Brain Glucose Level Is Associated With Alzheimer’s Disease Severity

Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.

An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].

Is it Better to Be Asleep or Awake for DBS Implantation?

Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake. Assessments included an off-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson’s Disease Questionnaire, motor diaries, and speech fluency. No difference was observed in improvement of UPDRS III or UPDRS II. Improvement in on time without dyskinesia was superior in asleep implantation. Quality of life scores improved in both groups. Improvement in summary index and subscores for cognition and communication were superior in implantation while asleep.

Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.

Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?

People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular volume, 110 mm³ smaller hippocampal volume, 519 mm³ smaller occipital volume, and 532 mm³ smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.

Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].

Novel Wristbands Improve Seizure Detection

Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.

Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.

Focused Ultrasound Reduces Parkinson’s Disease Tremor

Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.

Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].

Biomarker of Multiple Sclerosis Identified

MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.

Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.

Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?

The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.

Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].

Dendritic Spine Plasticity May Protect Against Dementia

Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.

Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.

Opioid Versus Nonopioid Treatment for Acute Migraine

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.

Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].

Frontotemporal Degeneration Entails High Economic Burden

The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.

Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].

FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy

The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.

—Kimberly Williams

Brain Glucose Level Is Associated With Alzheimer’s Disease Severity

Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.

An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].

Is it Better to Be Asleep or Awake for DBS Implantation?

Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake. Assessments included an off-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson’s Disease Questionnaire, motor diaries, and speech fluency. No difference was observed in improvement of UPDRS III or UPDRS II. Improvement in on time without dyskinesia was superior in asleep implantation. Quality of life scores improved in both groups. Improvement in summary index and subscores for cognition and communication were superior in implantation while asleep.

Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.

Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?

People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular volume, 110 mm³ smaller hippocampal volume, 519 mm³ smaller occipital volume, and 532 mm³ smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.

Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].

Novel Wristbands Improve Seizure Detection

Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.

Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.

Focused Ultrasound Reduces Parkinson’s Disease Tremor

Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.

Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].

Biomarker of Multiple Sclerosis Identified

MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.

Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.

Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?

The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.

Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].

Dendritic Spine Plasticity May Protect Against Dementia

Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.

Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.

Opioid Versus Nonopioid Treatment for Acute Migraine

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.

Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].

Frontotemporal Degeneration Entails High Economic Burden

The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.

Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].

FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy

The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.

—Kimberly Williams

Brain Glucose Level Is Associated With Alzheimer’s Disease Severity

Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.

An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].

Is it Better to Be Asleep or Awake for DBS Implantation?

Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake. Assessments included an off-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson’s Disease Questionnaire, motor diaries, and speech fluency. No difference was observed in improvement of UPDRS III or UPDRS II. Improvement in on time without dyskinesia was superior in asleep implantation. Quality of life scores improved in both groups. Improvement in summary index and subscores for cognition and communication were superior in implantation while asleep.

Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.

Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?

People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular volume, 110 mm³ smaller hippocampal volume, 519 mm³ smaller occipital volume, and 532 mm³ smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.

Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].

Novel Wristbands Improve Seizure Detection

Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.

Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.

Focused Ultrasound Reduces Parkinson’s Disease Tremor

Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.

Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].

Biomarker of Multiple Sclerosis Identified

MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.

Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.

Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?

The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.

Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].

Dendritic Spine Plasticity May Protect Against Dementia

Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.

Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.

Opioid Versus Nonopioid Treatment for Acute Migraine

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.

Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].

Frontotemporal Degeneration Entails High Economic Burden

The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.

Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].

FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy

The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.

—Kimberly Williams

SAN DIEGO – The first validation study of proposed new classification criteria for systemic lupus erythematosus (SLE) yielded a sensitivity of 98% and a specificity of 97%.

The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SAN DIEGO – The first validation study of proposed new classification criteria for systemic lupus erythematosus (SLE) yielded a sensitivity of 98% and a specificity of 97%.

The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SAN DIEGO – The first validation study of proposed new classification criteria for systemic lupus erythematosus (SLE) yielded a sensitivity of 98% and a specificity of 97%.

The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SAN DIEGO – A study of procedures at academic centers provides evidence that obese Hispanics in the United States undergo bariatric surgery at a much lower rate than whites and blacks. It also reveals marked regional variations in overall weight-loss surgery.

“Our findings do suggest that severely obese Hispanics are utilizing bariatric surgery much lower than other ethnic groups,” said study coauthor Ninh T. Nguyen, MD, FACS, chair of the department of surgery at the University of California Irvine Medical Center, in an interview. “Our research does not specifically address the reasons for this gap in the delivery of care. Further research will need to be done to understand the reasons and the ways to close this gap.”

SAN DIEGO – A study of procedures at academic centers provides evidence that obese Hispanics in the United States undergo bariatric surgery at a much lower rate than whites and blacks. It also reveals marked regional variations in overall weight-loss surgery.

“Our findings do suggest that severely obese Hispanics are utilizing bariatric surgery much lower than other ethnic groups,” said study coauthor Ninh T. Nguyen, MD, FACS, chair of the department of surgery at the University of California Irvine Medical Center, in an interview. “Our research does not specifically address the reasons for this gap in the delivery of care. Further research will need to be done to understand the reasons and the ways to close this gap.”

SAN DIEGO – A study of procedures at academic centers provides evidence that obese Hispanics in the United States undergo bariatric surgery at a much lower rate than whites and blacks. It also reveals marked regional variations in overall weight-loss surgery.

“Our findings do suggest that severely obese Hispanics are utilizing bariatric surgery much lower than other ethnic groups,” said study coauthor Ninh T. Nguyen, MD, FACS, chair of the department of surgery at the University of California Irvine Medical Center, in an interview. “Our research does not specifically address the reasons for this gap in the delivery of care. Further research will need to be done to understand the reasons and the ways to close this gap.”

Do you know we have record rates of physician burnout, dissatisfaction, and suicide? Ongoing shortages in primary care, without improvement in sight? Physicians exiting medicine earlier than in the past?

What about burnout? Do you know it affects patients as well as their doctors? Affects physicians’ families and friends? Increases mistakes and malpractice risk? Affects patient adherence and outcomes? Is costly to the entire system?

How do we start to fix this? The framework for a discussion on physician wellness begins with attention to three levels: personal wellness, organizational wellness, and wellness within the culture of medicine.

Darrin Klimek/Thinkstock

Dr. Stepien practices pediatrics in Juneau, Alaska. She is on the Pediatric News editorial advisory board. Email her at pdnews@frontlinemedcom.com

Do you know we have record rates of physician burnout, dissatisfaction, and suicide? Ongoing shortages in primary care, without improvement in sight? Physicians exiting medicine earlier than in the past?

What about burnout? Do you know it affects patients as well as their doctors? Affects physicians’ families and friends? Increases mistakes and malpractice risk? Affects patient adherence and outcomes? Is costly to the entire system?

How do we start to fix this? The framework for a discussion on physician wellness begins with attention to three levels: personal wellness, organizational wellness, and wellness within the culture of medicine.

Darrin Klimek/Thinkstock

Dr. Stepien practices pediatrics in Juneau, Alaska. She is on the Pediatric News editorial advisory board. Email her at pdnews@frontlinemedcom.com

Do you know we have record rates of physician burnout, dissatisfaction, and suicide? Ongoing shortages in primary care, without improvement in sight? Physicians exiting medicine earlier than in the past?

What about burnout? Do you know it affects patients as well as their doctors? Affects physicians’ families and friends? Increases mistakes and malpractice risk? Affects patient adherence and outcomes? Is costly to the entire system?

How do we start to fix this? The framework for a discussion on physician wellness begins with attention to three levels: personal wellness, organizational wellness, and wellness within the culture of medicine.

Darrin Klimek/Thinkstock

Dr. Stepien practices pediatrics in Juneau, Alaska. She is on the Pediatric News editorial advisory board. Email her at pdnews@frontlinemedcom.com

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Advances in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, venous thromboembolism (VTE), and acquired thrombotic thrombocytopenic purpura will headline the late-breaking trials session at this year’s annual meeting of the American Society of Hematology in Atlanta.

In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.

In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.

The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.

In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.

In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.

“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.

Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.

In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.

Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”

Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.

With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.

The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.

This year’s late-breaking abstracts at ASH are:

LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.

LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.

LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).

LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.

LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

Advances in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, venous thromboembolism (VTE), and acquired thrombotic thrombocytopenic purpura will headline the late-breaking trials session at this year’s annual meeting of the American Society of Hematology in Atlanta.

In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.

In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.

The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.

In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.

In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.

“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.

Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.

In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.

Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”

Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.

With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.

The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.

This year’s late-breaking abstracts at ASH are:

LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.

LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.

LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).

LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.

LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

Advances in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, venous thromboembolism (VTE), and acquired thrombotic thrombocytopenic purpura will headline the late-breaking trials session at this year’s annual meeting of the American Society of Hematology in Atlanta.

In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.

In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.

The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.

In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.

In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.

“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.

Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.

In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.

Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”

Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.

With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.

The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.

This year’s late-breaking abstracts at ASH are:

LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.

LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.

LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).

LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.

LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

Over the last several years, there’s been increasing interest and ultimately a growing number of mandates across dozens of states to screen women for postpartum depression (PPD). As PPD is the most common, and often devastating, complication in modern obstetrics, screening for it is a movement that I fully support.

What’s been challenging is how to roll out screening in a widespread fashion using a standardized tool that is both easy to use and to score, and that has only a modest number of false positives (i.e., it has good specificity).

KrisCole/Thinkstock

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Over the last several years, there’s been increasing interest and ultimately a growing number of mandates across dozens of states to screen women for postpartum depression (PPD). As PPD is the most common, and often devastating, complication in modern obstetrics, screening for it is a movement that I fully support.

What’s been challenging is how to roll out screening in a widespread fashion using a standardized tool that is both easy to use and to score, and that has only a modest number of false positives (i.e., it has good specificity).

KrisCole/Thinkstock

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Over the last several years, there’s been increasing interest and ultimately a growing number of mandates across dozens of states to screen women for postpartum depression (PPD). As PPD is the most common, and often devastating, complication in modern obstetrics, screening for it is a movement that I fully support.

What’s been challenging is how to roll out screening in a widespread fashion using a standardized tool that is both easy to use and to score, and that has only a modest number of false positives (i.e., it has good specificity).

KrisCole/Thinkstock

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

The benefits of integrating hysteroscopy into office practice have been compelling for some time. An in-office approach is patient centered, more efficient, and clinically valuable. It also has had the potential to be economically valuable for practices that are able to perform a mix of diagnostic and therapeutic/operative hysteroscopies.

Dramatic shifts within the Centers for Medicare & Medicaid Services fee schedule in 2017 – and commensurate changes in the private insurance market – have now ramped up this value, making it all the more important that physicians consider investing in equipment and adopting an in-office approach.

Weighing an investment

In the Medicare resource-based relative value scale payment system, relative value units (RVUs) are calculated based on three elements: physician work, practice expenses, and malpractice cost. Each component is multiplied by a factor that accounts for geographic cost variations, and each total RVU is multiplied by a dollar amount known as the conversion factor.

This isn’t the first year that the payment system – a standard for many other payers in determining compensation – allows for higher reimbursement for some hysteroscopic procedures performed in the office. The practice expense relative units have been higher for some time for certain hysteroscopic procedures – such as diagnostic hysteroscopy (code 58555), removal of a foreign body (58562), endometrial ablation (58353), and biopsy/polypectomy (58558) – when these procedures are performed in the office, compared with the hospital or an ambulatory surgical center.

However, the new increase in physician office payment for 58558 changes the equation significantly and ensures a better return on investment. In 2017, CMS offered a 12% increase in the facility fee paid to hospitals and a 2% increase in the facility fee paid to outpatient surgery centers when a hysteroscopic biopsy/polypectomy is performed in these settings, but the physician reimbursement in these cases declined 11%-19%.

On the flip side, an in-office approach to hysteroscopic biopsy/polypectomy has been rewarded in 2017 through a significantly higher practice expense RVU and a “non-facility” total RVU of 38.51 – a 237% increase over the 2016 practice expense RVU of 11.4. Such dramatic differences between the practice RVUs – and total RVUs – for in-office and out-of-office hysteroscopic procedures will continue for 2018.

Private insurers are following suit, and some are increasing their reimbursement even more. As of June 2017 in metropolitan Chicago, Blue Cross Blue Shield has been reimbursing in-office hysteroscopic biopsy/polypectomy at approximately $2,424.00; prior to June, the allowable charge was $742.81.

Equipment costs for in-office hysteroscopy can range from $15,000 to $35,000, based on whether equipment is new or used, the number of trays, and the style of camera and monitor system. Ancillary equipment/disposables cost $10 or less, and $40-$50 or less for diagnostic and many operative procedures, respectively. The prices for handpiece mechanical resection disposables or tissue removal devices vary based on company and blade type, so these costs will need to be accounted for if such equipment is incorporated. Again, the CMS increase in reimbursement for offices accommodates for the inclusion of these disposables as well as fluid management disposable costs.

If diagnostic hysteroscopy (as a separate procedure) is the procedure that you perform most often, the investment will look less favorable. However, if you anticipate performing hysteroscopic biopsies and/or polypectomies as well, the investment will look significantly more favorable now than it has in past years.

Once you have established your in-office system, even those procedures that are weighted equally for the practice setting (non-facility) and hospital/surgery center setting, such as hysteroscopic lysis of adhesions (58559), can be easily incorporated from a financial point of view.

In addition to reimbursement levels, it’s important to consider the efficiencies of in-office hysteroscopy. The setup is relatively simple and requires a dedicated exam room, not a surgical suite. You can perform one or two annual exams while the assistant sets up the room and greets each patient, for instance, or see another established patient while the assistant discharges your patient and turns the room over. Hysteroscopy at the hospital, or even at an ambulatory surgical center, involves time driving, changing, and waiting for anesthesia.

For our patients, most importantly, an in-office approach offers less out-of-pocket expense (deductibles), less time away from family/work, avoidance of general anesthesia/intubation, and greater patient comfort from being within a familiar environment. For diagnostic procedures, the patient can be in and out in less than 30 minutes, and for operative procedures, she can be in and out in 1-2 hours, compared with more than 4 hours at the hospital.
 

Preparing the office

Physicians in Europe have been performing in-office hysteroscopy for years. But in the United States, it is a newer concept, with most gynecologic surgeons having been taught to perform surgical procedures in the operating room. Undoubtedly, our unfamiliarity with in-office surgery has played a role in the slow uptake of hysteroscopy in our practices.

Courtesy Dr. Amy Garcia

Dr. Cholkeri-Singh is with the University of Illinois at Chicago, and is director of gynecologic surgical education and associate director of minimally invasive gynecology at Advocate Lutheran General Hospital in Park Ridge, Ill. She is in private practice in Chicago. She is a consultant for Hologic, Bayer HealthCare, Olympus, Caldera Medical, Karl Storz, Medtronic, DYSIS Medical, and Channel Medsystems.

The benefits of integrating hysteroscopy into office practice have been compelling for some time. An in-office approach is patient centered, more efficient, and clinically valuable. It also has had the potential to be economically valuable for practices that are able to perform a mix of diagnostic and therapeutic/operative hysteroscopies.

Dramatic shifts within the Centers for Medicare & Medicaid Services fee schedule in 2017 – and commensurate changes in the private insurance market – have now ramped up this value, making it all the more important that physicians consider investing in equipment and adopting an in-office approach.

Weighing an investment

In the Medicare resource-based relative value scale payment system, relative value units (RVUs) are calculated based on three elements: physician work, practice expenses, and malpractice cost. Each component is multiplied by a factor that accounts for geographic cost variations, and each total RVU is multiplied by a dollar amount known as the conversion factor.

This isn’t the first year that the payment system – a standard for many other payers in determining compensation – allows for higher reimbursement for some hysteroscopic procedures performed in the office. The practice expense relative units have been higher for some time for certain hysteroscopic procedures – such as diagnostic hysteroscopy (code 58555), removal of a foreign body (58562), endometrial ablation (58353), and biopsy/polypectomy (58558) – when these procedures are performed in the office, compared with the hospital or an ambulatory surgical center.

However, the new increase in physician office payment for 58558 changes the equation significantly and ensures a better return on investment. In 2017, CMS offered a 12% increase in the facility fee paid to hospitals and a 2% increase in the facility fee paid to outpatient surgery centers when a hysteroscopic biopsy/polypectomy is performed in these settings, but the physician reimbursement in these cases declined 11%-19%.

On the flip side, an in-office approach to hysteroscopic biopsy/polypectomy has been rewarded in 2017 through a significantly higher practice expense RVU and a “non-facility” total RVU of 38.51 – a 237% increase over the 2016 practice expense RVU of 11.4. Such dramatic differences between the practice RVUs – and total RVUs – for in-office and out-of-office hysteroscopic procedures will continue for 2018.

Private insurers are following suit, and some are increasing their reimbursement even more. As of June 2017 in metropolitan Chicago, Blue Cross Blue Shield has been reimbursing in-office hysteroscopic biopsy/polypectomy at approximately $2,424.00; prior to June, the allowable charge was $742.81.

Equipment costs for in-office hysteroscopy can range from $15,000 to $35,000, based on whether equipment is new or used, the number of trays, and the style of camera and monitor system. Ancillary equipment/disposables cost $10 or less, and $40-$50 or less for diagnostic and many operative procedures, respectively. The prices for handpiece mechanical resection disposables or tissue removal devices vary based on company and blade type, so these costs will need to be accounted for if such equipment is incorporated. Again, the CMS increase in reimbursement for offices accommodates for the inclusion of these disposables as well as fluid management disposable costs.

If diagnostic hysteroscopy (as a separate procedure) is the procedure that you perform most often, the investment will look less favorable. However, if you anticipate performing hysteroscopic biopsies and/or polypectomies as well, the investment will look significantly more favorable now than it has in past years.

Once you have established your in-office system, even those procedures that are weighted equally for the practice setting (non-facility) and hospital/surgery center setting, such as hysteroscopic lysis of adhesions (58559), can be easily incorporated from a financial point of view.

In addition to reimbursement levels, it’s important to consider the efficiencies of in-office hysteroscopy. The setup is relatively simple and requires a dedicated exam room, not a surgical suite. You can perform one or two annual exams while the assistant sets up the room and greets each patient, for instance, or see another established patient while the assistant discharges your patient and turns the room over. Hysteroscopy at the hospital, or even at an ambulatory surgical center, involves time driving, changing, and waiting for anesthesia.

For our patients, most importantly, an in-office approach offers less out-of-pocket expense (deductibles), less time away from family/work, avoidance of general anesthesia/intubation, and greater patient comfort from being within a familiar environment. For diagnostic procedures, the patient can be in and out in less than 30 minutes, and for operative procedures, she can be in and out in 1-2 hours, compared with more than 4 hours at the hospital.
 

Preparing the office

Physicians in Europe have been performing in-office hysteroscopy for years. But in the United States, it is a newer concept, with most gynecologic surgeons having been taught to perform surgical procedures in the operating room. Undoubtedly, our unfamiliarity with in-office surgery has played a role in the slow uptake of hysteroscopy in our practices.

Courtesy Dr. Amy Garcia

Dr. Cholkeri-Singh is with the University of Illinois at Chicago, and is director of gynecologic surgical education and associate director of minimally invasive gynecology at Advocate Lutheran General Hospital in Park Ridge, Ill. She is in private practice in Chicago. She is a consultant for Hologic, Bayer HealthCare, Olympus, Caldera Medical, Karl Storz, Medtronic, DYSIS Medical, and Channel Medsystems.

The benefits of integrating hysteroscopy into office practice have been compelling for some time. An in-office approach is patient centered, more efficient, and clinically valuable. It also has had the potential to be economically valuable for practices that are able to perform a mix of diagnostic and therapeutic/operative hysteroscopies.

Dramatic shifts within the Centers for Medicare & Medicaid Services fee schedule in 2017 – and commensurate changes in the private insurance market – have now ramped up this value, making it all the more important that physicians consider investing in equipment and adopting an in-office approach.

Weighing an investment

In the Medicare resource-based relative value scale payment system, relative value units (RVUs) are calculated based on three elements: physician work, practice expenses, and malpractice cost. Each component is multiplied by a factor that accounts for geographic cost variations, and each total RVU is multiplied by a dollar amount known as the conversion factor.

This isn’t the first year that the payment system – a standard for many other payers in determining compensation – allows for higher reimbursement for some hysteroscopic procedures performed in the office. The practice expense relative units have been higher for some time for certain hysteroscopic procedures – such as diagnostic hysteroscopy (code 58555), removal of a foreign body (58562), endometrial ablation (58353), and biopsy/polypectomy (58558) – when these procedures are performed in the office, compared with the hospital or an ambulatory surgical center.

However, the new increase in physician office payment for 58558 changes the equation significantly and ensures a better return on investment. In 2017, CMS offered a 12% increase in the facility fee paid to hospitals and a 2% increase in the facility fee paid to outpatient surgery centers when a hysteroscopic biopsy/polypectomy is performed in these settings, but the physician reimbursement in these cases declined 11%-19%.

On the flip side, an in-office approach to hysteroscopic biopsy/polypectomy has been rewarded in 2017 through a significantly higher practice expense RVU and a “non-facility” total RVU of 38.51 – a 237% increase over the 2016 practice expense RVU of 11.4. Such dramatic differences between the practice RVUs – and total RVUs – for in-office and out-of-office hysteroscopic procedures will continue for 2018.

Private insurers are following suit, and some are increasing their reimbursement even more. As of June 2017 in metropolitan Chicago, Blue Cross Blue Shield has been reimbursing in-office hysteroscopic biopsy/polypectomy at approximately $2,424.00; prior to June, the allowable charge was $742.81.

Equipment costs for in-office hysteroscopy can range from $15,000 to $35,000, based on whether equipment is new or used, the number of trays, and the style of camera and monitor system. Ancillary equipment/disposables cost $10 or less, and $40-$50 or less for diagnostic and many operative procedures, respectively. The prices for handpiece mechanical resection disposables or tissue removal devices vary based on company and blade type, so these costs will need to be accounted for if such equipment is incorporated. Again, the CMS increase in reimbursement for offices accommodates for the inclusion of these disposables as well as fluid management disposable costs.

If diagnostic hysteroscopy (as a separate procedure) is the procedure that you perform most often, the investment will look less favorable. However, if you anticipate performing hysteroscopic biopsies and/or polypectomies as well, the investment will look significantly more favorable now than it has in past years.

Once you have established your in-office system, even those procedures that are weighted equally for the practice setting (non-facility) and hospital/surgery center setting, such as hysteroscopic lysis of adhesions (58559), can be easily incorporated from a financial point of view.

In addition to reimbursement levels, it’s important to consider the efficiencies of in-office hysteroscopy. The setup is relatively simple and requires a dedicated exam room, not a surgical suite. You can perform one or two annual exams while the assistant sets up the room and greets each patient, for instance, or see another established patient while the assistant discharges your patient and turns the room over. Hysteroscopy at the hospital, or even at an ambulatory surgical center, involves time driving, changing, and waiting for anesthesia.

For our patients, most importantly, an in-office approach offers less out-of-pocket expense (deductibles), less time away from family/work, avoidance of general anesthesia/intubation, and greater patient comfort from being within a familiar environment. For diagnostic procedures, the patient can be in and out in less than 30 minutes, and for operative procedures, she can be in and out in 1-2 hours, compared with more than 4 hours at the hospital.
 

Preparing the office

Physicians in Europe have been performing in-office hysteroscopy for years. But in the United States, it is a newer concept, with most gynecologic surgeons having been taught to perform surgical procedures in the operating room. Undoubtedly, our unfamiliarity with in-office surgery has played a role in the slow uptake of hysteroscopy in our practices.

Courtesy Dr. Amy Garcia

Dr. Cholkeri-Singh is with the University of Illinois at Chicago, and is director of gynecologic surgical education and associate director of minimally invasive gynecology at Advocate Lutheran General Hospital in Park Ridge, Ill. She is in private practice in Chicago. She is a consultant for Hologic, Bayer HealthCare, Olympus, Caldera Medical, Karl Storz, Medtronic, DYSIS Medical, and Channel Medsystems.

As a practicing reproductive endocrinologist and minimally invasive gynecologic surgeon, falling reimbursement has become routine. Furthermore, it was disadvantageous to perform in-office procedures while physician reimbursement was similar whether cases were performed in office, the hospital, or a surgery center. Higher procedural costs in the office, including reusable and disposable instrumentation and staffing, actually discouraged the physician who wanted to perform cases in the office, as it led to an overall reduction in reimbursement. Of course, certain outlying procedures have been reimbursed at a far greater rate in office and, as a result, global endometrial ablation and the Essure procedure now are generally performed in office.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago; director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column. He is a consultant for Medtronic.

As a practicing reproductive endocrinologist and minimally invasive gynecologic surgeon, falling reimbursement has become routine. Furthermore, it was disadvantageous to perform in-office procedures while physician reimbursement was similar whether cases were performed in office, the hospital, or a surgery center. Higher procedural costs in the office, including reusable and disposable instrumentation and staffing, actually discouraged the physician who wanted to perform cases in the office, as it led to an overall reduction in reimbursement. Of course, certain outlying procedures have been reimbursed at a far greater rate in office and, as a result, global endometrial ablation and the Essure procedure now are generally performed in office.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago; director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column. He is a consultant for Medtronic.

As a practicing reproductive endocrinologist and minimally invasive gynecologic surgeon, falling reimbursement has become routine. Furthermore, it was disadvantageous to perform in-office procedures while physician reimbursement was similar whether cases were performed in office, the hospital, or a surgery center. Higher procedural costs in the office, including reusable and disposable instrumentation and staffing, actually discouraged the physician who wanted to perform cases in the office, as it led to an overall reduction in reimbursement. Of course, certain outlying procedures have been reimbursed at a far greater rate in office and, as a result, global endometrial ablation and the Essure procedure now are generally performed in office.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago; director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column. He is a consultant for Medtronic.

Given the frequency, potential preventability, and costs associated with hospital readmissions, reducing readmissions is a priority in efforts to improve the quality and value of healthcare.^1,2 State and national bodies have created diverse initiatives to facilitate improvements in hospital discharge practices and reduce 30-day readmission rates across payers.^3-5 For example, the Agency for Healthcare Research and Quality (AHRQ) and the Institute for Healthcare Improvement have published tools for improving discharge practices.^6,7 Medicare instituted financial penalties for hospitals with higher-than-expected readmission rates for acute myocardial infarction (AMI), heart failure (HF), and pneumonia in 2012, while private payers and Medicaid programs have established their own policies.^8-13 Furthermore, private payers and Medicaid programs shifted toward capitated and value-based reimbursement models in which readmissions lead to financial losses for hospitals.^14,15 Accordingly, hospitals have implemented diverse interventions to reduce readmissions.^16,17 From 2009 to 2013, 30-day readmissions declined among privately insured adults (from 12.4% to 11.7%), Medicare patients (from 22.0% to 20.0%), and uninsured individuals (11.5% to 11.0%) but climbed among patients with Medicaid (from 19.8% to 20.5%) after index admissions for AMI, HF, pneumonia, or chronic obstructive pulmonary disease.¹⁸

To date, research, policies, and quality improvement interventions have largely focused on improvements to one aspect of the system of care—that provided in the inpatient setting—among older adults with Medicare. Yet, inpatient readmissions may underestimate how often patients return to the hospital because patients can be placed under observation or stabilized and discharged from the emergency department (ED) instead of being readmitted. Observation and ED visits are less costly to payers than inpatient admissions.¹⁹ Thus, information about utilization of inpatient, observation, and ED visits within 30 days of hospital discharge may be more informative than inpatient readmissions alone. However, little is known about trends in returns to the hospital for observation and ED visits and whether such trends vary by payer.

Our objective was to assess whether changes have occurred in rates of total 30-day, all-cause, unplanned returns to the hospital among adults with index admissions for AMI, HF, and pneumonia in which returns to the hospital included inpatient readmissions, observation visits, and ED visits. We also assessed whether changes in the rate of hospital inpatient readmissions coincided with changes in rates of returns for ED or observation visits. To examine the effects of readmission policies implemented by diverse payers and broad changes to the health system following the Affordable Care Act, we compared data from 201 hospitals in 4 states in 2009 and 2010 with data from the same hospitals for 2013 and 2014.

Data Sources, Populations, and Study Variables

We used Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases, State Emergency Department Databases, and State Ambulatory Surgery and Services Databases from Georgia, Nebraska, South Carolina, and Tennessee. These states comprise 7% of the US population and were the only states with data that included all observation and ED visits as well as encrypted patient identification numbers that permitted linkage across facilities and hospitals.²⁰

Index admissions for patients aged 18 years and older were eligible if they occurred at nonfederal general medical/surgical hospitals (excluding critical access hospitals) that had at least 1 index admission per target condition per year and at least 5 inpatient, observation, and ED visits for any condition per year.

We classified patients into the following 4 populations by age and insurance coverage: 18 to 64 years with private insurance, 65 years and older with Medicare (excluding younger adults with Medicare), 18 to 64 years with Medicaid, and 18 to 64 years without insurance. We identified patients aged 65 years and older with Medicare by using the primary or secondary expected payer for the index admission. This group included patients who were dually eligible for Medicare and Medicaid. If Medicare was not the primary or secondary payer, we used the primary payer to identify Medicaid, privately insured, and uninsured patients aged 18 to 64 years. None of the states expanded Medicaid coverage during the years studied.

The primary outcome of interest was the rate of having 1 or more all-cause, unplanned return(s) to an acute care hospital within 30 days of discharge after an index admission for AMI, HF, and pneumonia as defined by a modified version of Centers for Medicare & Medicaid Services’ readmission metrics.^21,22 We examined total return rates as well as rates for inpatient, observation, and ED care. We also examined the leading diagnoses associated with returns to the hospital. For each index admission, we included only 1 return visit, giving priority to inpatient readmissions, then observation visits, and then ED visits.

The HCUP databases are consistent with the definition of limited data sets under the Health Insurance Portability and Accountability Act Privacy Rule and contain no direct patient identifiers. The AHRQ Institutional Review Board considers research using HCUP data to have exempt status.

Statistical Analysis

To compare rates at which patients returned to the hospital during 2 cohort periods (2009 and 2010 vs 2013 and 2014), we used coarsened exact matching, a well-established matching technique for balancing covariates between 2 populations of patients that may be related to the outcome.²³ For observational datasets, coarsened exact matching is preferable to traditional matching because it enables the investigator to assess balance between the 2 populations, select the desired degree of balance, and eliminate observations for which comparable matches cannot be found.

We assembled sets of index admissions in each study period that were similar with respect to payer, primary diagnosis, and other factors. Matching variables included the patient’s age group, sex, and Elixhauser Comorbidity Index²⁴ (in deciles), as well as the hospital’s ratio of observation visits relative to inpatient admissions in 2009 and 2010 combined (in quartiles; see supplementary Appendix). For Medicare beneficiaries, we also matched on dual enrollment in Medicaid.

We conducted the matching process separately for each target condition and payer population. First, we grouped index admissions in both periods into strata defined by all possible combinations of the matching variables and allowing one-to-many random matching within strata. We then dropped records in any strata for which there were no records in 1 of the time periods. Finally, we calculated weights based on the size of each stratum. We used these weights to account for the different numbers of index admissions in each stratum between the 2 study periods. For example, if a stratum contained 10 index admissions in 2009 and 2010 combined and 20 in 2013 and 2014 combined, an admission weighed double in the earlier period. After weighting, the index admissions in each period (2009 and 2010; 2013 and 2014) had similar characteristics (Table 1).

There were 423,503 eligible index admissions for AMI, HF, and pneumonia in the 2 periods combined; 422,840 (99.8%) were successfully matched and included in this analysis. After matching weights were applied, there were few statistically significant differences across the 2 time periods (see Table 1 and supplementary Appendix).

From 2009 and 2010 to 2013 and 2014, the percentage of patients hospitalized for AMI, HF, and pneumonia who had only observation or ED visits when they returned to the hospital increased from 41.4% to 46.7% among patients with private insurance (P < 0.001), from 27.8% to 32.1% among older patients with Medicare (P < 0.001), from 39.5% to 41.8% among patients with Medicaid (P = 0.03), and from 49.2% to 52.8% among patients without insurance (P = 0.004; Table 1). The percentage of returns to the hospital for observation increased across all payers (P < 0.001); in 2013 and 2014 combined, observation visits ranged from 6.8% of hospital returns among patients with Medicare to 11.1% among patients with private insurance. The percentage of returns to the hospital for an ED visit increased among patients with private insurance (P = 0.02) and Medicare (P < 0.001); in 2013 and 2014, ED visits ranged from 25.3% of returns to the hospital among patients with Medicare to 42.9% among uninsured patients.

The increases in 30-day observation and ED visits coincided with reductions in inpatient readmissions among patients with private insurance and Medicare and contributed to growth in total returns to the hospital among patients with Medicaid or no insurance (Figure 1).

Matching index admissions for AMI, HF, or pneumonia in 201 hospitals in 2009 and 2010 with those in 2013 and 2014, we observed that increases in observation and ED visits coincided with reductions in inpatient readmissions among patients with private insurance and Medicare and contributed to growth in total returns to the hospital among patients with Medicaid or no insurance. Among patients with private insurance and Medicare, inpatient readmissions declined significantly for all 3 target conditions, but total returns to the hospital remained constant for AMI and HF, rose for privately insured patients with pneumonia, and declined modestly for Medicare patients with pneumonia. Inpatient readmissions were unchanged for adults aged 18 to 64 years with Medicaid or no insurance, but total returns to the hospital increased significantly, reaching 32% among those with Medicaid.

These findings add to recent literature, which has primarily emphasized inpatient readmissions among Medicare beneficiaries with several exceptions. A prior analysis indicates that readmissions have declined among diverse payer populations nationally.¹⁸ Gerhardt et al²⁵ found that from 2011 to 2012, all-cause 30-day readmissions declined among fee-for-service (FFS) Medicare beneficiaries following any index admission, while ED revisits remained stable and observation revisits increased slightly. Evaluating the CMS Hospital Readmission Reductions Program (HRRP), Zuckerman et al¹⁷ reported that from 2007 to 2015, inpatient readmissions declined among FFS Medicare beneficiaries aged 65 years and older who were hospitalized with AMI, HF, or pneumonia, while returns to the hospital for observation rose approximately 2%; ED visits were not included. We found that Medicare (FFS and Medicare Advantage) patients with AMI and HF returned to the hospital with the same frequency in 2009 and 2010 as in 2013 and 2014, and those patients with pneumonia returned slightly less often. In aggregate, declines in inpatient readmissions in the 4 states we studied coincided with increases in observation and ED care. Moreover, these shifts occurred not only among Medicare beneficiaries but also among privately insured adults, Medicaid recipients, and the uninsured.

Three factors may have contributed to these apparent shifts from readmissions to observation and ED visits. First, some authors have suggested that hospitals may reduce readmissions by intentionally placing some of the patients who return to the hospital under observation instead of admitting them.^17,26 If true, hospitals with greater declines in readmissions would have larger increases in observation revisits. Zuckerman et al¹⁷ found no correlation among Medicare beneficiaries between hospital-level trends in observation revisits and readmissions, but returns to observation rose more rapidly for AMI, HF, and pneumonia (compared with other conditions) during long term follow-up than during the HRRP implementation period. Other authors have documented that declines in readmissions have been greatest at hospitals with the highest baseline readmission rates,^27,28 and hospitals with lower readmission rates have more observation return visits.²⁹

Second, shifts from inpatient readmissions to return visits for observation may reflect unintentional rather than intentional changes in the services provided. Clinical practice patterns are evolving such that patients who present to the hospital for acute care increasingly are placed under observation or discharged from the ED instead of being admitted, regardless of whether they recently were hospitalized.³⁰ Inpatient admissions, which are strongly correlated with readmission rates,^28,31 are declining nationally,³² and both observation and ED visits are rising.^33-35 Although little is known about effects on health outcomes and patient out-of-pocket costs,shifts from inpatient admissions to observation and ED visits reduce costs to payers.^36,37

Third, instead of substitution, more patients may be returning for lower-acuity conditions that can be treated in the ED or under observation. Hospitals are implementing diverse and multifaceted interventions to reduce readmissions that can involve assessing patient needs and the risk for readmission, educating patients about self-care and risks after discharge, reconciling medication, scheduling follow-up visits, and monitoring patients through telephone calls and home nursing visits.^26,38,39 Although the intent may be to reduce patients’ need to return to the hospital, interventions that educate patients about risks after discharge may lower the threshold at which they find symptoms worrisome enough to return. This could increase lower-acuity return visits. We found that reasons for returning were similar in 2009 and 2010 versus 2013 and 2014, but we did not examine acuity of illness at the time of return.

Other areas of concern are the high rates at which Medicaid patients are returning to the hospital and the increases in rates of returns among Medicaid patients and the uninsured. Individuals in these disadvantaged populations may be having difficulty accessing ambulatory care or may be turning to the ED more often for lower acuity problems that arise after discharge. In 3 of the 4 states we studied, 15% to 16% of adults live in poverty and 10% to 30% live in primary care health professional shortage areas.^40,41 Given the implications for patient outcomes and costs, trends among these populations warrant further scrutiny.^42,43

This analysis has several limitations. Data were from 4 states, but trends in readmissions are similar nationally. From 2010 through 2015, the all-condition readmission rate declined by 8% among Medicare beneficiaries nationally and by 6.1% in South Carolina, 7.4% in Georgia, 8.3% in Nebraska, and 8.7% in Tennessee.⁴⁴ We report trends across hospitals and did not examine hospital-level revisits. Therefore, further research is needed to determine whether these findings are related to co-occurring trends, intentional substitution, or other factors.

In conclusion, measuring inpatient readmissions without accounting for return visits to the ED and observation underestimates the rate at which patients return to the hospital following an inpatient hospitalization. Because of growth in observation and ED visits, trends in the total rates at which patients return to the hospital can differ from trends in inpatient readmissions. In the 4 states we studied, total return rates were particularly high and rising among patients with Medicaid and lower, but also rising, among the uninsured. Policy analysts and researchers should investigate the factors contributing to growth in readmissions in these vulnerable populations and determine whether similar trends are occurring nationwide. Hospitalists play critical roles in admitting and discharging inpatients, caring for patients under observation, and implementing quality improvement programs. Irrespective of payer, hospitalists’ efforts to improve the quality and value of care should include observation and ED visits as well as inpatient readmissions.

Acknowledgments

The authors gratefully acknowledge Minya Sheng, M.S. (Truven Health Analytics) for assistance in programming and data management and Linda Lee, Ph.D. (Truven Health Analytics) for providing editorial review of the manuscript. We also wish to acknowledge the 4 HCUP Partner organizations that contributed to the HCUP State Databases used in this study: Georgia Hospital Association, Nebraska Hospital Association, South Carolina Revenue and Fiscal Affairs Office, and Tennessee Hospital Association.

Disclosure

Funding for this study was provided by the AHRQ Center for Delivery, Organization, and Markets, HCUP (Contract No. HHSA-290-2013-00002-C). The views expressed in this article are those of the authors and do not necessarily reflect those of the AHRQ or the U.S. Department of Health and Human Services. The authors have no conflicts of interest or financial disclosures to declare.

Given the frequency, potential preventability, and costs associated with hospital readmissions, reducing readmissions is a priority in efforts to improve the quality and value of healthcare.^1,2 State and national bodies have created diverse initiatives to facilitate improvements in hospital discharge practices and reduce 30-day readmission rates across payers.^3-5 For example, the Agency for Healthcare Research and Quality (AHRQ) and the Institute for Healthcare Improvement have published tools for improving discharge practices.^6,7 Medicare instituted financial penalties for hospitals with higher-than-expected readmission rates for acute myocardial infarction (AMI), heart failure (HF), and pneumonia in 2012, while private payers and Medicaid programs have established their own policies.^8-13 Furthermore, private payers and Medicaid programs shifted toward capitated and value-based reimbursement models in which readmissions lead to financial losses for hospitals.^14,15 Accordingly, hospitals have implemented diverse interventions to reduce readmissions.^16,17 From 2009 to 2013, 30-day readmissions declined among privately insured adults (from 12.4% to 11.7%), Medicare patients (from 22.0% to 20.0%), and uninsured individuals (11.5% to 11.0%) but climbed among patients with Medicaid (from 19.8% to 20.5%) after index admissions for AMI, HF, pneumonia, or chronic obstructive pulmonary disease.¹⁸

To date, research, policies, and quality improvement interventions have largely focused on improvements to one aspect of the system of care—that provided in the inpatient setting—among older adults with Medicare. Yet, inpatient readmissions may underestimate how often patients return to the hospital because patients can be placed under observation or stabilized and discharged from the emergency department (ED) instead of being readmitted. Observation and ED visits are less costly to payers than inpatient admissions.¹⁹ Thus, information about utilization of inpatient, observation, and ED visits within 30 days of hospital discharge may be more informative than inpatient readmissions alone. However, little is known about trends in returns to the hospital for observation and ED visits and whether such trends vary by payer.

Our objective was to assess whether changes have occurred in rates of total 30-day, all-cause, unplanned returns to the hospital among adults with index admissions for AMI, HF, and pneumonia in which returns to the hospital included inpatient readmissions, observation visits, and ED visits. We also assessed whether changes in the rate of hospital inpatient readmissions coincided with changes in rates of returns for ED or observation visits. To examine the effects of readmission policies implemented by diverse payers and broad changes to the health system following the Affordable Care Act, we compared data from 201 hospitals in 4 states in 2009 and 2010 with data from the same hospitals for 2013 and 2014.

Data Sources, Populations, and Study Variables

We used Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases, State Emergency Department Databases, and State Ambulatory Surgery and Services Databases from Georgia, Nebraska, South Carolina, and Tennessee. These states comprise 7% of the US population and were the only states with data that included all observation and ED visits as well as encrypted patient identification numbers that permitted linkage across facilities and hospitals.²⁰

Index admissions for patients aged 18 years and older were eligible if they occurred at nonfederal general medical/surgical hospitals (excluding critical access hospitals) that had at least 1 index admission per target condition per year and at least 5 inpatient, observation, and ED visits for any condition per year.

We classified patients into the following 4 populations by age and insurance coverage: 18 to 64 years with private insurance, 65 years and older with Medicare (excluding younger adults with Medicare), 18 to 64 years with Medicaid, and 18 to 64 years without insurance. We identified patients aged 65 years and older with Medicare by using the primary or secondary expected payer for the index admission. This group included patients who were dually eligible for Medicare and Medicaid. If Medicare was not the primary or secondary payer, we used the primary payer to identify Medicaid, privately insured, and uninsured patients aged 18 to 64 years. None of the states expanded Medicaid coverage during the years studied.

The primary outcome of interest was the rate of having 1 or more all-cause, unplanned return(s) to an acute care hospital within 30 days of discharge after an index admission for AMI, HF, and pneumonia as defined by a modified version of Centers for Medicare & Medicaid Services’ readmission metrics.^21,22 We examined total return rates as well as rates for inpatient, observation, and ED care. We also examined the leading diagnoses associated with returns to the hospital. For each index admission, we included only 1 return visit, giving priority to inpatient readmissions, then observation visits, and then ED visits.

The HCUP databases are consistent with the definition of limited data sets under the Health Insurance Portability and Accountability Act Privacy Rule and contain no direct patient identifiers. The AHRQ Institutional Review Board considers research using HCUP data to have exempt status.

Statistical Analysis

To compare rates at which patients returned to the hospital during 2 cohort periods (2009 and 2010 vs 2013 and 2014), we used coarsened exact matching, a well-established matching technique for balancing covariates between 2 populations of patients that may be related to the outcome.²³ For observational datasets, coarsened exact matching is preferable to traditional matching because it enables the investigator to assess balance between the 2 populations, select the desired degree of balance, and eliminate observations for which comparable matches cannot be found.

We assembled sets of index admissions in each study period that were similar with respect to payer, primary diagnosis, and other factors. Matching variables included the patient’s age group, sex, and Elixhauser Comorbidity Index²⁴ (in deciles), as well as the hospital’s ratio of observation visits relative to inpatient admissions in 2009 and 2010 combined (in quartiles; see supplementary Appendix). For Medicare beneficiaries, we also matched on dual enrollment in Medicaid.

We conducted the matching process separately for each target condition and payer population. First, we grouped index admissions in both periods into strata defined by all possible combinations of the matching variables and allowing one-to-many random matching within strata. We then dropped records in any strata for which there were no records in 1 of the time periods. Finally, we calculated weights based on the size of each stratum. We used these weights to account for the different numbers of index admissions in each stratum between the 2 study periods. For example, if a stratum contained 10 index admissions in 2009 and 2010 combined and 20 in 2013 and 2014 combined, an admission weighed double in the earlier period. After weighting, the index admissions in each period (2009 and 2010; 2013 and 2014) had similar characteristics (Table 1).

There were 423,503 eligible index admissions for AMI, HF, and pneumonia in the 2 periods combined; 422,840 (99.8%) were successfully matched and included in this analysis. After matching weights were applied, there were few statistically significant differences across the 2 time periods (see Table 1 and supplementary Appendix).

From 2009 and 2010 to 2013 and 2014, the percentage of patients hospitalized for AMI, HF, and pneumonia who had only observation or ED visits when they returned to the hospital increased from 41.4% to 46.7% among patients with private insurance (P < 0.001), from 27.8% to 32.1% among older patients with Medicare (P < 0.001), from 39.5% to 41.8% among patients with Medicaid (P = 0.03), and from 49.2% to 52.8% among patients without insurance (P = 0.004; Table 1). The percentage of returns to the hospital for observation increased across all payers (P < 0.001); in 2013 and 2014 combined, observation visits ranged from 6.8% of hospital returns among patients with Medicare to 11.1% among patients with private insurance. The percentage of returns to the hospital for an ED visit increased among patients with private insurance (P = 0.02) and Medicare (P < 0.001); in 2013 and 2014, ED visits ranged from 25.3% of returns to the hospital among patients with Medicare to 42.9% among uninsured patients.

The increases in 30-day observation and ED visits coincided with reductions in inpatient readmissions among patients with private insurance and Medicare and contributed to growth in total returns to the hospital among patients with Medicaid or no insurance (Figure 1).

Matching index admissions for AMI, HF, or pneumonia in 201 hospitals in 2009 and 2010 with those in 2013 and 2014, we observed that increases in observation and ED visits coincided with reductions in inpatient readmissions among patients with private insurance and Medicare and contributed to growth in total returns to the hospital among patients with Medicaid or no insurance. Among patients with private insurance and Medicare, inpatient readmissions declined significantly for all 3 target conditions, but total returns to the hospital remained constant for AMI and HF, rose for privately insured patients with pneumonia, and declined modestly for Medicare patients with pneumonia. Inpatient readmissions were unchanged for adults aged 18 to 64 years with Medicaid or no insurance, but total returns to the hospital increased significantly, reaching 32% among those with Medicaid.

These findings add to recent literature, which has primarily emphasized inpatient readmissions among Medicare beneficiaries with several exceptions. A prior analysis indicates that readmissions have declined among diverse payer populations nationally.¹⁸ Gerhardt et al²⁵ found that from 2011 to 2012, all-cause 30-day readmissions declined among fee-for-service (FFS) Medicare beneficiaries following any index admission, while ED revisits remained stable and observation revisits increased slightly. Evaluating the CMS Hospital Readmission Reductions Program (HRRP), Zuckerman et al¹⁷ reported that from 2007 to 2015, inpatient readmissions declined among FFS Medicare beneficiaries aged 65 years and older who were hospitalized with AMI, HF, or pneumonia, while returns to the hospital for observation rose approximately 2%; ED visits were not included. We found that Medicare (FFS and Medicare Advantage) patients with AMI and HF returned to the hospital with the same frequency in 2009 and 2010 as in 2013 and 2014, and those patients with pneumonia returned slightly less often. In aggregate, declines in inpatient readmissions in the 4 states we studied coincided with increases in observation and ED care. Moreover, these shifts occurred not only among Medicare beneficiaries but also among privately insured adults, Medicaid recipients, and the uninsured.

Three factors may have contributed to these apparent shifts from readmissions to observation and ED visits. First, some authors have suggested that hospitals may reduce readmissions by intentionally placing some of the patients who return to the hospital under observation instead of admitting them.^17,26 If true, hospitals with greater declines in readmissions would have larger increases in observation revisits. Zuckerman et al¹⁷ found no correlation among Medicare beneficiaries between hospital-level trends in observation revisits and readmissions, but returns to observation rose more rapidly for AMI, HF, and pneumonia (compared with other conditions) during long term follow-up than during the HRRP implementation period. Other authors have documented that declines in readmissions have been greatest at hospitals with the highest baseline readmission rates,^27,28 and hospitals with lower readmission rates have more observation return visits.²⁹

Second, shifts from inpatient readmissions to return visits for observation may reflect unintentional rather than intentional changes in the services provided. Clinical practice patterns are evolving such that patients who present to the hospital for acute care increasingly are placed under observation or discharged from the ED instead of being admitted, regardless of whether they recently were hospitalized.³⁰ Inpatient admissions, which are strongly correlated with readmission rates,^28,31 are declining nationally,³² and both observation and ED visits are rising.^33-35 Although little is known about effects on health outcomes and patient out-of-pocket costs,shifts from inpatient admissions to observation and ED visits reduce costs to payers.^36,37

Third, instead of substitution, more patients may be returning for lower-acuity conditions that can be treated in the ED or under observation. Hospitals are implementing diverse and multifaceted interventions to reduce readmissions that can involve assessing patient needs and the risk for readmission, educating patients about self-care and risks after discharge, reconciling medication, scheduling follow-up visits, and monitoring patients through telephone calls and home nursing visits.^26,38,39 Although the intent may be to reduce patients’ need to return to the hospital, interventions that educate patients about risks after discharge may lower the threshold at which they find symptoms worrisome enough to return. This could increase lower-acuity return visits. We found that reasons for returning were similar in 2009 and 2010 versus 2013 and 2014, but we did not examine acuity of illness at the time of return.

Other areas of concern are the high rates at which Medicaid patients are returning to the hospital and the increases in rates of returns among Medicaid patients and the uninsured. Individuals in these disadvantaged populations may be having difficulty accessing ambulatory care or may be turning to the ED more often for lower acuity problems that arise after discharge. In 3 of the 4 states we studied, 15% to 16% of adults live in poverty and 10% to 30% live in primary care health professional shortage areas.^40,41 Given the implications for patient outcomes and costs, trends among these populations warrant further scrutiny.^42,43

This analysis has several limitations. Data were from 4 states, but trends in readmissions are similar nationally. From 2010 through 2015, the all-condition readmission rate declined by 8% among Medicare beneficiaries nationally and by 6.1% in South Carolina, 7.4% in Georgia, 8.3% in Nebraska, and 8.7% in Tennessee.⁴⁴ We report trends across hospitals and did not examine hospital-level revisits. Therefore, further research is needed to determine whether these findings are related to co-occurring trends, intentional substitution, or other factors.

In conclusion, measuring inpatient readmissions without accounting for return visits to the ED and observation underestimates the rate at which patients return to the hospital following an inpatient hospitalization. Because of growth in observation and ED visits, trends in the total rates at which patients return to the hospital can differ from trends in inpatient readmissions. In the 4 states we studied, total return rates were particularly high and rising among patients with Medicaid and lower, but also rising, among the uninsured. Policy analysts and researchers should investigate the factors contributing to growth in readmissions in these vulnerable populations and determine whether similar trends are occurring nationwide. Hospitalists play critical roles in admitting and discharging inpatients, caring for patients under observation, and implementing quality improvement programs. Irrespective of payer, hospitalists’ efforts to improve the quality and value of care should include observation and ED visits as well as inpatient readmissions.

Acknowledgments

The authors gratefully acknowledge Minya Sheng, M.S. (Truven Health Analytics) for assistance in programming and data management and Linda Lee, Ph.D. (Truven Health Analytics) for providing editorial review of the manuscript. We also wish to acknowledge the 4 HCUP Partner organizations that contributed to the HCUP State Databases used in this study: Georgia Hospital Association, Nebraska Hospital Association, South Carolina Revenue and Fiscal Affairs Office, and Tennessee Hospital Association.

Disclosure

Funding for this study was provided by the AHRQ Center for Delivery, Organization, and Markets, HCUP (Contract No. HHSA-290-2013-00002-C). The views expressed in this article are those of the authors and do not necessarily reflect those of the AHRQ or the U.S. Department of Health and Human Services. The authors have no conflicts of interest or financial disclosures to declare.

Given the frequency, potential preventability, and costs associated with hospital readmissions, reducing readmissions is a priority in efforts to improve the quality and value of healthcare.^1,2 State and national bodies have created diverse initiatives to facilitate improvements in hospital discharge practices and reduce 30-day readmission rates across payers.^3-5 For example, the Agency for Healthcare Research and Quality (AHRQ) and the Institute for Healthcare Improvement have published tools for improving discharge practices.^6,7 Medicare instituted financial penalties for hospitals with higher-than-expected readmission rates for acute myocardial infarction (AMI), heart failure (HF), and pneumonia in 2012, while private payers and Medicaid programs have established their own policies.^8-13 Furthermore, private payers and Medicaid programs shifted toward capitated and value-based reimbursement models in which readmissions lead to financial losses for hospitals.^14,15 Accordingly, hospitals have implemented diverse interventions to reduce readmissions.^16,17 From 2009 to 2013, 30-day readmissions declined among privately insured adults (from 12.4% to 11.7%), Medicare patients (from 22.0% to 20.0%), and uninsured individuals (11.5% to 11.0%) but climbed among patients with Medicaid (from 19.8% to 20.5%) after index admissions for AMI, HF, pneumonia, or chronic obstructive pulmonary disease.¹⁸

To date, research, policies, and quality improvement interventions have largely focused on improvements to one aspect of the system of care—that provided in the inpatient setting—among older adults with Medicare. Yet, inpatient readmissions may underestimate how often patients return to the hospital because patients can be placed under observation or stabilized and discharged from the emergency department (ED) instead of being readmitted. Observation and ED visits are less costly to payers than inpatient admissions.¹⁹ Thus, information about utilization of inpatient, observation, and ED visits within 30 days of hospital discharge may be more informative than inpatient readmissions alone. However, little is known about trends in returns to the hospital for observation and ED visits and whether such trends vary by payer.

Our objective was to assess whether changes have occurred in rates of total 30-day, all-cause, unplanned returns to the hospital among adults with index admissions for AMI, HF, and pneumonia in which returns to the hospital included inpatient readmissions, observation visits, and ED visits. We also assessed whether changes in the rate of hospital inpatient readmissions coincided with changes in rates of returns for ED or observation visits. To examine the effects of readmission policies implemented by diverse payers and broad changes to the health system following the Affordable Care Act, we compared data from 201 hospitals in 4 states in 2009 and 2010 with data from the same hospitals for 2013 and 2014.

Data Sources, Populations, and Study Variables

We used Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases, State Emergency Department Databases, and State Ambulatory Surgery and Services Databases from Georgia, Nebraska, South Carolina, and Tennessee. These states comprise 7% of the US population and were the only states with data that included all observation and ED visits as well as encrypted patient identification numbers that permitted linkage across facilities and hospitals.²⁰

Index admissions for patients aged 18 years and older were eligible if they occurred at nonfederal general medical/surgical hospitals (excluding critical access hospitals) that had at least 1 index admission per target condition per year and at least 5 inpatient, observation, and ED visits for any condition per year.

We classified patients into the following 4 populations by age and insurance coverage: 18 to 64 years with private insurance, 65 years and older with Medicare (excluding younger adults with Medicare), 18 to 64 years with Medicaid, and 18 to 64 years without insurance. We identified patients aged 65 years and older with Medicare by using the primary or secondary expected payer for the index admission. This group included patients who were dually eligible for Medicare and Medicaid. If Medicare was not the primary or secondary payer, we used the primary payer to identify Medicaid, privately insured, and uninsured patients aged 18 to 64 years. None of the states expanded Medicaid coverage during the years studied.

The primary outcome of interest was the rate of having 1 or more all-cause, unplanned return(s) to an acute care hospital within 30 days of discharge after an index admission for AMI, HF, and pneumonia as defined by a modified version of Centers for Medicare & Medicaid Services’ readmission metrics.^21,22 We examined total return rates as well as rates for inpatient, observation, and ED care. We also examined the leading diagnoses associated with returns to the hospital. For each index admission, we included only 1 return visit, giving priority to inpatient readmissions, then observation visits, and then ED visits.

The HCUP databases are consistent with the definition of limited data sets under the Health Insurance Portability and Accountability Act Privacy Rule and contain no direct patient identifiers. The AHRQ Institutional Review Board considers research using HCUP data to have exempt status.

Statistical Analysis

To compare rates at which patients returned to the hospital during 2 cohort periods (2009 and 2010 vs 2013 and 2014), we used coarsened exact matching, a well-established matching technique for balancing covariates between 2 populations of patients that may be related to the outcome.²³ For observational datasets, coarsened exact matching is preferable to traditional matching because it enables the investigator to assess balance between the 2 populations, select the desired degree of balance, and eliminate observations for which comparable matches cannot be found.

We assembled sets of index admissions in each study period that were similar with respect to payer, primary diagnosis, and other factors. Matching variables included the patient’s age group, sex, and Elixhauser Comorbidity Index²⁴ (in deciles), as well as the hospital’s ratio of observation visits relative to inpatient admissions in 2009 and 2010 combined (in quartiles; see supplementary Appendix). For Medicare beneficiaries, we also matched on dual enrollment in Medicaid.

We conducted the matching process separately for each target condition and payer population. First, we grouped index admissions in both periods into strata defined by all possible combinations of the matching variables and allowing one-to-many random matching within strata. We then dropped records in any strata for which there were no records in 1 of the time periods. Finally, we calculated weights based on the size of each stratum. We used these weights to account for the different numbers of index admissions in each stratum between the 2 study periods. For example, if a stratum contained 10 index admissions in 2009 and 2010 combined and 20 in 2013 and 2014 combined, an admission weighed double in the earlier period. After weighting, the index admissions in each period (2009 and 2010; 2013 and 2014) had similar characteristics (Table 1).

There were 423,503 eligible index admissions for AMI, HF, and pneumonia in the 2 periods combined; 422,840 (99.8%) were successfully matched and included in this analysis. After matching weights were applied, there were few statistically significant differences across the 2 time periods (see Table 1 and supplementary Appendix).

From 2009 and 2010 to 2013 and 2014, the percentage of patients hospitalized for AMI, HF, and pneumonia who had only observation or ED visits when they returned to the hospital increased from 41.4% to 46.7% among patients with private insurance (P < 0.001), from 27.8% to 32.1% among older patients with Medicare (P < 0.001), from 39.5% to 41.8% among patients with Medicaid (P = 0.03), and from 49.2% to 52.8% among patients without insurance (P = 0.004; Table 1). The percentage of returns to the hospital for observation increased across all payers (P < 0.001); in 2013 and 2014 combined, observation visits ranged from 6.8% of hospital returns among patients with Medicare to 11.1% among patients with private insurance. The percentage of returns to the hospital for an ED visit increased among patients with private insurance (P = 0.02) and Medicare (P < 0.001); in 2013 and 2014, ED visits ranged from 25.3% of returns to the hospital among patients with Medicare to 42.9% among uninsured patients.

The increases in 30-day observation and ED visits coincided with reductions in inpatient readmissions among patients with private insurance and Medicare and contributed to growth in total returns to the hospital among patients with Medicaid or no insurance (Figure 1).

Matching index admissions for AMI, HF, or pneumonia in 201 hospitals in 2009 and 2010 with those in 2013 and 2014, we observed that increases in observation and ED visits coincided with reductions in inpatient readmissions among patients with private insurance and Medicare and contributed to growth in total returns to the hospital among patients with Medicaid or no insurance. Among patients with private insurance and Medicare, inpatient readmissions declined significantly for all 3 target conditions, but total returns to the hospital remained constant for AMI and HF, rose for privately insured patients with pneumonia, and declined modestly for Medicare patients with pneumonia. Inpatient readmissions were unchanged for adults aged 18 to 64 years with Medicaid or no insurance, but total returns to the hospital increased significantly, reaching 32% among those with Medicaid.

These findings add to recent literature, which has primarily emphasized inpatient readmissions among Medicare beneficiaries with several exceptions. A prior analysis indicates that readmissions have declined among diverse payer populations nationally.¹⁸ Gerhardt et al²⁵ found that from 2011 to 2012, all-cause 30-day readmissions declined among fee-for-service (FFS) Medicare beneficiaries following any index admission, while ED revisits remained stable and observation revisits increased slightly. Evaluating the CMS Hospital Readmission Reductions Program (HRRP), Zuckerman et al¹⁷ reported that from 2007 to 2015, inpatient readmissions declined among FFS Medicare beneficiaries aged 65 years and older who were hospitalized with AMI, HF, or pneumonia, while returns to the hospital for observation rose approximately 2%; ED visits were not included. We found that Medicare (FFS and Medicare Advantage) patients with AMI and HF returned to the hospital with the same frequency in 2009 and 2010 as in 2013 and 2014, and those patients with pneumonia returned slightly less often. In aggregate, declines in inpatient readmissions in the 4 states we studied coincided with increases in observation and ED care. Moreover, these shifts occurred not only among Medicare beneficiaries but also among privately insured adults, Medicaid recipients, and the uninsured.

Three factors may have contributed to these apparent shifts from readmissions to observation and ED visits. First, some authors have suggested that hospitals may reduce readmissions by intentionally placing some of the patients who return to the hospital under observation instead of admitting them.^17,26 If true, hospitals with greater declines in readmissions would have larger increases in observation revisits. Zuckerman et al¹⁷ found no correlation among Medicare beneficiaries between hospital-level trends in observation revisits and readmissions, but returns to observation rose more rapidly for AMI, HF, and pneumonia (compared with other conditions) during long term follow-up than during the HRRP implementation period. Other authors have documented that declines in readmissions have been greatest at hospitals with the highest baseline readmission rates,^27,28 and hospitals with lower readmission rates have more observation return visits.²⁹

Second, shifts from inpatient readmissions to return visits for observation may reflect unintentional rather than intentional changes in the services provided. Clinical practice patterns are evolving such that patients who present to the hospital for acute care increasingly are placed under observation or discharged from the ED instead of being admitted, regardless of whether they recently were hospitalized.³⁰ Inpatient admissions, which are strongly correlated with readmission rates,^28,31 are declining nationally,³² and both observation and ED visits are rising.^33-35 Although little is known about effects on health outcomes and patient out-of-pocket costs,shifts from inpatient admissions to observation and ED visits reduce costs to payers.^36,37

Third, instead of substitution, more patients may be returning for lower-acuity conditions that can be treated in the ED or under observation. Hospitals are implementing diverse and multifaceted interventions to reduce readmissions that can involve assessing patient needs and the risk for readmission, educating patients about self-care and risks after discharge, reconciling medication, scheduling follow-up visits, and monitoring patients through telephone calls and home nursing visits.^26,38,39 Although the intent may be to reduce patients’ need to return to the hospital, interventions that educate patients about risks after discharge may lower the threshold at which they find symptoms worrisome enough to return. This could increase lower-acuity return visits. We found that reasons for returning were similar in 2009 and 2010 versus 2013 and 2014, but we did not examine acuity of illness at the time of return.

Other areas of concern are the high rates at which Medicaid patients are returning to the hospital and the increases in rates of returns among Medicaid patients and the uninsured. Individuals in these disadvantaged populations may be having difficulty accessing ambulatory care or may be turning to the ED more often for lower acuity problems that arise after discharge. In 3 of the 4 states we studied, 15% to 16% of adults live in poverty and 10% to 30% live in primary care health professional shortage areas.^40,41 Given the implications for patient outcomes and costs, trends among these populations warrant further scrutiny.^42,43

This analysis has several limitations. Data were from 4 states, but trends in readmissions are similar nationally. From 2010 through 2015, the all-condition readmission rate declined by 8% among Medicare beneficiaries nationally and by 6.1% in South Carolina, 7.4% in Georgia, 8.3% in Nebraska, and 8.7% in Tennessee.⁴⁴ We report trends across hospitals and did not examine hospital-level revisits. Therefore, further research is needed to determine whether these findings are related to co-occurring trends, intentional substitution, or other factors.

In conclusion, measuring inpatient readmissions without accounting for return visits to the ED and observation underestimates the rate at which patients return to the hospital following an inpatient hospitalization. Because of growth in observation and ED visits, trends in the total rates at which patients return to the hospital can differ from trends in inpatient readmissions. In the 4 states we studied, total return rates were particularly high and rising among patients with Medicaid and lower, but also rising, among the uninsured. Policy analysts and researchers should investigate the factors contributing to growth in readmissions in these vulnerable populations and determine whether similar trends are occurring nationwide. Hospitalists play critical roles in admitting and discharging inpatients, caring for patients under observation, and implementing quality improvement programs. Irrespective of payer, hospitalists’ efforts to improve the quality and value of care should include observation and ED visits as well as inpatient readmissions.

Acknowledgments

The authors gratefully acknowledge Minya Sheng, M.S. (Truven Health Analytics) for assistance in programming and data management and Linda Lee, Ph.D. (Truven Health Analytics) for providing editorial review of the manuscript. We also wish to acknowledge the 4 HCUP Partner organizations that contributed to the HCUP State Databases used in this study: Georgia Hospital Association, Nebraska Hospital Association, South Carolina Revenue and Fiscal Affairs Office, and Tennessee Hospital Association.

Disclosure

Funding for this study was provided by the AHRQ Center for Delivery, Organization, and Markets, HCUP (Contract No. HHSA-290-2013-00002-C). The views expressed in this article are those of the authors and do not necessarily reflect those of the AHRQ or the U.S. Department of Health and Human Services. The authors have no conflicts of interest or financial disclosures to declare.