Literature Review

Although migraine prevalence is associated with sex, sex is not associated with response to IV migraine medication, according to research published online ahead of print October 21 in Headache. Age, however, is inversely associated with the efficacy of IV migraine medication and directly associated with the risk of adverse events.

An Analysis of Three Migraine Trials

Benjamin W. Friedman, MD, Associate Professor of Emergency Medicine at Albert Einstein College of Medicine in Bronx, New York, and colleagues examined data gathered during three emergency-department-based randomized comparative efficacy trials of various migraine medications to determine whether sex and age are associated with short-term headache relief, sustained headache freedom, or adverse medication effects. The medications studied in the trials included metoclopramide, an antiemetic dopamine antagonist; ketorolac, a nonsteroidal anti-inflammatory drug; dexamethasone, a corticosteroid; and valproate, an antiepileptic drug. In each of the clinical trials, patients presenting to an emergency department with acute migraine were randomized to treatment with one or a combination of the IV drugs.

Eligible patients had an acute headache that fulfilled all International Classification of Headache Disorders criteria for migraine without aura. Patients were not excluded for prolonged duration of headache, however. Nor were patients required to have had more than one similar previous headache. Dr. Friedman and colleagues assessed pain levels and medication side effects at baseline, at one and two hours after medication administration, and by telephone at 24–48 hours after discharge from the emergency department. Patients described their pain as none, mild, moderate, or severe.

The researchers chose short-term headache relief (ie, a headache level of mild or none within one hour of treatment) and sustained headache freedom (ie, a reported headache level of none in the emergency department and a period of headache freedom of at least 24 hours after discharge) as their efficacy end points. The investigators’ third outcome was side effects.

For the primary analysis, Dr. Friedman and colleagues used the population’s median age to separate participants into an older and a younger group. In a secondary analysis, they considered age as continuous data.

Nausea Was More Common in Older Patients

The three original studies included 884 participants. The investigators found no differences between men and women in terms of age, race, duration of headache, or presence of aura. Compared with men, women were more likely to be nauseated (56% vs 41%) and to report severe pain at baseline (69% vs 59%). Similarly, patients age 36 or older were more likely to be nauseated (57% vs 50%) and to report severe pain at baseline (72% vs 64%) than patients younger than 36. “We are the first to report [this finding],” said Dr. Friedman.

Men and women were approximately equally likely to report short-term and sustained headache improvements and adverse events. Patients age 36 or older, however, were less likely than younger patients to respond favorably to headache medication and more likely to have adverse events. Most of the difference in efficacy outcomes between older and younger patients can be explained by differential response to metoclopramide regimens, according to the authors.

Bivariate analyses performed for various medication types indicated that adults age 36 or older were less likely to respond to combinations of metoclopramide and diphenhydramine. Age was not associated with the efficacy of ketorolac or valproate, however. “Because the bulk of our data comes from patients who received metoclopramide, these data do not necessarily translate to other medication classes,” said Dr. Friedman. Although adults older than 35 may be less likely to respond to metoclopramide regimens, it is uncertain that they are more likely to respond to alternate treatment regimens, he added. “Therefore, one should not reject metoclopramide in adults older than 35 based solely on these data.”

The higher rate of adverse events in older patients primarily resulted from a disparity in response to dexamethasone. Adults older than 35 who received dexamethasone had an adverse event rate of more than 50%. “Because the benefit of dexamethasone for patients with acute episodic migraine is relatively modest, clinicians may wish to avoid administering this medication to these patients,” said Dr. Friedman.

After the investigators performed multivariate logistic regression modeling, they found that sex did not meaningfully influence the association between age and the study outcomes. Likewise, age did not influence the lack of association between sex and the study outcomes.

Bioavailability May Decline With Age

The reasons for age-related differences in the efficacy of IV migraine medication are a matter of debate. One hypothesis is that age-related alterations in pharmacodynamics may affect the drugs’ bioavailability, said the authors. In addition, previous research indicates that endogenous pain modulation declines with age and affects the middle-aged and the elderly. Another potential explanation involves the psychologic response to investigational medicine. In outpatient triptan trials, middle-aged adults with migraine were less likely to respond to oral placebo than younger adults were. “Thus, these data may not represent a difference in true efficacy at all, but rather a diminished expectation of treatment benefit,” said Dr. Friedman.

“Other investigators reported that women experience migraine recurrence after successful treatment with oral triptans more frequently than men,” said Dr. Friedman. “We were not able to replicate this latter finding in our analysis of sustained headache response, which incorporates the potential for headache recurrence.

“We were unable to find other clinical data that addressed the association between age and response to acute parenteral migraine medication,” he continued. “As with sex, other investigators have reported that middle-aged adults were more likely than younger adults to report recurrence of headache after using an oral triptan. This finding was not supported in our assessment of sustained outcomes.”

The authors acknowledged several limitations of their study, including a gender imbalance in the patient population that resulted from the higher prevalence of migraine among women. Although the imbalance decreased the power of the sex analysis, the data appear sufficiently robust to detect meaningful differences, said Dr. Friedman.

“Future work should investigate sex- and age-based response to other parenteral migraine medications, including migraine-specific agents such as sumatriptan and dihydroergotamine,” Dr. Friedman concluded.

—Erik Greb

Although migraine prevalence is associated with sex, sex is not associated with response to IV migraine medication, according to research published online ahead of print October 21 in Headache. Age, however, is inversely associated with the efficacy of IV migraine medication and directly associated with the risk of adverse events.

An Analysis of Three Migraine Trials

Benjamin W. Friedman, MD, Associate Professor of Emergency Medicine at Albert Einstein College of Medicine in Bronx, New York, and colleagues examined data gathered during three emergency-department-based randomized comparative efficacy trials of various migraine medications to determine whether sex and age are associated with short-term headache relief, sustained headache freedom, or adverse medication effects. The medications studied in the trials included metoclopramide, an antiemetic dopamine antagonist; ketorolac, a nonsteroidal anti-inflammatory drug; dexamethasone, a corticosteroid; and valproate, an antiepileptic drug. In each of the clinical trials, patients presenting to an emergency department with acute migraine were randomized to treatment with one or a combination of the IV drugs.

Eligible patients had an acute headache that fulfilled all International Classification of Headache Disorders criteria for migraine without aura. Patients were not excluded for prolonged duration of headache, however. Nor were patients required to have had more than one similar previous headache. Dr. Friedman and colleagues assessed pain levels and medication side effects at baseline, at one and two hours after medication administration, and by telephone at 24–48 hours after discharge from the emergency department. Patients described their pain as none, mild, moderate, or severe.

The researchers chose short-term headache relief (ie, a headache level of mild or none within one hour of treatment) and sustained headache freedom (ie, a reported headache level of none in the emergency department and a period of headache freedom of at least 24 hours after discharge) as their efficacy end points. The investigators’ third outcome was side effects.

For the primary analysis, Dr. Friedman and colleagues used the population’s median age to separate participants into an older and a younger group. In a secondary analysis, they considered age as continuous data.

Nausea Was More Common in Older Patients

The three original studies included 884 participants. The investigators found no differences between men and women in terms of age, race, duration of headache, or presence of aura. Compared with men, women were more likely to be nauseated (56% vs 41%) and to report severe pain at baseline (69% vs 59%). Similarly, patients age 36 or older were more likely to be nauseated (57% vs 50%) and to report severe pain at baseline (72% vs 64%) than patients younger than 36. “We are the first to report [this finding],” said Dr. Friedman.

Men and women were approximately equally likely to report short-term and sustained headache improvements and adverse events. Patients age 36 or older, however, were less likely than younger patients to respond favorably to headache medication and more likely to have adverse events. Most of the difference in efficacy outcomes between older and younger patients can be explained by differential response to metoclopramide regimens, according to the authors.

Bivariate analyses performed for various medication types indicated that adults age 36 or older were less likely to respond to combinations of metoclopramide and diphenhydramine. Age was not associated with the efficacy of ketorolac or valproate, however. “Because the bulk of our data comes from patients who received metoclopramide, these data do not necessarily translate to other medication classes,” said Dr. Friedman. Although adults older than 35 may be less likely to respond to metoclopramide regimens, it is uncertain that they are more likely to respond to alternate treatment regimens, he added. “Therefore, one should not reject metoclopramide in adults older than 35 based solely on these data.”

The higher rate of adverse events in older patients primarily resulted from a disparity in response to dexamethasone. Adults older than 35 who received dexamethasone had an adverse event rate of more than 50%. “Because the benefit of dexamethasone for patients with acute episodic migraine is relatively modest, clinicians may wish to avoid administering this medication to these patients,” said Dr. Friedman.

After the investigators performed multivariate logistic regression modeling, they found that sex did not meaningfully influence the association between age and the study outcomes. Likewise, age did not influence the lack of association between sex and the study outcomes.

Bioavailability May Decline With Age

The reasons for age-related differences in the efficacy of IV migraine medication are a matter of debate. One hypothesis is that age-related alterations in pharmacodynamics may affect the drugs’ bioavailability, said the authors. In addition, previous research indicates that endogenous pain modulation declines with age and affects the middle-aged and the elderly. Another potential explanation involves the psychologic response to investigational medicine. In outpatient triptan trials, middle-aged adults with migraine were less likely to respond to oral placebo than younger adults were. “Thus, these data may not represent a difference in true efficacy at all, but rather a diminished expectation of treatment benefit,” said Dr. Friedman.

“Other investigators reported that women experience migraine recurrence after successful treatment with oral triptans more frequently than men,” said Dr. Friedman. “We were not able to replicate this latter finding in our analysis of sustained headache response, which incorporates the potential for headache recurrence.

“We were unable to find other clinical data that addressed the association between age and response to acute parenteral migraine medication,” he continued. “As with sex, other investigators have reported that middle-aged adults were more likely than younger adults to report recurrence of headache after using an oral triptan. This finding was not supported in our assessment of sustained outcomes.”

The authors acknowledged several limitations of their study, including a gender imbalance in the patient population that resulted from the higher prevalence of migraine among women. Although the imbalance decreased the power of the sex analysis, the data appear sufficiently robust to detect meaningful differences, said Dr. Friedman.

“Future work should investigate sex- and age-based response to other parenteral migraine medications, including migraine-specific agents such as sumatriptan and dihydroergotamine,” Dr. Friedman concluded.

—Erik Greb

Although migraine prevalence is associated with sex, sex is not associated with response to IV migraine medication, according to research published online ahead of print October 21 in Headache. Age, however, is inversely associated with the efficacy of IV migraine medication and directly associated with the risk of adverse events.

An Analysis of Three Migraine Trials

Benjamin W. Friedman, MD, Associate Professor of Emergency Medicine at Albert Einstein College of Medicine in Bronx, New York, and colleagues examined data gathered during three emergency-department-based randomized comparative efficacy trials of various migraine medications to determine whether sex and age are associated with short-term headache relief, sustained headache freedom, or adverse medication effects. The medications studied in the trials included metoclopramide, an antiemetic dopamine antagonist; ketorolac, a nonsteroidal anti-inflammatory drug; dexamethasone, a corticosteroid; and valproate, an antiepileptic drug. In each of the clinical trials, patients presenting to an emergency department with acute migraine were randomized to treatment with one or a combination of the IV drugs.

Eligible patients had an acute headache that fulfilled all International Classification of Headache Disorders criteria for migraine without aura. Patients were not excluded for prolonged duration of headache, however. Nor were patients required to have had more than one similar previous headache. Dr. Friedman and colleagues assessed pain levels and medication side effects at baseline, at one and two hours after medication administration, and by telephone at 24–48 hours after discharge from the emergency department. Patients described their pain as none, mild, moderate, or severe.

The researchers chose short-term headache relief (ie, a headache level of mild or none within one hour of treatment) and sustained headache freedom (ie, a reported headache level of none in the emergency department and a period of headache freedom of at least 24 hours after discharge) as their efficacy end points. The investigators’ third outcome was side effects.

For the primary analysis, Dr. Friedman and colleagues used the population’s median age to separate participants into an older and a younger group. In a secondary analysis, they considered age as continuous data.

Nausea Was More Common in Older Patients

The three original studies included 884 participants. The investigators found no differences between men and women in terms of age, race, duration of headache, or presence of aura. Compared with men, women were more likely to be nauseated (56% vs 41%) and to report severe pain at baseline (69% vs 59%). Similarly, patients age 36 or older were more likely to be nauseated (57% vs 50%) and to report severe pain at baseline (72% vs 64%) than patients younger than 36. “We are the first to report [this finding],” said Dr. Friedman.

Men and women were approximately equally likely to report short-term and sustained headache improvements and adverse events. Patients age 36 or older, however, were less likely than younger patients to respond favorably to headache medication and more likely to have adverse events. Most of the difference in efficacy outcomes between older and younger patients can be explained by differential response to metoclopramide regimens, according to the authors.

Bivariate analyses performed for various medication types indicated that adults age 36 or older were less likely to respond to combinations of metoclopramide and diphenhydramine. Age was not associated with the efficacy of ketorolac or valproate, however. “Because the bulk of our data comes from patients who received metoclopramide, these data do not necessarily translate to other medication classes,” said Dr. Friedman. Although adults older than 35 may be less likely to respond to metoclopramide regimens, it is uncertain that they are more likely to respond to alternate treatment regimens, he added. “Therefore, one should not reject metoclopramide in adults older than 35 based solely on these data.”

The higher rate of adverse events in older patients primarily resulted from a disparity in response to dexamethasone. Adults older than 35 who received dexamethasone had an adverse event rate of more than 50%. “Because the benefit of dexamethasone for patients with acute episodic migraine is relatively modest, clinicians may wish to avoid administering this medication to these patients,” said Dr. Friedman.

After the investigators performed multivariate logistic regression modeling, they found that sex did not meaningfully influence the association between age and the study outcomes. Likewise, age did not influence the lack of association between sex and the study outcomes.

Bioavailability May Decline With Age

The reasons for age-related differences in the efficacy of IV migraine medication are a matter of debate. One hypothesis is that age-related alterations in pharmacodynamics may affect the drugs’ bioavailability, said the authors. In addition, previous research indicates that endogenous pain modulation declines with age and affects the middle-aged and the elderly. Another potential explanation involves the psychologic response to investigational medicine. In outpatient triptan trials, middle-aged adults with migraine were less likely to respond to oral placebo than younger adults were. “Thus, these data may not represent a difference in true efficacy at all, but rather a diminished expectation of treatment benefit,” said Dr. Friedman.

“Other investigators reported that women experience migraine recurrence after successful treatment with oral triptans more frequently than men,” said Dr. Friedman. “We were not able to replicate this latter finding in our analysis of sustained headache response, which incorporates the potential for headache recurrence.

“We were unable to find other clinical data that addressed the association between age and response to acute parenteral migraine medication,” he continued. “As with sex, other investigators have reported that middle-aged adults were more likely than younger adults to report recurrence of headache after using an oral triptan. This finding was not supported in our assessment of sustained outcomes.”

The authors acknowledged several limitations of their study, including a gender imbalance in the patient population that resulted from the higher prevalence of migraine among women. Although the imbalance decreased the power of the sex analysis, the data appear sufficiently robust to detect meaningful differences, said Dr. Friedman.

“Future work should investigate sex- and age-based response to other parenteral migraine medications, including migraine-specific agents such as sumatriptan and dihydroergotamine,” Dr. Friedman concluded.

—Erik Greb

Pisa syndrome may be a relatively frequent and often disabling complication in Parkinson’s disease, especially in the advanced disease stages, according to research published in the November 17 issue of Neurology.

Variables associated with Pisa syndrome include Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, and veering gait, said Michele Tinazzi, MD, PhD, Associate Professor of Neurology at the University of Verona, Italy, and colleagues.

Pisa syndrome, which is characterized by lateral trunk flexion, has been described in patients with dementia and other neurodegenerative diseases. It was first described as a side effect of antipsychotic treatment and also has been associated with medications such as antiemetics, antidepressants, central cholinesterase inhibitors, and lithium carbonate. Pisa syndrome’s pathophysiologic explanation, however, is uncertain, and case series have produced conflicting findings, the researchers said.

A Cross-Sectional Study of Patients With Parkinson’s Disease

To assess the prevalence of Pisa syndrome in patients with Parkinson’s disease and the association between Pisa syndrome and demographic and clinical variables, Dr. Tinazzi and colleagues conducted a cross-sectional study of consecutive outpatients with Parkinson’s disease who attended 21 tertiary movement disorders centers in Italy.

The investigators enrolled patients between February 2012 and July 2013. Patients diagnosed with Pisa syndrome (ie, lateral trunk deviation of 10° or more that was almost completely reverted by passive mobilization or supine positioning) completed an ad hoc questionnaire and neurologic examination. The researchers diagnosed Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria and excluded patients who had other postural deformities, concomitant neurologic diseases known to affect posture, history of major spinal surgery or muscle or skeletal disease, treatment with drugs that can induce Pisa syndrome in the six months before enrollment, and clinical features that were consistent with a diagnosis of atypical parkinsonism.

A neurologist at each center recorded patients’ sex, age, age at Parkinson’s disease onset, BMI, disease duration, Parkinson’s disease phenotype (ie, rigid-akinetic, tremor-dominant, or mixed type), laterality of motor symptoms at disease onset, latency between disease onset and the start of antiparkinsonian therapy, and pharmacologic treatment at disease onset and at their latest visit.

The researchers also evaluated falls in the previous month; comorbidities; quality of life, as assessed by Parkinson’s Disease Questionnaire–8; and disease severity, as assessed by Unified Parkinson’s Disease Rating Scale, Parts I–IV. Clinical asymmetry and Hoehn and Yahr scale staging also were assessed. Investigators measured trunk deviation using a wall goniometer. Patients underwent a spine x-ray to disclose orthopedic conditions that could lead to lateral bending of the trunk.

Pisa Syndrome Was Associated With Age

Of the 1,631 patients who met the eligibility criteria, 143 patients fulfilled the diagnostic criteria for Pisa syndrome, representing a prevalence of 8.8%. Trunk flexion ranged from 10° to 50°, with an average of 17°. Pisa syndrome appeared on average seven years after the onset of Parkinson’s disease, and the patients had had Pisa syndrome for a mean of 2.6 years.

The investigators found that patients with Pisa syndrome were older and had lower BMI, a significantly longer disease duration, more severe disease, and worse quality of life, compared with patients who did not have Pisa syndrome. In addition, patients with Pisa syndrome had higher levodopa equivalent daily dose. Osteoporosis, arthrosis, veering gait, and falls were more common in the Pisa-syndrome group, compared with the group without Pisa syndrome. Multivariate logistic regression analysis confirmed that Hoehn and Yahr stage, ongoing antiparkinsonian treatment, associated medical conditions, and veering gait were associated with Pisa syndrome.

Most patients were aware of their leaning posture, and half adopted a head compensation to correct their visual alignment. Those with more severe Pisa syndrome (ie, trunk flexion of 20° or greater) were not significantly different from those with mild Pisa syndrome, in terms of demographic or clinical variables.

“The association of poor quality of life with Pisa syndrome in our cohort supports its clinical effect as motor manifestation of Parkinson’s disease; however, this was not confirmed by multivariate logistic regression analysis, suggesting that Pisa syndrome might not be the principal determinant of poor quality of life, but other factors associated with longer disease duration are also contributing,” the researchers said.

The study did not confirm a finding of previous studies that patients with Pisa syndrome lean away from their dominant Parkinson’s disease side.

These results may inform future studies that investigate the pathophysiologic mechanisms of Pisa syndrome in Parkinson’s disease and help identify “at-risk patients who may benefit from tailored therapeutic strategies,” said Dr. Tinazzi and colleagues.

“Early detection and treatment of Pisa syndrome may prevent fixed, irreversible deformities, thereby avoiding complications that may arise from such a disabling condition,” concluded the researchers.

—Jake Remaly

Pisa syndrome may be a relatively frequent and often disabling complication in Parkinson’s disease, especially in the advanced disease stages, according to research published in the November 17 issue of Neurology.

Variables associated with Pisa syndrome include Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, and veering gait, said Michele Tinazzi, MD, PhD, Associate Professor of Neurology at the University of Verona, Italy, and colleagues.

Pisa syndrome, which is characterized by lateral trunk flexion, has been described in patients with dementia and other neurodegenerative diseases. It was first described as a side effect of antipsychotic treatment and also has been associated with medications such as antiemetics, antidepressants, central cholinesterase inhibitors, and lithium carbonate. Pisa syndrome’s pathophysiologic explanation, however, is uncertain, and case series have produced conflicting findings, the researchers said.

A Cross-Sectional Study of Patients With Parkinson’s Disease

To assess the prevalence of Pisa syndrome in patients with Parkinson’s disease and the association between Pisa syndrome and demographic and clinical variables, Dr. Tinazzi and colleagues conducted a cross-sectional study of consecutive outpatients with Parkinson’s disease who attended 21 tertiary movement disorders centers in Italy.

The investigators enrolled patients between February 2012 and July 2013. Patients diagnosed with Pisa syndrome (ie, lateral trunk deviation of 10° or more that was almost completely reverted by passive mobilization or supine positioning) completed an ad hoc questionnaire and neurologic examination. The researchers diagnosed Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria and excluded patients who had other postural deformities, concomitant neurologic diseases known to affect posture, history of major spinal surgery or muscle or skeletal disease, treatment with drugs that can induce Pisa syndrome in the six months before enrollment, and clinical features that were consistent with a diagnosis of atypical parkinsonism.

A neurologist at each center recorded patients’ sex, age, age at Parkinson’s disease onset, BMI, disease duration, Parkinson’s disease phenotype (ie, rigid-akinetic, tremor-dominant, or mixed type), laterality of motor symptoms at disease onset, latency between disease onset and the start of antiparkinsonian therapy, and pharmacologic treatment at disease onset and at their latest visit.

The researchers also evaluated falls in the previous month; comorbidities; quality of life, as assessed by Parkinson’s Disease Questionnaire–8; and disease severity, as assessed by Unified Parkinson’s Disease Rating Scale, Parts I–IV. Clinical asymmetry and Hoehn and Yahr scale staging also were assessed. Investigators measured trunk deviation using a wall goniometer. Patients underwent a spine x-ray to disclose orthopedic conditions that could lead to lateral bending of the trunk.

Pisa Syndrome Was Associated With Age

Of the 1,631 patients who met the eligibility criteria, 143 patients fulfilled the diagnostic criteria for Pisa syndrome, representing a prevalence of 8.8%. Trunk flexion ranged from 10° to 50°, with an average of 17°. Pisa syndrome appeared on average seven years after the onset of Parkinson’s disease, and the patients had had Pisa syndrome for a mean of 2.6 years.

The investigators found that patients with Pisa syndrome were older and had lower BMI, a significantly longer disease duration, more severe disease, and worse quality of life, compared with patients who did not have Pisa syndrome. In addition, patients with Pisa syndrome had higher levodopa equivalent daily dose. Osteoporosis, arthrosis, veering gait, and falls were more common in the Pisa-syndrome group, compared with the group without Pisa syndrome. Multivariate logistic regression analysis confirmed that Hoehn and Yahr stage, ongoing antiparkinsonian treatment, associated medical conditions, and veering gait were associated with Pisa syndrome.

Most patients were aware of their leaning posture, and half adopted a head compensation to correct their visual alignment. Those with more severe Pisa syndrome (ie, trunk flexion of 20° or greater) were not significantly different from those with mild Pisa syndrome, in terms of demographic or clinical variables.

“The association of poor quality of life with Pisa syndrome in our cohort supports its clinical effect as motor manifestation of Parkinson’s disease; however, this was not confirmed by multivariate logistic regression analysis, suggesting that Pisa syndrome might not be the principal determinant of poor quality of life, but other factors associated with longer disease duration are also contributing,” the researchers said.

The study did not confirm a finding of previous studies that patients with Pisa syndrome lean away from their dominant Parkinson’s disease side.

These results may inform future studies that investigate the pathophysiologic mechanisms of Pisa syndrome in Parkinson’s disease and help identify “at-risk patients who may benefit from tailored therapeutic strategies,” said Dr. Tinazzi and colleagues.

“Early detection and treatment of Pisa syndrome may prevent fixed, irreversible deformities, thereby avoiding complications that may arise from such a disabling condition,” concluded the researchers.

—Jake Remaly

Pisa syndrome may be a relatively frequent and often disabling complication in Parkinson’s disease, especially in the advanced disease stages, according to research published in the November 17 issue of Neurology.

Variables associated with Pisa syndrome include Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, and veering gait, said Michele Tinazzi, MD, PhD, Associate Professor of Neurology at the University of Verona, Italy, and colleagues.

Pisa syndrome, which is characterized by lateral trunk flexion, has been described in patients with dementia and other neurodegenerative diseases. It was first described as a side effect of antipsychotic treatment and also has been associated with medications such as antiemetics, antidepressants, central cholinesterase inhibitors, and lithium carbonate. Pisa syndrome’s pathophysiologic explanation, however, is uncertain, and case series have produced conflicting findings, the researchers said.

A Cross-Sectional Study of Patients With Parkinson’s Disease

To assess the prevalence of Pisa syndrome in patients with Parkinson’s disease and the association between Pisa syndrome and demographic and clinical variables, Dr. Tinazzi and colleagues conducted a cross-sectional study of consecutive outpatients with Parkinson’s disease who attended 21 tertiary movement disorders centers in Italy.

The investigators enrolled patients between February 2012 and July 2013. Patients diagnosed with Pisa syndrome (ie, lateral trunk deviation of 10° or more that was almost completely reverted by passive mobilization or supine positioning) completed an ad hoc questionnaire and neurologic examination. The researchers diagnosed Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria and excluded patients who had other postural deformities, concomitant neurologic diseases known to affect posture, history of major spinal surgery or muscle or skeletal disease, treatment with drugs that can induce Pisa syndrome in the six months before enrollment, and clinical features that were consistent with a diagnosis of atypical parkinsonism.

A neurologist at each center recorded patients’ sex, age, age at Parkinson’s disease onset, BMI, disease duration, Parkinson’s disease phenotype (ie, rigid-akinetic, tremor-dominant, or mixed type), laterality of motor symptoms at disease onset, latency between disease onset and the start of antiparkinsonian therapy, and pharmacologic treatment at disease onset and at their latest visit.

The researchers also evaluated falls in the previous month; comorbidities; quality of life, as assessed by Parkinson’s Disease Questionnaire–8; and disease severity, as assessed by Unified Parkinson’s Disease Rating Scale, Parts I–IV. Clinical asymmetry and Hoehn and Yahr scale staging also were assessed. Investigators measured trunk deviation using a wall goniometer. Patients underwent a spine x-ray to disclose orthopedic conditions that could lead to lateral bending of the trunk.

Pisa Syndrome Was Associated With Age

Of the 1,631 patients who met the eligibility criteria, 143 patients fulfilled the diagnostic criteria for Pisa syndrome, representing a prevalence of 8.8%. Trunk flexion ranged from 10° to 50°, with an average of 17°. Pisa syndrome appeared on average seven years after the onset of Parkinson’s disease, and the patients had had Pisa syndrome for a mean of 2.6 years.

The investigators found that patients with Pisa syndrome were older and had lower BMI, a significantly longer disease duration, more severe disease, and worse quality of life, compared with patients who did not have Pisa syndrome. In addition, patients with Pisa syndrome had higher levodopa equivalent daily dose. Osteoporosis, arthrosis, veering gait, and falls were more common in the Pisa-syndrome group, compared with the group without Pisa syndrome. Multivariate logistic regression analysis confirmed that Hoehn and Yahr stage, ongoing antiparkinsonian treatment, associated medical conditions, and veering gait were associated with Pisa syndrome.

Most patients were aware of their leaning posture, and half adopted a head compensation to correct their visual alignment. Those with more severe Pisa syndrome (ie, trunk flexion of 20° or greater) were not significantly different from those with mild Pisa syndrome, in terms of demographic or clinical variables.

“The association of poor quality of life with Pisa syndrome in our cohort supports its clinical effect as motor manifestation of Parkinson’s disease; however, this was not confirmed by multivariate logistic regression analysis, suggesting that Pisa syndrome might not be the principal determinant of poor quality of life, but other factors associated with longer disease duration are also contributing,” the researchers said.

The study did not confirm a finding of previous studies that patients with Pisa syndrome lean away from their dominant Parkinson’s disease side.

These results may inform future studies that investigate the pathophysiologic mechanisms of Pisa syndrome in Parkinson’s disease and help identify “at-risk patients who may benefit from tailored therapeutic strategies,” said Dr. Tinazzi and colleagues.

“Early detection and treatment of Pisa syndrome may prevent fixed, irreversible deformities, thereby avoiding complications that may arise from such a disabling condition,” concluded the researchers.

—Jake Remaly

Clinical questions: Are antipsychotics for the treatment of delirium safe and effective? Does efficacy differ between ICU and non-ICU settings? Does efficacy differ between first- and second-generation antipsychotics (SGA)?

Background: Delirium is common in hospitalized patients. Data are mixed about the use of antipsychotics for treatment of delirium, and safety concerns are well founded. A 2007 Cochrane review failed to show compelling evidence for their efficacy, yet they remain widely used for this purpose.

Study design: Systematic review and meta-analysis.

Setting: Fifteen RCTs of adults with delirium.

Synopsis: The primary outcome measure was response rate at the study endpoint, defined using severity of delirium and global scales.

In a comparison of pooled or individual antipsychotics vs. placebo or usual care (UC), antipsychotics were found to be superior, with a response rate of 0.22 (95% CI, 0.15-0.34, P<.00001), NNT=2. Subgroup analysis revealed this superiority to be greater in non-ICU settings, with ICU antipsychotic use only marginally better than UC. Antipsychotics were superior in time to response (TTR). Mortality rates were no different.

There were no differences between chlorpromazine and haloperidol in any outcomes. Among head-to-head comparisons of SGAs, no differences were found. Pooled or individual SGAs, however, had the same overall efficacy as haloperidol but shorter TTR and fewer extrapyramidal side effects. Subgroup analysis showed a small but significant advantage in the use of SGAs over haloperidol in the ICU.

Bottom line: Antipsychotics are more effective than placebo or usual care in the treatment of delirium. There appears to be a benefit to using second-generation antipsychotics over haloperidol.

Citation: Kishi T, Hirota T, Matsunaga S, Iwata N. Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2015;0:1-8.

Clinical questions: Are antipsychotics for the treatment of delirium safe and effective? Does efficacy differ between ICU and non-ICU settings? Does efficacy differ between first- and second-generation antipsychotics (SGA)?

Background: Delirium is common in hospitalized patients. Data are mixed about the use of antipsychotics for treatment of delirium, and safety concerns are well founded. A 2007 Cochrane review failed to show compelling evidence for their efficacy, yet they remain widely used for this purpose.

Study design: Systematic review and meta-analysis.

Setting: Fifteen RCTs of adults with delirium.

Synopsis: The primary outcome measure was response rate at the study endpoint, defined using severity of delirium and global scales.

In a comparison of pooled or individual antipsychotics vs. placebo or usual care (UC), antipsychotics were found to be superior, with a response rate of 0.22 (95% CI, 0.15-0.34, P<.00001), NNT=2. Subgroup analysis revealed this superiority to be greater in non-ICU settings, with ICU antipsychotic use only marginally better than UC. Antipsychotics were superior in time to response (TTR). Mortality rates were no different.

There were no differences between chlorpromazine and haloperidol in any outcomes. Among head-to-head comparisons of SGAs, no differences were found. Pooled or individual SGAs, however, had the same overall efficacy as haloperidol but shorter TTR and fewer extrapyramidal side effects. Subgroup analysis showed a small but significant advantage in the use of SGAs over haloperidol in the ICU.

Bottom line: Antipsychotics are more effective than placebo or usual care in the treatment of delirium. There appears to be a benefit to using second-generation antipsychotics over haloperidol.

Citation: Kishi T, Hirota T, Matsunaga S, Iwata N. Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2015;0:1-8.

Clinical questions: Are antipsychotics for the treatment of delirium safe and effective? Does efficacy differ between ICU and non-ICU settings? Does efficacy differ between first- and second-generation antipsychotics (SGA)?

Background: Delirium is common in hospitalized patients. Data are mixed about the use of antipsychotics for treatment of delirium, and safety concerns are well founded. A 2007 Cochrane review failed to show compelling evidence for their efficacy, yet they remain widely used for this purpose.

Study design: Systematic review and meta-analysis.

Setting: Fifteen RCTs of adults with delirium.

Synopsis: The primary outcome measure was response rate at the study endpoint, defined using severity of delirium and global scales.

In a comparison of pooled or individual antipsychotics vs. placebo or usual care (UC), antipsychotics were found to be superior, with a response rate of 0.22 (95% CI, 0.15-0.34, P<.00001), NNT=2. Subgroup analysis revealed this superiority to be greater in non-ICU settings, with ICU antipsychotic use only marginally better than UC. Antipsychotics were superior in time to response (TTR). Mortality rates were no different.

There were no differences between chlorpromazine and haloperidol in any outcomes. Among head-to-head comparisons of SGAs, no differences were found. Pooled or individual SGAs, however, had the same overall efficacy as haloperidol but shorter TTR and fewer extrapyramidal side effects. Subgroup analysis showed a small but significant advantage in the use of SGAs over haloperidol in the ICU.

Bottom line: Antipsychotics are more effective than placebo or usual care in the treatment of delirium. There appears to be a benefit to using second-generation antipsychotics over haloperidol.

Citation: Kishi T, Hirota T, Matsunaga S, Iwata N. Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2015;0:1-8.

Clinical question: Are there clinical or computerized tomography (CT) findings that identify which patients will need early surgical management in adhesive small bowel obstruction (ASBO)?

Background: Previous studies determined adverse outcomes resulting from delayed surgery in patients with ASBO: increased length of stay (LOS), complications, and mortality. Most patients respond to nonoperative management, however.

Study design: Prospective observational study.

Setting: Three academic and tertiary referral medical centers.

Synopsis: Using multivariate analysis of 202 patients admitted with presumed adhesive ASBO without immediate surgical need, of whom 52 required eventual surgical intervention, this study found three predictors for needing operative care: no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; P=0.003), as well as the CT findings of a high-grade obstruction, defined as only minimal passage of air and fluid into the distal small bowel or colon (OR, 2.44; 95% CI, 1.10-5.43; P=0.028) or the presence of free fluid (OR, 2.59; 95% CI, 1.13-5.90; P=0.023).

Despite these associations, clinicians should not view these findings as indications for surgery. Of the patients who responded to nonoperative management, one-third had no flatus, and on CT one-third had high-grade obstruction and half had free fluid. Instead, because patients with these findings are at an increased risk of failing nonoperative management, they should be observed more closely and reassessed more frequently.

Bottom line: Patients without flatus or with the presence of free fluid or high-grade obstruction on CT are at an increased risk of requiring surgical management for ASBO.

Citation: Kulvatunyou N, Pandit V, Moutamn S, et al. A multi-institution prospective observational study of small bowel obstruction: clinical and computerized tomography predictors of which patients may require early surgery. J Trauma Acute Care Surg. 2015;79(3):393-398.

Clinical question: Are there clinical or computerized tomography (CT) findings that identify which patients will need early surgical management in adhesive small bowel obstruction (ASBO)?

Background: Previous studies determined adverse outcomes resulting from delayed surgery in patients with ASBO: increased length of stay (LOS), complications, and mortality. Most patients respond to nonoperative management, however.

Study design: Prospective observational study.

Setting: Three academic and tertiary referral medical centers.

Synopsis: Using multivariate analysis of 202 patients admitted with presumed adhesive ASBO without immediate surgical need, of whom 52 required eventual surgical intervention, this study found three predictors for needing operative care: no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; P=0.003), as well as the CT findings of a high-grade obstruction, defined as only minimal passage of air and fluid into the distal small bowel or colon (OR, 2.44; 95% CI, 1.10-5.43; P=0.028) or the presence of free fluid (OR, 2.59; 95% CI, 1.13-5.90; P=0.023).

Despite these associations, clinicians should not view these findings as indications for surgery. Of the patients who responded to nonoperative management, one-third had no flatus, and on CT one-third had high-grade obstruction and half had free fluid. Instead, because patients with these findings are at an increased risk of failing nonoperative management, they should be observed more closely and reassessed more frequently.

Bottom line: Patients without flatus or with the presence of free fluid or high-grade obstruction on CT are at an increased risk of requiring surgical management for ASBO.

Citation: Kulvatunyou N, Pandit V, Moutamn S, et al. A multi-institution prospective observational study of small bowel obstruction: clinical and computerized tomography predictors of which patients may require early surgery. J Trauma Acute Care Surg. 2015;79(3):393-398.

Clinical question: Are there clinical or computerized tomography (CT) findings that identify which patients will need early surgical management in adhesive small bowel obstruction (ASBO)?

Background: Previous studies determined adverse outcomes resulting from delayed surgery in patients with ASBO: increased length of stay (LOS), complications, and mortality. Most patients respond to nonoperative management, however.

Study design: Prospective observational study.

Setting: Three academic and tertiary referral medical centers.

Synopsis: Using multivariate analysis of 202 patients admitted with presumed adhesive ASBO without immediate surgical need, of whom 52 required eventual surgical intervention, this study found three predictors for needing operative care: no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; P=0.003), as well as the CT findings of a high-grade obstruction, defined as only minimal passage of air and fluid into the distal small bowel or colon (OR, 2.44; 95% CI, 1.10-5.43; P=0.028) or the presence of free fluid (OR, 2.59; 95% CI, 1.13-5.90; P=0.023).

Despite these associations, clinicians should not view these findings as indications for surgery. Of the patients who responded to nonoperative management, one-third had no flatus, and on CT one-third had high-grade obstruction and half had free fluid. Instead, because patients with these findings are at an increased risk of failing nonoperative management, they should be observed more closely and reassessed more frequently.

Bottom line: Patients without flatus or with the presence of free fluid or high-grade obstruction on CT are at an increased risk of requiring surgical management for ASBO.

Citation: Kulvatunyou N, Pandit V, Moutamn S, et al. A multi-institution prospective observational study of small bowel obstruction: clinical and computerized tomography predictors of which patients may require early surgery. J Trauma Acute Care Surg. 2015;79(3):393-398.

Clinical question: Does the addition of rapid multiplex polymerase chain reaction molecular techniques to standard blood culture bottle (BCB) processing, with or without antimicrobial stewardship recommendations, affect antimicrobial utilization and patient outcomes?

Background: Standard BCB processing typically requires two days to provide identification and susceptibility testing results. PCR-based molecular testing is available to test positive BCB and deliver specific susceptibility results more rapidly, typically within one hour. Earlier results could improve antimicrobial utilization, limit antimicrobial resistance, decrease the risk of Clostridium difficile colitis, improve patient outcomes, and decrease healthcare costs. The impact of these techniques on outcomes is uncertain.

Study design: Prospective, randomized controlled trial (RCT).

Setting: Single large tertiary academic medical center.

Synopsis: Nearly 750 patients were randomized to conventional BCB processing (control), BCB with rapid multiplex PCR and templated recommendations (rmPCR), or BCB with rapid multiplex PCR and real-time antimicrobial stewardship provided by an infectious disease physician or specially trained pharmacist (rmPCR/AS). Time to microorganism identification was reduced from 22.3 hours in the control arm to 1.3 hours in the intervention arms. Both intervention groups had decreased use of broad spectrum piperacillin-tazobactam, increased use of narrow spectrum β-lactam, and decreased treatment of contaminants. Time to appropriate empiric treatment modification was shortest in the rmPCR/AS group.

Groups did not differ in mortality, length of stay, or cost, although an adequately powered study may show beneficial effects in these outcomes.

Bottom line: The addition of rapid multiplex PCR, ideally combined with antimicrobial stewardship, improves antimicrobial utilization in patients with positive blood cultures.

Citation: Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080.

Clinical question: Does the addition of rapid multiplex polymerase chain reaction molecular techniques to standard blood culture bottle (BCB) processing, with or without antimicrobial stewardship recommendations, affect antimicrobial utilization and patient outcomes?

Background: Standard BCB processing typically requires two days to provide identification and susceptibility testing results. PCR-based molecular testing is available to test positive BCB and deliver specific susceptibility results more rapidly, typically within one hour. Earlier results could improve antimicrobial utilization, limit antimicrobial resistance, decrease the risk of Clostridium difficile colitis, improve patient outcomes, and decrease healthcare costs. The impact of these techniques on outcomes is uncertain.

Study design: Prospective, randomized controlled trial (RCT).

Setting: Single large tertiary academic medical center.

Synopsis: Nearly 750 patients were randomized to conventional BCB processing (control), BCB with rapid multiplex PCR and templated recommendations (rmPCR), or BCB with rapid multiplex PCR and real-time antimicrobial stewardship provided by an infectious disease physician or specially trained pharmacist (rmPCR/AS). Time to microorganism identification was reduced from 22.3 hours in the control arm to 1.3 hours in the intervention arms. Both intervention groups had decreased use of broad spectrum piperacillin-tazobactam, increased use of narrow spectrum β-lactam, and decreased treatment of contaminants. Time to appropriate empiric treatment modification was shortest in the rmPCR/AS group.

Groups did not differ in mortality, length of stay, or cost, although an adequately powered study may show beneficial effects in these outcomes.

Bottom line: The addition of rapid multiplex PCR, ideally combined with antimicrobial stewardship, improves antimicrobial utilization in patients with positive blood cultures.

Citation: Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080.

Clinical question: Does the addition of rapid multiplex polymerase chain reaction molecular techniques to standard blood culture bottle (BCB) processing, with or without antimicrobial stewardship recommendations, affect antimicrobial utilization and patient outcomes?

Background: Standard BCB processing typically requires two days to provide identification and susceptibility testing results. PCR-based molecular testing is available to test positive BCB and deliver specific susceptibility results more rapidly, typically within one hour. Earlier results could improve antimicrobial utilization, limit antimicrobial resistance, decrease the risk of Clostridium difficile colitis, improve patient outcomes, and decrease healthcare costs. The impact of these techniques on outcomes is uncertain.

Study design: Prospective, randomized controlled trial (RCT).

Setting: Single large tertiary academic medical center.

Synopsis: Nearly 750 patients were randomized to conventional BCB processing (control), BCB with rapid multiplex PCR and templated recommendations (rmPCR), or BCB with rapid multiplex PCR and real-time antimicrobial stewardship provided by an infectious disease physician or specially trained pharmacist (rmPCR/AS). Time to microorganism identification was reduced from 22.3 hours in the control arm to 1.3 hours in the intervention arms. Both intervention groups had decreased use of broad spectrum piperacillin-tazobactam, increased use of narrow spectrum β-lactam, and decreased treatment of contaminants. Time to appropriate empiric treatment modification was shortest in the rmPCR/AS group.

Groups did not differ in mortality, length of stay, or cost, although an adequately powered study may show beneficial effects in these outcomes.

Bottom line: The addition of rapid multiplex PCR, ideally combined with antimicrobial stewardship, improves antimicrobial utilization in patients with positive blood cultures.

Citation: Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080.

Clinical question: Are there patient characteristics not currently measured by the Medicare readmission program that account for differences in hospital readmission rates?

Background: The Medicare Hospital Readmissions Reduction Program (HRRP) financially penalizes hospitals with higher than expected 30-day readmission rates. During 2014, more than 2,000 U.S. hospitals were fined $480 million for high readmission rates. HRRP accounts for differences in patient age, gender, discharge diagnosis, and diagnoses identified in Medicare claims over the previous 12 months; however, the impact of other factors is uncertain.

Study design: Survey data from the Health and Retirement Study, with linked Medicare claims.

Setting: Community-dwelling U.S. adults, older than 50 years.

Synopsis: Investigators analyzed more than 33,000 admissions from 2000 to 2012. They found 22 patient characteristics not included in the HRRP calculation that were statistically significantly predictive of hospital-wide, 30-day readmission and were more likely to be present among patients cared for in hospitals in the highest quintile of readmission rates. These characteristics reduced by 48% the differences in readmission rate between the highest- and lowest-performing quintiles. Examples include patient ethnicity, education level, personal as well as household income level, presence of prescription drug plan, Medicaid enrollment, cognitive status, and numerous others.

Bottom line: Patient characteristics account for much of the difference in readmission rates between high- and low-performing hospitals, suggesting that HRRP penalties reflect who hospitals treat as much as how well they treat them.

Citation: Barnett ML, Hsu J, McWilliams JM. Patient characteristics and differences in hospital readmission rates. JAMA Intern Med. 2015;175(11):1803-1812.

Clinical question: Are there patient characteristics not currently measured by the Medicare readmission program that account for differences in hospital readmission rates?

Background: The Medicare Hospital Readmissions Reduction Program (HRRP) financially penalizes hospitals with higher than expected 30-day readmission rates. During 2014, more than 2,000 U.S. hospitals were fined $480 million for high readmission rates. HRRP accounts for differences in patient age, gender, discharge diagnosis, and diagnoses identified in Medicare claims over the previous 12 months; however, the impact of other factors is uncertain.

Study design: Survey data from the Health and Retirement Study, with linked Medicare claims.

Setting: Community-dwelling U.S. adults, older than 50 years.

Synopsis: Investigators analyzed more than 33,000 admissions from 2000 to 2012. They found 22 patient characteristics not included in the HRRP calculation that were statistically significantly predictive of hospital-wide, 30-day readmission and were more likely to be present among patients cared for in hospitals in the highest quintile of readmission rates. These characteristics reduced by 48% the differences in readmission rate between the highest- and lowest-performing quintiles. Examples include patient ethnicity, education level, personal as well as household income level, presence of prescription drug plan, Medicaid enrollment, cognitive status, and numerous others.

Bottom line: Patient characteristics account for much of the difference in readmission rates between high- and low-performing hospitals, suggesting that HRRP penalties reflect who hospitals treat as much as how well they treat them.

Citation: Barnett ML, Hsu J, McWilliams JM. Patient characteristics and differences in hospital readmission rates. JAMA Intern Med. 2015;175(11):1803-1812.

Clinical question: Are there patient characteristics not currently measured by the Medicare readmission program that account for differences in hospital readmission rates?

Background: The Medicare Hospital Readmissions Reduction Program (HRRP) financially penalizes hospitals with higher than expected 30-day readmission rates. During 2014, more than 2,000 U.S. hospitals were fined $480 million for high readmission rates. HRRP accounts for differences in patient age, gender, discharge diagnosis, and diagnoses identified in Medicare claims over the previous 12 months; however, the impact of other factors is uncertain.

Study design: Survey data from the Health and Retirement Study, with linked Medicare claims.

Setting: Community-dwelling U.S. adults, older than 50 years.

Synopsis: Investigators analyzed more than 33,000 admissions from 2000 to 2012. They found 22 patient characteristics not included in the HRRP calculation that were statistically significantly predictive of hospital-wide, 30-day readmission and were more likely to be present among patients cared for in hospitals in the highest quintile of readmission rates. These characteristics reduced by 48% the differences in readmission rate between the highest- and lowest-performing quintiles. Examples include patient ethnicity, education level, personal as well as household income level, presence of prescription drug plan, Medicaid enrollment, cognitive status, and numerous others.

Bottom line: Patient characteristics account for much of the difference in readmission rates between high- and low-performing hospitals, suggesting that HRRP penalties reflect who hospitals treat as much as how well they treat them.

Citation: Barnett ML, Hsu J, McWilliams JM. Patient characteristics and differences in hospital readmission rates. JAMA Intern Med. 2015;175(11):1803-1812.

Clinical question: In patients with atrial fibrillation (AF) or flutter, is heparin bridging needed during interruption of warfarin therapy for surgery or invasive procedures?

Background: Bridging is intended to decrease the risk of stroke or other arterial thromboembolism by minimizing time off anticoagulation. Bridging may increase the risk of serious bleeding, offsetting any benefit. Guidelines have provided weak and inconsistent recommendations due to a lack of randomized trials.

Study design: Randomized, double blind, placebo-controlled trial.

Setting: More than 100 centers in the U.S. and Canada, from 2009-2014.

Synopsis: Investigators randomized 1,884 patients on warfarin with a CHADS² risk factor of one or higher undergoing elective surgery or procedure to dalteparin or placebo, from three days to 24 hours before the procedure and for five to 10 days after. Mean CHADS² score was 2.3; 3% of patients had scores of five to six. Approximately one-third of patients were on aspirin, and most procedures (89%) were classified as minor. Patients with mechanical heart valves, stroke/transient ischemic attack (TIA)/systemic embolization within 12 weeks, major bleeding within six weeks, renal insufficiency, thrombocytopenia or planned cardiac, intracranial, or intraspinal surgery were excluded.

Thirty-day incidence of arterial thromboembolism (stroke, TIA, systemic embolization) was 0.4% in the non-bridging group and 0.3% in the bridging group (P=0.01 for noninferiority). Patients suffering arterial thromboembolism had mean CHADS² scores of 2.6; most events occurred after minor procedures. Major bleeding was less common with no bridge (1.3% vs. 3.2%, relative risk 0.41, P=0.005 for superiority).

In this trial, most patients underwent minor procedures and few CHADS² 5-6 patients were enrolled; however, this well-designed, randomized trial adds important evidence to existing observational data.

Bottom line: Bridging is not warranted for most AF patients with CHADS2 scores of four or lower, at least for low-risk procedures.

Citation: Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833.

Clinical question: In patients with atrial fibrillation (AF) or flutter, is heparin bridging needed during interruption of warfarin therapy for surgery or invasive procedures?

Background: Bridging is intended to decrease the risk of stroke or other arterial thromboembolism by minimizing time off anticoagulation. Bridging may increase the risk of serious bleeding, offsetting any benefit. Guidelines have provided weak and inconsistent recommendations due to a lack of randomized trials.

Study design: Randomized, double blind, placebo-controlled trial.

Setting: More than 100 centers in the U.S. and Canada, from 2009-2014.

Synopsis: Investigators randomized 1,884 patients on warfarin with a CHADS² risk factor of one or higher undergoing elective surgery or procedure to dalteparin or placebo, from three days to 24 hours before the procedure and for five to 10 days after. Mean CHADS² score was 2.3; 3% of patients had scores of five to six. Approximately one-third of patients were on aspirin, and most procedures (89%) were classified as minor. Patients with mechanical heart valves, stroke/transient ischemic attack (TIA)/systemic embolization within 12 weeks, major bleeding within six weeks, renal insufficiency, thrombocytopenia or planned cardiac, intracranial, or intraspinal surgery were excluded.

Thirty-day incidence of arterial thromboembolism (stroke, TIA, systemic embolization) was 0.4% in the non-bridging group and 0.3% in the bridging group (P=0.01 for noninferiority). Patients suffering arterial thromboembolism had mean CHADS² scores of 2.6; most events occurred after minor procedures. Major bleeding was less common with no bridge (1.3% vs. 3.2%, relative risk 0.41, P=0.005 for superiority).

In this trial, most patients underwent minor procedures and few CHADS² 5-6 patients were enrolled; however, this well-designed, randomized trial adds important evidence to existing observational data.

Bottom line: Bridging is not warranted for most AF patients with CHADS2 scores of four or lower, at least for low-risk procedures.

Citation: Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833.

Clinical question: In patients with atrial fibrillation (AF) or flutter, is heparin bridging needed during interruption of warfarin therapy for surgery or invasive procedures?

Background: Bridging is intended to decrease the risk of stroke or other arterial thromboembolism by minimizing time off anticoagulation. Bridging may increase the risk of serious bleeding, offsetting any benefit. Guidelines have provided weak and inconsistent recommendations due to a lack of randomized trials.

Study design: Randomized, double blind, placebo-controlled trial.

Setting: More than 100 centers in the U.S. and Canada, from 2009-2014.

Synopsis: Investigators randomized 1,884 patients on warfarin with a CHADS² risk factor of one or higher undergoing elective surgery or procedure to dalteparin or placebo, from three days to 24 hours before the procedure and for five to 10 days after. Mean CHADS² score was 2.3; 3% of patients had scores of five to six. Approximately one-third of patients were on aspirin, and most procedures (89%) were classified as minor. Patients with mechanical heart valves, stroke/transient ischemic attack (TIA)/systemic embolization within 12 weeks, major bleeding within six weeks, renal insufficiency, thrombocytopenia or planned cardiac, intracranial, or intraspinal surgery were excluded.

Thirty-day incidence of arterial thromboembolism (stroke, TIA, systemic embolization) was 0.4% in the non-bridging group and 0.3% in the bridging group (P=0.01 for noninferiority). Patients suffering arterial thromboembolism had mean CHADS² scores of 2.6; most events occurred after minor procedures. Major bleeding was less common with no bridge (1.3% vs. 3.2%, relative risk 0.41, P=0.005 for superiority).

In this trial, most patients underwent minor procedures and few CHADS² 5-6 patients were enrolled; however, this well-designed, randomized trial adds important evidence to existing observational data.

Bottom line: Bridging is not warranted for most AF patients with CHADS2 scores of four or lower, at least for low-risk procedures.

Citation: Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833.

Clinical question: Does a postural modification to the Valsalva maneuver improve its effectiveness?

Background: The Valsalva maneuver, often used to treat supraventricular tachycardia, is rarely successful. A modification to the maneuver to increase relaxation phase venous return and vagal stimulation could improve its efficacy.

Study design: Multicenter, randomized controlled trial (RCT).

Setting: Ten emergency departments in England.

Synopsis: Four hundred thirty-three patients with stable supraventricular tachycardia (excluding atrial fibrillation or flutter) were randomized to use the Valsalva maneuver (control) or modified Valsalva maneuver (intervention). In the control group, strain was standardized using a manometer (40 mm Hg for 15 seconds). In the intervention group, patients underwent the same maneuver, followed by lying supine with passive leg raise to 45 degrees for 15 seconds. Participants could repeat the maneuver if it was initially unsuccessful. Randomization was stratified by center.

Using an intention-to-treat analysis, 43% of the intervention group achieved the primary outcome of sinus rhythm one minute after straining, compared with 17% of the control group (P<0.0001). The intervention group was less likely to receive adenosine (50% vs. 69%, P=0.0002) or any emergency, anti-arrhythmic treatment (80% vs. 57%, P<0.0001).

No significant differences were seen in hospital admissions, length of ED stay, or adverse events between groups.

Bottom line: In patients with stable supraventricular tachycardia, modifying the Valsalva maneuver is significantly more effective in restoring sinus rhythm.

Citation: Appelboam A, Reuben A, Mann C, et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial [published online ahead of print August 24, 2015]. Lancet. doi: 10.1016/S0140-6736(15)61485-4.

Clinical question: Does a postural modification to the Valsalva maneuver improve its effectiveness?

Background: The Valsalva maneuver, often used to treat supraventricular tachycardia, is rarely successful. A modification to the maneuver to increase relaxation phase venous return and vagal stimulation could improve its efficacy.

Study design: Multicenter, randomized controlled trial (RCT).

Setting: Ten emergency departments in England.

Synopsis: Four hundred thirty-three patients with stable supraventricular tachycardia (excluding atrial fibrillation or flutter) were randomized to use the Valsalva maneuver (control) or modified Valsalva maneuver (intervention). In the control group, strain was standardized using a manometer (40 mm Hg for 15 seconds). In the intervention group, patients underwent the same maneuver, followed by lying supine with passive leg raise to 45 degrees for 15 seconds. Participants could repeat the maneuver if it was initially unsuccessful. Randomization was stratified by center.

Using an intention-to-treat analysis, 43% of the intervention group achieved the primary outcome of sinus rhythm one minute after straining, compared with 17% of the control group (P<0.0001). The intervention group was less likely to receive adenosine (50% vs. 69%, P=0.0002) or any emergency, anti-arrhythmic treatment (80% vs. 57%, P<0.0001).

No significant differences were seen in hospital admissions, length of ED stay, or adverse events between groups.

Bottom line: In patients with stable supraventricular tachycardia, modifying the Valsalva maneuver is significantly more effective in restoring sinus rhythm.

Citation: Appelboam A, Reuben A, Mann C, et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial [published online ahead of print August 24, 2015]. Lancet. doi: 10.1016/S0140-6736(15)61485-4.

Clinical question: Does a postural modification to the Valsalva maneuver improve its effectiveness?

Background: The Valsalva maneuver, often used to treat supraventricular tachycardia, is rarely successful. A modification to the maneuver to increase relaxation phase venous return and vagal stimulation could improve its efficacy.

Study design: Multicenter, randomized controlled trial (RCT).

Setting: Ten emergency departments in England.

Synopsis: Four hundred thirty-three patients with stable supraventricular tachycardia (excluding atrial fibrillation or flutter) were randomized to use the Valsalva maneuver (control) or modified Valsalva maneuver (intervention). In the control group, strain was standardized using a manometer (40 mm Hg for 15 seconds). In the intervention group, patients underwent the same maneuver, followed by lying supine with passive leg raise to 45 degrees for 15 seconds. Participants could repeat the maneuver if it was initially unsuccessful. Randomization was stratified by center.

Using an intention-to-treat analysis, 43% of the intervention group achieved the primary outcome of sinus rhythm one minute after straining, compared with 17% of the control group (P<0.0001). The intervention group was less likely to receive adenosine (50% vs. 69%, P=0.0002) or any emergency, anti-arrhythmic treatment (80% vs. 57%, P<0.0001).

No significant differences were seen in hospital admissions, length of ED stay, or adverse events between groups.

Bottom line: In patients with stable supraventricular tachycardia, modifying the Valsalva maneuver is significantly more effective in restoring sinus rhythm.

Citation: Appelboam A, Reuben A, Mann C, et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial [published online ahead of print August 24, 2015]. Lancet. doi: 10.1016/S0140-6736(15)61485-4.