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Ketamine for Depression: Adverse Effects Are Mild and Brief
A single subanesthetic dose of ketamine infusion can often relieve depressive symptoms within hours when conventional antidepressants have not worked. But off-label use of IV ketamine—especially given its history of abuse—has raised concerns about adverse effects (AEs).
However, a single low-dose infusion was “relatively free of side effects” for patients with treatment-resistant depression, according to researchers from the National Institute of Mental Health. They compiled data on AEs from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls from 5 placebo-controlled crossover clinical trials and 1 open-label study conducted at the National Institutes of Health (NIH) Clinical Center over 13 years.
The assessments included active and structured surveillance of emerging AEs in an inpatient setting and used both a rating scale and clinician interviews.
The most common effect was feeling “strange or loopy,” the researchers say. Most AEs peaked within an hour of administration and were gone within 2 hours. The researchers did not see any serious, drug-related AEs or increased ketamine cravings.
The researchers evaluated 120 possible AEs. Of the 44 that occurred in at least 5% of participants over all trials, 33 were significantly associated with treatment. At least half the participants reported the “spacey” feeling, visual distortions, difficulty speaking, and numbness. No AEs lasted beyond 4 hours.
The study did not address AEs associated with repeated infusions or long-term use, but during the approximately 3-month follow-up period, the researchers found no drug-related serious AEs, propensity for recreational use, or significant cognitive or memory deficits.
A single subanesthetic dose of ketamine infusion can often relieve depressive symptoms within hours when conventional antidepressants have not worked. But off-label use of IV ketamine—especially given its history of abuse—has raised concerns about adverse effects (AEs).
However, a single low-dose infusion was “relatively free of side effects” for patients with treatment-resistant depression, according to researchers from the National Institute of Mental Health. They compiled data on AEs from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls from 5 placebo-controlled crossover clinical trials and 1 open-label study conducted at the National Institutes of Health (NIH) Clinical Center over 13 years.
The assessments included active and structured surveillance of emerging AEs in an inpatient setting and used both a rating scale and clinician interviews.
The most common effect was feeling “strange or loopy,” the researchers say. Most AEs peaked within an hour of administration and were gone within 2 hours. The researchers did not see any serious, drug-related AEs or increased ketamine cravings.
The researchers evaluated 120 possible AEs. Of the 44 that occurred in at least 5% of participants over all trials, 33 were significantly associated with treatment. At least half the participants reported the “spacey” feeling, visual distortions, difficulty speaking, and numbness. No AEs lasted beyond 4 hours.
The study did not address AEs associated with repeated infusions or long-term use, but during the approximately 3-month follow-up period, the researchers found no drug-related serious AEs, propensity for recreational use, or significant cognitive or memory deficits.
A single subanesthetic dose of ketamine infusion can often relieve depressive symptoms within hours when conventional antidepressants have not worked. But off-label use of IV ketamine—especially given its history of abuse—has raised concerns about adverse effects (AEs).
However, a single low-dose infusion was “relatively free of side effects” for patients with treatment-resistant depression, according to researchers from the National Institute of Mental Health. They compiled data on AEs from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls from 5 placebo-controlled crossover clinical trials and 1 open-label study conducted at the National Institutes of Health (NIH) Clinical Center over 13 years.
The assessments included active and structured surveillance of emerging AEs in an inpatient setting and used both a rating scale and clinician interviews.
The most common effect was feeling “strange or loopy,” the researchers say. Most AEs peaked within an hour of administration and were gone within 2 hours. The researchers did not see any serious, drug-related AEs or increased ketamine cravings.
The researchers evaluated 120 possible AEs. Of the 44 that occurred in at least 5% of participants over all trials, 33 were significantly associated with treatment. At least half the participants reported the “spacey” feeling, visual distortions, difficulty speaking, and numbness. No AEs lasted beyond 4 hours.
The study did not address AEs associated with repeated infusions or long-term use, but during the approximately 3-month follow-up period, the researchers found no drug-related serious AEs, propensity for recreational use, or significant cognitive or memory deficits.
Trial finds three drugs equally effective for established status epilepticus
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
FROM NEJM
Key clinical point: Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients.
Major finding: Absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
Study details: The Established Status Epilepticus Treatment Trial (ESETT) was a blinded, comparative-effectiveness trial that enrolled 384 patients at 57 hospital EDs in the United States.
Disclosures: The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Source: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
Supplemental MRI found to benefit women with dense breast tissue
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.
“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.
“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.
In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.
“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”
Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”
In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”
The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.
“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.
“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.
In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.
“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”
Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”
In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”
The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.
“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.
“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.
In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.
“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”
Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”
In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”
The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: The interval cancer rate was 2.5 per 1,000 screenings among women in the MRI invitation group, compared with 5 per 1,000 among women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001).
Study details: A multicenter, randomized study of 40,373 women between the ages of 50 and 75 years. One-quarter were offered supplemental MRI to the mammography all received.
Disclosures: The trial was supported by the University Medical Center Utrecht, the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
Source: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
ART treatment at birth found to benefit neonates with HIV
Initiating antiretroviral therapy within an hour after birth, rather than waiting a few weeks, lowers the reservoir of HIV virus and improves immune response, early results from an ongoing study in Botswana, Africa, showed.
Despite advances in treatment programs during pregnancy that prevent mother to child HIV transmission, 300-500 pediatric HIV infections occur each day in sub-Saharan Africa, Roger Shapiro, MD, MPH, said during a media teleconference organized by the American Association for the Advancement of Science. “Most pediatric HIV diagnosis programs currently test children at 4-6 weeks of age to identify infections that occur either in pregnancy or during delivery,” said Dr. Shapiro, associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, Boston. “However, these programs miss the opportunity to begin immediate antiretroviral treatment for children who can be identified earlier. There are benefits to starting treatment and arresting HIV replication in the first week of life. These include limiting the viral reservoir or the population of infected cells, limiting potentially harmful immune responses to the virus, and preventing the rapid decline in health that can occur in the early weeks of HIV infection in infants. Without treatment, 50% of HIV-infected children regress to death by 2 years. Starting treatment in the first weeks or months of life has been shown to improve survival.”
With these benefits in mind, he and his associates initiated the Early Infant Treatment (EIT) study in 2015 to diagnose and treat HIV infected infants in Botswana in the first week of life or as early as possible after infection. They screened more than 10,000 children and identified 40 that were HIV infected. “This low transmission rate is a testament to the fact that most HIV-positive women in Botswana receive three-drug treatment in pregnancy, which is highly successful in blocking transmission,” Dr. Shapiro said. “When we identified an HIV-infected infant, we consented mothers to allow us to start treatment right away. We used a series of regimens because there are limited options. The available options include older drugs, some of which are no longer used for adults but which were the only options for children.”
The researchers initiated three initial drugs approved for newborns: nevirapine, zidovudine, and lamivudine, and then changed the regimen slightly after a few weeks, when they used ritonavir-boosted lopinavir, plus the lamivudine and zidovudine. “We followed the children weekly at first, then at monthly refill visits, and kept close track of how they were taking the medicines and the level of virus in each child’s blood,” Dr. Shapiro said.
In a manuscript published online in Science Translational Medicine on Nov. 27, 2019, he and his associates reported results of the first 10 children enrolled in the EIT study who reached about 96 weeks on treatment. For comparison, they also enrolled a group of children as controls, who started treatment later in the first year of life, after being identified at a more standard time of 4-6 weeks. Tests performed included droplet digital polymerase chain reaction, HIV near-full-genome sequencing, whole-genome amplification, and flow cytometry.
“What we wanted to focus on are the HIV reservoir cells that are persisting in the setting of antiretroviral treatment,” study coauthor Mathias Lichterfeld, MD, PhD, explained during the teleconference. “Those are the cells that would cause viral rebound if treatment were to be interrupted. We used complex technology to look at these cells, using next-generation sequencing, which allows us to identify those cells that harbor HIV that has the ability to initiate new viral replication.”
He and his colleagues observed that the number of reservoir cells was significantly smaller than in adults who were on ART for a median of 16 years. It also was smaller than in infected infants who started ART treatment weeks after birth.
In addition, immune activation was reduced in the cohort of infants who were treated immediately after birth.
“We are seeing a distinct advantage of early treatment initiation,” said Dr. Lichterfeld of the infectious disease division at Brigham and Women’s Hospital, Boston. “By doing these assays we see both virological benefits in terms of a very-low reservoir size, and we see immune system characteristics that are also associated with better abilities for antimicrobial immune defense and a lower level of immune activation.”
Another study coauthor, Daniel R. Kuritzkes, MD, chief of the infectious disease division at Brigham and Women’s Hospital, said the findings show “how critically important” it is to extend studies of HIV cure or long-term remission to infants and children. “Very-early intervention in neonates limits the size of the reservoir and offers us the best opportunity for future interventions aimed at cure and long-term drug-free remission of HIV infection,” he said. “We don’t think the current intervention is itself curative, but it sets the stage for the capacity to offer additional innovative interventions in the future. Beyond the importance of this work for cure research per se, this very early intervention in neonates also has the potential of conferring important clinical benefits to the children who participated in this study. Finally, our study demonstrates the feasibility and importance of doing this type of research in neonates in resource-limited settings, given the appropriate infrastructure.”
EIT is supported by the National Institutes of Health. Dr. Lichterfeld disclosed having received speaking and consulting honoraria from Merck and Gilead. Dr. Kuritzkes disclosed having received consulting honoraria and/or research support from Gilead, Merck, and ViiV.
SOURCE: Garcia-Broncano P et al. Sci Transl Med. 2019 Nov 27. eaax7350.
Initiating antiretroviral therapy within an hour after birth, rather than waiting a few weeks, lowers the reservoir of HIV virus and improves immune response, early results from an ongoing study in Botswana, Africa, showed.
Despite advances in treatment programs during pregnancy that prevent mother to child HIV transmission, 300-500 pediatric HIV infections occur each day in sub-Saharan Africa, Roger Shapiro, MD, MPH, said during a media teleconference organized by the American Association for the Advancement of Science. “Most pediatric HIV diagnosis programs currently test children at 4-6 weeks of age to identify infections that occur either in pregnancy or during delivery,” said Dr. Shapiro, associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, Boston. “However, these programs miss the opportunity to begin immediate antiretroviral treatment for children who can be identified earlier. There are benefits to starting treatment and arresting HIV replication in the first week of life. These include limiting the viral reservoir or the population of infected cells, limiting potentially harmful immune responses to the virus, and preventing the rapid decline in health that can occur in the early weeks of HIV infection in infants. Without treatment, 50% of HIV-infected children regress to death by 2 years. Starting treatment in the first weeks or months of life has been shown to improve survival.”
With these benefits in mind, he and his associates initiated the Early Infant Treatment (EIT) study in 2015 to diagnose and treat HIV infected infants in Botswana in the first week of life or as early as possible after infection. They screened more than 10,000 children and identified 40 that were HIV infected. “This low transmission rate is a testament to the fact that most HIV-positive women in Botswana receive three-drug treatment in pregnancy, which is highly successful in blocking transmission,” Dr. Shapiro said. “When we identified an HIV-infected infant, we consented mothers to allow us to start treatment right away. We used a series of regimens because there are limited options. The available options include older drugs, some of which are no longer used for adults but which were the only options for children.”
The researchers initiated three initial drugs approved for newborns: nevirapine, zidovudine, and lamivudine, and then changed the regimen slightly after a few weeks, when they used ritonavir-boosted lopinavir, plus the lamivudine and zidovudine. “We followed the children weekly at first, then at monthly refill visits, and kept close track of how they were taking the medicines and the level of virus in each child’s blood,” Dr. Shapiro said.
In a manuscript published online in Science Translational Medicine on Nov. 27, 2019, he and his associates reported results of the first 10 children enrolled in the EIT study who reached about 96 weeks on treatment. For comparison, they also enrolled a group of children as controls, who started treatment later in the first year of life, after being identified at a more standard time of 4-6 weeks. Tests performed included droplet digital polymerase chain reaction, HIV near-full-genome sequencing, whole-genome amplification, and flow cytometry.
“What we wanted to focus on are the HIV reservoir cells that are persisting in the setting of antiretroviral treatment,” study coauthor Mathias Lichterfeld, MD, PhD, explained during the teleconference. “Those are the cells that would cause viral rebound if treatment were to be interrupted. We used complex technology to look at these cells, using next-generation sequencing, which allows us to identify those cells that harbor HIV that has the ability to initiate new viral replication.”
He and his colleagues observed that the number of reservoir cells was significantly smaller than in adults who were on ART for a median of 16 years. It also was smaller than in infected infants who started ART treatment weeks after birth.
In addition, immune activation was reduced in the cohort of infants who were treated immediately after birth.
“We are seeing a distinct advantage of early treatment initiation,” said Dr. Lichterfeld of the infectious disease division at Brigham and Women’s Hospital, Boston. “By doing these assays we see both virological benefits in terms of a very-low reservoir size, and we see immune system characteristics that are also associated with better abilities for antimicrobial immune defense and a lower level of immune activation.”
Another study coauthor, Daniel R. Kuritzkes, MD, chief of the infectious disease division at Brigham and Women’s Hospital, said the findings show “how critically important” it is to extend studies of HIV cure or long-term remission to infants and children. “Very-early intervention in neonates limits the size of the reservoir and offers us the best opportunity for future interventions aimed at cure and long-term drug-free remission of HIV infection,” he said. “We don’t think the current intervention is itself curative, but it sets the stage for the capacity to offer additional innovative interventions in the future. Beyond the importance of this work for cure research per se, this very early intervention in neonates also has the potential of conferring important clinical benefits to the children who participated in this study. Finally, our study demonstrates the feasibility and importance of doing this type of research in neonates in resource-limited settings, given the appropriate infrastructure.”
EIT is supported by the National Institutes of Health. Dr. Lichterfeld disclosed having received speaking and consulting honoraria from Merck and Gilead. Dr. Kuritzkes disclosed having received consulting honoraria and/or research support from Gilead, Merck, and ViiV.
SOURCE: Garcia-Broncano P et al. Sci Transl Med. 2019 Nov 27. eaax7350.
Initiating antiretroviral therapy within an hour after birth, rather than waiting a few weeks, lowers the reservoir of HIV virus and improves immune response, early results from an ongoing study in Botswana, Africa, showed.
Despite advances in treatment programs during pregnancy that prevent mother to child HIV transmission, 300-500 pediatric HIV infections occur each day in sub-Saharan Africa, Roger Shapiro, MD, MPH, said during a media teleconference organized by the American Association for the Advancement of Science. “Most pediatric HIV diagnosis programs currently test children at 4-6 weeks of age to identify infections that occur either in pregnancy or during delivery,” said Dr. Shapiro, associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, Boston. “However, these programs miss the opportunity to begin immediate antiretroviral treatment for children who can be identified earlier. There are benefits to starting treatment and arresting HIV replication in the first week of life. These include limiting the viral reservoir or the population of infected cells, limiting potentially harmful immune responses to the virus, and preventing the rapid decline in health that can occur in the early weeks of HIV infection in infants. Without treatment, 50% of HIV-infected children regress to death by 2 years. Starting treatment in the first weeks or months of life has been shown to improve survival.”
With these benefits in mind, he and his associates initiated the Early Infant Treatment (EIT) study in 2015 to diagnose and treat HIV infected infants in Botswana in the first week of life or as early as possible after infection. They screened more than 10,000 children and identified 40 that were HIV infected. “This low transmission rate is a testament to the fact that most HIV-positive women in Botswana receive three-drug treatment in pregnancy, which is highly successful in blocking transmission,” Dr. Shapiro said. “When we identified an HIV-infected infant, we consented mothers to allow us to start treatment right away. We used a series of regimens because there are limited options. The available options include older drugs, some of which are no longer used for adults but which were the only options for children.”
The researchers initiated three initial drugs approved for newborns: nevirapine, zidovudine, and lamivudine, and then changed the regimen slightly after a few weeks, when they used ritonavir-boosted lopinavir, plus the lamivudine and zidovudine. “We followed the children weekly at first, then at monthly refill visits, and kept close track of how they were taking the medicines and the level of virus in each child’s blood,” Dr. Shapiro said.
In a manuscript published online in Science Translational Medicine on Nov. 27, 2019, he and his associates reported results of the first 10 children enrolled in the EIT study who reached about 96 weeks on treatment. For comparison, they also enrolled a group of children as controls, who started treatment later in the first year of life, after being identified at a more standard time of 4-6 weeks. Tests performed included droplet digital polymerase chain reaction, HIV near-full-genome sequencing, whole-genome amplification, and flow cytometry.
“What we wanted to focus on are the HIV reservoir cells that are persisting in the setting of antiretroviral treatment,” study coauthor Mathias Lichterfeld, MD, PhD, explained during the teleconference. “Those are the cells that would cause viral rebound if treatment were to be interrupted. We used complex technology to look at these cells, using next-generation sequencing, which allows us to identify those cells that harbor HIV that has the ability to initiate new viral replication.”
He and his colleagues observed that the number of reservoir cells was significantly smaller than in adults who were on ART for a median of 16 years. It also was smaller than in infected infants who started ART treatment weeks after birth.
In addition, immune activation was reduced in the cohort of infants who were treated immediately after birth.
“We are seeing a distinct advantage of early treatment initiation,” said Dr. Lichterfeld of the infectious disease division at Brigham and Women’s Hospital, Boston. “By doing these assays we see both virological benefits in terms of a very-low reservoir size, and we see immune system characteristics that are also associated with better abilities for antimicrobial immune defense and a lower level of immune activation.”
Another study coauthor, Daniel R. Kuritzkes, MD, chief of the infectious disease division at Brigham and Women’s Hospital, said the findings show “how critically important” it is to extend studies of HIV cure or long-term remission to infants and children. “Very-early intervention in neonates limits the size of the reservoir and offers us the best opportunity for future interventions aimed at cure and long-term drug-free remission of HIV infection,” he said. “We don’t think the current intervention is itself curative, but it sets the stage for the capacity to offer additional innovative interventions in the future. Beyond the importance of this work for cure research per se, this very early intervention in neonates also has the potential of conferring important clinical benefits to the children who participated in this study. Finally, our study demonstrates the feasibility and importance of doing this type of research in neonates in resource-limited settings, given the appropriate infrastructure.”
EIT is supported by the National Institutes of Health. Dr. Lichterfeld disclosed having received speaking and consulting honoraria from Merck and Gilead. Dr. Kuritzkes disclosed having received consulting honoraria and/or research support from Gilead, Merck, and ViiV.
SOURCE: Garcia-Broncano P et al. Sci Transl Med. 2019 Nov 27. eaax7350.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: Antiretroviral treatment initiation immediately after birth reduced HIV-1 viral reservoir size and alters innate immune responses in neonates.
Major finding: Very-early ART intervention in neonates infected with HIV limited the number of virally infected cells and improves immune response.
Study details: A cohort study of 10 infants infected with HIV who were born in Botswana, Africa.
Disclosures: The Early Infant Treatment study is supported by the National Institutes of Health. Dr. Lichterfeld disclosed having received speaking and consulting honoraria from Merck and Gilead. Dr. Kuritzkes disclosed having received consulting honoraria and/or research support from Gilead, Merck, and ViiV.
Source: Garcia-Broncano P et al. Sci Transl Med. 2019 Nov 27. eaax7350.
Benefiting from hospitalist-directed transfers
A ‘unique opportunity’ for hospitalists
Emergency department overcrowding is common, and it can result in both increased costs and poor clinical outcomes.
“We sought to evaluate the impact and safety of hospitalist-directed transfers on patients boarding in the ER as a means to alleviate overcrowding,” said Yihan Chen, MD, MPH, of the University of California, Los Angeles. “High inpatient census has been shown to impair ER throughput by increasing the number of ER ‘boarders,’ which creates a suboptimal care environment for practicing hospitalists. For example, some studies have shown associations with delays in medical decision making when admitted patients remain and receive care in the emergency department.”
Dr. Chen was the lead author of an abstract describing a chart review on 1,016 admissions to the hospitalist service. About half remained at the reference hospital and half were transferred to a nearby affiliate hospital.
In analyzing the data, the researchers’ top takeaway was the many benefits for the transferred patients. “Hospitalist-directed transfer and direct admission of stable ER patients to an affiliate facility with greater bed availability is associated with shorter ER lengths of stay, fewer adverse events, and lower rates of readmission within 30 days of hospitalization,” Dr. Chen said. “Having a system in place to transfer patients to an affiliate hospital with lower census is a way to improve flow.”
Hospitalists have a unique opportunity to take on a triage role in the ED to safely and effectively decrease ED overcrowding and throughput, improve resource utilization at the hospital level, and allow for other hospitalists at their institution to optimize patient care on the inpatient ward rather than in the ED, Dr. Chen said.
“Health systems privileged to have more than one facility should consider an intra–health system transfer process lead by triage hospitalists to identify stable patients who can be directly admitted to the off-site, affiliate hospital,” she said. “By improving patient throughput, hospitalists would play a critical role in relieving institutional stressors, impacting cost and quality of care, and enhancing clinical outcomes.”
Reference
1. Chen Y et al. Hospitalist-Directed Transfers Improve Emergency Room Length of Stay. Hospital Medicine 2018, Abstract 12. Accessed April 3, 2019.
A ‘unique opportunity’ for hospitalists
A ‘unique opportunity’ for hospitalists
Emergency department overcrowding is common, and it can result in both increased costs and poor clinical outcomes.
“We sought to evaluate the impact and safety of hospitalist-directed transfers on patients boarding in the ER as a means to alleviate overcrowding,” said Yihan Chen, MD, MPH, of the University of California, Los Angeles. “High inpatient census has been shown to impair ER throughput by increasing the number of ER ‘boarders,’ which creates a suboptimal care environment for practicing hospitalists. For example, some studies have shown associations with delays in medical decision making when admitted patients remain and receive care in the emergency department.”
Dr. Chen was the lead author of an abstract describing a chart review on 1,016 admissions to the hospitalist service. About half remained at the reference hospital and half were transferred to a nearby affiliate hospital.
In analyzing the data, the researchers’ top takeaway was the many benefits for the transferred patients. “Hospitalist-directed transfer and direct admission of stable ER patients to an affiliate facility with greater bed availability is associated with shorter ER lengths of stay, fewer adverse events, and lower rates of readmission within 30 days of hospitalization,” Dr. Chen said. “Having a system in place to transfer patients to an affiliate hospital with lower census is a way to improve flow.”
Hospitalists have a unique opportunity to take on a triage role in the ED to safely and effectively decrease ED overcrowding and throughput, improve resource utilization at the hospital level, and allow for other hospitalists at their institution to optimize patient care on the inpatient ward rather than in the ED, Dr. Chen said.
“Health systems privileged to have more than one facility should consider an intra–health system transfer process lead by triage hospitalists to identify stable patients who can be directly admitted to the off-site, affiliate hospital,” she said. “By improving patient throughput, hospitalists would play a critical role in relieving institutional stressors, impacting cost and quality of care, and enhancing clinical outcomes.”
Reference
1. Chen Y et al. Hospitalist-Directed Transfers Improve Emergency Room Length of Stay. Hospital Medicine 2018, Abstract 12. Accessed April 3, 2019.
Emergency department overcrowding is common, and it can result in both increased costs and poor clinical outcomes.
“We sought to evaluate the impact and safety of hospitalist-directed transfers on patients boarding in the ER as a means to alleviate overcrowding,” said Yihan Chen, MD, MPH, of the University of California, Los Angeles. “High inpatient census has been shown to impair ER throughput by increasing the number of ER ‘boarders,’ which creates a suboptimal care environment for practicing hospitalists. For example, some studies have shown associations with delays in medical decision making when admitted patients remain and receive care in the emergency department.”
Dr. Chen was the lead author of an abstract describing a chart review on 1,016 admissions to the hospitalist service. About half remained at the reference hospital and half were transferred to a nearby affiliate hospital.
In analyzing the data, the researchers’ top takeaway was the many benefits for the transferred patients. “Hospitalist-directed transfer and direct admission of stable ER patients to an affiliate facility with greater bed availability is associated with shorter ER lengths of stay, fewer adverse events, and lower rates of readmission within 30 days of hospitalization,” Dr. Chen said. “Having a system in place to transfer patients to an affiliate hospital with lower census is a way to improve flow.”
Hospitalists have a unique opportunity to take on a triage role in the ED to safely and effectively decrease ED overcrowding and throughput, improve resource utilization at the hospital level, and allow for other hospitalists at their institution to optimize patient care on the inpatient ward rather than in the ED, Dr. Chen said.
“Health systems privileged to have more than one facility should consider an intra–health system transfer process lead by triage hospitalists to identify stable patients who can be directly admitted to the off-site, affiliate hospital,” she said. “By improving patient throughput, hospitalists would play a critical role in relieving institutional stressors, impacting cost and quality of care, and enhancing clinical outcomes.”
Reference
1. Chen Y et al. Hospitalist-Directed Transfers Improve Emergency Room Length of Stay. Hospital Medicine 2018, Abstract 12. Accessed April 3, 2019.
CMS announces application process for Direct Contracting model
The Centers for Medicare & Medicaid Services will be accepting letters of intent from physician practices interested in participating in the Direct Contracting model, a new payment model aimed at practices serving at least 5,000 Medicare beneficiaries.
First announced in April 2019, the Direct Contracting program is an advanced alternative payment model designed for organizations that are ready to take on more financial risk and have experience managing large populations through accountable care organizations or working with Medicare Advantage plans.
Interested practices will be able to choose from the Professional population-based payment, which has a lower risk-sharing arrangement (50% savings/losses), and the Global model, which offers a 100% savings/loss risk-sharing arrangement.
“The payment model options available under Direct Contracting aim to reduce expenditures while preserving or enhancing quality of care for beneficiaries,” agency officials said on a web page detailing information for the payment model.
The model offers a prospectively determined and predictable revenue stream for participants and aims to transform risk-sharing arrangements through capitated and partially capitated population-based payments, open up participation in alternative payment models to more physicians, and reduce clinician burden by using smaller sets of quality measures and waivers to help facilitate the delivery of care.
Letters of intent are due to the agency by Dec. 10. CMS noted that submission of a letter of intent will not bind the organization to participating in the program.
The Centers for Medicare & Medicaid Services will be accepting letters of intent from physician practices interested in participating in the Direct Contracting model, a new payment model aimed at practices serving at least 5,000 Medicare beneficiaries.
First announced in April 2019, the Direct Contracting program is an advanced alternative payment model designed for organizations that are ready to take on more financial risk and have experience managing large populations through accountable care organizations or working with Medicare Advantage plans.
Interested practices will be able to choose from the Professional population-based payment, which has a lower risk-sharing arrangement (50% savings/losses), and the Global model, which offers a 100% savings/loss risk-sharing arrangement.
“The payment model options available under Direct Contracting aim to reduce expenditures while preserving or enhancing quality of care for beneficiaries,” agency officials said on a web page detailing information for the payment model.
The model offers a prospectively determined and predictable revenue stream for participants and aims to transform risk-sharing arrangements through capitated and partially capitated population-based payments, open up participation in alternative payment models to more physicians, and reduce clinician burden by using smaller sets of quality measures and waivers to help facilitate the delivery of care.
Letters of intent are due to the agency by Dec. 10. CMS noted that submission of a letter of intent will not bind the organization to participating in the program.
The Centers for Medicare & Medicaid Services will be accepting letters of intent from physician practices interested in participating in the Direct Contracting model, a new payment model aimed at practices serving at least 5,000 Medicare beneficiaries.
First announced in April 2019, the Direct Contracting program is an advanced alternative payment model designed for organizations that are ready to take on more financial risk and have experience managing large populations through accountable care organizations or working with Medicare Advantage plans.
Interested practices will be able to choose from the Professional population-based payment, which has a lower risk-sharing arrangement (50% savings/losses), and the Global model, which offers a 100% savings/loss risk-sharing arrangement.
“The payment model options available under Direct Contracting aim to reduce expenditures while preserving or enhancing quality of care for beneficiaries,” agency officials said on a web page detailing information for the payment model.
The model offers a prospectively determined and predictable revenue stream for participants and aims to transform risk-sharing arrangements through capitated and partially capitated population-based payments, open up participation in alternative payment models to more physicians, and reduce clinician burden by using smaller sets of quality measures and waivers to help facilitate the delivery of care.
Letters of intent are due to the agency by Dec. 10. CMS noted that submission of a letter of intent will not bind the organization to participating in the program.
FDA approves Tula system for recurrent pediatric ear infections
The Food and Drug Administration has approved the Tubes Under Local Anesthesia (Tula) System for treatment of recurrent ear infections (otitis media) via tympanostomy in young children, according to a release from the agency.
Consisting of Tymbion anesthetic, tympanostomy tubes developed by Tusker Medical, and several devices that deliver them into the ear drum,
“This approval has the potential to expand patient access to a treatment that can be administered in a physician’s office with local anesthesia and minimal discomfort,” said Jeff Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.
The approval was based on data from 222 children treated with the device, with a procedural success rate of 86% in children under 5 years and 89% in children aged 5-12 years. The most common adverse event was insufficient anesthetic.
The system should not be used in children with allergies to some local anesthetics or those younger than 6 months. It also is not intended for patients with preexisting issues with their eardrums, such as perforated ear drums, according to the press release.
The Tula system was granted a Breakthrough Device designation, which means the FDA provided intensive engagement and guidance during its development. The full release can be found on the FDA website.
The Food and Drug Administration has approved the Tubes Under Local Anesthesia (Tula) System for treatment of recurrent ear infections (otitis media) via tympanostomy in young children, according to a release from the agency.
Consisting of Tymbion anesthetic, tympanostomy tubes developed by Tusker Medical, and several devices that deliver them into the ear drum,
“This approval has the potential to expand patient access to a treatment that can be administered in a physician’s office with local anesthesia and minimal discomfort,” said Jeff Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.
The approval was based on data from 222 children treated with the device, with a procedural success rate of 86% in children under 5 years and 89% in children aged 5-12 years. The most common adverse event was insufficient anesthetic.
The system should not be used in children with allergies to some local anesthetics or those younger than 6 months. It also is not intended for patients with preexisting issues with their eardrums, such as perforated ear drums, according to the press release.
The Tula system was granted a Breakthrough Device designation, which means the FDA provided intensive engagement and guidance during its development. The full release can be found on the FDA website.
The Food and Drug Administration has approved the Tubes Under Local Anesthesia (Tula) System for treatment of recurrent ear infections (otitis media) via tympanostomy in young children, according to a release from the agency.
Consisting of Tymbion anesthetic, tympanostomy tubes developed by Tusker Medical, and several devices that deliver them into the ear drum,
“This approval has the potential to expand patient access to a treatment that can be administered in a physician’s office with local anesthesia and minimal discomfort,” said Jeff Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.
The approval was based on data from 222 children treated with the device, with a procedural success rate of 86% in children under 5 years and 89% in children aged 5-12 years. The most common adverse event was insufficient anesthetic.
The system should not be used in children with allergies to some local anesthetics or those younger than 6 months. It also is not intended for patients with preexisting issues with their eardrums, such as perforated ear drums, according to the press release.
The Tula system was granted a Breakthrough Device designation, which means the FDA provided intensive engagement and guidance during its development. The full release can be found on the FDA website.
Question 2
Q2. Correct Answer: D
Rationale
Elbasvir and grazoprevir are hepaticaly metabo¬lized and undergo minimal renal elimination making them safe for use in patients with end stage renal disease. The C-Surfer trial evaluated elbasvir and grazoprevir in genotype 1 patients with advanced renal disease inclusive of patients on hemodialysis. Cure rates in this trial were 94- 99 percent. Sofosbuvir containing regimen are not approved for patient with CKD stage 4-5 or those on hemodialysis, even when given in a dose reduced or post-dialysis fashion.
References
https://www.hcvguidelines.org/unique-popula¬tions/renal-impairment
Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treat¬ment experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-45.
Q2. Correct Answer: D
Rationale
Elbasvir and grazoprevir are hepaticaly metabo¬lized and undergo minimal renal elimination making them safe for use in patients with end stage renal disease. The C-Surfer trial evaluated elbasvir and grazoprevir in genotype 1 patients with advanced renal disease inclusive of patients on hemodialysis. Cure rates in this trial were 94- 99 percent. Sofosbuvir containing regimen are not approved for patient with CKD stage 4-5 or those on hemodialysis, even when given in a dose reduced or post-dialysis fashion.
References
https://www.hcvguidelines.org/unique-popula¬tions/renal-impairment
Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treat¬ment experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-45.
Q2. Correct Answer: D
Rationale
Elbasvir and grazoprevir are hepaticaly metabo¬lized and undergo minimal renal elimination making them safe for use in patients with end stage renal disease. The C-Surfer trial evaluated elbasvir and grazoprevir in genotype 1 patients with advanced renal disease inclusive of patients on hemodialysis. Cure rates in this trial were 94- 99 percent. Sofosbuvir containing regimen are not approved for patient with CKD stage 4-5 or those on hemodialysis, even when given in a dose reduced or post-dialysis fashion.
References
https://www.hcvguidelines.org/unique-popula¬tions/renal-impairment
Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treat¬ment experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-45.
A 47-year-old man with stage 5 chronic kidney disease on hemodialysis is referred to your clinic. He has genotype 1a HCV and F2 fibrosis. He wants to discuss treatment options.
Question 1
Q1. Correct answer: C
Rationale
There are many potential reasons for PPI failure in patients with symptoms of gastroesophageal reflux. However, the single most important reason is inappropriate drug administration. Patients should be counseled to take their medication 30-60 minutes prior to meals for optimal physiologic gastric acid inhibition, with the morning meal favored over the evening meal due to relative more gastric acid production at this time.
Reference
Fass R, Shapiro M, Dekel R. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease – where next? Aliment Pharmacol Ther. 2005;22:79-94.
Q1. Correct answer: C
Rationale
There are many potential reasons for PPI failure in patients with symptoms of gastroesophageal reflux. However, the single most important reason is inappropriate drug administration. Patients should be counseled to take their medication 30-60 minutes prior to meals for optimal physiologic gastric acid inhibition, with the morning meal favored over the evening meal due to relative more gastric acid production at this time.
Reference
Fass R, Shapiro M, Dekel R. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease – where next? Aliment Pharmacol Ther. 2005;22:79-94.
Q1. Correct answer: C
Rationale
There are many potential reasons for PPI failure in patients with symptoms of gastroesophageal reflux. However, the single most important reason is inappropriate drug administration. Patients should be counseled to take their medication 30-60 minutes prior to meals for optimal physiologic gastric acid inhibition, with the morning meal favored over the evening meal due to relative more gastric acid production at this time.
Reference
Fass R, Shapiro M, Dekel R. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease – where next? Aliment Pharmacol Ther. 2005;22:79-94.
.
What is your diagnosis?
Hodgkins lymphoma of the liver
The gallbladder (Figure B) as well as the intraoperative liver biopsy (Figure C; insert showing cells under higher power) showed non-necrotizing granulomas along with scattered infiltration by atypical large cells morphologically consistent with Hodgkin-Reed-Sternberg cells in a lymphoid background (Figures B, C, green arrows). Immunohistochemistry showed these were positive for CD30 (Figure D, liver biopsy), weakly positive for PAX5, and negative for CD15, CD20, CD79a, and ALK-1. Given the pathologic findings, the patient was diagnosed with Hodgkins lymphoma.
The patient had a history of mediastinoscopy and lymph node biopsy in the past at an outside hospital with reported noncaseating granulomas and no other abnormalities; those slides could not be obtained for independent review. Primary lymphomas of the liver are exceedingly rare, but advanced lymphoma can have liver involvement.1 Hodgkins lymphoma of the liver is extremely uncommon.2 It can present with fever, hepatomegaly, and jaundice.1 The diagnostic yield of a liver biopsy ranges from 5% to 10% depending on core versus wedge biopsy.1 Pathologically, there is portal inflammation and atypical histiocytic aggregates but Hodgkin-Reed-Sternberg cells are required for diagnosis. These cells stain positive for CD15 and CD30 in around 80% of cases.3 Lymphoma should remain in the differential when granulomas are seen in the liver biopsy. Our patient clinically decompensated by the time the diagnosis was confirmed. The family decided not to pursue aggressive treatment in hospital and the patient was discharged home where she expired.
References
1. in: R.N.M. MacSween (Ed.) Pathology of the liver. Edinburgh: Churchill Livingstone. ; 1979
2. Levitan R, Diamond H, Lloyd C. The liver in Hodgkin’s disease. Gut. 1961;2:60.
3. Kanel GC, Korula J. Atlas of liver pathology. Elsevier/Saunders, Philadelphia; 2005.
Hodgkins lymphoma of the liver
The gallbladder (Figure B) as well as the intraoperative liver biopsy (Figure C; insert showing cells under higher power) showed non-necrotizing granulomas along with scattered infiltration by atypical large cells morphologically consistent with Hodgkin-Reed-Sternberg cells in a lymphoid background (Figures B, C, green arrows). Immunohistochemistry showed these were positive for CD30 (Figure D, liver biopsy), weakly positive for PAX5, and negative for CD15, CD20, CD79a, and ALK-1. Given the pathologic findings, the patient was diagnosed with Hodgkins lymphoma.
The patient had a history of mediastinoscopy and lymph node biopsy in the past at an outside hospital with reported noncaseating granulomas and no other abnormalities; those slides could not be obtained for independent review. Primary lymphomas of the liver are exceedingly rare, but advanced lymphoma can have liver involvement.1 Hodgkins lymphoma of the liver is extremely uncommon.2 It can present with fever, hepatomegaly, and jaundice.1 The diagnostic yield of a liver biopsy ranges from 5% to 10% depending on core versus wedge biopsy.1 Pathologically, there is portal inflammation and atypical histiocytic aggregates but Hodgkin-Reed-Sternberg cells are required for diagnosis. These cells stain positive for CD15 and CD30 in around 80% of cases.3 Lymphoma should remain in the differential when granulomas are seen in the liver biopsy. Our patient clinically decompensated by the time the diagnosis was confirmed. The family decided not to pursue aggressive treatment in hospital and the patient was discharged home where she expired.
References
1. in: R.N.M. MacSween (Ed.) Pathology of the liver. Edinburgh: Churchill Livingstone. ; 1979
2. Levitan R, Diamond H, Lloyd C. The liver in Hodgkin’s disease. Gut. 1961;2:60.
3. Kanel GC, Korula J. Atlas of liver pathology. Elsevier/Saunders, Philadelphia; 2005.
Hodgkins lymphoma of the liver
The gallbladder (Figure B) as well as the intraoperative liver biopsy (Figure C; insert showing cells under higher power) showed non-necrotizing granulomas along with scattered infiltration by atypical large cells morphologically consistent with Hodgkin-Reed-Sternberg cells in a lymphoid background (Figures B, C, green arrows). Immunohistochemistry showed these were positive for CD30 (Figure D, liver biopsy), weakly positive for PAX5, and negative for CD15, CD20, CD79a, and ALK-1. Given the pathologic findings, the patient was diagnosed with Hodgkins lymphoma.
The patient had a history of mediastinoscopy and lymph node biopsy in the past at an outside hospital with reported noncaseating granulomas and no other abnormalities; those slides could not be obtained for independent review. Primary lymphomas of the liver are exceedingly rare, but advanced lymphoma can have liver involvement.1 Hodgkins lymphoma of the liver is extremely uncommon.2 It can present with fever, hepatomegaly, and jaundice.1 The diagnostic yield of a liver biopsy ranges from 5% to 10% depending on core versus wedge biopsy.1 Pathologically, there is portal inflammation and atypical histiocytic aggregates but Hodgkin-Reed-Sternberg cells are required for diagnosis. These cells stain positive for CD15 and CD30 in around 80% of cases.3 Lymphoma should remain in the differential when granulomas are seen in the liver biopsy. Our patient clinically decompensated by the time the diagnosis was confirmed. The family decided not to pursue aggressive treatment in hospital and the patient was discharged home where she expired.
References
1. in: R.N.M. MacSween (Ed.) Pathology of the liver. Edinburgh: Churchill Livingstone. ; 1979
2. Levitan R, Diamond H, Lloyd C. The liver in Hodgkin’s disease. Gut. 1961;2:60.
3. Kanel GC, Korula J. Atlas of liver pathology. Elsevier/Saunders, Philadelphia; 2005.
Two months later, repeat laboratory tests showed aspartate aminotransferase of 213 U/L, alanine aminotransferase of 93 U/L, alkaline phosphatase of 1,472 U/L, and total bilirubin of 6.0 mg/dL. The initial ultrasound scan was normal. On further assessment, she complained of malaise, weight loss, shortness of breath, dry eyes, dry mouth, and insomnia. She denied any significant alcohol use. No new medications or supplements were started recently. Vital signs were normal. Physical examination was unremarkable. Viral hepatitis serologies were negative. Antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody were negative. She had a magnetic resonance cholangiopancreatography, which showed splenomegaly but was otherwise unremarkable. She had a liver biopsy (Figure A), which showed non-necrotizing granulomas (yellow arrows) with a chronic inflammatory lymphocytic infiltrate.
Given these findings, prednisone was increased to 20 mg. In the interim, the patient was admitted with acute acalculous cholecystitis. She had a laparoscopic cholecystectomy and an intraoperative liver biopsy. She developed respiratory failure postoperatively and was transferred to intensive care. Stress dose steroids and antibiotics were initiated. Laboratory tests showed a white blood cell count of 13.8 × 109/L, hemoglobin of 9.4 g/dL, platelets at 223 × 109/L, aspartate aminotransferase of 97 U/L, alanine aminotransferase of 63 U/L, alkaline phosphatase of 1,607 U/L, total bilirubin of 5.8 mg/dL (direct 3.3), and albumin of 2.4 g/dL. Pathology from the gallbladder (Figure B) and the intraoperative liver biopsy (Figure C) showed cells pathognomonic for the condition (green arrows).
On the basis of these findings, what is the final diagnosis?
