Most adults do not realize that suicide is a more frequent cause of death than homicide, according to the first nationally representative study of public perceptions of firearm and non-firearm-related violent death in the United States.

“These findings are consistent with the well-established relationship between risk perception and the ease with which a pertinent categorical example can be summoned from memory, which in most persons is probably affected by the salience of homicides in media coverage,” lead author Erin R. Morgan, MS, and her coauthors wrote in the Annals of Internal Medicine.

The coauthors reviewed 3,811 responses to a question in the National Firearms Survey on the intent and means of violent death; participants were given 4 options – homicide with a gun, homicide with a weapon other than a gun, suicide with a gun, and suicide by a method other than a gun – and asked to rank them by frequency. A study of those responses found that only 13.5% of U.S. adults could correctly identify their state’s most frequent cause of violent death. Of the 1,880 respondents who shared their occupations, only 20% of health care professionals answered the question correctly.

The survey was conducted in April 2015; between 2014 and 2015, suicide was more common than homicide in all 50 states. Suicide by firearm was also more common than homicide by firearm in every state but Illinois, Maryland, and New Jersey. When reviewing firearm options only, the percentage of respondents who identified suicide as most frequent increased to 25.9%, according to Ms. Morgan of the School of Public Health and of Harborview Injury Prevention & Research Center at the University of Washington in Seattle, and her colleagues.

The coauthors noted that accurate identification was not impacted by the respondents’ firearm ownership status, but also that future research should evaluate if promoting awareness of suicide frequency and risk might “motivate behavioral change regarding firearm storage.”

“Our findings suggest that correcting misperceptions about the relative frequency of firearm-related violent deaths may make persons more cognizant of the actuarial risks to themselves and their family, thus creating new opportunities for prevention,” they wrote.

The study was funded by the Fund for a Safer Future and the Joyce Foundation. No conflicts of interest were reported.
 

SOURCE: Morgan E et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1533.

Most adults do not realize that suicide is a more frequent cause of death than homicide, according to the first nationally representative study of public perceptions of firearm and non-firearm-related violent death in the United States.

“These findings are consistent with the well-established relationship between risk perception and the ease with which a pertinent categorical example can be summoned from memory, which in most persons is probably affected by the salience of homicides in media coverage,” lead author Erin R. Morgan, MS, and her coauthors wrote in the Annals of Internal Medicine.

The coauthors reviewed 3,811 responses to a question in the National Firearms Survey on the intent and means of violent death; participants were given 4 options – homicide with a gun, homicide with a weapon other than a gun, suicide with a gun, and suicide by a method other than a gun – and asked to rank them by frequency. A study of those responses found that only 13.5% of U.S. adults could correctly identify their state’s most frequent cause of violent death. Of the 1,880 respondents who shared their occupations, only 20% of health care professionals answered the question correctly.

The survey was conducted in April 2015; between 2014 and 2015, suicide was more common than homicide in all 50 states. Suicide by firearm was also more common than homicide by firearm in every state but Illinois, Maryland, and New Jersey. When reviewing firearm options only, the percentage of respondents who identified suicide as most frequent increased to 25.9%, according to Ms. Morgan of the School of Public Health and of Harborview Injury Prevention & Research Center at the University of Washington in Seattle, and her colleagues.

The coauthors noted that accurate identification was not impacted by the respondents’ firearm ownership status, but also that future research should evaluate if promoting awareness of suicide frequency and risk might “motivate behavioral change regarding firearm storage.”

“Our findings suggest that correcting misperceptions about the relative frequency of firearm-related violent deaths may make persons more cognizant of the actuarial risks to themselves and their family, thus creating new opportunities for prevention,” they wrote.

The study was funded by the Fund for a Safer Future and the Joyce Foundation. No conflicts of interest were reported.
 

SOURCE: Morgan E et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1533.

Most adults do not realize that suicide is a more frequent cause of death than homicide, according to the first nationally representative study of public perceptions of firearm and non-firearm-related violent death in the United States.

“These findings are consistent with the well-established relationship between risk perception and the ease with which a pertinent categorical example can be summoned from memory, which in most persons is probably affected by the salience of homicides in media coverage,” lead author Erin R. Morgan, MS, and her coauthors wrote in the Annals of Internal Medicine.

The coauthors reviewed 3,811 responses to a question in the National Firearms Survey on the intent and means of violent death; participants were given 4 options – homicide with a gun, homicide with a weapon other than a gun, suicide with a gun, and suicide by a method other than a gun – and asked to rank them by frequency. A study of those responses found that only 13.5% of U.S. adults could correctly identify their state’s most frequent cause of violent death. Of the 1,880 respondents who shared their occupations, only 20% of health care professionals answered the question correctly.

The survey was conducted in April 2015; between 2014 and 2015, suicide was more common than homicide in all 50 states. Suicide by firearm was also more common than homicide by firearm in every state but Illinois, Maryland, and New Jersey. When reviewing firearm options only, the percentage of respondents who identified suicide as most frequent increased to 25.9%, according to Ms. Morgan of the School of Public Health and of Harborview Injury Prevention & Research Center at the University of Washington in Seattle, and her colleagues.

The coauthors noted that accurate identification was not impacted by the respondents’ firearm ownership status, but also that future research should evaluate if promoting awareness of suicide frequency and risk might “motivate behavioral change regarding firearm storage.”

“Our findings suggest that correcting misperceptions about the relative frequency of firearm-related violent deaths may make persons more cognizant of the actuarial risks to themselves and their family, thus creating new opportunities for prevention,” they wrote.

The study was funded by the Fund for a Safer Future and the Joyce Foundation. No conflicts of interest were reported.
 

SOURCE: Morgan E et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1533.

ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.

“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”

According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used ¹⁸F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”

The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 10¹¹ vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 10¹¹ vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 10¹² vg/mL and were followed for 12 months.

At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.

In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.

“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”

He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.

Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.

[email protected]

Source: Christine et al. ANA 2018, Abstract M300.




 

ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.

“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”

According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used ¹⁸F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”

The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 10¹¹ vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 10¹¹ vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 10¹² vg/mL and were followed for 12 months.

At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.

In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.

“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”

He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.

Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.

[email protected]

Source: Christine et al. ANA 2018, Abstract M300.




 

ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.

“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”

According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used ¹⁸F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”

The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 10¹¹ vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 10¹¹ vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 10¹² vg/mL and were followed for 12 months.

At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.

In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.

“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”

He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.

Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.

[email protected]

Source: Christine et al. ANA 2018, Abstract M300.




 

ATLANTA – A majority of oromandibular dystonia patients treated with botulinum toxin injections reported improvement in symptoms in the largest cohort of patients to date.

Doug Brunk/MDedge News

Improvements in the range of 50%-100% occurred in 78% of oromandibular dystonia (OMD) patients who received botulinum toxin injections in the retrospective, multicenter analysis, which was presented by Laura Scorr, MD, at the annual meeting of the American Neurological Association.

In an effort to better describe the clinical characteristics of patients with OMD, Dr. Scorr, a movement disorders specialist at Emory University, Atlanta, and her colleagues analyzed data collected from 164 OMD patients enrolled at 26 international sites in the Dystonia Coalition and 37 additional patients who were evaluated at the Emory University within the last year. Subjects enrolled at Dystonia Coalition centers underwent evaluation by a movement disorders specialist to determine distribution of dystonia, areas affected, and severity as measured by the Global Dystonia Rating Scale. A subgroup of patients also completed the SF 36-item Health Survey, the Beck Depression Scale, and the Liebowitz social anxiety scale. Meanwhile, the charts of patients seen at Emory underwent review for data on clinical characteristics, treatment type, botulinum toxin doses, and response.

Among all 201 patients, the average age of onset was 54 years and 65% were female. About 45% were determined to have focal dystonia, 36% had segmental dystonia, and 19% had generalized dystonia. Among a cohort of 47 patients evaluated in the Dystonia Coalition biorepository, the researchers observed significantly increased social anxiety and impaired quality of life on the Liebowitz social anxiety scale and the SF-36 Health Survey.

Of the 37 Emory patients, 31 (84%) received botulinum toxin injections. Of these, 39% reported symptom improvement that ranged from 75%-100% while 39% reported symptom improvement that ranged from 50%-74%. Only 13% had a minimal response, defined as improvement that ranged from 1%-24%.

“Oromandibular dystonia is particularly disabling,” Dr. Scorr said. “There have been a few reports in the literature that say it does not respond to botulinum toxin injections. But in our retrospective review, the majority of patients not only have a response, but a response that’s greater than 50% improvement, which is significant.” She acknowledged that the study’s retrospective design is a limitation. “I think we need more prospective studies, specifically on response to treatment with botulinum toxin,” she said.

The study was funded in part by the Dystonia Medical Research Foundation. Dr. Scorr reported having no financial disclosures.

[email protected]

SOURCE: Scorr L et al. Ann Neurol. 2018;84[S22]:S90, Abstract S216.

ATLANTA – A majority of oromandibular dystonia patients treated with botulinum toxin injections reported improvement in symptoms in the largest cohort of patients to date.

Doug Brunk/MDedge News

Improvements in the range of 50%-100% occurred in 78% of oromandibular dystonia (OMD) patients who received botulinum toxin injections in the retrospective, multicenter analysis, which was presented by Laura Scorr, MD, at the annual meeting of the American Neurological Association.

In an effort to better describe the clinical characteristics of patients with OMD, Dr. Scorr, a movement disorders specialist at Emory University, Atlanta, and her colleagues analyzed data collected from 164 OMD patients enrolled at 26 international sites in the Dystonia Coalition and 37 additional patients who were evaluated at the Emory University within the last year. Subjects enrolled at Dystonia Coalition centers underwent evaluation by a movement disorders specialist to determine distribution of dystonia, areas affected, and severity as measured by the Global Dystonia Rating Scale. A subgroup of patients also completed the SF 36-item Health Survey, the Beck Depression Scale, and the Liebowitz social anxiety scale. Meanwhile, the charts of patients seen at Emory underwent review for data on clinical characteristics, treatment type, botulinum toxin doses, and response.

Among all 201 patients, the average age of onset was 54 years and 65% were female. About 45% were determined to have focal dystonia, 36% had segmental dystonia, and 19% had generalized dystonia. Among a cohort of 47 patients evaluated in the Dystonia Coalition biorepository, the researchers observed significantly increased social anxiety and impaired quality of life on the Liebowitz social anxiety scale and the SF-36 Health Survey.

Of the 37 Emory patients, 31 (84%) received botulinum toxin injections. Of these, 39% reported symptom improvement that ranged from 75%-100% while 39% reported symptom improvement that ranged from 50%-74%. Only 13% had a minimal response, defined as improvement that ranged from 1%-24%.

“Oromandibular dystonia is particularly disabling,” Dr. Scorr said. “There have been a few reports in the literature that say it does not respond to botulinum toxin injections. But in our retrospective review, the majority of patients not only have a response, but a response that’s greater than 50% improvement, which is significant.” She acknowledged that the study’s retrospective design is a limitation. “I think we need more prospective studies, specifically on response to treatment with botulinum toxin,” she said.

The study was funded in part by the Dystonia Medical Research Foundation. Dr. Scorr reported having no financial disclosures.

[email protected]

SOURCE: Scorr L et al. Ann Neurol. 2018;84[S22]:S90, Abstract S216.

ATLANTA – A majority of oromandibular dystonia patients treated with botulinum toxin injections reported improvement in symptoms in the largest cohort of patients to date.

Doug Brunk/MDedge News

Improvements in the range of 50%-100% occurred in 78% of oromandibular dystonia (OMD) patients who received botulinum toxin injections in the retrospective, multicenter analysis, which was presented by Laura Scorr, MD, at the annual meeting of the American Neurological Association.

In an effort to better describe the clinical characteristics of patients with OMD, Dr. Scorr, a movement disorders specialist at Emory University, Atlanta, and her colleagues analyzed data collected from 164 OMD patients enrolled at 26 international sites in the Dystonia Coalition and 37 additional patients who were evaluated at the Emory University within the last year. Subjects enrolled at Dystonia Coalition centers underwent evaluation by a movement disorders specialist to determine distribution of dystonia, areas affected, and severity as measured by the Global Dystonia Rating Scale. A subgroup of patients also completed the SF 36-item Health Survey, the Beck Depression Scale, and the Liebowitz social anxiety scale. Meanwhile, the charts of patients seen at Emory underwent review for data on clinical characteristics, treatment type, botulinum toxin doses, and response.

Among all 201 patients, the average age of onset was 54 years and 65% were female. About 45% were determined to have focal dystonia, 36% had segmental dystonia, and 19% had generalized dystonia. Among a cohort of 47 patients evaluated in the Dystonia Coalition biorepository, the researchers observed significantly increased social anxiety and impaired quality of life on the Liebowitz social anxiety scale and the SF-36 Health Survey.

Of the 37 Emory patients, 31 (84%) received botulinum toxin injections. Of these, 39% reported symptom improvement that ranged from 75%-100% while 39% reported symptom improvement that ranged from 50%-74%. Only 13% had a minimal response, defined as improvement that ranged from 1%-24%.

“Oromandibular dystonia is particularly disabling,” Dr. Scorr said. “There have been a few reports in the literature that say it does not respond to botulinum toxin injections. But in our retrospective review, the majority of patients not only have a response, but a response that’s greater than 50% improvement, which is significant.” She acknowledged that the study’s retrospective design is a limitation. “I think we need more prospective studies, specifically on response to treatment with botulinum toxin,” she said.

The study was funded in part by the Dystonia Medical Research Foundation. Dr. Scorr reported having no financial disclosures.

[email protected]

SOURCE: Scorr L et al. Ann Neurol. 2018;84[S22]:S90, Abstract S216.

Hospital costs for children with firearm-related injuries rose from 2006 to 2014, while the incidence of emergency department visits declined over the same period, according to the first national study of such visits in children.

Median charges were $2,445 for an ED visit and $44,966 for inpatient management of individuals under 18 years of age for the entire study period, with both increasing over time and all data adjusted to 2018 dollars. The median charge for an ED visit rose from over $2,100 in 2006 to under $2,900 in 2014, while the inpatient median increased from approximately $43,000 to about $59,000. Total charges for firearm-related injuries in children were $2.5 billion during 2006-2014, with a mean of $270 million a year, Faiz Gani, MBBS, and Joseph K. Canner, MHS, said in JAMA Pediatrics.

The overall incidence of ED visits was 11.3/100,000 children under 18 years of age for the study period, with a steady decline seen from 2006, when incidence was about 15 visits/100,000, to 10/100,000 in 2014. The rate had dropped to about 7.5 visits/100,000 in 2013 before increasing in 2014, Dr. Gani and Mr. Canner of Johns Hopkins University, Baltimore, said based on data for 75,086 visits from the Nationwide Emergency Medicine Sample.

A trend observed throughout the course of the study was the higher incidence of ED visits among males, which was consistently more than five times higher than that of females. The highest incidence by age group was 85.9/100,000 for males aged 15-17 years. The most common intent of injury was assault at 49%, with unintentional injury next at 39% and suicide at 2%, the investigators reported.

This “first and largest nationally representative study” demonstrates the “substantial clinical and financial burden associated with firearm-related injuries among pediatric patients. Moving forward, additional resources and funds should be allocated to the study of firearm-related injuries. Only through further understanding of the social, political, and health-related risk factors for these injuries can we develop and implement effective policies to address this public health concern, wrote Dr. Gani and Mr. Canner, who reported no conflicts of interest.

[email protected]

SOURCE: JAMA Pediatr. 2018 Oct 29. doi: 10.1001/jamapediatrics.2018.3091.

Hospital costs for children with firearm-related injuries rose from 2006 to 2014, while the incidence of emergency department visits declined over the same period, according to the first national study of such visits in children.

Median charges were $2,445 for an ED visit and $44,966 for inpatient management of individuals under 18 years of age for the entire study period, with both increasing over time and all data adjusted to 2018 dollars. The median charge for an ED visit rose from over $2,100 in 2006 to under $2,900 in 2014, while the inpatient median increased from approximately $43,000 to about $59,000. Total charges for firearm-related injuries in children were $2.5 billion during 2006-2014, with a mean of $270 million a year, Faiz Gani, MBBS, and Joseph K. Canner, MHS, said in JAMA Pediatrics.

The overall incidence of ED visits was 11.3/100,000 children under 18 years of age for the study period, with a steady decline seen from 2006, when incidence was about 15 visits/100,000, to 10/100,000 in 2014. The rate had dropped to about 7.5 visits/100,000 in 2013 before increasing in 2014, Dr. Gani and Mr. Canner of Johns Hopkins University, Baltimore, said based on data for 75,086 visits from the Nationwide Emergency Medicine Sample.

A trend observed throughout the course of the study was the higher incidence of ED visits among males, which was consistently more than five times higher than that of females. The highest incidence by age group was 85.9/100,000 for males aged 15-17 years. The most common intent of injury was assault at 49%, with unintentional injury next at 39% and suicide at 2%, the investigators reported.

This “first and largest nationally representative study” demonstrates the “substantial clinical and financial burden associated with firearm-related injuries among pediatric patients. Moving forward, additional resources and funds should be allocated to the study of firearm-related injuries. Only through further understanding of the social, political, and health-related risk factors for these injuries can we develop and implement effective policies to address this public health concern, wrote Dr. Gani and Mr. Canner, who reported no conflicts of interest.

[email protected]

SOURCE: JAMA Pediatr. 2018 Oct 29. doi: 10.1001/jamapediatrics.2018.3091.

Hospital costs for children with firearm-related injuries rose from 2006 to 2014, while the incidence of emergency department visits declined over the same period, according to the first national study of such visits in children.

Median charges were $2,445 for an ED visit and $44,966 for inpatient management of individuals under 18 years of age for the entire study period, with both increasing over time and all data adjusted to 2018 dollars. The median charge for an ED visit rose from over $2,100 in 2006 to under $2,900 in 2014, while the inpatient median increased from approximately $43,000 to about $59,000. Total charges for firearm-related injuries in children were $2.5 billion during 2006-2014, with a mean of $270 million a year, Faiz Gani, MBBS, and Joseph K. Canner, MHS, said in JAMA Pediatrics.

The overall incidence of ED visits was 11.3/100,000 children under 18 years of age for the study period, with a steady decline seen from 2006, when incidence was about 15 visits/100,000, to 10/100,000 in 2014. The rate had dropped to about 7.5 visits/100,000 in 2013 before increasing in 2014, Dr. Gani and Mr. Canner of Johns Hopkins University, Baltimore, said based on data for 75,086 visits from the Nationwide Emergency Medicine Sample.

A trend observed throughout the course of the study was the higher incidence of ED visits among males, which was consistently more than five times higher than that of females. The highest incidence by age group was 85.9/100,000 for males aged 15-17 years. The most common intent of injury was assault at 49%, with unintentional injury next at 39% and suicide at 2%, the investigators reported.

This “first and largest nationally representative study” demonstrates the “substantial clinical and financial burden associated with firearm-related injuries among pediatric patients. Moving forward, additional resources and funds should be allocated to the study of firearm-related injuries. Only through further understanding of the social, political, and health-related risk factors for these injuries can we develop and implement effective policies to address this public health concern, wrote Dr. Gani and Mr. Canner, who reported no conflicts of interest.

[email protected]

SOURCE: JAMA Pediatr. 2018 Oct 29. doi: 10.1001/jamapediatrics.2018.3091.

The recent rise in pertussis rates may have peaked, but the experts are responding by reinstating a working group.

The new working group for pertussis was announced at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices. The ACIP’s new group, led by Fiona Havers, MD, of the CDC, heard data on the currently available pertussis vaccines and solicited ideas from ACIP members about what other data they would like before the February meeting.

One question on the agenda is whether the current recommendation that nonpregnant adults receive a single lifetime dose of Tdap and then tetanus-diphtheria (Td) boosters every 10 years be expanded to allow either Tdap or Td as the booster. Reasons for considering the change include possible changes in the circulating pertussis strain, improved diagnosis and reporting, and the waning of protection under the current guidelines, as well as the potential economic impact, Dr. Havers said.

This change could make booster administration easier for many physicians who do not routinely stock Td, some committee members noted. In addition, the Food and Drug Administration has approved a label change for one Tdap manufacturer to remove “single use” language.

In a study presented by David P. Greenberg, MD, associate vice president of Sanofi Pasteur, seroprotection rates to tetanus and diphtheria were similar in a comparison between groups of adults aged 18 years and older, receiving either Tdap (Adacel) or Td as a booster. “Seroprotection was greater than 99% in both groups,” he said.

Pain was the most common injection site reaction in both groups, rates of serious adverse events were similarly low (0.8% and 0.3%, respectively), and no deaths occurred in patients given either vaccine.

The postvaccination antipertussis geometric mean concentrations were noninferior in the Tdap group, compared with the Td group, Dr. Greenberg said.

A phase III open label study presented by Leonard Silverstein, MD, of GlaxoSmithKline also showed similar seroprotection rates for adults revaccinated with Tdap after an initial vaccination with either of two different Tdap vaccines.

Also at the February meeting, the committee will address whether any vaccine that contained Td should be allowed for use as tetanus prophylaxis in the setting of wound management, said Dr. Havers.

The committee members expressed interest in more information on several topics including pregnancy and pertussis, whether manufacturers could discuss vaccines in the pipeline, data on responses to multiple doses and if there is a point of diminishing returns, and whether some states are covering Tdap for adults.

The committee members had no financial conflicts to disclose.

The recent rise in pertussis rates may have peaked, but the experts are responding by reinstating a working group.

The new working group for pertussis was announced at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices. The ACIP’s new group, led by Fiona Havers, MD, of the CDC, heard data on the currently available pertussis vaccines and solicited ideas from ACIP members about what other data they would like before the February meeting.

One question on the agenda is whether the current recommendation that nonpregnant adults receive a single lifetime dose of Tdap and then tetanus-diphtheria (Td) boosters every 10 years be expanded to allow either Tdap or Td as the booster. Reasons for considering the change include possible changes in the circulating pertussis strain, improved diagnosis and reporting, and the waning of protection under the current guidelines, as well as the potential economic impact, Dr. Havers said.

This change could make booster administration easier for many physicians who do not routinely stock Td, some committee members noted. In addition, the Food and Drug Administration has approved a label change for one Tdap manufacturer to remove “single use” language.

In a study presented by David P. Greenberg, MD, associate vice president of Sanofi Pasteur, seroprotection rates to tetanus and diphtheria were similar in a comparison between groups of adults aged 18 years and older, receiving either Tdap (Adacel) or Td as a booster. “Seroprotection was greater than 99% in both groups,” he said.

Pain was the most common injection site reaction in both groups, rates of serious adverse events were similarly low (0.8% and 0.3%, respectively), and no deaths occurred in patients given either vaccine.

The postvaccination antipertussis geometric mean concentrations were noninferior in the Tdap group, compared with the Td group, Dr. Greenberg said.

A phase III open label study presented by Leonard Silverstein, MD, of GlaxoSmithKline also showed similar seroprotection rates for adults revaccinated with Tdap after an initial vaccination with either of two different Tdap vaccines.

Also at the February meeting, the committee will address whether any vaccine that contained Td should be allowed for use as tetanus prophylaxis in the setting of wound management, said Dr. Havers.

The committee members expressed interest in more information on several topics including pregnancy and pertussis, whether manufacturers could discuss vaccines in the pipeline, data on responses to multiple doses and if there is a point of diminishing returns, and whether some states are covering Tdap for adults.

The committee members had no financial conflicts to disclose.

The recent rise in pertussis rates may have peaked, but the experts are responding by reinstating a working group.

The new working group for pertussis was announced at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices. The ACIP’s new group, led by Fiona Havers, MD, of the CDC, heard data on the currently available pertussis vaccines and solicited ideas from ACIP members about what other data they would like before the February meeting.

One question on the agenda is whether the current recommendation that nonpregnant adults receive a single lifetime dose of Tdap and then tetanus-diphtheria (Td) boosters every 10 years be expanded to allow either Tdap or Td as the booster. Reasons for considering the change include possible changes in the circulating pertussis strain, improved diagnosis and reporting, and the waning of protection under the current guidelines, as well as the potential economic impact, Dr. Havers said.

This change could make booster administration easier for many physicians who do not routinely stock Td, some committee members noted. In addition, the Food and Drug Administration has approved a label change for one Tdap manufacturer to remove “single use” language.

In a study presented by David P. Greenberg, MD, associate vice president of Sanofi Pasteur, seroprotection rates to tetanus and diphtheria were similar in a comparison between groups of adults aged 18 years and older, receiving either Tdap (Adacel) or Td as a booster. “Seroprotection was greater than 99% in both groups,” he said.

Pain was the most common injection site reaction in both groups, rates of serious adverse events were similarly low (0.8% and 0.3%, respectively), and no deaths occurred in patients given either vaccine.

The postvaccination antipertussis geometric mean concentrations were noninferior in the Tdap group, compared with the Td group, Dr. Greenberg said.

A phase III open label study presented by Leonard Silverstein, MD, of GlaxoSmithKline also showed similar seroprotection rates for adults revaccinated with Tdap after an initial vaccination with either of two different Tdap vaccines.

Also at the February meeting, the committee will address whether any vaccine that contained Td should be allowed for use as tetanus prophylaxis in the setting of wound management, said Dr. Havers.

The committee members expressed interest in more information on several topics including pregnancy and pertussis, whether manufacturers could discuss vaccines in the pipeline, data on responses to multiple doses and if there is a point of diminishing returns, and whether some states are covering Tdap for adults.

The committee members had no financial conflicts to disclose.

ABSTRACT

Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. However, the rate of injury to smaller periarticular vessels and the clinical significance of such an injury have not been well investigated. The purpose of this study is to describe the rate and outcomes of geniculate artery (GA) injury, the time at which injury occurs, and any associations with tourniquet use.

From November 2015 to February 2016, 3 surgeons at a single institution performed 100 consecutive primary TKAs and documented the presence or absence and the timing of GA injury. The data were then retrospectively reviewed. All TKAs had no prior surgery on the operative extremity. Other variables collected included tourniquet use, tranexamic acid (TXA) administration, intraoperative blood loss, postoperative drain output, and blood transfusion.

The overall rate of GA injury was 38%, with lateral inferior and middle GA injury in 31% and 15% of TKAs, respectively. Most of the injuries were visualized during bone cuts or meniscectomy. The rate of overall or isolated GA injury was not significantly different (P > .05) with either use of intravenous (84 patients) or topical (14 patients) TXA administration. Comparing selective tourniquet use (only during cementation) vs routine use showed no differences in GA injury rate (P = .37), blood loss (P = .07), or drain output (P = .46).

There is a relatively high rate of GA injury, with injury to the lateral GA occurring more often than the middle GA. Routine or selective tourniquet use does not affect the rate of injury.

Continue to: Major arterial injury...

Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. The majority of literature in this context consists of case reports, small case series, and large retrospective studies that have examined the type, location, and mechanism of injury present in these cases.^1-13 Reported arterial injuries include occlusion, laceration, aneurysm, pseudoaneurysm, and arteriovenous fistula formation in the femoral (believed to be due to the tourniquet around the proximal thigh) and popliteal arteries causing combinations of ischemia and hemorrhage necessitating treatment ranging from endovascular arterial intervention to amputation.^{4,5,9-11,13-17} In addition, several studies have asserted that the risk of major arterial injury may be increased with tourniquet use, suggesting that tourniquet use should be minimized for routine primary TKAs.^3,6

There are very few cases in the literature specifically addressing injury to the more commonly encountered geniculate arteries (GAs). The medial GAs are typically visualized and coagulated during the standard medial parapatellar approach. In addition, if performed, a lateral release can damage the lateral superior and inferior GAs and the middle GA can be cut with posterior cruciate ligament resection. However, the middle and lateral inferior GAs are anecdotally the most difficult to detect and treat intraoperatively, especially after implantation of TKA and deflation of the tourniquet. The potential lack of recognition of such GA injury can result in harmful sequelae, including ischemia of the patella, hemorrhage, and painful pseudoaneurysms.^2,18-29 Currently, there are only 2 case reports of lateral inferior GA injury, 2 cases of medial inferior GA injury, and no reports of middle GA injury.^2,23,24,29

The rate, the timing within surgery, the risk factors, including tourniquet use, and the clinical effects of GA injury are largely unknown. If these factors were better understood, prophylactic measures and/or awareness could be better applied to prevent adverse outcomes, especially in cases of the middle and lateral inferior GAs. The aims of this study are to elucidate the rate and timing of middle and lateral inferior GA injury during primary TKA; determine the factors related to injury, including intraoperative blood loss, postoperative drain output, and tranexamic (TXA) acid use; and investigate any differences in the rate of injury with and without the use of a tourniquet.

MATERIALS AND METHODS

PATIENT DEMOGRAPHICS AND SURGICAL TECHNIQUE

From November 2015 to February 2016, 3 surgeons (MJT, TMM, and RTT) at a single institution performed 100 consecutive unilateral primary TKAs and documented the presence or absence and the timing of GA injury. After obtaining approval from our Institutional Review Board, a retrospective study was performed to investigate the prospectively recorded rate of middle and lateral inferior GA injuries occurring during primary TKAs. Patients with a diagnosis of isolated osteoarthritis were included, and those with any previous surgery on the operative knee were excluded. The average age of patients at the time of surgery was 67 years (range, 25-91 years), the average body mass index was 33 kg/m² (range, 18-54 kg/m²), and there were 63 (63%) female patients.

All TKAs were performed through a medial parapatellar approach with a posterior-stabilized, cemented design, and each patient received a postoperative surgical drain. One of the 3 lead surgeons (TMM) in this study used a tourniquet from the time of incision until the completion of cementation, and the other 2 (MJT and RTT) predominantly used the tourniquet only during cementation. To elucidate any differences in GA injury between these 2 methods of tourniquet use, the patients were categorized into 2 groups base d on tourniquet use. Group 1 included patients in whom a tourniquet was used to maintain a bloodless surgical field from the time of incision until the completion of cementation, and Group 2 included patients in whom tourniquet use was more selective (ie, applied only during cementation). Group 1 comprised 31% (31/100) of patients, while Group 2 comprised 67% (67/100) of patients; no tourniquet was used in 2% (2/100) of cases. In addition, TXA was used in 98% (98/100) of patients: 84 patients received intravenous (IV) and 14 received topical TXA administration.

Continue to: ANALYSIS OF GENICULATE ARTERY INJURY

The senior authors critically evaluated the GA during the primary TKAs and documented the presence or absence of injury in the operative reports. GA injury was reported if there was intraoperative visualization of pulsatile bleeding or visualization of arterial lumen in the anatomic areas of the middle and lateral inferior GAs. At 3 separate occasions during the operation, the surgeon looked specifically for pulsatile bleeding or arterial lumen in the areas of the middle and lateral inferior GAs, including after all the femoral and tibial bone cuts were completed, immediately before preparing to cement (before the tourniquet was inflated if there was not one inflated from the start of the procedure), and immediately after the tourniquet was deflated (Figure 1). All bleeding GAs that were visualized were effectively coagulated by cautery. Details regarding the use of TXA (topical or IV), intraoperative blood loss, postsurgical drain output for 24 hours after surgery, and blood transfusion were collected from the patients’ medical records (Table 1).

Operative variables other than geniculate artery injury. Data presented as mean (range) or n (%). TXA = tranexamic acid.

STATISTICAL METHODS

Statistical analysis was performed using the JMP software version 10.0.0 (SAS Institute, Inc). The overall rate of GA injury was determined, including the rates of GA injury based on location, time point, and method of diagnosis (pulsatile bleeding or arterial lumen visualization). If >1 GA injury occurred in the same knee, only 1 GA injury was calculated for the overall rate; however, each injury was specified separately when calculating the injury rate for the specific GA. Intraoperative blood loss, postoperative drain output, and the use of TXA were compared between cases in which a GA injury was detected and those in which it was not detected. Before conducting the retrospective review, a power analysis determined that we would require 100 patients to detect a difference in GA injury between Groups 1 and 2 (33 in Group 1 and 67 in Group 2), assuming a 30% rate in Group 1 and a 5% rate of GA injury in Group 2 using Fisher’s exact test. The Fisher’s exact test was used to compare categorical variables, and the Wilcoxon rank sum test was used to compare continuous variables. An alpha value of .05 was considered as statistically significant.

RESULTS

RATE OF GENICULATE ARTERY INJURY

The overall rate of any GA injury was 38% (38/100). Lateral inferior GA injury was more frequently detected than middle GA injury (31% vs 15% of TKAs, respectively; Table 2). Among the 31 lateral inferior GA injuries, 14 were identified as pulsatile bleeding, 7 as lumen visualizations, and 6 as both pulsatile bleeding and lumen visualization; 4 were detected by methods not recorded in the operative report. Of the lateral inferior GA injuries, 11 were identified after the bone cuts, 7 during meniscus removal, 3 during exposure, 1 after tourniquet deflation, and 9 at a time not recorded in the operative report. Of the 15 middle GA injuries, 9 were identified as pulsatile bleeding, 2 as lumen visualizations, and 4 as both pulsatile bleeding and lumen visualization. In addition, 7 of these GA injuries were identified after the bone cuts, 3 during cruciate removal, 1 after meniscus removal, 1 during exposure, and 3 at a time not recorded in the operative report (Table 3).

Rates of geniculate artery injury based on location and method of diagnosis. Data presented as n (%). There were 4 additional lateral inferior and 9 middle GA injuries identified by a method not specified in the operative report. GA = geniculate artery.

Rates of geniculate artery injury based on time point and method of diagnosis. GA = geniculate artery. Data presented as n (%).

FACTORS ASSOCIATED WITH GENICULATE ARTERY INJURY

Mean intraoperative estimated blood loss was 186 mL (standard deviation [SD], 111; range 50–500 mL) in those with a GA injury versus 147 mL (range, 82.25–400 mL) in those without injury (P = .14). Postoperative drain output in the 24 hours after surgery was 467 mL (SD 253, range 100–1105 mL) versus 502 mL (SD 378, range 75–1980 mL) in TKAs with and without GA injury, respectively (P = .82). Total estimated blood loss (combined intraoperative blood loss and 24-hour postoperative drain output) was 613 mL (SD 252, range 150–1105 mL) in TKAs with GA injury versus 620 mL (SD 393, range 75–2130 mL) without injury (P = .44) (Table 4). Overall, there was no statistical difference in blood loss, drain output, or combined output when analyzed according to lateral inferior or middle GA injury (P = .24–.82) (Table 5 and Table 6). No patients required blood transfusion postoperatively after TKA.

Differences in outcomes based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery.

Differences in outcomes based on presence or absence of LIGA injury. Note that there were no significant differences. Values are reported as average (range). LIGA = lateral inferior geniculate artery.

Differences in outcomes based on presence or absence of MGA injury. Note that there were no significant differences. Values are reported as average (range). MGA = middle geniculate artery.

IV administration of TXA was associated with a 37% (31/84) rate of GA injury, whereas topical TXA administration was associated with a 43% (6/14) rate of GA injury (P = .77). The rate of overall or isolated GA injury was not significantly different (P = .35–1.0) between IV and topical TXA administration (Table 7). In addition, total combined output was not significantly different (P = .1032) when comparing GA injury and noninjury in the subgroup analysis based on TXA use (IV or topical); however, topical administration was associated with lower intraoperative blood loss than IV administration (P = .0489), whereas IV administration was associated with lower 24-hour postoperative drain output than topical administration (P = .0169). There was no difference in blood loss, 24-hour drain output, or total output between those who did and did not sustain a GA injury in the group of patients who received IV TXA administration (Table 8, P = .2118–.7091). The same was true for those receiving topical TXA administration (Table 9, P = .0912–.9485).

Differences in outcomes based on presence or absence of MGA injury. Note that there were no significant differences. Values are reported as n (%) or average (range). TXA = tranexamic acid, GA = geniculate artery, LIGA = lateral inferior geniculate artery, MGA = middle geniculate artery. *denotes statistical significance (P < .05).

Differences in outcomes of those patients who received IV TXA based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery, TXA = tranexamic acid.

Differences in outcomes based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery.

Continue to: TOURNIQUET USE

Comparison between Groups 1 (tourniquet use) and 2 (selective tourniquet use) revealed similar rates of overall and specific GA injury, intraoperative blood loss, and 24-hour postoperative drain output (Table 10). Group 1 demonstrated a 29% (9/31) rate of any GA injury versus 40% (27/67) in Group 2 (P = .37). For the specific lateral inferior GA injury, there was an equivalent rate of injury at 29% (9/31 in Group 1, 20/67 in Group 2; P = 1.0). Similarly, Group 1 patients had a 10% (3/31) rate of middle GA injury compared to 16% (11/67) in Group 2 patients (P = .53). Intraoperative estimated blood loss was lower in Group 1 (140 mL; range 25–400 mL) than in Group 2 (171 mL; range 40–500 mL) (P = .07), whereas the average 24-hour postoperative drain output was similar for Groups 1 (484 mL; range 75–1800 mL) and 2 (488 mL; range 100–1980 mL) (P = .46). Total estimated output was slightly less for Group 1 (593 mL; range 75–1900 mL) than for Group 2 (626 mL; range 125–2130 mL) (P = .38). A post hoc power analysis showed that with these rates of GA injury in Groups 1 and 2 and given a 2:1 ratio of the number of patients in Group 2 versus Group 1, a total of 185 patients in Group 1 and 370 patients in Group 2 would be needed to detect a statistically significant difference (P < .05) with a power of 80%.

Differences in outcomes separated based on use of a tourniquet for the entire case (Group 1) vs use of a tourniquet only during cementation (Group 2). Note that there were no significant differences. Values are reported as n (%) or average (range). GA = geniculate artery.

DISCUSSION

Major arterial injury associated with TKA is a well-known, rare, and potentially devastating complication.^1-13 However, the rate of injury to smaller periarticular vessels and the clinical significance of such injury have not been studied. The present study found a high rate of GA injury but no clinically significant difference in intraoperative blood loss or postoperative drain output between patients with GA injury (which was identified and managed with cautery) and those without GA injury. In addition, tourniquet use did not affect the rate of injury or the associated blood loss. To our knowledge, this is the first study that has critically evaluated the rate of GA injury occurring during TKA.

The overall rate of GA injury occurring during primary TKA was 38% with a higher predominance of lateral inferior than middle GA injury (31% vs 15%). Anatomically, it would follow that the lateral GA could be injured at a higher rate as it courses on top of the lateral meniscus, thus being susceptible to injury during cutting of the tibial plateau and meniscectomy. In addition, because the meniscectomy is performed longitudinally along the course of the artery, it may also be potentially lacerated in multiple locations and lengthwise. In theory, there should be a 100% rate of middle GA injury during posterior-stabilized TKA as this artery runs through the cruciate ligaments, which are resected during these cases. However, vessel injury was defined in this study as the visualization of pulsatile bleeding or vessel lumen. It is probable that in the cases in which injury to the middle GA was not visualized, it was cut but simultaneously cauterized. Thus, a lower rate (15%) of injury was detected. Nonetheless, these results still suggest that these periarticular arteries are injured at a higher rate; therefore, it is important for surgeons to specifically identify these injuries intraoperatively and adequately cauterize these vessels. As long as these arteries are cauterized, additional blood loss and potential vascular pseudoaneurysms should be prevented.

The effect of GA injury on intraoperative blood loss, 24-hour postoperative drain output, and total estimated blood loss showed no significant clinical findings in the present study cohort. In addition, examining the injury rate and blood loss based on TXA use also revealed no detrimental clinical associations. Although GA injury could inherently be associated with higher levels of blood loss and drain output, it is important to note that all GA injuries were also effectively coagulated, thus explaining the indifferent results. Accordingly, it should be recommended to surgeons performing primary TKAs to carefully evaluate for GA injury to prevent excessive blood loss or painful pseudoaneurysms. However, there is also a potential for beta error in this study in which a true difference did exist but no statistical difference was found due to the study being underpowered.

Full or selective tourniquet use during TKA did not appear to have any effect on the rate of GA injury, intraoperative blood loss, or 24-hour postoperative drain output. The similarity between GA injury rates perhaps further indicates an equivalent ability to detect these injuries between these two methods because of operative inspection for such injuries. With regard to intraoperative blood loss and drain output, the present findings are similar to previous studies demonstrating equivocal results despite variable tourniquet utilization in TKA.^15,30 However, these results differ from those of Harvey and colleagues³¹, who demonstrated that blood loss inversely correlated with intraoperative tourniquet time. There are risks and benefits related to the use of both full and selective tourniquet methods, but either method does not appear to be advantageous in decreasing the rate of GA injury.

Continue to: Although this is the first study...

Although this is the first study to investigate the rates of GA injury and the potential clinical effects, there are limitations to this research. First, the study was retrospective in nature despite the fact that the data were collected prospectively. Only acute perioperative follow-up was performed, and thus, we were unable to evaluate longer term effects of GA injury on TKA outcomes. Furthermore, this study is potentially prone to beta error. As discussed above, 185 patients in Group 1 and 370 patients in Group 2 would be needed to detect a statistical difference in the rate of GA injury based on the rates found in this study. This study could also have been underpowered to identify differences in other aspects, such as differences in blood loss and drain. Furthermore, the data collected regarding intraoperative blood loss are estimated data and can be variable. Finally, visualization of vessel lumen and pulsatile bleeding is not a validated method to diagnose GA injuries, and potential injuries may have been missed. Despite such disadvantages, the strengths of this study include the concise results in consecutive patients, the generalizability of the data as multiple surgeons participated, and its first report of nonmajor periarticular artery injury.

CONCLUSIONS

There is a relatively high rate of GA injury, with injury to the lateral GA being visualized more often than injury to the middle GA. The majority of GA injuries occur around the time of bone cuts and meniscectomy, and tourniquet use does not affect the rate of injury. To reduce intraoperative blood loss and postoperative drain output, surgeons should identify and coagulate GA injuries routinely during primary TKA.

ABSTRACT

Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. However, the rate of injury to smaller periarticular vessels and the clinical significance of such an injury have not been well investigated. The purpose of this study is to describe the rate and outcomes of geniculate artery (GA) injury, the time at which injury occurs, and any associations with tourniquet use.

From November 2015 to February 2016, 3 surgeons at a single institution performed 100 consecutive primary TKAs and documented the presence or absence and the timing of GA injury. The data were then retrospectively reviewed. All TKAs had no prior surgery on the operative extremity. Other variables collected included tourniquet use, tranexamic acid (TXA) administration, intraoperative blood loss, postoperative drain output, and blood transfusion.

The overall rate of GA injury was 38%, with lateral inferior and middle GA injury in 31% and 15% of TKAs, respectively. Most of the injuries were visualized during bone cuts or meniscectomy. The rate of overall or isolated GA injury was not significantly different (P > .05) with either use of intravenous (84 patients) or topical (14 patients) TXA administration. Comparing selective tourniquet use (only during cementation) vs routine use showed no differences in GA injury rate (P = .37), blood loss (P = .07), or drain output (P = .46).

There is a relatively high rate of GA injury, with injury to the lateral GA occurring more often than the middle GA. Routine or selective tourniquet use does not affect the rate of injury.

Continue to: Major arterial injury...

Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. The majority of literature in this context consists of case reports, small case series, and large retrospective studies that have examined the type, location, and mechanism of injury present in these cases.^1-13 Reported arterial injuries include occlusion, laceration, aneurysm, pseudoaneurysm, and arteriovenous fistula formation in the femoral (believed to be due to the tourniquet around the proximal thigh) and popliteal arteries causing combinations of ischemia and hemorrhage necessitating treatment ranging from endovascular arterial intervention to amputation.^{4,5,9-11,13-17} In addition, several studies have asserted that the risk of major arterial injury may be increased with tourniquet use, suggesting that tourniquet use should be minimized for routine primary TKAs.^3,6

There are very few cases in the literature specifically addressing injury to the more commonly encountered geniculate arteries (GAs). The medial GAs are typically visualized and coagulated during the standard medial parapatellar approach. In addition, if performed, a lateral release can damage the lateral superior and inferior GAs and the middle GA can be cut with posterior cruciate ligament resection. However, the middle and lateral inferior GAs are anecdotally the most difficult to detect and treat intraoperatively, especially after implantation of TKA and deflation of the tourniquet. The potential lack of recognition of such GA injury can result in harmful sequelae, including ischemia of the patella, hemorrhage, and painful pseudoaneurysms.^2,18-29 Currently, there are only 2 case reports of lateral inferior GA injury, 2 cases of medial inferior GA injury, and no reports of middle GA injury.^2,23,24,29

The rate, the timing within surgery, the risk factors, including tourniquet use, and the clinical effects of GA injury are largely unknown. If these factors were better understood, prophylactic measures and/or awareness could be better applied to prevent adverse outcomes, especially in cases of the middle and lateral inferior GAs. The aims of this study are to elucidate the rate and timing of middle and lateral inferior GA injury during primary TKA; determine the factors related to injury, including intraoperative blood loss, postoperative drain output, and tranexamic (TXA) acid use; and investigate any differences in the rate of injury with and without the use of a tourniquet.

MATERIALS AND METHODS

PATIENT DEMOGRAPHICS AND SURGICAL TECHNIQUE

From November 2015 to February 2016, 3 surgeons (MJT, TMM, and RTT) at a single institution performed 100 consecutive unilateral primary TKAs and documented the presence or absence and the timing of GA injury. After obtaining approval from our Institutional Review Board, a retrospective study was performed to investigate the prospectively recorded rate of middle and lateral inferior GA injuries occurring during primary TKAs. Patients with a diagnosis of isolated osteoarthritis were included, and those with any previous surgery on the operative knee were excluded. The average age of patients at the time of surgery was 67 years (range, 25-91 years), the average body mass index was 33 kg/m² (range, 18-54 kg/m²), and there were 63 (63%) female patients.

All TKAs were performed through a medial parapatellar approach with a posterior-stabilized, cemented design, and each patient received a postoperative surgical drain. One of the 3 lead surgeons (TMM) in this study used a tourniquet from the time of incision until the completion of cementation, and the other 2 (MJT and RTT) predominantly used the tourniquet only during cementation. To elucidate any differences in GA injury between these 2 methods of tourniquet use, the patients were categorized into 2 groups base d on tourniquet use. Group 1 included patients in whom a tourniquet was used to maintain a bloodless surgical field from the time of incision until the completion of cementation, and Group 2 included patients in whom tourniquet use was more selective (ie, applied only during cementation). Group 1 comprised 31% (31/100) of patients, while Group 2 comprised 67% (67/100) of patients; no tourniquet was used in 2% (2/100) of cases. In addition, TXA was used in 98% (98/100) of patients: 84 patients received intravenous (IV) and 14 received topical TXA administration.

Continue to: ANALYSIS OF GENICULATE ARTERY INJURY

The senior authors critically evaluated the GA during the primary TKAs and documented the presence or absence of injury in the operative reports. GA injury was reported if there was intraoperative visualization of pulsatile bleeding or visualization of arterial lumen in the anatomic areas of the middle and lateral inferior GAs. At 3 separate occasions during the operation, the surgeon looked specifically for pulsatile bleeding or arterial lumen in the areas of the middle and lateral inferior GAs, including after all the femoral and tibial bone cuts were completed, immediately before preparing to cement (before the tourniquet was inflated if there was not one inflated from the start of the procedure), and immediately after the tourniquet was deflated (Figure 1). All bleeding GAs that were visualized were effectively coagulated by cautery. Details regarding the use of TXA (topical or IV), intraoperative blood loss, postsurgical drain output for 24 hours after surgery, and blood transfusion were collected from the patients’ medical records (Table 1).

Operative variables other than geniculate artery injury. Data presented as mean (range) or n (%). TXA = tranexamic acid.

STATISTICAL METHODS

Statistical analysis was performed using the JMP software version 10.0.0 (SAS Institute, Inc). The overall rate of GA injury was determined, including the rates of GA injury based on location, time point, and method of diagnosis (pulsatile bleeding or arterial lumen visualization). If >1 GA injury occurred in the same knee, only 1 GA injury was calculated for the overall rate; however, each injury was specified separately when calculating the injury rate for the specific GA. Intraoperative blood loss, postoperative drain output, and the use of TXA were compared between cases in which a GA injury was detected and those in which it was not detected. Before conducting the retrospective review, a power analysis determined that we would require 100 patients to detect a difference in GA injury between Groups 1 and 2 (33 in Group 1 and 67 in Group 2), assuming a 30% rate in Group 1 and a 5% rate of GA injury in Group 2 using Fisher’s exact test. The Fisher’s exact test was used to compare categorical variables, and the Wilcoxon rank sum test was used to compare continuous variables. An alpha value of .05 was considered as statistically significant.

RESULTS

RATE OF GENICULATE ARTERY INJURY

The overall rate of any GA injury was 38% (38/100). Lateral inferior GA injury was more frequently detected than middle GA injury (31% vs 15% of TKAs, respectively; Table 2). Among the 31 lateral inferior GA injuries, 14 were identified as pulsatile bleeding, 7 as lumen visualizations, and 6 as both pulsatile bleeding and lumen visualization; 4 were detected by methods not recorded in the operative report. Of the lateral inferior GA injuries, 11 were identified after the bone cuts, 7 during meniscus removal, 3 during exposure, 1 after tourniquet deflation, and 9 at a time not recorded in the operative report. Of the 15 middle GA injuries, 9 were identified as pulsatile bleeding, 2 as lumen visualizations, and 4 as both pulsatile bleeding and lumen visualization. In addition, 7 of these GA injuries were identified after the bone cuts, 3 during cruciate removal, 1 after meniscus removal, 1 during exposure, and 3 at a time not recorded in the operative report (Table 3).

Rates of geniculate artery injury based on location and method of diagnosis. Data presented as n (%). There were 4 additional lateral inferior and 9 middle GA injuries identified by a method not specified in the operative report. GA = geniculate artery.

Rates of geniculate artery injury based on time point and method of diagnosis. GA = geniculate artery. Data presented as n (%).

FACTORS ASSOCIATED WITH GENICULATE ARTERY INJURY

Mean intraoperative estimated blood loss was 186 mL (standard deviation [SD], 111; range 50–500 mL) in those with a GA injury versus 147 mL (range, 82.25–400 mL) in those without injury (P = .14). Postoperative drain output in the 24 hours after surgery was 467 mL (SD 253, range 100–1105 mL) versus 502 mL (SD 378, range 75–1980 mL) in TKAs with and without GA injury, respectively (P = .82). Total estimated blood loss (combined intraoperative blood loss and 24-hour postoperative drain output) was 613 mL (SD 252, range 150–1105 mL) in TKAs with GA injury versus 620 mL (SD 393, range 75–2130 mL) without injury (P = .44) (Table 4). Overall, there was no statistical difference in blood loss, drain output, or combined output when analyzed according to lateral inferior or middle GA injury (P = .24–.82) (Table 5 and Table 6). No patients required blood transfusion postoperatively after TKA.

Differences in outcomes based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery.

Differences in outcomes based on presence or absence of LIGA injury. Note that there were no significant differences. Values are reported as average (range). LIGA = lateral inferior geniculate artery.

Differences in outcomes based on presence or absence of MGA injury. Note that there were no significant differences. Values are reported as average (range). MGA = middle geniculate artery.

IV administration of TXA was associated with a 37% (31/84) rate of GA injury, whereas topical TXA administration was associated with a 43% (6/14) rate of GA injury (P = .77). The rate of overall or isolated GA injury was not significantly different (P = .35–1.0) between IV and topical TXA administration (Table 7). In addition, total combined output was not significantly different (P = .1032) when comparing GA injury and noninjury in the subgroup analysis based on TXA use (IV or topical); however, topical administration was associated with lower intraoperative blood loss than IV administration (P = .0489), whereas IV administration was associated with lower 24-hour postoperative drain output than topical administration (P = .0169). There was no difference in blood loss, 24-hour drain output, or total output between those who did and did not sustain a GA injury in the group of patients who received IV TXA administration (Table 8, P = .2118–.7091). The same was true for those receiving topical TXA administration (Table 9, P = .0912–.9485).

Differences in outcomes based on presence or absence of MGA injury. Note that there were no significant differences. Values are reported as n (%) or average (range). TXA = tranexamic acid, GA = geniculate artery, LIGA = lateral inferior geniculate artery, MGA = middle geniculate artery. *denotes statistical significance (P < .05).

Differences in outcomes of those patients who received IV TXA based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery, TXA = tranexamic acid.

Differences in outcomes based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery.

Continue to: TOURNIQUET USE

Comparison between Groups 1 (tourniquet use) and 2 (selective tourniquet use) revealed similar rates of overall and specific GA injury, intraoperative blood loss, and 24-hour postoperative drain output (Table 10). Group 1 demonstrated a 29% (9/31) rate of any GA injury versus 40% (27/67) in Group 2 (P = .37). For the specific lateral inferior GA injury, there was an equivalent rate of injury at 29% (9/31 in Group 1, 20/67 in Group 2; P = 1.0). Similarly, Group 1 patients had a 10% (3/31) rate of middle GA injury compared to 16% (11/67) in Group 2 patients (P = .53). Intraoperative estimated blood loss was lower in Group 1 (140 mL; range 25–400 mL) than in Group 2 (171 mL; range 40–500 mL) (P = .07), whereas the average 24-hour postoperative drain output was similar for Groups 1 (484 mL; range 75–1800 mL) and 2 (488 mL; range 100–1980 mL) (P = .46). Total estimated output was slightly less for Group 1 (593 mL; range 75–1900 mL) than for Group 2 (626 mL; range 125–2130 mL) (P = .38). A post hoc power analysis showed that with these rates of GA injury in Groups 1 and 2 and given a 2:1 ratio of the number of patients in Group 2 versus Group 1, a total of 185 patients in Group 1 and 370 patients in Group 2 would be needed to detect a statistically significant difference (P < .05) with a power of 80%.

Differences in outcomes separated based on use of a tourniquet for the entire case (Group 1) vs use of a tourniquet only during cementation (Group 2). Note that there were no significant differences. Values are reported as n (%) or average (range). GA = geniculate artery.

DISCUSSION

Major arterial injury associated with TKA is a well-known, rare, and potentially devastating complication.^1-13 However, the rate of injury to smaller periarticular vessels and the clinical significance of such injury have not been studied. The present study found a high rate of GA injury but no clinically significant difference in intraoperative blood loss or postoperative drain output between patients with GA injury (which was identified and managed with cautery) and those without GA injury. In addition, tourniquet use did not affect the rate of injury or the associated blood loss. To our knowledge, this is the first study that has critically evaluated the rate of GA injury occurring during TKA.

The overall rate of GA injury occurring during primary TKA was 38% with a higher predominance of lateral inferior than middle GA injury (31% vs 15%). Anatomically, it would follow that the lateral GA could be injured at a higher rate as it courses on top of the lateral meniscus, thus being susceptible to injury during cutting of the tibial plateau and meniscectomy. In addition, because the meniscectomy is performed longitudinally along the course of the artery, it may also be potentially lacerated in multiple locations and lengthwise. In theory, there should be a 100% rate of middle GA injury during posterior-stabilized TKA as this artery runs through the cruciate ligaments, which are resected during these cases. However, vessel injury was defined in this study as the visualization of pulsatile bleeding or vessel lumen. It is probable that in the cases in which injury to the middle GA was not visualized, it was cut but simultaneously cauterized. Thus, a lower rate (15%) of injury was detected. Nonetheless, these results still suggest that these periarticular arteries are injured at a higher rate; therefore, it is important for surgeons to specifically identify these injuries intraoperatively and adequately cauterize these vessels. As long as these arteries are cauterized, additional blood loss and potential vascular pseudoaneurysms should be prevented.

The effect of GA injury on intraoperative blood loss, 24-hour postoperative drain output, and total estimated blood loss showed no significant clinical findings in the present study cohort. In addition, examining the injury rate and blood loss based on TXA use also revealed no detrimental clinical associations. Although GA injury could inherently be associated with higher levels of blood loss and drain output, it is important to note that all GA injuries were also effectively coagulated, thus explaining the indifferent results. Accordingly, it should be recommended to surgeons performing primary TKAs to carefully evaluate for GA injury to prevent excessive blood loss or painful pseudoaneurysms. However, there is also a potential for beta error in this study in which a true difference did exist but no statistical difference was found due to the study being underpowered.

Full or selective tourniquet use during TKA did not appear to have any effect on the rate of GA injury, intraoperative blood loss, or 24-hour postoperative drain output. The similarity between GA injury rates perhaps further indicates an equivalent ability to detect these injuries between these two methods because of operative inspection for such injuries. With regard to intraoperative blood loss and drain output, the present findings are similar to previous studies demonstrating equivocal results despite variable tourniquet utilization in TKA.^15,30 However, these results differ from those of Harvey and colleagues³¹, who demonstrated that blood loss inversely correlated with intraoperative tourniquet time. There are risks and benefits related to the use of both full and selective tourniquet methods, but either method does not appear to be advantageous in decreasing the rate of GA injury.

Continue to: Although this is the first study...

Although this is the first study to investigate the rates of GA injury and the potential clinical effects, there are limitations to this research. First, the study was retrospective in nature despite the fact that the data were collected prospectively. Only acute perioperative follow-up was performed, and thus, we were unable to evaluate longer term effects of GA injury on TKA outcomes. Furthermore, this study is potentially prone to beta error. As discussed above, 185 patients in Group 1 and 370 patients in Group 2 would be needed to detect a statistical difference in the rate of GA injury based on the rates found in this study. This study could also have been underpowered to identify differences in other aspects, such as differences in blood loss and drain. Furthermore, the data collected regarding intraoperative blood loss are estimated data and can be variable. Finally, visualization of vessel lumen and pulsatile bleeding is not a validated method to diagnose GA injuries, and potential injuries may have been missed. Despite such disadvantages, the strengths of this study include the concise results in consecutive patients, the generalizability of the data as multiple surgeons participated, and its first report of nonmajor periarticular artery injury.

CONCLUSIONS

There is a relatively high rate of GA injury, with injury to the lateral GA being visualized more often than injury to the middle GA. The majority of GA injuries occur around the time of bone cuts and meniscectomy, and tourniquet use does not affect the rate of injury. To reduce intraoperative blood loss and postoperative drain output, surgeons should identify and coagulate GA injuries routinely during primary TKA.

ABSTRACT

Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. However, the rate of injury to smaller periarticular vessels and the clinical significance of such an injury have not been well investigated. The purpose of this study is to describe the rate and outcomes of geniculate artery (GA) injury, the time at which injury occurs, and any associations with tourniquet use.

From November 2015 to February 2016, 3 surgeons at a single institution performed 100 consecutive primary TKAs and documented the presence or absence and the timing of GA injury. The data were then retrospectively reviewed. All TKAs had no prior surgery on the operative extremity. Other variables collected included tourniquet use, tranexamic acid (TXA) administration, intraoperative blood loss, postoperative drain output, and blood transfusion.

The overall rate of GA injury was 38%, with lateral inferior and middle GA injury in 31% and 15% of TKAs, respectively. Most of the injuries were visualized during bone cuts or meniscectomy. The rate of overall or isolated GA injury was not significantly different (P > .05) with either use of intravenous (84 patients) or topical (14 patients) TXA administration. Comparing selective tourniquet use (only during cementation) vs routine use showed no differences in GA injury rate (P = .37), blood loss (P = .07), or drain output (P = .46).

There is a relatively high rate of GA injury, with injury to the lateral GA occurring more often than the middle GA. Routine or selective tourniquet use does not affect the rate of injury.

Continue to: Major arterial injury...

Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. The majority of literature in this context consists of case reports, small case series, and large retrospective studies that have examined the type, location, and mechanism of injury present in these cases.^1-13 Reported arterial injuries include occlusion, laceration, aneurysm, pseudoaneurysm, and arteriovenous fistula formation in the femoral (believed to be due to the tourniquet around the proximal thigh) and popliteal arteries causing combinations of ischemia and hemorrhage necessitating treatment ranging from endovascular arterial intervention to amputation.^{4,5,9-11,13-17} In addition, several studies have asserted that the risk of major arterial injury may be increased with tourniquet use, suggesting that tourniquet use should be minimized for routine primary TKAs.^3,6

There are very few cases in the literature specifically addressing injury to the more commonly encountered geniculate arteries (GAs). The medial GAs are typically visualized and coagulated during the standard medial parapatellar approach. In addition, if performed, a lateral release can damage the lateral superior and inferior GAs and the middle GA can be cut with posterior cruciate ligament resection. However, the middle and lateral inferior GAs are anecdotally the most difficult to detect and treat intraoperatively, especially after implantation of TKA and deflation of the tourniquet. The potential lack of recognition of such GA injury can result in harmful sequelae, including ischemia of the patella, hemorrhage, and painful pseudoaneurysms.^2,18-29 Currently, there are only 2 case reports of lateral inferior GA injury, 2 cases of medial inferior GA injury, and no reports of middle GA injury.^2,23,24,29

The rate, the timing within surgery, the risk factors, including tourniquet use, and the clinical effects of GA injury are largely unknown. If these factors were better understood, prophylactic measures and/or awareness could be better applied to prevent adverse outcomes, especially in cases of the middle and lateral inferior GAs. The aims of this study are to elucidate the rate and timing of middle and lateral inferior GA injury during primary TKA; determine the factors related to injury, including intraoperative blood loss, postoperative drain output, and tranexamic (TXA) acid use; and investigate any differences in the rate of injury with and without the use of a tourniquet.

MATERIALS AND METHODS

PATIENT DEMOGRAPHICS AND SURGICAL TECHNIQUE

From November 2015 to February 2016, 3 surgeons (MJT, TMM, and RTT) at a single institution performed 100 consecutive unilateral primary TKAs and documented the presence or absence and the timing of GA injury. After obtaining approval from our Institutional Review Board, a retrospective study was performed to investigate the prospectively recorded rate of middle and lateral inferior GA injuries occurring during primary TKAs. Patients with a diagnosis of isolated osteoarthritis were included, and those with any previous surgery on the operative knee were excluded. The average age of patients at the time of surgery was 67 years (range, 25-91 years), the average body mass index was 33 kg/m² (range, 18-54 kg/m²), and there were 63 (63%) female patients.

All TKAs were performed through a medial parapatellar approach with a posterior-stabilized, cemented design, and each patient received a postoperative surgical drain. One of the 3 lead surgeons (TMM) in this study used a tourniquet from the time of incision until the completion of cementation, and the other 2 (MJT and RTT) predominantly used the tourniquet only during cementation. To elucidate any differences in GA injury between these 2 methods of tourniquet use, the patients were categorized into 2 groups base d on tourniquet use. Group 1 included patients in whom a tourniquet was used to maintain a bloodless surgical field from the time of incision until the completion of cementation, and Group 2 included patients in whom tourniquet use was more selective (ie, applied only during cementation). Group 1 comprised 31% (31/100) of patients, while Group 2 comprised 67% (67/100) of patients; no tourniquet was used in 2% (2/100) of cases. In addition, TXA was used in 98% (98/100) of patients: 84 patients received intravenous (IV) and 14 received topical TXA administration.

Continue to: ANALYSIS OF GENICULATE ARTERY INJURY

The senior authors critically evaluated the GA during the primary TKAs and documented the presence or absence of injury in the operative reports. GA injury was reported if there was intraoperative visualization of pulsatile bleeding or visualization of arterial lumen in the anatomic areas of the middle and lateral inferior GAs. At 3 separate occasions during the operation, the surgeon looked specifically for pulsatile bleeding or arterial lumen in the areas of the middle and lateral inferior GAs, including after all the femoral and tibial bone cuts were completed, immediately before preparing to cement (before the tourniquet was inflated if there was not one inflated from the start of the procedure), and immediately after the tourniquet was deflated (Figure 1). All bleeding GAs that were visualized were effectively coagulated by cautery. Details regarding the use of TXA (topical or IV), intraoperative blood loss, postsurgical drain output for 24 hours after surgery, and blood transfusion were collected from the patients’ medical records (Table 1).

Operative variables other than geniculate artery injury. Data presented as mean (range) or n (%). TXA = tranexamic acid.

STATISTICAL METHODS

Statistical analysis was performed using the JMP software version 10.0.0 (SAS Institute, Inc). The overall rate of GA injury was determined, including the rates of GA injury based on location, time point, and method of diagnosis (pulsatile bleeding or arterial lumen visualization). If >1 GA injury occurred in the same knee, only 1 GA injury was calculated for the overall rate; however, each injury was specified separately when calculating the injury rate for the specific GA. Intraoperative blood loss, postoperative drain output, and the use of TXA were compared between cases in which a GA injury was detected and those in which it was not detected. Before conducting the retrospective review, a power analysis determined that we would require 100 patients to detect a difference in GA injury between Groups 1 and 2 (33 in Group 1 and 67 in Group 2), assuming a 30% rate in Group 1 and a 5% rate of GA injury in Group 2 using Fisher’s exact test. The Fisher’s exact test was used to compare categorical variables, and the Wilcoxon rank sum test was used to compare continuous variables. An alpha value of .05 was considered as statistically significant.

RESULTS

RATE OF GENICULATE ARTERY INJURY

The overall rate of any GA injury was 38% (38/100). Lateral inferior GA injury was more frequently detected than middle GA injury (31% vs 15% of TKAs, respectively; Table 2). Among the 31 lateral inferior GA injuries, 14 were identified as pulsatile bleeding, 7 as lumen visualizations, and 6 as both pulsatile bleeding and lumen visualization; 4 were detected by methods not recorded in the operative report. Of the lateral inferior GA injuries, 11 were identified after the bone cuts, 7 during meniscus removal, 3 during exposure, 1 after tourniquet deflation, and 9 at a time not recorded in the operative report. Of the 15 middle GA injuries, 9 were identified as pulsatile bleeding, 2 as lumen visualizations, and 4 as both pulsatile bleeding and lumen visualization. In addition, 7 of these GA injuries were identified after the bone cuts, 3 during cruciate removal, 1 after meniscus removal, 1 during exposure, and 3 at a time not recorded in the operative report (Table 3).

Rates of geniculate artery injury based on location and method of diagnosis. Data presented as n (%). There were 4 additional lateral inferior and 9 middle GA injuries identified by a method not specified in the operative report. GA = geniculate artery.

Rates of geniculate artery injury based on time point and method of diagnosis. GA = geniculate artery. Data presented as n (%).

FACTORS ASSOCIATED WITH GENICULATE ARTERY INJURY

Mean intraoperative estimated blood loss was 186 mL (standard deviation [SD], 111; range 50–500 mL) in those with a GA injury versus 147 mL (range, 82.25–400 mL) in those without injury (P = .14). Postoperative drain output in the 24 hours after surgery was 467 mL (SD 253, range 100–1105 mL) versus 502 mL (SD 378, range 75–1980 mL) in TKAs with and without GA injury, respectively (P = .82). Total estimated blood loss (combined intraoperative blood loss and 24-hour postoperative drain output) was 613 mL (SD 252, range 150–1105 mL) in TKAs with GA injury versus 620 mL (SD 393, range 75–2130 mL) without injury (P = .44) (Table 4). Overall, there was no statistical difference in blood loss, drain output, or combined output when analyzed according to lateral inferior or middle GA injury (P = .24–.82) (Table 5 and Table 6). No patients required blood transfusion postoperatively after TKA.

Differences in outcomes based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery.

Differences in outcomes based on presence or absence of LIGA injury. Note that there were no significant differences. Values are reported as average (range). LIGA = lateral inferior geniculate artery.

Differences in outcomes based on presence or absence of MGA injury. Note that there were no significant differences. Values are reported as average (range). MGA = middle geniculate artery.

IV administration of TXA was associated with a 37% (31/84) rate of GA injury, whereas topical TXA administration was associated with a 43% (6/14) rate of GA injury (P = .77). The rate of overall or isolated GA injury was not significantly different (P = .35–1.0) between IV and topical TXA administration (Table 7). In addition, total combined output was not significantly different (P = .1032) when comparing GA injury and noninjury in the subgroup analysis based on TXA use (IV or topical); however, topical administration was associated with lower intraoperative blood loss than IV administration (P = .0489), whereas IV administration was associated with lower 24-hour postoperative drain output than topical administration (P = .0169). There was no difference in blood loss, 24-hour drain output, or total output between those who did and did not sustain a GA injury in the group of patients who received IV TXA administration (Table 8, P = .2118–.7091). The same was true for those receiving topical TXA administration (Table 9, P = .0912–.9485).

Differences in outcomes based on presence or absence of MGA injury. Note that there were no significant differences. Values are reported as n (%) or average (range). TXA = tranexamic acid, GA = geniculate artery, LIGA = lateral inferior geniculate artery, MGA = middle geniculate artery. *denotes statistical significance (P < .05).

Differences in outcomes of those patients who received IV TXA based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery, TXA = tranexamic acid.

Differences in outcomes based on presence or absence of GA injury. Note that there were no significant differences. Values are reported as average (range). GA = geniculate artery.

Continue to: TOURNIQUET USE

Comparison between Groups 1 (tourniquet use) and 2 (selective tourniquet use) revealed similar rates of overall and specific GA injury, intraoperative blood loss, and 24-hour postoperative drain output (Table 10). Group 1 demonstrated a 29% (9/31) rate of any GA injury versus 40% (27/67) in Group 2 (P = .37). For the specific lateral inferior GA injury, there was an equivalent rate of injury at 29% (9/31 in Group 1, 20/67 in Group 2; P = 1.0). Similarly, Group 1 patients had a 10% (3/31) rate of middle GA injury compared to 16% (11/67) in Group 2 patients (P = .53). Intraoperative estimated blood loss was lower in Group 1 (140 mL; range 25–400 mL) than in Group 2 (171 mL; range 40–500 mL) (P = .07), whereas the average 24-hour postoperative drain output was similar for Groups 1 (484 mL; range 75–1800 mL) and 2 (488 mL; range 100–1980 mL) (P = .46). Total estimated output was slightly less for Group 1 (593 mL; range 75–1900 mL) than for Group 2 (626 mL; range 125–2130 mL) (P = .38). A post hoc power analysis showed that with these rates of GA injury in Groups 1 and 2 and given a 2:1 ratio of the number of patients in Group 2 versus Group 1, a total of 185 patients in Group 1 and 370 patients in Group 2 would be needed to detect a statistically significant difference (P < .05) with a power of 80%.

Differences in outcomes separated based on use of a tourniquet for the entire case (Group 1) vs use of a tourniquet only during cementation (Group 2). Note that there were no significant differences. Values are reported as n (%) or average (range). GA = geniculate artery.

DISCUSSION

Major arterial injury associated with TKA is a well-known, rare, and potentially devastating complication.^1-13 However, the rate of injury to smaller periarticular vessels and the clinical significance of such injury have not been studied. The present study found a high rate of GA injury but no clinically significant difference in intraoperative blood loss or postoperative drain output between patients with GA injury (which was identified and managed with cautery) and those without GA injury. In addition, tourniquet use did not affect the rate of injury or the associated blood loss. To our knowledge, this is the first study that has critically evaluated the rate of GA injury occurring during TKA.

The overall rate of GA injury occurring during primary TKA was 38% with a higher predominance of lateral inferior than middle GA injury (31% vs 15%). Anatomically, it would follow that the lateral GA could be injured at a higher rate as it courses on top of the lateral meniscus, thus being susceptible to injury during cutting of the tibial plateau and meniscectomy. In addition, because the meniscectomy is performed longitudinally along the course of the artery, it may also be potentially lacerated in multiple locations and lengthwise. In theory, there should be a 100% rate of middle GA injury during posterior-stabilized TKA as this artery runs through the cruciate ligaments, which are resected during these cases. However, vessel injury was defined in this study as the visualization of pulsatile bleeding or vessel lumen. It is probable that in the cases in which injury to the middle GA was not visualized, it was cut but simultaneously cauterized. Thus, a lower rate (15%) of injury was detected. Nonetheless, these results still suggest that these periarticular arteries are injured at a higher rate; therefore, it is important for surgeons to specifically identify these injuries intraoperatively and adequately cauterize these vessels. As long as these arteries are cauterized, additional blood loss and potential vascular pseudoaneurysms should be prevented.

The effect of GA injury on intraoperative blood loss, 24-hour postoperative drain output, and total estimated blood loss showed no significant clinical findings in the present study cohort. In addition, examining the injury rate and blood loss based on TXA use also revealed no detrimental clinical associations. Although GA injury could inherently be associated with higher levels of blood loss and drain output, it is important to note that all GA injuries were also effectively coagulated, thus explaining the indifferent results. Accordingly, it should be recommended to surgeons performing primary TKAs to carefully evaluate for GA injury to prevent excessive blood loss or painful pseudoaneurysms. However, there is also a potential for beta error in this study in which a true difference did exist but no statistical difference was found due to the study being underpowered.

Full or selective tourniquet use during TKA did not appear to have any effect on the rate of GA injury, intraoperative blood loss, or 24-hour postoperative drain output. The similarity between GA injury rates perhaps further indicates an equivalent ability to detect these injuries between these two methods because of operative inspection for such injuries. With regard to intraoperative blood loss and drain output, the present findings are similar to previous studies demonstrating equivocal results despite variable tourniquet utilization in TKA.^15,30 However, these results differ from those of Harvey and colleagues³¹, who demonstrated that blood loss inversely correlated with intraoperative tourniquet time. There are risks and benefits related to the use of both full and selective tourniquet methods, but either method does not appear to be advantageous in decreasing the rate of GA injury.

Continue to: Although this is the first study...

Although this is the first study to investigate the rates of GA injury and the potential clinical effects, there are limitations to this research. First, the study was retrospective in nature despite the fact that the data were collected prospectively. Only acute perioperative follow-up was performed, and thus, we were unable to evaluate longer term effects of GA injury on TKA outcomes. Furthermore, this study is potentially prone to beta error. As discussed above, 185 patients in Group 1 and 370 patients in Group 2 would be needed to detect a statistical difference in the rate of GA injury based on the rates found in this study. This study could also have been underpowered to identify differences in other aspects, such as differences in blood loss and drain. Furthermore, the data collected regarding intraoperative blood loss are estimated data and can be variable. Finally, visualization of vessel lumen and pulsatile bleeding is not a validated method to diagnose GA injuries, and potential injuries may have been missed. Despite such disadvantages, the strengths of this study include the concise results in consecutive patients, the generalizability of the data as multiple surgeons participated, and its first report of nonmajor periarticular artery injury.

CONCLUSIONS

There is a relatively high rate of GA injury, with injury to the lateral GA being visualized more often than injury to the middle GA. The majority of GA injuries occur around the time of bone cuts and meniscectomy, and tourniquet use does not affect the rate of injury. To reduce intraoperative blood loss and postoperative drain output, surgeons should identify and coagulate GA injuries routinely during primary TKA.

BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.

In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.

The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:

• The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
• Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.

To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.

He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.

The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.

“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”


Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.

Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.

Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.

“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”

“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”

Gil Rabinovici, MD, also expressed some reservations.

Courtesy Dr. Gil D. Rabinovici

“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
 

Biomarkers support subanalysis finding

Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:

• Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
• Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
• Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.

The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.

“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”

Eisai has made its subanalysis presentation slides publicly available.

Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.

[email protected]

SOURCE: Swanson C et al. CTAD, Symposium 3.

BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.

In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.

The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:

• The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
• Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.

To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.

He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.

The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.

“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”


Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.

Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.

Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.

“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”

“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”

Gil Rabinovici, MD, also expressed some reservations.

Courtesy Dr. Gil D. Rabinovici

“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
 

Biomarkers support subanalysis finding

Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:

• Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
• Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
• Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.

The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.

“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”

Eisai has made its subanalysis presentation slides publicly available.

Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.

[email protected]

SOURCE: Swanson C et al. CTAD, Symposium 3.

BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.

In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.

The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:

• The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
• Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.

To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.

He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.

The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.

“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”


Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.

Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.

Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.

“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”

“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”

Gil Rabinovici, MD, also expressed some reservations.

Courtesy Dr. Gil D. Rabinovici

“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
 

Biomarkers support subanalysis finding

Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:

• Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
• Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
• Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.

The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.

“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”

Eisai has made its subanalysis presentation slides publicly available.

Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.

[email protected]

SOURCE: Swanson C et al. CTAD, Symposium 3.

When hospital medicine and surgical departments (usually orthopedics or neurosurgery) have joined in comanagement programs, improvements in quality metrics and patient satisfaction have often resulted.

At the Level 1 regional trauma center in which he works, Charles L. Kast, MD, and his colleagues wanted to try a comanagement agreement between hospital medicine and trauma surgery.

“The surgical team identified a need within their own department, which was to improve patient mortality and satisfaction in the inpatient setting,” said Dr. Kast, who is based at North Shore University Hospital, Manhasset, N.Y. “Their leadership sought out our hospital medicine leadership team, who then worked together to synthesize their metrics. We were able to identify other quality indicators, such as readmission rates and hospital-acquired conditions, which we felt could also benefit from our services in order to help them improve.”

Five hospitalists became members of the comanagement team. A single hospitalist rotated for 2 weeks at a time, during which they were relieved of routine hospital medicine rounding responsibilities. The hospitalist attended daily interdisciplinary rounds with the trauma surgery team, during which he/she identified patients that could benefit from hospital medicine comanagement: Patients who were over age 65 years, had multiple chronic medical conditions, or were on high-risk medications were preferentially selected. Approximately 10 patients were seen daily.

The comanagement program was well received by trauma surgeons, who talked about improved patient communication and a fostered sense of collegiality. Preliminary quality and patient satisfaction metrics were also positive.

A top takeaway is that the benefits of surgical comanagement can be demonstrated in “atypical” collaborations, depending on the needs of the department and the hospital’s vision.

“The gains in improved patient quality metrics are only half of the story,” Dr. Kast said. “Collaborating in surgical comanagement improves the satisfaction of the hospitalists and surgeons involved and can lead to future quality improvement projects or original research, both of which we are currently pursuing.”
 

Reference

Kast C et al. The successful development of a hospital medicine-trauma surgery co-management program [abstract]. J Hosp Med. 2017;12(suppl 2). Accessed Feb. 2, 2018.

When hospital medicine and surgical departments (usually orthopedics or neurosurgery) have joined in comanagement programs, improvements in quality metrics and patient satisfaction have often resulted.

At the Level 1 regional trauma center in which he works, Charles L. Kast, MD, and his colleagues wanted to try a comanagement agreement between hospital medicine and trauma surgery.

“The surgical team identified a need within their own department, which was to improve patient mortality and satisfaction in the inpatient setting,” said Dr. Kast, who is based at North Shore University Hospital, Manhasset, N.Y. “Their leadership sought out our hospital medicine leadership team, who then worked together to synthesize their metrics. We were able to identify other quality indicators, such as readmission rates and hospital-acquired conditions, which we felt could also benefit from our services in order to help them improve.”

Five hospitalists became members of the comanagement team. A single hospitalist rotated for 2 weeks at a time, during which they were relieved of routine hospital medicine rounding responsibilities. The hospitalist attended daily interdisciplinary rounds with the trauma surgery team, during which he/she identified patients that could benefit from hospital medicine comanagement: Patients who were over age 65 years, had multiple chronic medical conditions, or were on high-risk medications were preferentially selected. Approximately 10 patients were seen daily.

The comanagement program was well received by trauma surgeons, who talked about improved patient communication and a fostered sense of collegiality. Preliminary quality and patient satisfaction metrics were also positive.

A top takeaway is that the benefits of surgical comanagement can be demonstrated in “atypical” collaborations, depending on the needs of the department and the hospital’s vision.

“The gains in improved patient quality metrics are only half of the story,” Dr. Kast said. “Collaborating in surgical comanagement improves the satisfaction of the hospitalists and surgeons involved and can lead to future quality improvement projects or original research, both of which we are currently pursuing.”
 

Reference

Kast C et al. The successful development of a hospital medicine-trauma surgery co-management program [abstract]. J Hosp Med. 2017;12(suppl 2). Accessed Feb. 2, 2018.

When hospital medicine and surgical departments (usually orthopedics or neurosurgery) have joined in comanagement programs, improvements in quality metrics and patient satisfaction have often resulted.

At the Level 1 regional trauma center in which he works, Charles L. Kast, MD, and his colleagues wanted to try a comanagement agreement between hospital medicine and trauma surgery.

“The surgical team identified a need within their own department, which was to improve patient mortality and satisfaction in the inpatient setting,” said Dr. Kast, who is based at North Shore University Hospital, Manhasset, N.Y. “Their leadership sought out our hospital medicine leadership team, who then worked together to synthesize their metrics. We were able to identify other quality indicators, such as readmission rates and hospital-acquired conditions, which we felt could also benefit from our services in order to help them improve.”

Five hospitalists became members of the comanagement team. A single hospitalist rotated for 2 weeks at a time, during which they were relieved of routine hospital medicine rounding responsibilities. The hospitalist attended daily interdisciplinary rounds with the trauma surgery team, during which he/she identified patients that could benefit from hospital medicine comanagement: Patients who were over age 65 years, had multiple chronic medical conditions, or were on high-risk medications were preferentially selected. Approximately 10 patients were seen daily.

The comanagement program was well received by trauma surgeons, who talked about improved patient communication and a fostered sense of collegiality. Preliminary quality and patient satisfaction metrics were also positive.

A top takeaway is that the benefits of surgical comanagement can be demonstrated in “atypical” collaborations, depending on the needs of the department and the hospital’s vision.

“The gains in improved patient quality metrics are only half of the story,” Dr. Kast said. “Collaborating in surgical comanagement improves the satisfaction of the hospitalists and surgeons involved and can lead to future quality improvement projects or original research, both of which we are currently pursuing.”
 

Reference

Kast C et al. The successful development of a hospital medicine-trauma surgery co-management program [abstract]. J Hosp Med. 2017;12(suppl 2). Accessed Feb. 2, 2018.

CHICAGO – Researchers have derived and validated a 10-item formula to estimate a patient’s risk for developing a major adverse event while on NSAID treatment.

Mitchel L. Zoler/MDedge News

The calculator could “help guide use of NSAIDs in clinical practice,” said Daniel H. Solomon, MD, at the annual meeting of the American College of Rheumatology. Although he called for further validation of the risk-score formula using other databases, he noted that it uses readily available data and could easily be calculated with standard inputs in an electronic medical record. The formula predicts the risk for a major adverse effect during 1 year of daily NSAID use.

Dr. Solomon and his associates devised the risk-score calculator with data collected in the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen) trial, a safety study designed to test whether treatment with celecoxib was noninferior to treatment with naproxen or ibuprofen for producing cardiovascular adverse events, a hypothesis proven by the study’s results (N Engl J Med. 2016 Dec 29;375[26]:2519-29). They had full data available for 23,950 of the more than 24,000 enrolled patients. The patients averaged 63 years old, just over a third were men, their average body mass index was 31 kg/m², and 90% had osteoarthritis and 10% had rheumatoid arthritis. The study enrolled patients with an elevated risk for a cardiovascular event, so 63% had hypertension and 36% had diabetes.

The adverse events included as possible outcomes estimated by the formula were all-cause death, major adverse cardiovascular events, clinically significant GI events, or renal insufficiency or failure. The investigators used data from more than 15,000 patients enrolled during the first 4 years of the study to derive the risk-score formula, and data from the nearly 9,000 patients enrolled during the next 5 years to validate it.

The analysis identified and validated 10 baseline items that, when plugged into the formula, calculated a predicted rate for the subsequent development of a major averse event during 1 year of NSAID treatment. The 10 parameters are: age, sex, known cardiovascular disease, hypertension, diabetes, current cigarette use, on treatment with a statin, baseline serum creatinine level, rheumatoid arthritis, and hematocrit.

As examples of the accuracy of the prediction score, Dr. Solomon reported that, among the patients with a predicted risk for a major adverse event of less than 1%, the observed rate was 0.4%; among people with a predicted rate of 1%-4%, the observed rate was 1.7%; and among those with a predicted risk of more than 4% the observed rate was 5.6%. Major cardiovascular events were the most common type of adverse events observed among the nearly 24,000 patients enrolled in PRECISION. A total of 5% of the patients fell into the lowest risk category, with a risk of less than 1%; 70% were in the intermediate risk category, with a predicted risk of 1%-4%; and 25% had a predicted risk of more than 4%, reported Dr. Solomon, a professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital in Boston.

Age is a major driver of risk, he noted. A patient who is at least 65 years old would have a greater than 1% risk for an adverse event regardless of the other nine risk factors in the scoring formula.

PRECISION was funded by Pfizer. Dr. Solomon has received research funding from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Pfizer.

[email protected]

SOURCE: Solomon D et al. ACR Annual Meeting, Abstract 2952. Arthritis Rheumatol. 2018;70(Suppl 10).

CHICAGO – Researchers have derived and validated a 10-item formula to estimate a patient’s risk for developing a major adverse event while on NSAID treatment.

Mitchel L. Zoler/MDedge News

The calculator could “help guide use of NSAIDs in clinical practice,” said Daniel H. Solomon, MD, at the annual meeting of the American College of Rheumatology. Although he called for further validation of the risk-score formula using other databases, he noted that it uses readily available data and could easily be calculated with standard inputs in an electronic medical record. The formula predicts the risk for a major adverse effect during 1 year of daily NSAID use.

Dr. Solomon and his associates devised the risk-score calculator with data collected in the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen) trial, a safety study designed to test whether treatment with celecoxib was noninferior to treatment with naproxen or ibuprofen for producing cardiovascular adverse events, a hypothesis proven by the study’s results (N Engl J Med. 2016 Dec 29;375[26]:2519-29). They had full data available for 23,950 of the more than 24,000 enrolled patients. The patients averaged 63 years old, just over a third were men, their average body mass index was 31 kg/m², and 90% had osteoarthritis and 10% had rheumatoid arthritis. The study enrolled patients with an elevated risk for a cardiovascular event, so 63% had hypertension and 36% had diabetes.

The adverse events included as possible outcomes estimated by the formula were all-cause death, major adverse cardiovascular events, clinically significant GI events, or renal insufficiency or failure. The investigators used data from more than 15,000 patients enrolled during the first 4 years of the study to derive the risk-score formula, and data from the nearly 9,000 patients enrolled during the next 5 years to validate it.

The analysis identified and validated 10 baseline items that, when plugged into the formula, calculated a predicted rate for the subsequent development of a major averse event during 1 year of NSAID treatment. The 10 parameters are: age, sex, known cardiovascular disease, hypertension, diabetes, current cigarette use, on treatment with a statin, baseline serum creatinine level, rheumatoid arthritis, and hematocrit.

As examples of the accuracy of the prediction score, Dr. Solomon reported that, among the patients with a predicted risk for a major adverse event of less than 1%, the observed rate was 0.4%; among people with a predicted rate of 1%-4%, the observed rate was 1.7%; and among those with a predicted risk of more than 4% the observed rate was 5.6%. Major cardiovascular events were the most common type of adverse events observed among the nearly 24,000 patients enrolled in PRECISION. A total of 5% of the patients fell into the lowest risk category, with a risk of less than 1%; 70% were in the intermediate risk category, with a predicted risk of 1%-4%; and 25% had a predicted risk of more than 4%, reported Dr. Solomon, a professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital in Boston.

Age is a major driver of risk, he noted. A patient who is at least 65 years old would have a greater than 1% risk for an adverse event regardless of the other nine risk factors in the scoring formula.

PRECISION was funded by Pfizer. Dr. Solomon has received research funding from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Pfizer.

[email protected]

SOURCE: Solomon D et al. ACR Annual Meeting, Abstract 2952. Arthritis Rheumatol. 2018;70(Suppl 10).

CHICAGO – Researchers have derived and validated a 10-item formula to estimate a patient’s risk for developing a major adverse event while on NSAID treatment.

Mitchel L. Zoler/MDedge News

The calculator could “help guide use of NSAIDs in clinical practice,” said Daniel H. Solomon, MD, at the annual meeting of the American College of Rheumatology. Although he called for further validation of the risk-score formula using other databases, he noted that it uses readily available data and could easily be calculated with standard inputs in an electronic medical record. The formula predicts the risk for a major adverse effect during 1 year of daily NSAID use.

Dr. Solomon and his associates devised the risk-score calculator with data collected in the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen) trial, a safety study designed to test whether treatment with celecoxib was noninferior to treatment with naproxen or ibuprofen for producing cardiovascular adverse events, a hypothesis proven by the study’s results (N Engl J Med. 2016 Dec 29;375[26]:2519-29). They had full data available for 23,950 of the more than 24,000 enrolled patients. The patients averaged 63 years old, just over a third were men, their average body mass index was 31 kg/m², and 90% had osteoarthritis and 10% had rheumatoid arthritis. The study enrolled patients with an elevated risk for a cardiovascular event, so 63% had hypertension and 36% had diabetes.

The adverse events included as possible outcomes estimated by the formula were all-cause death, major adverse cardiovascular events, clinically significant GI events, or renal insufficiency or failure. The investigators used data from more than 15,000 patients enrolled during the first 4 years of the study to derive the risk-score formula, and data from the nearly 9,000 patients enrolled during the next 5 years to validate it.

The analysis identified and validated 10 baseline items that, when plugged into the formula, calculated a predicted rate for the subsequent development of a major averse event during 1 year of NSAID treatment. The 10 parameters are: age, sex, known cardiovascular disease, hypertension, diabetes, current cigarette use, on treatment with a statin, baseline serum creatinine level, rheumatoid arthritis, and hematocrit.

As examples of the accuracy of the prediction score, Dr. Solomon reported that, among the patients with a predicted risk for a major adverse event of less than 1%, the observed rate was 0.4%; among people with a predicted rate of 1%-4%, the observed rate was 1.7%; and among those with a predicted risk of more than 4% the observed rate was 5.6%. Major cardiovascular events were the most common type of adverse events observed among the nearly 24,000 patients enrolled in PRECISION. A total of 5% of the patients fell into the lowest risk category, with a risk of less than 1%; 70% were in the intermediate risk category, with a predicted risk of 1%-4%; and 25% had a predicted risk of more than 4%, reported Dr. Solomon, a professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital in Boston.

Age is a major driver of risk, he noted. A patient who is at least 65 years old would have a greater than 1% risk for an adverse event regardless of the other nine risk factors in the scoring formula.

PRECISION was funded by Pfizer. Dr. Solomon has received research funding from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Pfizer.

[email protected]

SOURCE: Solomon D et al. ACR Annual Meeting, Abstract 2952. Arthritis Rheumatol. 2018;70(Suppl 10).

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.