and interprofessional solutions,” he said.

“This is not a problem that can be solved by a single sector. It is truly a whole of society problem,” said Adm. Brett P. Giroir, MD, assistant secretary for health at the U.S. Department of Health and Human Services, said during the webinar. “And the only way that we are going to be able to begin making inroads to reverse the trends of this crisis is if we work together.” Dr. Giroir also serves as cochair of the steering committee for the collaborative.

In its overview of the collaborative, the NAM outlined four working groups developed through a series of surveys and planning meetings that would identify the resources that currently exist to combat the opioid epidemic and determine which resources still need to be developed. In the Health Professional Education and Training Working Group, for example, the objective is to examine what is being taught to health professionals about acute and chronic pain management at an accreditation, certification, and regulatory level to develop educational tools based around knowledge gaps in those areas and analyze how the new resources are affecting health professions after they have been adopted, said Steve Singer, PhD, vice president of education and outreach at the Accreditation Council for Graduate Medical Education and colead of the working group.“Our goal is really to provide guidance and resources across the continuum of health professions and education with an interprofessional – and patient-informed view,” he said.

The Opioid Prescribing Guidelines and Evidence Standards Working Group plans to address the disparities in prescribing and tapering guidelines for acute and chronic pain as well as identify where pain management guidelines in different specialties “cannot be justified,” based on available evidence.

“Further, we think it’s really important to not just have guidelines that will sit on a shelf, but we also want to think about how we can support implementation of these guidelines into practice ... ” said Helen Burstin, MD, MPH, executive vice president and CEO for the Council of Medical Specialty Societies and colead of the working group.

Alonzo L. Plough, PhD, MPH, vice president of research-evaluation-learning at the Robert Wood Johnson Foundation and colead of the Prevention, Treatment, and Recovery Services Working Group, explained that the goal of his group is to identify the “essential elements and components” and best practices of prevention, treatment, and recovery for OUD. He noted that, although the working group will not be able to reach all patient populations affected by OUD, it has discussed targeting vulnerable high-risk populations, such as those involved in the criminal justice system, homeless veterans, mothers, and children.

“This is an ecosystem that requires great concentration and effort to make sure that there are integrated approaches throughout the continuum that work for patients and clients from different walks of life, and I think that our overall guidance is how we can recognize and use evidence to find those approaches and build on them for guidance,” he said.

The Research, Data, and Metrics Needs Working Group is tasked with collaborating with the other groups to obtain currently available information and identify what barriers exist to greater transparency, sharing and interoperability of data as well as what gaps in research currently exist that would further the collaborative’s mission, said Kelly J. Clark, MD, MBA, of the ASAM. “It is simply critical for us to utilize the data that’s out there, to pool it into more actionable information – and then to act on it,” Dr. Clark said.

The NAM is seeking new organizations interested in joining the collaborative as a network organization, which would receive updates and provide input on the collaborative but would not be a part of the working groups.

The first public meeting of the Action Collaborative on Countering the U.S. Opioid Epidemic will take place on April 30, 2019, in Washington.

Most people who could benefit from FDA-approved medications for opioid use disorder do not receive them, and access to those treatments is not equitable, according to a new consensus study report from the National Academies of Sciences, Engineering, and Medicine.

“Methadone, buprenorphine, and extended-release naltrexone are safe and highly effective medications that are already approved by the U.S. Food and Drug Administration to treat OUD,” the report said. “These medications save lives, but the majority of people with OUD in the United States receive no treatment at all.”

The report, called “Medications for Opioid Use Disorder Save Lives,” said a critical factor in addressing the crisis is “confronting the major barriers” to using those medications. It also said additional research will be needed to address opioid use disorder among subpopulations in the United States, such as adolescents, older adults, people with comorbidities, racial and ethnic groups, and people with low socioeconomic status. The National Academies’ report was sponsored by NIDA and SAMHSA.

A few weeks before the release of National Academies report, the National Academy of Medicine (NAM) held a webinar providing details on its Action Collaborative on Countering the U.S. Opioid Epidemic. The collaborative, a partnership of public and private stakeholders, aims to address the opioid crisis through a multidisciplinary, cross-sector effort.

The collaborative is represented by federal agencies, state and local governments, health care systems, provider groups, nonprofits, payers, industry, academia, patient organizations, and communities across about 55 organizations, according to Victor J. Dzau, MD, chair of the Action Collaborative and current NAM president. Over a 2-year period, the collaborative’s goal is to accelerate progress in overcoming the opioid crisis by recognizing the challenges, research gaps, and needs of organizations involved in the crisis and “elevate and accelerate evidence-based, multisectoral, and interprofessional solutions,” he said.

“This is not a problem that can be solved by a single sector. It is truly a whole of society problem,” said Adm. Brett P. Giroir, MD, assistant secretary for health at the U.S. Department of Health and Human Services, said during the webinar. “And the only way that we are going to be able to begin making inroads to reverse the trends of this crisis is if we work together.” Dr. Giroir also serves as cochair of the steering committee for the collaborative.

In its overview of the collaborative, the NAM outlined four working groups developed through a series of surveys and planning meetings that would identify the resources that currently exist to combat the opioid epidemic and determine which resources still need to be developed. In the Health Professional Education and Training Working Group, for example, the objective is to examine what is being taught to health professionals about acute and chronic pain management at an accreditation, certification, and regulatory level to develop educational tools based around knowledge gaps in those areas and analyze how the new resources are affecting health professions after they have been adopted, said Steve Singer, PhD, vice president of education and outreach at the Accreditation Council for Graduate Medical Education and colead of the working group.“Our goal is really to provide guidance and resources across the continuum of health professions and education with an interprofessional – and patient-informed view,” he said.

The Opioid Prescribing Guidelines and Evidence Standards Working Group plans to address the disparities in prescribing and tapering guidelines for acute and chronic pain as well as identify where pain management guidelines in different specialties “cannot be justified,” based on available evidence.

“Further, we think it’s really important to not just have guidelines that will sit on a shelf, but we also want to think about how we can support implementation of these guidelines into practice ... ” said Helen Burstin, MD, MPH, executive vice president and CEO for the Council of Medical Specialty Societies and colead of the working group.

Alonzo L. Plough, PhD, MPH, vice president of research-evaluation-learning at the Robert Wood Johnson Foundation and colead of the Prevention, Treatment, and Recovery Services Working Group, explained that the goal of his group is to identify the “essential elements and components” and best practices of prevention, treatment, and recovery for OUD. He noted that, although the working group will not be able to reach all patient populations affected by OUD, it has discussed targeting vulnerable high-risk populations, such as those involved in the criminal justice system, homeless veterans, mothers, and children.

“This is an ecosystem that requires great concentration and effort to make sure that there are integrated approaches throughout the continuum that work for patients and clients from different walks of life, and I think that our overall guidance is how we can recognize and use evidence to find those approaches and build on them for guidance,” he said.

The Research, Data, and Metrics Needs Working Group is tasked with collaborating with the other groups to obtain currently available information and identify what barriers exist to greater transparency, sharing and interoperability of data as well as what gaps in research currently exist that would further the collaborative’s mission, said Kelly J. Clark, MD, MBA, of the ASAM. “It is simply critical for us to utilize the data that’s out there, to pool it into more actionable information – and then to act on it,” Dr. Clark said.

The NAM is seeking new organizations interested in joining the collaborative as a network organization, which would receive updates and provide input on the collaborative but would not be a part of the working groups.

The first public meeting of the Action Collaborative on Countering the U.S. Opioid Epidemic will take place on April 30, 2019, in Washington.

LAS VEGAS – Communicate with your pharmacists to keep nurse phone calls and empty medication-dispensing devices at bay. Watch out for overlapping medication orders. Beware of gabapentin mishaps, and embrace Tylenol – but not always.

Randy Dotinga/MDedge News

April Smith, PharmD, associate professor of pharmacy practice at Creighton University, Omaha, offered these tips about postoperative care to surgeons at the 2019 Annual Minimally Invasive Surgery Symposium by Global Academy for Medical Education.

“We’re probably one of the most underutilized professions you have on your team,” she said, adding that “we have to know what you’re doing to help you.”

As she explained, “if you’re going to have a new order set, let us know that, so we can be your allies in helping nurses and other people understand why we’re doing what we’re doing. I’m on the same floor, and the nurses are coming up to me and asking me questions. If I can explain to them why we’re doing these things, they’ll get on board a lot faster and save you a lot of phone calls. I know you’re surgeons and you hate that [phone calls].”

Better communication with pharmacists can also boost the stocking of enhanced-recovery medications in automatic dispensing machines, she said, so they’re ready when patients need them.

Dr. Smith offered these tips about specific postsurgery medications:

• Scopolamine is a “great drug for post-op vomiting and nausea,” Dr. Smith said. But do not use it in patients over 65, and it’s contraindicated in glaucoma. Beware of these notable side effects: Blurry vision, constipation, and urinary retention. Dexamethasone and ondansetron can be used as an alternative, she said.
• Use of the blood thinner enoxaparin after discharge may become more common as surgical stays become shorter, Dr. Smith said. She urged surgeons to keep its cost in mind: a 10-day course can be as little as $2 with Medicaid or as much as $140 (a cash price for patients without coverage).
• Make sure to adjust medications based on preoperative or intraoperative doses, she said, to avoid endangering patients by inadvertently doubling up on doses. And watch out for previous use of gabapentin, which is part of enhanced-recovery protocols. Patients who take the drug at home should be put back on their typical dose.
• Also, she warned, “don’t give gabapentin to someone who’s never had it before plus an opioid.” This, she said, can cause delirium.
• Consider starting liquids the night of surgery so patients can begin taking their home medications such as sleep, chronic pain, and psychiatric drugs. Patients will be more stable and satisfied, Dr. Smith said.
• Don’t prescribe hard-to-find medications like oxycodone oral solution or oral ketorolac. These drugs will send patients from pharmacy to pharmacy in search of them, Dr. Smith said.
• Embrace a “Meds to Beds” program if possible. These programs enlist on-site pharmacies to deliver medications to bedside for patients to take home.
• Consider Tylenol as a postoperative painkiller with scheduled doses and be aware that you can prescribe the over-the-counter adult liquid form. However, Dr. Smith cautioned that Tylenol is “not great” on an as-needed basis. Gabapentin and celecoxib (unless contraindicated) are also helpful for postop pain relief, and they’re inexpensive, she said. Three to five days should be enough in most minimally invasive surgeries.
• Don’t overprescribe opioids. “The more we prescribe, the more they will consume,” Dr. Smith said. Check the American College of Surgeons guidelines regarding the ideal number of postsurgery, 5-mg doses of oxycodone to prescribe to opioid-naive patients at discharge. No more than 10 or 15 pills are recommended for several types of general surgery (J Amer Coll Surg. 2018;227:411-8).

Global Academy for Medical Education and this news organization are owned by the same parent company. Dr. Smith reports no relevant disclosures.

LAS VEGAS – Communicate with your pharmacists to keep nurse phone calls and empty medication-dispensing devices at bay. Watch out for overlapping medication orders. Beware of gabapentin mishaps, and embrace Tylenol – but not always.

Randy Dotinga/MDedge News

April Smith, PharmD, associate professor of pharmacy practice at Creighton University, Omaha, offered these tips about postoperative care to surgeons at the 2019 Annual Minimally Invasive Surgery Symposium by Global Academy for Medical Education.

“We’re probably one of the most underutilized professions you have on your team,” she said, adding that “we have to know what you’re doing to help you.”

As she explained, “if you’re going to have a new order set, let us know that, so we can be your allies in helping nurses and other people understand why we’re doing what we’re doing. I’m on the same floor, and the nurses are coming up to me and asking me questions. If I can explain to them why we’re doing these things, they’ll get on board a lot faster and save you a lot of phone calls. I know you’re surgeons and you hate that [phone calls].”

Better communication with pharmacists can also boost the stocking of enhanced-recovery medications in automatic dispensing machines, she said, so they’re ready when patients need them.

Dr. Smith offered these tips about specific postsurgery medications:

• Scopolamine is a “great drug for post-op vomiting and nausea,” Dr. Smith said. But do not use it in patients over 65, and it’s contraindicated in glaucoma. Beware of these notable side effects: Blurry vision, constipation, and urinary retention. Dexamethasone and ondansetron can be used as an alternative, she said.
• Use of the blood thinner enoxaparin after discharge may become more common as surgical stays become shorter, Dr. Smith said. She urged surgeons to keep its cost in mind: a 10-day course can be as little as $2 with Medicaid or as much as $140 (a cash price for patients without coverage).
• Make sure to adjust medications based on preoperative or intraoperative doses, she said, to avoid endangering patients by inadvertently doubling up on doses. And watch out for previous use of gabapentin, which is part of enhanced-recovery protocols. Patients who take the drug at home should be put back on their typical dose.
• Also, she warned, “don’t give gabapentin to someone who’s never had it before plus an opioid.” This, she said, can cause delirium.
• Consider starting liquids the night of surgery so patients can begin taking their home medications such as sleep, chronic pain, and psychiatric drugs. Patients will be more stable and satisfied, Dr. Smith said.
• Don’t prescribe hard-to-find medications like oxycodone oral solution or oral ketorolac. These drugs will send patients from pharmacy to pharmacy in search of them, Dr. Smith said.
• Embrace a “Meds to Beds” program if possible. These programs enlist on-site pharmacies to deliver medications to bedside for patients to take home.
• Consider Tylenol as a postoperative painkiller with scheduled doses and be aware that you can prescribe the over-the-counter adult liquid form. However, Dr. Smith cautioned that Tylenol is “not great” on an as-needed basis. Gabapentin and celecoxib (unless contraindicated) are also helpful for postop pain relief, and they’re inexpensive, she said. Three to five days should be enough in most minimally invasive surgeries.
• Don’t overprescribe opioids. “The more we prescribe, the more they will consume,” Dr. Smith said. Check the American College of Surgeons guidelines regarding the ideal number of postsurgery, 5-mg doses of oxycodone to prescribe to opioid-naive patients at discharge. No more than 10 or 15 pills are recommended for several types of general surgery (J Amer Coll Surg. 2018;227:411-8).

Global Academy for Medical Education and this news organization are owned by the same parent company. Dr. Smith reports no relevant disclosures.

LAS VEGAS – Communicate with your pharmacists to keep nurse phone calls and empty medication-dispensing devices at bay. Watch out for overlapping medication orders. Beware of gabapentin mishaps, and embrace Tylenol – but not always.

Randy Dotinga/MDedge News

April Smith, PharmD, associate professor of pharmacy practice at Creighton University, Omaha, offered these tips about postoperative care to surgeons at the 2019 Annual Minimally Invasive Surgery Symposium by Global Academy for Medical Education.

“We’re probably one of the most underutilized professions you have on your team,” she said, adding that “we have to know what you’re doing to help you.”

As she explained, “if you’re going to have a new order set, let us know that, so we can be your allies in helping nurses and other people understand why we’re doing what we’re doing. I’m on the same floor, and the nurses are coming up to me and asking me questions. If I can explain to them why we’re doing these things, they’ll get on board a lot faster and save you a lot of phone calls. I know you’re surgeons and you hate that [phone calls].”

Better communication with pharmacists can also boost the stocking of enhanced-recovery medications in automatic dispensing machines, she said, so they’re ready when patients need them.

Dr. Smith offered these tips about specific postsurgery medications:

• Scopolamine is a “great drug for post-op vomiting and nausea,” Dr. Smith said. But do not use it in patients over 65, and it’s contraindicated in glaucoma. Beware of these notable side effects: Blurry vision, constipation, and urinary retention. Dexamethasone and ondansetron can be used as an alternative, she said.
• Use of the blood thinner enoxaparin after discharge may become more common as surgical stays become shorter, Dr. Smith said. She urged surgeons to keep its cost in mind: a 10-day course can be as little as $2 with Medicaid or as much as $140 (a cash price for patients without coverage).
• Make sure to adjust medications based on preoperative or intraoperative doses, she said, to avoid endangering patients by inadvertently doubling up on doses. And watch out for previous use of gabapentin, which is part of enhanced-recovery protocols. Patients who take the drug at home should be put back on their typical dose.
• Also, she warned, “don’t give gabapentin to someone who’s never had it before plus an opioid.” This, she said, can cause delirium.
• Consider starting liquids the night of surgery so patients can begin taking their home medications such as sleep, chronic pain, and psychiatric drugs. Patients will be more stable and satisfied, Dr. Smith said.
• Don’t prescribe hard-to-find medications like oxycodone oral solution or oral ketorolac. These drugs will send patients from pharmacy to pharmacy in search of them, Dr. Smith said.
• Embrace a “Meds to Beds” program if possible. These programs enlist on-site pharmacies to deliver medications to bedside for patients to take home.
• Consider Tylenol as a postoperative painkiller with scheduled doses and be aware that you can prescribe the over-the-counter adult liquid form. However, Dr. Smith cautioned that Tylenol is “not great” on an as-needed basis. Gabapentin and celecoxib (unless contraindicated) are also helpful for postop pain relief, and they’re inexpensive, she said. Three to five days should be enough in most minimally invasive surgeries.
• Don’t overprescribe opioids. “The more we prescribe, the more they will consume,” Dr. Smith said. Check the American College of Surgeons guidelines regarding the ideal number of postsurgery, 5-mg doses of oxycodone to prescribe to opioid-naive patients at discharge. No more than 10 or 15 pills are recommended for several types of general surgery (J Amer Coll Surg. 2018;227:411-8).

Global Academy for Medical Education and this news organization are owned by the same parent company. Dr. Smith reports no relevant disclosures.

Emergency medical services (EMS) system protocols vary in how they define and treat generalized convulsive status epilepticus, according to a review of EMS treatment protocols in California. “Many protocols did not follow evidence-based guidelines and did not accurately define generalized convulsive status epilepticus,” said John P. Betjemann, MD, associate professor of neurology at the University of California, San Francisco, and his colleagues. They reported their findings in the March 26 issue of JAMA.

Generalized convulsive status epilepticus is a neurologic emergency, and trials published in 2001 and 2012 found that benzodiazepines are effective prehospital treatments for patients with generalized convulsive status epilepticus. These trials informed a 2016 evidence-based guideline that cites level A evidence for intramuscular midazolam, IV lorazepam, and IV diazepam as initial treatment options for adults.

To determine whether EMS system protocols follow these recommendations, the investigators reviewed treatment protocols from 33 EMS systems that cover the 58 counties in California. The researchers reviewed EMS system protocols between May and June 2018 to determine when they were last updated and whether they defined generalized convulsive status epilepticus according to the guideline (namely, 5 or more minutes of continuous seizure or two or more discrete seizures between which a patient has incomplete recovery of consciousness). They also determined whether the protocols included any of the three benzodiazepines in the guideline and, if so, at what dose and using which route of administration.

Protocols’ most recent revision dates ranged between 2007 and 2018. Twenty-seven protocols (81.8%) were revised after the second clinical trial was published in 2012, and 17 (51.5%) were revised after the 2016 guideline. Seven EMS system protocols (21.2%) defined generalized convulsive status epilepticus according to the guideline. Thirty-two protocols (97.0%) included intramuscular midazolam, 2 (6.1%) included IV lorazepam, and 5 (15.2%) included IV diazepam.

Although the protocols “appropriately emphasized” intramuscular midazolam, the protocol doses often were lower than those used in the trials or recommended in the guideline. In addition, most protocols listed IV and intraosseous midazolam as options, although these treatments were not studied in the trials nor recommended in the guideline. In all, six of the protocols (18.2%) recommended at least one medication by the route and dose suggested in the trials or in the guideline.

“Why EMS system protocols deviate from the evidence and how this affects patient outcomes deserves further study,” the authors said.

The researchers noted that they examined EMS protocols in only one state and that “protocols may not necessarily reflect what emergency medical technicians actually do in practice.” In addition, the researchers accessed the most recent protocols by consulting EMS system websites rather than by contacting each EMS system for its most up-to-date protocol.

The authors reported personal compensation from JAMA Neurology and from Continuum Audio unrelated to the present study, as well as grants from the National Institutes of Health.

[email protected]

SOURCE: Betjemann JP et al. JAMA. 2019 Mar 26.

Emergency medical services (EMS) system protocols vary in how they define and treat generalized convulsive status epilepticus, according to a review of EMS treatment protocols in California. “Many protocols did not follow evidence-based guidelines and did not accurately define generalized convulsive status epilepticus,” said John P. Betjemann, MD, associate professor of neurology at the University of California, San Francisco, and his colleagues. They reported their findings in the March 26 issue of JAMA.

Generalized convulsive status epilepticus is a neurologic emergency, and trials published in 2001 and 2012 found that benzodiazepines are effective prehospital treatments for patients with generalized convulsive status epilepticus. These trials informed a 2016 evidence-based guideline that cites level A evidence for intramuscular midazolam, IV lorazepam, and IV diazepam as initial treatment options for adults.

To determine whether EMS system protocols follow these recommendations, the investigators reviewed treatment protocols from 33 EMS systems that cover the 58 counties in California. The researchers reviewed EMS system protocols between May and June 2018 to determine when they were last updated and whether they defined generalized convulsive status epilepticus according to the guideline (namely, 5 or more minutes of continuous seizure or two or more discrete seizures between which a patient has incomplete recovery of consciousness). They also determined whether the protocols included any of the three benzodiazepines in the guideline and, if so, at what dose and using which route of administration.

Protocols’ most recent revision dates ranged between 2007 and 2018. Twenty-seven protocols (81.8%) were revised after the second clinical trial was published in 2012, and 17 (51.5%) were revised after the 2016 guideline. Seven EMS system protocols (21.2%) defined generalized convulsive status epilepticus according to the guideline. Thirty-two protocols (97.0%) included intramuscular midazolam, 2 (6.1%) included IV lorazepam, and 5 (15.2%) included IV diazepam.

Although the protocols “appropriately emphasized” intramuscular midazolam, the protocol doses often were lower than those used in the trials or recommended in the guideline. In addition, most protocols listed IV and intraosseous midazolam as options, although these treatments were not studied in the trials nor recommended in the guideline. In all, six of the protocols (18.2%) recommended at least one medication by the route and dose suggested in the trials or in the guideline.

“Why EMS system protocols deviate from the evidence and how this affects patient outcomes deserves further study,” the authors said.

The researchers noted that they examined EMS protocols in only one state and that “protocols may not necessarily reflect what emergency medical technicians actually do in practice.” In addition, the researchers accessed the most recent protocols by consulting EMS system websites rather than by contacting each EMS system for its most up-to-date protocol.

The authors reported personal compensation from JAMA Neurology and from Continuum Audio unrelated to the present study, as well as grants from the National Institutes of Health.

[email protected]

SOURCE: Betjemann JP et al. JAMA. 2019 Mar 26.

Emergency medical services (EMS) system protocols vary in how they define and treat generalized convulsive status epilepticus, according to a review of EMS treatment protocols in California. “Many protocols did not follow evidence-based guidelines and did not accurately define generalized convulsive status epilepticus,” said John P. Betjemann, MD, associate professor of neurology at the University of California, San Francisco, and his colleagues. They reported their findings in the March 26 issue of JAMA.

Generalized convulsive status epilepticus is a neurologic emergency, and trials published in 2001 and 2012 found that benzodiazepines are effective prehospital treatments for patients with generalized convulsive status epilepticus. These trials informed a 2016 evidence-based guideline that cites level A evidence for intramuscular midazolam, IV lorazepam, and IV diazepam as initial treatment options for adults.

To determine whether EMS system protocols follow these recommendations, the investigators reviewed treatment protocols from 33 EMS systems that cover the 58 counties in California. The researchers reviewed EMS system protocols between May and June 2018 to determine when they were last updated and whether they defined generalized convulsive status epilepticus according to the guideline (namely, 5 or more minutes of continuous seizure or two or more discrete seizures between which a patient has incomplete recovery of consciousness). They also determined whether the protocols included any of the three benzodiazepines in the guideline and, if so, at what dose and using which route of administration.

Protocols’ most recent revision dates ranged between 2007 and 2018. Twenty-seven protocols (81.8%) were revised after the second clinical trial was published in 2012, and 17 (51.5%) were revised after the 2016 guideline. Seven EMS system protocols (21.2%) defined generalized convulsive status epilepticus according to the guideline. Thirty-two protocols (97.0%) included intramuscular midazolam, 2 (6.1%) included IV lorazepam, and 5 (15.2%) included IV diazepam.

Although the protocols “appropriately emphasized” intramuscular midazolam, the protocol doses often were lower than those used in the trials or recommended in the guideline. In addition, most protocols listed IV and intraosseous midazolam as options, although these treatments were not studied in the trials nor recommended in the guideline. In all, six of the protocols (18.2%) recommended at least one medication by the route and dose suggested in the trials or in the guideline.

“Why EMS system protocols deviate from the evidence and how this affects patient outcomes deserves further study,” the authors said.

The researchers noted that they examined EMS protocols in only one state and that “protocols may not necessarily reflect what emergency medical technicians actually do in practice.” In addition, the researchers accessed the most recent protocols by consulting EMS system websites rather than by contacting each EMS system for its most up-to-date protocol.

The authors reported personal compensation from JAMA Neurology and from Continuum Audio unrelated to the present study, as well as grants from the National Institutes of Health.

[email protected]

SOURCE: Betjemann JP et al. JAMA. 2019 Mar 26.

Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

Ingram Publishing/Thinkstock

Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses,” the investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid ‘misuse and abuse’ as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

Ingram Publishing/Thinkstock

Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses,” the investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid ‘misuse and abuse’ as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

Ingram Publishing/Thinkstock

Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses,” the investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid ‘misuse and abuse’ as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

HONOLULU – A little more than a year ago, results from the DAWN and DEFUSE 3 trials substantially broadened the time window for endovascular thrombectomy of acute ischemic stroke by selecting patients using brain imaging. Stroke clinicians are now trying to reconcile widespread, routine use of this life-changing treatment against an uncertain need to replicate the higher-end perfusion CT and analytical software imaging that these landmark trials used for patient selection. This has produced a schism in what experts advise for using endovascular thrombectomy on acute ischemic stroke patients.

“Go open the artery, people!” Michael D. Hill, MD, exhorted during a talk at the International Stroke Conference, sponsored by the American Heart Association. “Don’t get over-selective; more people will benefit than you think,” said Dr. Hill, a professor of clinical neurosciences at the University of Calgary (Alta.).

“We are over-selecting, and depriving patients,” commented Raul C. Nogueira, MD, professor of neurology at Emory University in Atlanta and a lead investigator of the DAWN trial, speaking from the audience during a discussion at the session where Dr. Hill spoke.

“The prevalence of treatable [acute ischemic stroke] patients is far higher than the prevalence of patients who are not good candidates, so you just want to exclude the ‘wipe-outs’; that’s what we do,” Dr. Hill explained. “Fortunately, endovascular therapy is very safe, and you’re not going to harm many patients. With other treatments [used routinely in medicine] some patients don’t benefit, but when you have a large effect size we use the treatment on almost everyone. The effect size from thrombectomy is so large it’s an argument to treat almost everyone, although the patients in the trials were selected by imaging.”

Dr. Hill repeatedly stressed that for most patients a non-contrast CT image is usually adequate to identify patients with salvageable brain tissue and a low risk for hemorrhage from intervention, and he endorsed also doing CT angiography to further inform the diagnosis. But he dismissed CT perfusion imaging as unnecessary. “Noncontrast CT and CT angiography are more than adequate to make treatment decisions,” he said. “The prevalence of poor collaterals is quite low, about 10%,” which means that about 90% of acute ischemic stroke patients will have more slowly progressing infarction,” making them amenable to treatment in an expanded time window and boosting the volume of salvageable tissue.

Mitchel L. Zoler/MDedge News

But these appeals for more liberal use of thrombectomy without the perfusion CT imaging used in DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21)and DEFUSE-3 (N Engl J Med. 2018 Feb 22;378[8]:708-18) received push back. Maarten G. Lansberg, MD, a co-investigator on the DEFUSE 3 trial, highlighted the speed and simplicity of CT perfusion imaging, and its utility in helping to better target thrombectomy to the right patients. It’s “speedy, simple, and safe,” it “excludes patients who will not benefit” from thrombectomy, and it helps when the patient’s history and noncontrast CT images are inconclusive, said Dr. Lansberg, a neurologist at Stanford (Calif.) University.

Mitchel L. Zoler/MDedge News

“Clinical presentation will only tell you so much.” With imaging that includes CT perfusion, “you can find out, in 5, 10 minutes, whether there is an occlusion, its location, the extent of dead tissue – that’s all really helpful,” said Marc Fisher, MD, professor of neurology at Harvard Medical School in Boston. “There is a tension now between doing treatment really fast and the concept of slow and fast evolvers. For slow evolvers, the concern about speed is irrelevant because it can take days” for their brains to have substantial damage. “For the fast evolvers, time matters, but they could also possibly be harmed; that’s why we need more data.”

Mitchel L. Zoler/MDedge News

A pitch for more data also came from Pooja Khatri, MD, who also spoke at the session. “There is a real tension now between personalizing the imaging and figuring out exactly the right patients against the time trade off for doing that. Some argue to keep it simple and move fast, and by doing that you’ll wash out any difference from doing more fancy stuff. Plus some places, even in developed countries, can’t afford the image-processing software” used in the DAWN and DEFUSE 3 trials. The correct approach remains unclear and has created “an area ripe for a trial,” declared Dr. Khatri, professor of neurology at director of acute stroke at the University of Cincinnati.

Dr. Hill has received honoraria from Merck and received research funding from Boehringer Ingelheim, Covidien, Medtronic, and Stryker. He has an ownership interest in Calgary Scientific and holds a patent on acute stroke triage methods. Dr. Nogueira has financial relationships with many companies. Dr. Lansberg and Dr. Fisher had no disclosures. Dr. Khatri has been a consultant to Lumosa and has received research funding from Cerenovus/Johnson & Johnson, Genentech, and Nervive.

[email protected]

HONOLULU – A little more than a year ago, results from the DAWN and DEFUSE 3 trials substantially broadened the time window for endovascular thrombectomy of acute ischemic stroke by selecting patients using brain imaging. Stroke clinicians are now trying to reconcile widespread, routine use of this life-changing treatment against an uncertain need to replicate the higher-end perfusion CT and analytical software imaging that these landmark trials used for patient selection. This has produced a schism in what experts advise for using endovascular thrombectomy on acute ischemic stroke patients.

“Go open the artery, people!” Michael D. Hill, MD, exhorted during a talk at the International Stroke Conference, sponsored by the American Heart Association. “Don’t get over-selective; more people will benefit than you think,” said Dr. Hill, a professor of clinical neurosciences at the University of Calgary (Alta.).

“We are over-selecting, and depriving patients,” commented Raul C. Nogueira, MD, professor of neurology at Emory University in Atlanta and a lead investigator of the DAWN trial, speaking from the audience during a discussion at the session where Dr. Hill spoke.

“The prevalence of treatable [acute ischemic stroke] patients is far higher than the prevalence of patients who are not good candidates, so you just want to exclude the ‘wipe-outs’; that’s what we do,” Dr. Hill explained. “Fortunately, endovascular therapy is very safe, and you’re not going to harm many patients. With other treatments [used routinely in medicine] some patients don’t benefit, but when you have a large effect size we use the treatment on almost everyone. The effect size from thrombectomy is so large it’s an argument to treat almost everyone, although the patients in the trials were selected by imaging.”

Dr. Hill repeatedly stressed that for most patients a non-contrast CT image is usually adequate to identify patients with salvageable brain tissue and a low risk for hemorrhage from intervention, and he endorsed also doing CT angiography to further inform the diagnosis. But he dismissed CT perfusion imaging as unnecessary. “Noncontrast CT and CT angiography are more than adequate to make treatment decisions,” he said. “The prevalence of poor collaterals is quite low, about 10%,” which means that about 90% of acute ischemic stroke patients will have more slowly progressing infarction,” making them amenable to treatment in an expanded time window and boosting the volume of salvageable tissue.

Mitchel L. Zoler/MDedge News

But these appeals for more liberal use of thrombectomy without the perfusion CT imaging used in DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21)and DEFUSE-3 (N Engl J Med. 2018 Feb 22;378[8]:708-18) received push back. Maarten G. Lansberg, MD, a co-investigator on the DEFUSE 3 trial, highlighted the speed and simplicity of CT perfusion imaging, and its utility in helping to better target thrombectomy to the right patients. It’s “speedy, simple, and safe,” it “excludes patients who will not benefit” from thrombectomy, and it helps when the patient’s history and noncontrast CT images are inconclusive, said Dr. Lansberg, a neurologist at Stanford (Calif.) University.

Mitchel L. Zoler/MDedge News

“Clinical presentation will only tell you so much.” With imaging that includes CT perfusion, “you can find out, in 5, 10 minutes, whether there is an occlusion, its location, the extent of dead tissue – that’s all really helpful,” said Marc Fisher, MD, professor of neurology at Harvard Medical School in Boston. “There is a tension now between doing treatment really fast and the concept of slow and fast evolvers. For slow evolvers, the concern about speed is irrelevant because it can take days” for their brains to have substantial damage. “For the fast evolvers, time matters, but they could also possibly be harmed; that’s why we need more data.”

Mitchel L. Zoler/MDedge News

A pitch for more data also came from Pooja Khatri, MD, who also spoke at the session. “There is a real tension now between personalizing the imaging and figuring out exactly the right patients against the time trade off for doing that. Some argue to keep it simple and move fast, and by doing that you’ll wash out any difference from doing more fancy stuff. Plus some places, even in developed countries, can’t afford the image-processing software” used in the DAWN and DEFUSE 3 trials. The correct approach remains unclear and has created “an area ripe for a trial,” declared Dr. Khatri, professor of neurology at director of acute stroke at the University of Cincinnati.

Dr. Hill has received honoraria from Merck and received research funding from Boehringer Ingelheim, Covidien, Medtronic, and Stryker. He has an ownership interest in Calgary Scientific and holds a patent on acute stroke triage methods. Dr. Nogueira has financial relationships with many companies. Dr. Lansberg and Dr. Fisher had no disclosures. Dr. Khatri has been a consultant to Lumosa and has received research funding from Cerenovus/Johnson & Johnson, Genentech, and Nervive.

[email protected]

HONOLULU – A little more than a year ago, results from the DAWN and DEFUSE 3 trials substantially broadened the time window for endovascular thrombectomy of acute ischemic stroke by selecting patients using brain imaging. Stroke clinicians are now trying to reconcile widespread, routine use of this life-changing treatment against an uncertain need to replicate the higher-end perfusion CT and analytical software imaging that these landmark trials used for patient selection. This has produced a schism in what experts advise for using endovascular thrombectomy on acute ischemic stroke patients.

“Go open the artery, people!” Michael D. Hill, MD, exhorted during a talk at the International Stroke Conference, sponsored by the American Heart Association. “Don’t get over-selective; more people will benefit than you think,” said Dr. Hill, a professor of clinical neurosciences at the University of Calgary (Alta.).

“We are over-selecting, and depriving patients,” commented Raul C. Nogueira, MD, professor of neurology at Emory University in Atlanta and a lead investigator of the DAWN trial, speaking from the audience during a discussion at the session where Dr. Hill spoke.

“The prevalence of treatable [acute ischemic stroke] patients is far higher than the prevalence of patients who are not good candidates, so you just want to exclude the ‘wipe-outs’; that’s what we do,” Dr. Hill explained. “Fortunately, endovascular therapy is very safe, and you’re not going to harm many patients. With other treatments [used routinely in medicine] some patients don’t benefit, but when you have a large effect size we use the treatment on almost everyone. The effect size from thrombectomy is so large it’s an argument to treat almost everyone, although the patients in the trials were selected by imaging.”

Dr. Hill repeatedly stressed that for most patients a non-contrast CT image is usually adequate to identify patients with salvageable brain tissue and a low risk for hemorrhage from intervention, and he endorsed also doing CT angiography to further inform the diagnosis. But he dismissed CT perfusion imaging as unnecessary. “Noncontrast CT and CT angiography are more than adequate to make treatment decisions,” he said. “The prevalence of poor collaterals is quite low, about 10%,” which means that about 90% of acute ischemic stroke patients will have more slowly progressing infarction,” making them amenable to treatment in an expanded time window and boosting the volume of salvageable tissue.

Mitchel L. Zoler/MDedge News

But these appeals for more liberal use of thrombectomy without the perfusion CT imaging used in DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21)and DEFUSE-3 (N Engl J Med. 2018 Feb 22;378[8]:708-18) received push back. Maarten G. Lansberg, MD, a co-investigator on the DEFUSE 3 trial, highlighted the speed and simplicity of CT perfusion imaging, and its utility in helping to better target thrombectomy to the right patients. It’s “speedy, simple, and safe,” it “excludes patients who will not benefit” from thrombectomy, and it helps when the patient’s history and noncontrast CT images are inconclusive, said Dr. Lansberg, a neurologist at Stanford (Calif.) University.

Mitchel L. Zoler/MDedge News

“Clinical presentation will only tell you so much.” With imaging that includes CT perfusion, “you can find out, in 5, 10 minutes, whether there is an occlusion, its location, the extent of dead tissue – that’s all really helpful,” said Marc Fisher, MD, professor of neurology at Harvard Medical School in Boston. “There is a tension now between doing treatment really fast and the concept of slow and fast evolvers. For slow evolvers, the concern about speed is irrelevant because it can take days” for their brains to have substantial damage. “For the fast evolvers, time matters, but they could also possibly be harmed; that’s why we need more data.”

Mitchel L. Zoler/MDedge News

A pitch for more data also came from Pooja Khatri, MD, who also spoke at the session. “There is a real tension now between personalizing the imaging and figuring out exactly the right patients against the time trade off for doing that. Some argue to keep it simple and move fast, and by doing that you’ll wash out any difference from doing more fancy stuff. Plus some places, even in developed countries, can’t afford the image-processing software” used in the DAWN and DEFUSE 3 trials. The correct approach remains unclear and has created “an area ripe for a trial,” declared Dr. Khatri, professor of neurology at director of acute stroke at the University of Cincinnati.

Dr. Hill has received honoraria from Merck and received research funding from Boehringer Ingelheim, Covidien, Medtronic, and Stryker. He has an ownership interest in Calgary Scientific and holds a patent on acute stroke triage methods. Dr. Nogueira has financial relationships with many companies. Dr. Lansberg and Dr. Fisher had no disclosures. Dr. Khatri has been a consultant to Lumosa and has received research funding from Cerenovus/Johnson & Johnson, Genentech, and Nervive.

[email protected]

Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.

The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.

In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.

Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.

“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.

[email protected]

Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.

The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.

In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.

Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.

“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.

[email protected]

Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.

The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.

In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.

Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.

“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.

[email protected]

HONOLULU – Compared with standard treatment, intensive blood pressure reduction does not significantly reduce the risk of recurrent stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association.

Combined with data from previous trials, these results support a target systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg for secondary stroke prevention, said Kazuo Kitagawa, MD, PhD.

Lowering blood pressure reduces the risk of recurrent stroke, but investigators have not identified the best target blood pressure for this indication. The Secondary Prevention of Small Subcortical Strokes Trial (SPS3) examined the efficacy of intensive blood pressure treatment for secondary stroke prevention. The investigators randomized more than 3,000 patients with recent lacunar stroke to intensive or standard blood pressure treatment. Intensive treatment (a target systolic blood pressure of less than 130 mm Hg) conferred a nonsignificant reduction of the risk of recurrent stroke. A 2018 meta-analysis of SPS3 and two smaller randomized controlled trials also showed that intensive treatment did not significantly reduce the risk of recurrent stroke.
 

A new multicenter trial

Dr. Kitagawa, of Tokyo Women’s Medical University, and colleagues conducted a new trial to evaluate whether intensive blood pressure reduction significantly reduced the risk of recurrent stroke, compared with standard treatment (a systolic target of less than 140 mm Hg and a diastolic target of less than 90 mm Hg). Between 2010 and 2016, they enrolled patients with a history of stroke within the previous 3 years at 140 hospitals in Japan. Participants were randomized to standard blood pressure treatment or intensive blood pressure treatment (defined in this study as a systolic target of less than 120 mm Hg and a diastolic target of less than 80 mm Hg). The primary end point was recurrent stroke.

Both treatment regimens were based on stepwise multidrug rationing. Step 1 was an angiotensin II receptor blockade (ARB), step 2 was the addition of diuretics, step 3 was the addition of calcium channel blockers, step 4 was an increase of the ARB, step 5 was increase of the calcium channel blocker, and step 6 was the addition of spironolactone.

This trial was stopped at the end of 2016 because of slow recruitment and funding cessation. Investigators randomized 1,280 patients out of a planned 2,000. Seventeen patients were excluded from analysis. At baseline, participants’ mean age was 67 years, and mean systolic blood pressure was 145 mm Hg. The qualifying event was ischemic stroke for 85% of patients and intracerebral hemorrhage for 15%. Mean follow-up duration was 3.9 years.
 

Intensive treatment reduced blood pressure

At 1 year, the mean systolic blood pressure was 132.0 mm Hg in the standard-treatment group and 123.7 mm Hg in the intensive-treatment group. Mean diastolic blood pressure was 77.5 mm Hg in the standard-treatment group and 72.8 mm Hg in the intensive-treatment group. The investigators observed a significant difference in blood pressure between the groups throughout the study period.

The annual rate of stroke recurrence was 2.26% in the standard-treatment group and 1.65% in the intensive-treatment group. Intensive treatment tended to reduce stroke recurrence (hazard ratio, 0.73), but the result was not statistically significant. “The nonsignificant finding might be due to early termination or the modest difference in blood pressure level [between groups],” said Dr. Kitagawa.

Subgroup analyses did not indicate any interaction between treatment group and age, sex, qualifying event, mean systolic blood pressure at baseline, or diabetes. The rate of ischemic stroke was similar between the two groups, but the rate of intracerebral hemorrhage was lower in the intensive treatment group than in the standard treatment group. The rate of serious adverse events was similar between treatment groups.

When Dr. Kitagawa and colleagues pooled their data with those examined in the 2018 meta-analysis, they found that intensive treatment significantly reduced the risk of recurrent stroke (hazard ratio, 0.68), compared with standard treatment.

This study was sponsored by Biomedis International.

[email protected]

SOURCE: Kitagawa K et al. ISC 2019, Abstract LB10.

HONOLULU – Compared with standard treatment, intensive blood pressure reduction does not significantly reduce the risk of recurrent stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association.

Combined with data from previous trials, these results support a target systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg for secondary stroke prevention, said Kazuo Kitagawa, MD, PhD.

Lowering blood pressure reduces the risk of recurrent stroke, but investigators have not identified the best target blood pressure for this indication. The Secondary Prevention of Small Subcortical Strokes Trial (SPS3) examined the efficacy of intensive blood pressure treatment for secondary stroke prevention. The investigators randomized more than 3,000 patients with recent lacunar stroke to intensive or standard blood pressure treatment. Intensive treatment (a target systolic blood pressure of less than 130 mm Hg) conferred a nonsignificant reduction of the risk of recurrent stroke. A 2018 meta-analysis of SPS3 and two smaller randomized controlled trials also showed that intensive treatment did not significantly reduce the risk of recurrent stroke.
 

A new multicenter trial

Dr. Kitagawa, of Tokyo Women’s Medical University, and colleagues conducted a new trial to evaluate whether intensive blood pressure reduction significantly reduced the risk of recurrent stroke, compared with standard treatment (a systolic target of less than 140 mm Hg and a diastolic target of less than 90 mm Hg). Between 2010 and 2016, they enrolled patients with a history of stroke within the previous 3 years at 140 hospitals in Japan. Participants were randomized to standard blood pressure treatment or intensive blood pressure treatment (defined in this study as a systolic target of less than 120 mm Hg and a diastolic target of less than 80 mm Hg). The primary end point was recurrent stroke.

Both treatment regimens were based on stepwise multidrug rationing. Step 1 was an angiotensin II receptor blockade (ARB), step 2 was the addition of diuretics, step 3 was the addition of calcium channel blockers, step 4 was an increase of the ARB, step 5 was increase of the calcium channel blocker, and step 6 was the addition of spironolactone.

This trial was stopped at the end of 2016 because of slow recruitment and funding cessation. Investigators randomized 1,280 patients out of a planned 2,000. Seventeen patients were excluded from analysis. At baseline, participants’ mean age was 67 years, and mean systolic blood pressure was 145 mm Hg. The qualifying event was ischemic stroke for 85% of patients and intracerebral hemorrhage for 15%. Mean follow-up duration was 3.9 years.
 

Intensive treatment reduced blood pressure

At 1 year, the mean systolic blood pressure was 132.0 mm Hg in the standard-treatment group and 123.7 mm Hg in the intensive-treatment group. Mean diastolic blood pressure was 77.5 mm Hg in the standard-treatment group and 72.8 mm Hg in the intensive-treatment group. The investigators observed a significant difference in blood pressure between the groups throughout the study period.

The annual rate of stroke recurrence was 2.26% in the standard-treatment group and 1.65% in the intensive-treatment group. Intensive treatment tended to reduce stroke recurrence (hazard ratio, 0.73), but the result was not statistically significant. “The nonsignificant finding might be due to early termination or the modest difference in blood pressure level [between groups],” said Dr. Kitagawa.

Subgroup analyses did not indicate any interaction between treatment group and age, sex, qualifying event, mean systolic blood pressure at baseline, or diabetes. The rate of ischemic stroke was similar between the two groups, but the rate of intracerebral hemorrhage was lower in the intensive treatment group than in the standard treatment group. The rate of serious adverse events was similar between treatment groups.

When Dr. Kitagawa and colleagues pooled their data with those examined in the 2018 meta-analysis, they found that intensive treatment significantly reduced the risk of recurrent stroke (hazard ratio, 0.68), compared with standard treatment.

This study was sponsored by Biomedis International.

[email protected]

SOURCE: Kitagawa K et al. ISC 2019, Abstract LB10.

HONOLULU – Compared with standard treatment, intensive blood pressure reduction does not significantly reduce the risk of recurrent stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association.

Combined with data from previous trials, these results support a target systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg for secondary stroke prevention, said Kazuo Kitagawa, MD, PhD.

Lowering blood pressure reduces the risk of recurrent stroke, but investigators have not identified the best target blood pressure for this indication. The Secondary Prevention of Small Subcortical Strokes Trial (SPS3) examined the efficacy of intensive blood pressure treatment for secondary stroke prevention. The investigators randomized more than 3,000 patients with recent lacunar stroke to intensive or standard blood pressure treatment. Intensive treatment (a target systolic blood pressure of less than 130 mm Hg) conferred a nonsignificant reduction of the risk of recurrent stroke. A 2018 meta-analysis of SPS3 and two smaller randomized controlled trials also showed that intensive treatment did not significantly reduce the risk of recurrent stroke.
 

A new multicenter trial

Dr. Kitagawa, of Tokyo Women’s Medical University, and colleagues conducted a new trial to evaluate whether intensive blood pressure reduction significantly reduced the risk of recurrent stroke, compared with standard treatment (a systolic target of less than 140 mm Hg and a diastolic target of less than 90 mm Hg). Between 2010 and 2016, they enrolled patients with a history of stroke within the previous 3 years at 140 hospitals in Japan. Participants were randomized to standard blood pressure treatment or intensive blood pressure treatment (defined in this study as a systolic target of less than 120 mm Hg and a diastolic target of less than 80 mm Hg). The primary end point was recurrent stroke.

Both treatment regimens were based on stepwise multidrug rationing. Step 1 was an angiotensin II receptor blockade (ARB), step 2 was the addition of diuretics, step 3 was the addition of calcium channel blockers, step 4 was an increase of the ARB, step 5 was increase of the calcium channel blocker, and step 6 was the addition of spironolactone.

This trial was stopped at the end of 2016 because of slow recruitment and funding cessation. Investigators randomized 1,280 patients out of a planned 2,000. Seventeen patients were excluded from analysis. At baseline, participants’ mean age was 67 years, and mean systolic blood pressure was 145 mm Hg. The qualifying event was ischemic stroke for 85% of patients and intracerebral hemorrhage for 15%. Mean follow-up duration was 3.9 years.
 

Intensive treatment reduced blood pressure

At 1 year, the mean systolic blood pressure was 132.0 mm Hg in the standard-treatment group and 123.7 mm Hg in the intensive-treatment group. Mean diastolic blood pressure was 77.5 mm Hg in the standard-treatment group and 72.8 mm Hg in the intensive-treatment group. The investigators observed a significant difference in blood pressure between the groups throughout the study period.

The annual rate of stroke recurrence was 2.26% in the standard-treatment group and 1.65% in the intensive-treatment group. Intensive treatment tended to reduce stroke recurrence (hazard ratio, 0.73), but the result was not statistically significant. “The nonsignificant finding might be due to early termination or the modest difference in blood pressure level [between groups],” said Dr. Kitagawa.

Subgroup analyses did not indicate any interaction between treatment group and age, sex, qualifying event, mean systolic blood pressure at baseline, or diabetes. The rate of ischemic stroke was similar between the two groups, but the rate of intracerebral hemorrhage was lower in the intensive treatment group than in the standard treatment group. The rate of serious adverse events was similar between treatment groups.

When Dr. Kitagawa and colleagues pooled their data with those examined in the 2018 meta-analysis, they found that intensive treatment significantly reduced the risk of recurrent stroke (hazard ratio, 0.68), compared with standard treatment.

This study was sponsored by Biomedis International.

[email protected]

SOURCE: Kitagawa K et al. ISC 2019, Abstract LB10.

The findings could lead the way to understanding the brain’s intake and output of energy in good health and bad and the part that alcohol plays.

In previous studies, the researchers have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, assessed through changes in blood oxygenation. But regional differences in glucose metabolism are hard to interpret, they say. In a study with healthy volunteers, they used brain imaging techniques to help quantify “match and mismatch” in energy consumption and expenditure across the brain—what they termed power and cost.

The researchers assessed power by observing to what extent brain regions are active and use energy, and cost by observing how brain regions expended energy. They found that different brain regions that serve distinct functions have “notably different power and different cost.”

Next, they tested a group of light drinkers and heavy drinkers and found both acute and chronic exposure to alcohol affected power and cost. In heavy drinkers, the researchers say, they saw less regional power, for example, in the thalamus, the sensory gateway, and frontal cortex. The researchers interpreted the decreases in power as reflecting the toxic effects of long-term exposure to alcohol on the brain cells.

They also found power dropped in the visual regions during acute alcohol exposure, which was related to disruption of visual processing. Visual regions also had the most significant drops in cost of activity during intoxication. That is consistent with the reliance of those regions on alternative energy sources, such as acetate (a byproduct of alcohol metabolism), the researchers say.

Their approach for characterizing brain energetic patterns related to alcohol use could be useful in other ways, the researchers say. “Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction,” said co-lead investigator Dr. Ehsan Schokri-Kojori. “The measures of power and cost may provide new multimodal biomarkers.”

The findings could lead the way to understanding the brain’s intake and output of energy in good health and bad and the part that alcohol plays.

In previous studies, the researchers have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, assessed through changes in blood oxygenation. But regional differences in glucose metabolism are hard to interpret, they say. In a study with healthy volunteers, they used brain imaging techniques to help quantify “match and mismatch” in energy consumption and expenditure across the brain—what they termed power and cost.

The researchers assessed power by observing to what extent brain regions are active and use energy, and cost by observing how brain regions expended energy. They found that different brain regions that serve distinct functions have “notably different power and different cost.”

Next, they tested a group of light drinkers and heavy drinkers and found both acute and chronic exposure to alcohol affected power and cost. In heavy drinkers, the researchers say, they saw less regional power, for example, in the thalamus, the sensory gateway, and frontal cortex. The researchers interpreted the decreases in power as reflecting the toxic effects of long-term exposure to alcohol on the brain cells.

They also found power dropped in the visual regions during acute alcohol exposure, which was related to disruption of visual processing. Visual regions also had the most significant drops in cost of activity during intoxication. That is consistent with the reliance of those regions on alternative energy sources, such as acetate (a byproduct of alcohol metabolism), the researchers say.

Their approach for characterizing brain energetic patterns related to alcohol use could be useful in other ways, the researchers say. “Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction,” said co-lead investigator Dr. Ehsan Schokri-Kojori. “The measures of power and cost may provide new multimodal biomarkers.”

The findings could lead the way to understanding the brain’s intake and output of energy in good health and bad and the part that alcohol plays.

In previous studies, the researchers have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, assessed through changes in blood oxygenation. But regional differences in glucose metabolism are hard to interpret, they say. In a study with healthy volunteers, they used brain imaging techniques to help quantify “match and mismatch” in energy consumption and expenditure across the brain—what they termed power and cost.

The researchers assessed power by observing to what extent brain regions are active and use energy, and cost by observing how brain regions expended energy. They found that different brain regions that serve distinct functions have “notably different power and different cost.”

Next, they tested a group of light drinkers and heavy drinkers and found both acute and chronic exposure to alcohol affected power and cost. In heavy drinkers, the researchers say, they saw less regional power, for example, in the thalamus, the sensory gateway, and frontal cortex. The researchers interpreted the decreases in power as reflecting the toxic effects of long-term exposure to alcohol on the brain cells.

They also found power dropped in the visual regions during acute alcohol exposure, which was related to disruption of visual processing. Visual regions also had the most significant drops in cost of activity during intoxication. That is consistent with the reliance of those regions on alternative energy sources, such as acetate (a byproduct of alcohol metabolism), the researchers say.

Their approach for characterizing brain energetic patterns related to alcohol use could be useful in other ways, the researchers say. “Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction,” said co-lead investigator Dr. Ehsan Schokri-Kojori. “The measures of power and cost may provide new multimodal biomarkers.”