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Community-based therapy improved asthma outcomes in African American teens
, according to results published in Pediatrics.
In a study of 167 African American patients aged 12-16 years, the 84 randomly assigned to Multisystemic Therapy–Health Care (MST-HC) had greater improvement in forced expiratory volume in 1 second (FEV1) over time, compared with the 83 patients randomly assigned to family support (FS) therapy (beta = 0.097, t[164.27] = 2.52; P = .01). Improvements in secondary outcomes also were observed in this group, reported Sylvie Naar, PhD, of Florida State University, Tallahassee, and her coauthors.
They studied African American adolescents with moderate to severe persistent asthma who resided in a home setting with a caregiver and were at high risk for poorly controlled asthma. Families were randomized to either MST-HC (84 patients) or FS (83 patients) based on severity of urgent care use, and follow-up was completed 7 and 12 months after baseline assessment. Families were paid $50 for each assessment.
FEV1 was the primary outcome. Secondary outcomes were medication adherence, symptom severity and frequency, inpatient hospitalizations, and ED visits. Medication adherence was evaluated via the Family Asthma Management System Scale (FAMSS) and the Daily Phone Diary (DPD). Other outcomes were confirmed via medical records.
Patients in the FS control group received weekly home-based counseling for up to 6 months. Patients in the MST-HC treatment group were first engaged in a motivational session with a therapist and evaluated for asthma management with interviews and observations within the home and community. Once possible contributing factors to poor asthma management (such as medication underuse or low parental monitoring) were identified, targeted interventions such as skills training, behavioral and family therapy, or communication training with school and medical staff were chosen, and treatment goals continually monitored and modified, the authors said.
The mean length of treatment until termination in the MST-HC group was 5 months, and the mean number of sessions was 27. In the FS group, mean length of treatment was 4 months, and the mean number of sessions was 11.
FEV1 for the MST-HC group improved from 2.05 at baseline to 2.25 at 7 months (a 10% improvement), and to 2.37 (a 16% improvement) at 12 months, compared with an improvement from 2.21 to 2.31 at 7 months (a 4% improvement) and 2.33 (a 5% improvement) at 12 months in the control group, the authors reported.
At 12 months, FAMSS adherence scores improved from 4.19 to 5.24 in the MST-HC group and from 4.61 to 4.72 in the control group.
DPD adherence scores improved from a mean of 0.33 at baseline to 0.69 for the MST-HC group, and from 0.43 to 0.46 in the FS group.
At 12 months, the mean frequency of asthma symptoms in the MST-HC group improved from 2.75 at baseline to 1.43, compared with a decline of 2.67 to 2.58 in the control group. The mean number of hospitalizations in the MST-HC group improved from 0.87 to 0.24, compared with a change from 0.66 to 0.34 in the control group.
The study results are “especially noteworthy because African American adolescents experience greater morbidity and mortality from asthma than white adolescents even when controlling for socioeconomic variables,” Dr. Naar and her associates wrote. Future research should focus on the “transportability” of MST-HC treatment to community settings, which is “ready to be studied in effectiveness and implementation trials.”
The study was supported by a National Institutes of Health grant. Coauthor Phillippe Cunningham, PhD, is a co-owner of Evidence-Based Services, a network partner organization that is licensed to disseminate Multisystemic Therapy for drug court and juvenile delinquency settings. The other authors said they have no potential conflicts of interest.
SOURCE: Naar S et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3737.
, according to results published in Pediatrics.
In a study of 167 African American patients aged 12-16 years, the 84 randomly assigned to Multisystemic Therapy–Health Care (MST-HC) had greater improvement in forced expiratory volume in 1 second (FEV1) over time, compared with the 83 patients randomly assigned to family support (FS) therapy (beta = 0.097, t[164.27] = 2.52; P = .01). Improvements in secondary outcomes also were observed in this group, reported Sylvie Naar, PhD, of Florida State University, Tallahassee, and her coauthors.
They studied African American adolescents with moderate to severe persistent asthma who resided in a home setting with a caregiver and were at high risk for poorly controlled asthma. Families were randomized to either MST-HC (84 patients) or FS (83 patients) based on severity of urgent care use, and follow-up was completed 7 and 12 months after baseline assessment. Families were paid $50 for each assessment.
FEV1 was the primary outcome. Secondary outcomes were medication adherence, symptom severity and frequency, inpatient hospitalizations, and ED visits. Medication adherence was evaluated via the Family Asthma Management System Scale (FAMSS) and the Daily Phone Diary (DPD). Other outcomes were confirmed via medical records.
Patients in the FS control group received weekly home-based counseling for up to 6 months. Patients in the MST-HC treatment group were first engaged in a motivational session with a therapist and evaluated for asthma management with interviews and observations within the home and community. Once possible contributing factors to poor asthma management (such as medication underuse or low parental monitoring) were identified, targeted interventions such as skills training, behavioral and family therapy, or communication training with school and medical staff were chosen, and treatment goals continually monitored and modified, the authors said.
The mean length of treatment until termination in the MST-HC group was 5 months, and the mean number of sessions was 27. In the FS group, mean length of treatment was 4 months, and the mean number of sessions was 11.
FEV1 for the MST-HC group improved from 2.05 at baseline to 2.25 at 7 months (a 10% improvement), and to 2.37 (a 16% improvement) at 12 months, compared with an improvement from 2.21 to 2.31 at 7 months (a 4% improvement) and 2.33 (a 5% improvement) at 12 months in the control group, the authors reported.
At 12 months, FAMSS adherence scores improved from 4.19 to 5.24 in the MST-HC group and from 4.61 to 4.72 in the control group.
DPD adherence scores improved from a mean of 0.33 at baseline to 0.69 for the MST-HC group, and from 0.43 to 0.46 in the FS group.
At 12 months, the mean frequency of asthma symptoms in the MST-HC group improved from 2.75 at baseline to 1.43, compared with a decline of 2.67 to 2.58 in the control group. The mean number of hospitalizations in the MST-HC group improved from 0.87 to 0.24, compared with a change from 0.66 to 0.34 in the control group.
The study results are “especially noteworthy because African American adolescents experience greater morbidity and mortality from asthma than white adolescents even when controlling for socioeconomic variables,” Dr. Naar and her associates wrote. Future research should focus on the “transportability” of MST-HC treatment to community settings, which is “ready to be studied in effectiveness and implementation trials.”
The study was supported by a National Institutes of Health grant. Coauthor Phillippe Cunningham, PhD, is a co-owner of Evidence-Based Services, a network partner organization that is licensed to disseminate Multisystemic Therapy for drug court and juvenile delinquency settings. The other authors said they have no potential conflicts of interest.
SOURCE: Naar S et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3737.
, according to results published in Pediatrics.
In a study of 167 African American patients aged 12-16 years, the 84 randomly assigned to Multisystemic Therapy–Health Care (MST-HC) had greater improvement in forced expiratory volume in 1 second (FEV1) over time, compared with the 83 patients randomly assigned to family support (FS) therapy (beta = 0.097, t[164.27] = 2.52; P = .01). Improvements in secondary outcomes also were observed in this group, reported Sylvie Naar, PhD, of Florida State University, Tallahassee, and her coauthors.
They studied African American adolescents with moderate to severe persistent asthma who resided in a home setting with a caregiver and were at high risk for poorly controlled asthma. Families were randomized to either MST-HC (84 patients) or FS (83 patients) based on severity of urgent care use, and follow-up was completed 7 and 12 months after baseline assessment. Families were paid $50 for each assessment.
FEV1 was the primary outcome. Secondary outcomes were medication adherence, symptom severity and frequency, inpatient hospitalizations, and ED visits. Medication adherence was evaluated via the Family Asthma Management System Scale (FAMSS) and the Daily Phone Diary (DPD). Other outcomes were confirmed via medical records.
Patients in the FS control group received weekly home-based counseling for up to 6 months. Patients in the MST-HC treatment group were first engaged in a motivational session with a therapist and evaluated for asthma management with interviews and observations within the home and community. Once possible contributing factors to poor asthma management (such as medication underuse or low parental monitoring) were identified, targeted interventions such as skills training, behavioral and family therapy, or communication training with school and medical staff were chosen, and treatment goals continually monitored and modified, the authors said.
The mean length of treatment until termination in the MST-HC group was 5 months, and the mean number of sessions was 27. In the FS group, mean length of treatment was 4 months, and the mean number of sessions was 11.
FEV1 for the MST-HC group improved from 2.05 at baseline to 2.25 at 7 months (a 10% improvement), and to 2.37 (a 16% improvement) at 12 months, compared with an improvement from 2.21 to 2.31 at 7 months (a 4% improvement) and 2.33 (a 5% improvement) at 12 months in the control group, the authors reported.
At 12 months, FAMSS adherence scores improved from 4.19 to 5.24 in the MST-HC group and from 4.61 to 4.72 in the control group.
DPD adherence scores improved from a mean of 0.33 at baseline to 0.69 for the MST-HC group, and from 0.43 to 0.46 in the FS group.
At 12 months, the mean frequency of asthma symptoms in the MST-HC group improved from 2.75 at baseline to 1.43, compared with a decline of 2.67 to 2.58 in the control group. The mean number of hospitalizations in the MST-HC group improved from 0.87 to 0.24, compared with a change from 0.66 to 0.34 in the control group.
The study results are “especially noteworthy because African American adolescents experience greater morbidity and mortality from asthma than white adolescents even when controlling for socioeconomic variables,” Dr. Naar and her associates wrote. Future research should focus on the “transportability” of MST-HC treatment to community settings, which is “ready to be studied in effectiveness and implementation trials.”
The study was supported by a National Institutes of Health grant. Coauthor Phillippe Cunningham, PhD, is a co-owner of Evidence-Based Services, a network partner organization that is licensed to disseminate Multisystemic Therapy for drug court and juvenile delinquency settings. The other authors said they have no potential conflicts of interest.
SOURCE: Naar S et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3737.
FROM PEDIATRICS
Key clinical point: Multisystemic Therapy–Health Care (MST-HC) significantly improved outcomes in African American adolescents with moderate to severe asthma.
Major finding: Patients randomly assigned to MST-HC treatment had greater improvement in FEV1 over time, compared with controls (beta = 0.097; t(164.27) = 2.52; P = .01).
Study details: A study of 167 African American patients aged 12-16 years, randomly assigned to either MST-HC or FS.
Disclosures: The study was supported by a National Institutes of Health grant. Coauthor Phillippe Cunningham, PhD, is a co-owner of Evidence-Based Services, a network partner organization that is licensed to disseminate multisystemic therapy for drug court and juvenile delinquency settings. The other authors said they have no potential conflicts of interest.
Source: Naar S et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3737.
ED key to reducing pediatric asthma x-rays
ATLANTA – but accomplishing this goal takes more than a new clinical practice guideline, according to a quality improvement team at the Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tenn.
The team eventually reduced the chest x-ray rate for pediatric asthma exacerbations from 30% to 15% without increasing 3-day all-cause readmissions, but it took some sleuthing in the ED and good relations with staff. “We were way out in left field when we started this. Working in silos is never ideal,” said senior project member David Johnson, MD, a pediatric hospitalist and assistant professor of pediatrics at Vanderbilt.
It’s been known for a while that chest x-rays are almost always a waste of time and money for asthma exacerbations, and national guidelines recommend against them. X-rays don’t improve outcomes and needlessly expose children to radiation.
In 2014, some of the providers at Vanderbilt, which has about 1,700 asthma encounters a year, realized that the institution’s 30% x-ray rate was a problem. The quality improvement team hoped a new guideline would address the issue, but that didn’t happen. “We roll out clinical practice guidelines” from on high, “and think people will magically change their behavior,” but they don’t, Dr. Johnson said at the annual Pediatric Hospital Medicine meeting.
The guideline was not being fully implemented. So the team asked the ED what was the standard procedure for a child presenting with asthma exacerbation. It turned out that the ED had a dyspnea order set that the team ”had no idea existed.” Chest x-rays were at the top of the list; next came blood gases, ventilation-perfusion scans, and leg Dopplers, he said.
The investigators tried to get rid of the whole order set but were unsuccessful. The ED department did, however, let the team eliminate chest x-rays in the default order set in July 2015. That helped, but more changes were needed.
The next conversation was to figure out why x-rays were being ordered in the first place. ED staff said they were worried about missing something, especially pneumonia. They also thought they were helping hospitalists by getting x-rays before sending kids to the ward even though, in reality, it didn’t matter whether x-rays were done a few hours later on the floor. ED providers also said that ill-appearing children often got better after a few hours but were kept back from discharge because x-ray results were still pending and that sometimes these results revealed problems at 3 a.m. that had nothing to do with why the patients were in the ED but still required a work-up.
This discussion opened a door. The ED staff didn’t want to order unnecessary x-rays, either. That led to talks about letting kids declare themselves a bit before x-rays were ordered. ED staff liked the idea, so the guidelines were updated in early 2016 to say that chest x-rays should only be ordered if there is persistent severe respiratory distress with hypoxia, there are focal findings that don’t improve after 12 hours of treatment, or there were concerns for pneumomediastinum or collapsed lung. The updated guidelines were posted in work areas and brought home by resident education. A reminder was added to the electronic medical record system that popped up when someone tried to order a chest x-ray for an child with asthma.
It worked. Chest x-ray rates in asthma fell to 15%, and have remained there since.
“We gave them permission to take their foot off the throttle and wait a little bit, and we don’t have more kids bouncing back from reduced x-rays.” The approach is “probably generalizable everywhere,” Dr. Johnson said.
It was essential that an ED fellow, Caroline Watnick, MD, led the effort and eventually bridged the gap between hospitalists and ED providers. In the end, “the change wasn’t something from the outside,” Dr. Johnson said.
There was no industry funding, and Dr. Johnson didn’t have any disclosures. The Pediatric Hospital Medicine meeting is sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
ATLANTA – but accomplishing this goal takes more than a new clinical practice guideline, according to a quality improvement team at the Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tenn.
The team eventually reduced the chest x-ray rate for pediatric asthma exacerbations from 30% to 15% without increasing 3-day all-cause readmissions, but it took some sleuthing in the ED and good relations with staff. “We were way out in left field when we started this. Working in silos is never ideal,” said senior project member David Johnson, MD, a pediatric hospitalist and assistant professor of pediatrics at Vanderbilt.
It’s been known for a while that chest x-rays are almost always a waste of time and money for asthma exacerbations, and national guidelines recommend against them. X-rays don’t improve outcomes and needlessly expose children to radiation.
In 2014, some of the providers at Vanderbilt, which has about 1,700 asthma encounters a year, realized that the institution’s 30% x-ray rate was a problem. The quality improvement team hoped a new guideline would address the issue, but that didn’t happen. “We roll out clinical practice guidelines” from on high, “and think people will magically change their behavior,” but they don’t, Dr. Johnson said at the annual Pediatric Hospital Medicine meeting.
The guideline was not being fully implemented. So the team asked the ED what was the standard procedure for a child presenting with asthma exacerbation. It turned out that the ED had a dyspnea order set that the team ”had no idea existed.” Chest x-rays were at the top of the list; next came blood gases, ventilation-perfusion scans, and leg Dopplers, he said.
The investigators tried to get rid of the whole order set but were unsuccessful. The ED department did, however, let the team eliminate chest x-rays in the default order set in July 2015. That helped, but more changes were needed.
The next conversation was to figure out why x-rays were being ordered in the first place. ED staff said they were worried about missing something, especially pneumonia. They also thought they were helping hospitalists by getting x-rays before sending kids to the ward even though, in reality, it didn’t matter whether x-rays were done a few hours later on the floor. ED providers also said that ill-appearing children often got better after a few hours but were kept back from discharge because x-ray results were still pending and that sometimes these results revealed problems at 3 a.m. that had nothing to do with why the patients were in the ED but still required a work-up.
This discussion opened a door. The ED staff didn’t want to order unnecessary x-rays, either. That led to talks about letting kids declare themselves a bit before x-rays were ordered. ED staff liked the idea, so the guidelines were updated in early 2016 to say that chest x-rays should only be ordered if there is persistent severe respiratory distress with hypoxia, there are focal findings that don’t improve after 12 hours of treatment, or there were concerns for pneumomediastinum or collapsed lung. The updated guidelines were posted in work areas and brought home by resident education. A reminder was added to the electronic medical record system that popped up when someone tried to order a chest x-ray for an child with asthma.
It worked. Chest x-ray rates in asthma fell to 15%, and have remained there since.
“We gave them permission to take their foot off the throttle and wait a little bit, and we don’t have more kids bouncing back from reduced x-rays.” The approach is “probably generalizable everywhere,” Dr. Johnson said.
It was essential that an ED fellow, Caroline Watnick, MD, led the effort and eventually bridged the gap between hospitalists and ED providers. In the end, “the change wasn’t something from the outside,” Dr. Johnson said.
There was no industry funding, and Dr. Johnson didn’t have any disclosures. The Pediatric Hospital Medicine meeting is sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
ATLANTA – but accomplishing this goal takes more than a new clinical practice guideline, according to a quality improvement team at the Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tenn.
The team eventually reduced the chest x-ray rate for pediatric asthma exacerbations from 30% to 15% without increasing 3-day all-cause readmissions, but it took some sleuthing in the ED and good relations with staff. “We were way out in left field when we started this. Working in silos is never ideal,” said senior project member David Johnson, MD, a pediatric hospitalist and assistant professor of pediatrics at Vanderbilt.
It’s been known for a while that chest x-rays are almost always a waste of time and money for asthma exacerbations, and national guidelines recommend against them. X-rays don’t improve outcomes and needlessly expose children to radiation.
In 2014, some of the providers at Vanderbilt, which has about 1,700 asthma encounters a year, realized that the institution’s 30% x-ray rate was a problem. The quality improvement team hoped a new guideline would address the issue, but that didn’t happen. “We roll out clinical practice guidelines” from on high, “and think people will magically change their behavior,” but they don’t, Dr. Johnson said at the annual Pediatric Hospital Medicine meeting.
The guideline was not being fully implemented. So the team asked the ED what was the standard procedure for a child presenting with asthma exacerbation. It turned out that the ED had a dyspnea order set that the team ”had no idea existed.” Chest x-rays were at the top of the list; next came blood gases, ventilation-perfusion scans, and leg Dopplers, he said.
The investigators tried to get rid of the whole order set but were unsuccessful. The ED department did, however, let the team eliminate chest x-rays in the default order set in July 2015. That helped, but more changes were needed.
The next conversation was to figure out why x-rays were being ordered in the first place. ED staff said they were worried about missing something, especially pneumonia. They also thought they were helping hospitalists by getting x-rays before sending kids to the ward even though, in reality, it didn’t matter whether x-rays were done a few hours later on the floor. ED providers also said that ill-appearing children often got better after a few hours but were kept back from discharge because x-ray results were still pending and that sometimes these results revealed problems at 3 a.m. that had nothing to do with why the patients were in the ED but still required a work-up.
This discussion opened a door. The ED staff didn’t want to order unnecessary x-rays, either. That led to talks about letting kids declare themselves a bit before x-rays were ordered. ED staff liked the idea, so the guidelines were updated in early 2016 to say that chest x-rays should only be ordered if there is persistent severe respiratory distress with hypoxia, there are focal findings that don’t improve after 12 hours of treatment, or there were concerns for pneumomediastinum or collapsed lung. The updated guidelines were posted in work areas and brought home by resident education. A reminder was added to the electronic medical record system that popped up when someone tried to order a chest x-ray for an child with asthma.
It worked. Chest x-ray rates in asthma fell to 15%, and have remained there since.
“We gave them permission to take their foot off the throttle and wait a little bit, and we don’t have more kids bouncing back from reduced x-rays.” The approach is “probably generalizable everywhere,” Dr. Johnson said.
It was essential that an ED fellow, Caroline Watnick, MD, led the effort and eventually bridged the gap between hospitalists and ED providers. In the end, “the change wasn’t something from the outside,” Dr. Johnson said.
There was no industry funding, and Dr. Johnson didn’t have any disclosures. The Pediatric Hospital Medicine meeting is sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
REPORTING FROM PHM 2018
Key clinical point: Reduction of chest x-rays for routine pediatric asthma exacerbations in the ED can be accomplished with a team effort.
Major finding: A team project reduced x-rays for pediatric asthma exacerbations from 30% to 15% without increasing 3-day, all-cause readmissions.
Study details: Pre/post quality improvement analysis of asthma encounters in the Monroe Carell Jr. Children’s Hospital, Nashville, Tenn., starting in 2014.
Disclosures: There was no industry funding, and the presenter didn’t have any disclosures.
Asthma medication ratio identifies high-risk pediatric patients
ATLANTA – An according to researchers from the Medical University of South Carolina (MUSC), Charleston.
The asthma medication ratio (AMR) – the number of prescriptions for controller medications divided by the number of prescriptions for both controller and rescue medications – has been around for a while, but it’s mostly been used as a quality metric. The new study shows that it’s also useful in the clinic to identify children who could benefit from extra attention.
A perfect ratio of 1 means that control is good without rescue inhalers. The ratio falls as the number of rescue inhalers goes up, signaling poorer control. Children with a ratio below 0.5 are considered high risk; they’d hit that mark if, for instance, they were prescribed one control medication such as fluticasone propionate (Flovent) and two albuterol rescue inhalers in a month.
If control is good, “you should only need a rescue inhaler very, very sporadically;” high-risk children probably need a higher dose of their controller, or help with compliance, explained lead investigator Annie L. Andrews, MD, associate professor of pediatrics at MUSC.
The university uses the EPIC records system, which incorporates prescription data from Surescripts, so the number of asthma medication fills is already available. The system just needs to be adjusted to calculate and report AMRs monthly, something Dr. Andrews and her team are working on. “The information is right there, but it’s an untapped resource,” she said. “We just need to crunch the numbers, and operationalize it. Why are we waiting until kids are in the hospital” to intervene?
Dr. Andrews presented a proof-of-concept study at the Pediatric Hospital Medicine meeting. Her team identified 214,452 asthma patients aged 2-17 years with at least one claim for an inhaled corticosteroid in the Truven MarketScan Medicaid database from 2013-14.
They calculated AMRs for each child every 3 months over a 15-month period. About 9% of children at any given time had AMRs below 0.5.
The first AMR was at or above 0.5 in 93,512 children; 18.1% had a subsequent asthma-related event, meaning an ED visit or hospitalization, during the course of the study. Among the 17,635 children with an initial AMR below 0.5, 25% had asthma-related events. The initial AMR couldn’t be calculated in 103,305 children, which likely meant they had less-active disease. Those children had the lowest proportion of asthma events, at 13.9%.
An AMR below 0.5 nearly doubled the risk of an asthma-related hospitalization or ED visit in the subsequent 3 months, with an odds ratios ranging from 1.7 to 1.9, compared with other children. The findings were statistically significant.
In short, serial AMRs helped predict exacerbations among Medicaid children. The team showed the same trend among commercially insured children in a recently published study. The only difference was that Medicaid children had a higher proportion of high-risk AMRs, and a higher number of asthma events (Am J Manag Care. 2018 Jun;24[6]:294-300). Together, the studies validate “the rolling 3-month AMR as an appropriate method for identifying children at high risk for imminent exacerbation,” the investigators concluded.
With automatic AMR reporting already in the works at MUSC, “we are now trying to figure out how to intervene. Do we just tell providers who their high-risk kids are and let them figure out how to contact families, or do we use this information to contact families directly? That’s kind of what I favor: ‘Hey, your kid just popped up as high risk, so let’s figure out what you need. Do you need a new prescription or a reminder to see your doctor?’ ” Dr. Andrews said.
Her team is developing a mobile app to communicate with families.
The mean age in the study was 7.9 years; 59% of the children were boys, and 41% were black.
The work was funded by the National Institutes of Health, among others. Dr. Andrews had no disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
ATLANTA – An according to researchers from the Medical University of South Carolina (MUSC), Charleston.
The asthma medication ratio (AMR) – the number of prescriptions for controller medications divided by the number of prescriptions for both controller and rescue medications – has been around for a while, but it’s mostly been used as a quality metric. The new study shows that it’s also useful in the clinic to identify children who could benefit from extra attention.
A perfect ratio of 1 means that control is good without rescue inhalers. The ratio falls as the number of rescue inhalers goes up, signaling poorer control. Children with a ratio below 0.5 are considered high risk; they’d hit that mark if, for instance, they were prescribed one control medication such as fluticasone propionate (Flovent) and two albuterol rescue inhalers in a month.
If control is good, “you should only need a rescue inhaler very, very sporadically;” high-risk children probably need a higher dose of their controller, or help with compliance, explained lead investigator Annie L. Andrews, MD, associate professor of pediatrics at MUSC.
The university uses the EPIC records system, which incorporates prescription data from Surescripts, so the number of asthma medication fills is already available. The system just needs to be adjusted to calculate and report AMRs monthly, something Dr. Andrews and her team are working on. “The information is right there, but it’s an untapped resource,” she said. “We just need to crunch the numbers, and operationalize it. Why are we waiting until kids are in the hospital” to intervene?
Dr. Andrews presented a proof-of-concept study at the Pediatric Hospital Medicine meeting. Her team identified 214,452 asthma patients aged 2-17 years with at least one claim for an inhaled corticosteroid in the Truven MarketScan Medicaid database from 2013-14.
They calculated AMRs for each child every 3 months over a 15-month period. About 9% of children at any given time had AMRs below 0.5.
The first AMR was at or above 0.5 in 93,512 children; 18.1% had a subsequent asthma-related event, meaning an ED visit or hospitalization, during the course of the study. Among the 17,635 children with an initial AMR below 0.5, 25% had asthma-related events. The initial AMR couldn’t be calculated in 103,305 children, which likely meant they had less-active disease. Those children had the lowest proportion of asthma events, at 13.9%.
An AMR below 0.5 nearly doubled the risk of an asthma-related hospitalization or ED visit in the subsequent 3 months, with an odds ratios ranging from 1.7 to 1.9, compared with other children. The findings were statistically significant.
In short, serial AMRs helped predict exacerbations among Medicaid children. The team showed the same trend among commercially insured children in a recently published study. The only difference was that Medicaid children had a higher proportion of high-risk AMRs, and a higher number of asthma events (Am J Manag Care. 2018 Jun;24[6]:294-300). Together, the studies validate “the rolling 3-month AMR as an appropriate method for identifying children at high risk for imminent exacerbation,” the investigators concluded.
With automatic AMR reporting already in the works at MUSC, “we are now trying to figure out how to intervene. Do we just tell providers who their high-risk kids are and let them figure out how to contact families, or do we use this information to contact families directly? That’s kind of what I favor: ‘Hey, your kid just popped up as high risk, so let’s figure out what you need. Do you need a new prescription or a reminder to see your doctor?’ ” Dr. Andrews said.
Her team is developing a mobile app to communicate with families.
The mean age in the study was 7.9 years; 59% of the children were boys, and 41% were black.
The work was funded by the National Institutes of Health, among others. Dr. Andrews had no disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
ATLANTA – An according to researchers from the Medical University of South Carolina (MUSC), Charleston.
The asthma medication ratio (AMR) – the number of prescriptions for controller medications divided by the number of prescriptions for both controller and rescue medications – has been around for a while, but it’s mostly been used as a quality metric. The new study shows that it’s also useful in the clinic to identify children who could benefit from extra attention.
A perfect ratio of 1 means that control is good without rescue inhalers. The ratio falls as the number of rescue inhalers goes up, signaling poorer control. Children with a ratio below 0.5 are considered high risk; they’d hit that mark if, for instance, they were prescribed one control medication such as fluticasone propionate (Flovent) and two albuterol rescue inhalers in a month.
If control is good, “you should only need a rescue inhaler very, very sporadically;” high-risk children probably need a higher dose of their controller, or help with compliance, explained lead investigator Annie L. Andrews, MD, associate professor of pediatrics at MUSC.
The university uses the EPIC records system, which incorporates prescription data from Surescripts, so the number of asthma medication fills is already available. The system just needs to be adjusted to calculate and report AMRs monthly, something Dr. Andrews and her team are working on. “The information is right there, but it’s an untapped resource,” she said. “We just need to crunch the numbers, and operationalize it. Why are we waiting until kids are in the hospital” to intervene?
Dr. Andrews presented a proof-of-concept study at the Pediatric Hospital Medicine meeting. Her team identified 214,452 asthma patients aged 2-17 years with at least one claim for an inhaled corticosteroid in the Truven MarketScan Medicaid database from 2013-14.
They calculated AMRs for each child every 3 months over a 15-month period. About 9% of children at any given time had AMRs below 0.5.
The first AMR was at or above 0.5 in 93,512 children; 18.1% had a subsequent asthma-related event, meaning an ED visit or hospitalization, during the course of the study. Among the 17,635 children with an initial AMR below 0.5, 25% had asthma-related events. The initial AMR couldn’t be calculated in 103,305 children, which likely meant they had less-active disease. Those children had the lowest proportion of asthma events, at 13.9%.
An AMR below 0.5 nearly doubled the risk of an asthma-related hospitalization or ED visit in the subsequent 3 months, with an odds ratios ranging from 1.7 to 1.9, compared with other children. The findings were statistically significant.
In short, serial AMRs helped predict exacerbations among Medicaid children. The team showed the same trend among commercially insured children in a recently published study. The only difference was that Medicaid children had a higher proportion of high-risk AMRs, and a higher number of asthma events (Am J Manag Care. 2018 Jun;24[6]:294-300). Together, the studies validate “the rolling 3-month AMR as an appropriate method for identifying children at high risk for imminent exacerbation,” the investigators concluded.
With automatic AMR reporting already in the works at MUSC, “we are now trying to figure out how to intervene. Do we just tell providers who their high-risk kids are and let them figure out how to contact families, or do we use this information to contact families directly? That’s kind of what I favor: ‘Hey, your kid just popped up as high risk, so let’s figure out what you need. Do you need a new prescription or a reminder to see your doctor?’ ” Dr. Andrews said.
Her team is developing a mobile app to communicate with families.
The mean age in the study was 7.9 years; 59% of the children were boys, and 41% were black.
The work was funded by the National Institutes of Health, among others. Dr. Andrews had no disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
REPORTING FROM PHM 2018
Key clinical point: The asthma medication ratio is useful in the clinic to identify children who could benefit from extra attention.
Major finding: About 9% of children at any given time had AMRs below 0.5, meaning they were at high risk for acute exacerbations.
Study details: Review of more than 200,000 pediatric asthma patients on Medicaid
Disclosures: The work was funded by the National Institutes of Health, among others. The study lead had no disclosures.
New guidance offered for managing poorly controlled asthma in children
published in the Annals of Allergy, Asthma & Immunology.
“Although many children with asthma achieve symptom control with appropriate management, a substantial subset does not,” Bradley E. Chipps, MD, from the Capital Allergy & Respiratory Disease Center in Sacramento, Calif., and his colleagues wrote in the recommendations sponsored by the American College of Allergy, Asthma, and Immunology. “These children should undergo a step-up in care, but when and how to do that is not always straightforward. The Pediatric Asthma Yardstick is a practical resource for starting or adjusting controller therapy based on the options that are currently available for children, from infants to 18 years of age.”
In their recommendations, the authors grouped patients into age ranges of adolescent (12-18 years), school aged (6-11 years), and young children (5 years and under) as well as severity classifications.
Adolescents and school-aged children
For adolescents and school-aged children, step 1 was classified as intermittent asthma that can be controlled with low-dose inhaled corticosteroids (ICS) with short-acting beta2-agonist (SABA) for as-needed relief. Children considered for stepping up to the next therapy should show symptoms of mild persistent asthma that the authors recommended controlling with low-dose ICS, leukotriene receptor antagonist (LTRA), or low-dose theophylline with as-needed SABA.
In children 12-18 years with moderate persistent asthma (step 3), the authors recommended a combination of low-dose ICA and a long-acting beta2-agonist (LABA), while children 6-11 years should receive a medium dose of ICS; other considerations for school-aged children include a medium-high dose of ICS, a low-dose combination of ICS and LTRA, or low-dose ICS together with theophylline.
Adolescent or school-aged children with severe persistent asthma (step 4) should take a medium or high dose of ICS together with LABA, with the authors recommending adding tiotropium to a soft mist inhaler, combination high-dose ICS and LTRA, or a combination high-dose ICS and theophylline.
Dr. Chipps and his coauthors recommended children stepping up therapy beyond severe persistent asthma (step 5) should add on treatment such as low-dose oral corticosteroids, anti-immunoglobulin E therapy, and adding tiotropium to a soft-mist inhaler.
For adolescent and school-aged children going to steps 3-5, Dr. Chipps and his coauthors recommended prescribing as needed a short-acting beta2 agonist or low-dose ICS/LABA.
Children 5 years and younger
In children 5 years and younger, intermittent asthma (step 1) should be considered if the child has infrequent or viral wheezing but few or no symptoms in the interim that can be controlled with as-needed SABA. These young children who show symptoms of mild persistent asthma (step 2) can be treated with daily low-dose ICS, with other controller options of LTRA or intermittent ICS.
Stepping up therapy from mild to moderate persistent asthma (step 3), young children should receive double the daily dose of low-dose ICS from the previous step or use the low-dose ICS together with LTRA; if children show symptoms of severe persistent asthma (step 4), they should continue their daily controller and be referred to a specialist; other considerations for controllers at this step included adding LTRA, adding intermittent ICS, or increasing ICS frequency.
Other factors to consider
Inconsistencies in response to medication can occur because of comorbid conditions such as obesity, rhinosinusitis, respiratory infection or gastroesophageal reflux; suboptimal inhaled drug delivery; or failure to comply with treatment because of not wanting to take medication (common in adolescents), belief that even controller medicine can be taken intermittently, family stress, cost including lack of insurance or medication not covered by insurance. “Before adjusting therapy, it is important to ensure that the child’s change in symptoms is due to asthma and not to any of these factors that need to be addressed,” Dr. Chipps and his colleagues wrote.
Collaboration among children, their parents, and clinicians is needed to achieve good asthma control because of the “variable presentation within individuals and within the population of children affected” with asthma, they wrote.
The article summarizing the guidelines was sponsored by the American College of Allergy, Asthma, and Immunology. Most of the authors report various financial relationships with companies including AstraZeneca, Aerocrine, Aviragen, Boehringer Ingelheim, Cephalon, Circassia, Commense, Genentech, GlaxoSmithKline, Greer, Meda, Merck, Mylan, Novartis, Patara, Regeneron, Sanofi, TEVA, Theravance, and Vectura Group. Dr. Farrar and Dr. Szefler had no financial interests to disclose.
SOURCE: Chipps BE et al. Ann Allergy Asthma Immunol. 2018 Apr. doi: 1010.1016/j.anai.2018.04.002.
published in the Annals of Allergy, Asthma & Immunology.
“Although many children with asthma achieve symptom control with appropriate management, a substantial subset does not,” Bradley E. Chipps, MD, from the Capital Allergy & Respiratory Disease Center in Sacramento, Calif., and his colleagues wrote in the recommendations sponsored by the American College of Allergy, Asthma, and Immunology. “These children should undergo a step-up in care, but when and how to do that is not always straightforward. The Pediatric Asthma Yardstick is a practical resource for starting or adjusting controller therapy based on the options that are currently available for children, from infants to 18 years of age.”
In their recommendations, the authors grouped patients into age ranges of adolescent (12-18 years), school aged (6-11 years), and young children (5 years and under) as well as severity classifications.
Adolescents and school-aged children
For adolescents and school-aged children, step 1 was classified as intermittent asthma that can be controlled with low-dose inhaled corticosteroids (ICS) with short-acting beta2-agonist (SABA) for as-needed relief. Children considered for stepping up to the next therapy should show symptoms of mild persistent asthma that the authors recommended controlling with low-dose ICS, leukotriene receptor antagonist (LTRA), or low-dose theophylline with as-needed SABA.
In children 12-18 years with moderate persistent asthma (step 3), the authors recommended a combination of low-dose ICA and a long-acting beta2-agonist (LABA), while children 6-11 years should receive a medium dose of ICS; other considerations for school-aged children include a medium-high dose of ICS, a low-dose combination of ICS and LTRA, or low-dose ICS together with theophylline.
Adolescent or school-aged children with severe persistent asthma (step 4) should take a medium or high dose of ICS together with LABA, with the authors recommending adding tiotropium to a soft mist inhaler, combination high-dose ICS and LTRA, or a combination high-dose ICS and theophylline.
Dr. Chipps and his coauthors recommended children stepping up therapy beyond severe persistent asthma (step 5) should add on treatment such as low-dose oral corticosteroids, anti-immunoglobulin E therapy, and adding tiotropium to a soft-mist inhaler.
For adolescent and school-aged children going to steps 3-5, Dr. Chipps and his coauthors recommended prescribing as needed a short-acting beta2 agonist or low-dose ICS/LABA.
Children 5 years and younger
In children 5 years and younger, intermittent asthma (step 1) should be considered if the child has infrequent or viral wheezing but few or no symptoms in the interim that can be controlled with as-needed SABA. These young children who show symptoms of mild persistent asthma (step 2) can be treated with daily low-dose ICS, with other controller options of LTRA or intermittent ICS.
Stepping up therapy from mild to moderate persistent asthma (step 3), young children should receive double the daily dose of low-dose ICS from the previous step or use the low-dose ICS together with LTRA; if children show symptoms of severe persistent asthma (step 4), they should continue their daily controller and be referred to a specialist; other considerations for controllers at this step included adding LTRA, adding intermittent ICS, or increasing ICS frequency.
Other factors to consider
Inconsistencies in response to medication can occur because of comorbid conditions such as obesity, rhinosinusitis, respiratory infection or gastroesophageal reflux; suboptimal inhaled drug delivery; or failure to comply with treatment because of not wanting to take medication (common in adolescents), belief that even controller medicine can be taken intermittently, family stress, cost including lack of insurance or medication not covered by insurance. “Before adjusting therapy, it is important to ensure that the child’s change in symptoms is due to asthma and not to any of these factors that need to be addressed,” Dr. Chipps and his colleagues wrote.
Collaboration among children, their parents, and clinicians is needed to achieve good asthma control because of the “variable presentation within individuals and within the population of children affected” with asthma, they wrote.
The article summarizing the guidelines was sponsored by the American College of Allergy, Asthma, and Immunology. Most of the authors report various financial relationships with companies including AstraZeneca, Aerocrine, Aviragen, Boehringer Ingelheim, Cephalon, Circassia, Commense, Genentech, GlaxoSmithKline, Greer, Meda, Merck, Mylan, Novartis, Patara, Regeneron, Sanofi, TEVA, Theravance, and Vectura Group. Dr. Farrar and Dr. Szefler had no financial interests to disclose.
SOURCE: Chipps BE et al. Ann Allergy Asthma Immunol. 2018 Apr. doi: 1010.1016/j.anai.2018.04.002.
published in the Annals of Allergy, Asthma & Immunology.
“Although many children with asthma achieve symptom control with appropriate management, a substantial subset does not,” Bradley E. Chipps, MD, from the Capital Allergy & Respiratory Disease Center in Sacramento, Calif., and his colleagues wrote in the recommendations sponsored by the American College of Allergy, Asthma, and Immunology. “These children should undergo a step-up in care, but when and how to do that is not always straightforward. The Pediatric Asthma Yardstick is a practical resource for starting or adjusting controller therapy based on the options that are currently available for children, from infants to 18 years of age.”
In their recommendations, the authors grouped patients into age ranges of adolescent (12-18 years), school aged (6-11 years), and young children (5 years and under) as well as severity classifications.
Adolescents and school-aged children
For adolescents and school-aged children, step 1 was classified as intermittent asthma that can be controlled with low-dose inhaled corticosteroids (ICS) with short-acting beta2-agonist (SABA) for as-needed relief. Children considered for stepping up to the next therapy should show symptoms of mild persistent asthma that the authors recommended controlling with low-dose ICS, leukotriene receptor antagonist (LTRA), or low-dose theophylline with as-needed SABA.
In children 12-18 years with moderate persistent asthma (step 3), the authors recommended a combination of low-dose ICA and a long-acting beta2-agonist (LABA), while children 6-11 years should receive a medium dose of ICS; other considerations for school-aged children include a medium-high dose of ICS, a low-dose combination of ICS and LTRA, or low-dose ICS together with theophylline.
Adolescent or school-aged children with severe persistent asthma (step 4) should take a medium or high dose of ICS together with LABA, with the authors recommending adding tiotropium to a soft mist inhaler, combination high-dose ICS and LTRA, or a combination high-dose ICS and theophylline.
Dr. Chipps and his coauthors recommended children stepping up therapy beyond severe persistent asthma (step 5) should add on treatment such as low-dose oral corticosteroids, anti-immunoglobulin E therapy, and adding tiotropium to a soft-mist inhaler.
For adolescent and school-aged children going to steps 3-5, Dr. Chipps and his coauthors recommended prescribing as needed a short-acting beta2 agonist or low-dose ICS/LABA.
Children 5 years and younger
In children 5 years and younger, intermittent asthma (step 1) should be considered if the child has infrequent or viral wheezing but few or no symptoms in the interim that can be controlled with as-needed SABA. These young children who show symptoms of mild persistent asthma (step 2) can be treated with daily low-dose ICS, with other controller options of LTRA or intermittent ICS.
Stepping up therapy from mild to moderate persistent asthma (step 3), young children should receive double the daily dose of low-dose ICS from the previous step or use the low-dose ICS together with LTRA; if children show symptoms of severe persistent asthma (step 4), they should continue their daily controller and be referred to a specialist; other considerations for controllers at this step included adding LTRA, adding intermittent ICS, or increasing ICS frequency.
Other factors to consider
Inconsistencies in response to medication can occur because of comorbid conditions such as obesity, rhinosinusitis, respiratory infection or gastroesophageal reflux; suboptimal inhaled drug delivery; or failure to comply with treatment because of not wanting to take medication (common in adolescents), belief that even controller medicine can be taken intermittently, family stress, cost including lack of insurance or medication not covered by insurance. “Before adjusting therapy, it is important to ensure that the child’s change in symptoms is due to asthma and not to any of these factors that need to be addressed,” Dr. Chipps and his colleagues wrote.
Collaboration among children, their parents, and clinicians is needed to achieve good asthma control because of the “variable presentation within individuals and within the population of children affected” with asthma, they wrote.
The article summarizing the guidelines was sponsored by the American College of Allergy, Asthma, and Immunology. Most of the authors report various financial relationships with companies including AstraZeneca, Aerocrine, Aviragen, Boehringer Ingelheim, Cephalon, Circassia, Commense, Genentech, GlaxoSmithKline, Greer, Meda, Merck, Mylan, Novartis, Patara, Regeneron, Sanofi, TEVA, Theravance, and Vectura Group. Dr. Farrar and Dr. Szefler had no financial interests to disclose.
SOURCE: Chipps BE et al. Ann Allergy Asthma Immunol. 2018 Apr. doi: 1010.1016/j.anai.2018.04.002.
FROM ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
FDA reverses warning on LABA-containing asthma medications
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Combination LABA/inhaled glucocorticoid products appear safe for patients with asthma.
Major finding: The products reduced the risk of an asthma exacerbation by 17%, without increasing the risk of a serious adverse outcome.
Study details: The four randomized studies comprised more than 13,000 patients.
Disclosures: The studies were sponsored by AstraZeneca, GlaxoSmithKline, Merck, and Novartis. Dr. Busse disclosed a financial relationship with Novartis, but said it was not relevant to this work.
Source: Busse WW. N Engl J Med. 2018;78:2497-505.
Dupilumab reduces exacerbations, cuts glucocorticoid use in moderate to severe asthma
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Dupilumab allowed asthma patients to decrease glucocorticoids with no risk of asthma exacerbation.
Major finding: Dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%.
Study details: Liberty Asthma Quest comprised 1,902 patients and Liberty Asthma Venture comprised 210. Both were randomized, placebo-controlled trials.
Disclosures: Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
Sources: Castro M et al. N Engl J Med. 2018;378:2486-96; Rabe KF et al. N Engl J Med. 2018;378:2475-85.
Pediatric asthma patients should be considered priority for flu vaccine
Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.
Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.
In reviewing the findings of the study, Dr. Merckx and her colleagues sought to determine whether closely evaluating the effects of specific respiratory pathogens could be useful in further developing appropriate preventive treatments for children with asthma; improving efforts to diagnose pathogens at the time of ED treatment; and identifying patients at higher risk of treatment failure who could be candidates for more intensive treatment protocols.
Children aged 1-17 years presenting to one of five EDs in the Pediatric Emergency Research Canada network during 2011-2013 with moderate or severe asthma flares were considered for the study. All eligible DOORWAY study participants with a valid respiratory specimen were included in the study and received a standardized dose of oral and bronchodilator treatment with salbutamol; those with severe exacerbations also received ipratropium bromide (Atrovent).
Within 1 hour of study inclusion, patients were tested by way of nasopharyngeal aspirate or swab. Patients identified with coinfection presented with two or more pathogens. Failure of ED management was defined as patients admitted to the hospital for asthma; ED treatment lasting 8 or more hours after corticosteroid treatment; or returns to the ED within 72 hours after discharge that led to hospital admission or prolonged ED stay.
Of 1,012 children enrolled in the study, 958 were assessed for worsening of asthma symptoms. Of the 958 respiratory specimens tested, 62% tested positive for one or more pathogens, 8.5% were found to have coinfection, of which respiratory syncytial virus (RSV) and coronavirus were the most frequent copathogens. Rhinovirus was the most prevalent pathogen, occurring in 29%, and of these, rhinovirus C was the most frequent species (18.2%), followed by RSV (17.9%); only two patients tested positive for Mycoplasma pneumoniae.
Children with a laboratory-confirmed pathogen were younger, had higher tobacco exposure, and were slightly more likely to present with fever (29% vs. 24%), compared with children without a laboratory-confirmed pathogen. Children with rhinovirus were less often febrile (16% vs 41%) and less frequently diagnosed with pneumonia (5% vs. 16%.) than those without a rhinovirus infection The proportion of children presenting with a severe exacerbation of asthma was 33%.
Overall, 17% of patients experienced treatment failure. Those with current respiratory infection were at increased risk of treatment failure, for a risk difference of 8% (95% confidence interval, 3.3%-13.1%). RSV, influenza, and parainfluenza virus (PIV) were associated with 21%, 38%, and 47% higher risks of treatment failure, respectively, noted Dr. Merckx and her associates. These resulted in absolute risks of 9%, 25%, and 34%, respectively, the authors reported in Pediatrics.
Coronavirus, adenovirus, enterovirus D68, and the presence of a coinfection, however, were not found to increase the risk of treatment failure, they noted.
Although rhinovirus may play a role in triggering reactions that require medical attention, such cases still appear to respond favorably to treatment, they said.
A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.
“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.
In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.
Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.
While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.
Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.
Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.
Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.
Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.
In reviewing the findings of the study, Dr. Merckx and her colleagues sought to determine whether closely evaluating the effects of specific respiratory pathogens could be useful in further developing appropriate preventive treatments for children with asthma; improving efforts to diagnose pathogens at the time of ED treatment; and identifying patients at higher risk of treatment failure who could be candidates for more intensive treatment protocols.
Children aged 1-17 years presenting to one of five EDs in the Pediatric Emergency Research Canada network during 2011-2013 with moderate or severe asthma flares were considered for the study. All eligible DOORWAY study participants with a valid respiratory specimen were included in the study and received a standardized dose of oral and bronchodilator treatment with salbutamol; those with severe exacerbations also received ipratropium bromide (Atrovent).
Within 1 hour of study inclusion, patients were tested by way of nasopharyngeal aspirate or swab. Patients identified with coinfection presented with two or more pathogens. Failure of ED management was defined as patients admitted to the hospital for asthma; ED treatment lasting 8 or more hours after corticosteroid treatment; or returns to the ED within 72 hours after discharge that led to hospital admission or prolonged ED stay.
Of 1,012 children enrolled in the study, 958 were assessed for worsening of asthma symptoms. Of the 958 respiratory specimens tested, 62% tested positive for one or more pathogens, 8.5% were found to have coinfection, of which respiratory syncytial virus (RSV) and coronavirus were the most frequent copathogens. Rhinovirus was the most prevalent pathogen, occurring in 29%, and of these, rhinovirus C was the most frequent species (18.2%), followed by RSV (17.9%); only two patients tested positive for Mycoplasma pneumoniae.
Children with a laboratory-confirmed pathogen were younger, had higher tobacco exposure, and were slightly more likely to present with fever (29% vs. 24%), compared with children without a laboratory-confirmed pathogen. Children with rhinovirus were less often febrile (16% vs 41%) and less frequently diagnosed with pneumonia (5% vs. 16%.) than those without a rhinovirus infection The proportion of children presenting with a severe exacerbation of asthma was 33%.
Overall, 17% of patients experienced treatment failure. Those with current respiratory infection were at increased risk of treatment failure, for a risk difference of 8% (95% confidence interval, 3.3%-13.1%). RSV, influenza, and parainfluenza virus (PIV) were associated with 21%, 38%, and 47% higher risks of treatment failure, respectively, noted Dr. Merckx and her associates. These resulted in absolute risks of 9%, 25%, and 34%, respectively, the authors reported in Pediatrics.
Coronavirus, adenovirus, enterovirus D68, and the presence of a coinfection, however, were not found to increase the risk of treatment failure, they noted.
Although rhinovirus may play a role in triggering reactions that require medical attention, such cases still appear to respond favorably to treatment, they said.
A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.
“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.
In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.
Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.
While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.
Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.
Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.
Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.
Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.
In reviewing the findings of the study, Dr. Merckx and her colleagues sought to determine whether closely evaluating the effects of specific respiratory pathogens could be useful in further developing appropriate preventive treatments for children with asthma; improving efforts to diagnose pathogens at the time of ED treatment; and identifying patients at higher risk of treatment failure who could be candidates for more intensive treatment protocols.
Children aged 1-17 years presenting to one of five EDs in the Pediatric Emergency Research Canada network during 2011-2013 with moderate or severe asthma flares were considered for the study. All eligible DOORWAY study participants with a valid respiratory specimen were included in the study and received a standardized dose of oral and bronchodilator treatment with salbutamol; those with severe exacerbations also received ipratropium bromide (Atrovent).
Within 1 hour of study inclusion, patients were tested by way of nasopharyngeal aspirate or swab. Patients identified with coinfection presented with two or more pathogens. Failure of ED management was defined as patients admitted to the hospital for asthma; ED treatment lasting 8 or more hours after corticosteroid treatment; or returns to the ED within 72 hours after discharge that led to hospital admission or prolonged ED stay.
Of 1,012 children enrolled in the study, 958 were assessed for worsening of asthma symptoms. Of the 958 respiratory specimens tested, 62% tested positive for one or more pathogens, 8.5% were found to have coinfection, of which respiratory syncytial virus (RSV) and coronavirus were the most frequent copathogens. Rhinovirus was the most prevalent pathogen, occurring in 29%, and of these, rhinovirus C was the most frequent species (18.2%), followed by RSV (17.9%); only two patients tested positive for Mycoplasma pneumoniae.
Children with a laboratory-confirmed pathogen were younger, had higher tobacco exposure, and were slightly more likely to present with fever (29% vs. 24%), compared with children without a laboratory-confirmed pathogen. Children with rhinovirus were less often febrile (16% vs 41%) and less frequently diagnosed with pneumonia (5% vs. 16%.) than those without a rhinovirus infection The proportion of children presenting with a severe exacerbation of asthma was 33%.
Overall, 17% of patients experienced treatment failure. Those with current respiratory infection were at increased risk of treatment failure, for a risk difference of 8% (95% confidence interval, 3.3%-13.1%). RSV, influenza, and parainfluenza virus (PIV) were associated with 21%, 38%, and 47% higher risks of treatment failure, respectively, noted Dr. Merckx and her associates. These resulted in absolute risks of 9%, 25%, and 34%, respectively, the authors reported in Pediatrics.
Coronavirus, adenovirus, enterovirus D68, and the presence of a coinfection, however, were not found to increase the risk of treatment failure, they noted.
Although rhinovirus may play a role in triggering reactions that require medical attention, such cases still appear to respond favorably to treatment, they said.
A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.
“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.
In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.
Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.
While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.
Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.
Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.
FROM PEDIATRICS
Key clinical point: Nearly two-thirds of emergency asthma cases test positive for multiple pathogens.
Major finding: Risk of treatment failure is higher with respiratory syncytial virus, influenza, and parainfluenza virus.
Study details: Ancillary multicenter, prospective, ethics-approved cohort study of 958 children with asthma.
Disclosures: Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.
Source: Merckx J et al. Pediatrics. 2018;142(1):e20174105.
As-needed budesonide-formoterol prevented exacerbations in mild asthma
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: As-needed budesonide-formoterol (Symbicort) prevented exacerbations in patients with mild persistent asthma.
Major finding: In the SYGMA1 trial, the regimen outperformed as-needed terbutaline for asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (RR, 0.36; 95% CI, 0.27-0.49). In SYGMA2, the regimen was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% confidence limit, 1.16).
Study details: SYGMA1 and SYGMA2, randomized phase 3 trials of 8,012 patients aged 12 years and older with mild persistent asthma.
Disclosures: AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
Sources: O’Byrne PM et al. N Engl J Med. 2018 May 17;378(20);1865-76. Bateman ED et al. N Engl J Med. 2018 May 17;378(20):1877-87.
ADHD, asthma Rxs up
Use of prescription medication overall decreased in children and adolescents over the past 15 years, but certain medication classes saw increases over that time period, according to a comprehensive analysis of cross-sectional, nationally representative survey data.
Reported use of any prescription medication in the past 30 days decreased from 25% during 1999-2002 to 22% during 2011-2014 (P = .04), according to the analysis based on data from 38,277 children and adolescents aged 0-19 years in the National Health and Nutrition Examination Survey (NHANES).
However, the study showed increases over time in prescribing of medications for asthma, ADHD, and contraception, according to Craig M. Hales, MD, of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and his coinvestigators.
“Monitoring trends in use of prescription medications among children and adolescents provides insights on several important public health concerns, such as shifting disease burden, changes in access to health care and medicines, increases in the adoption of appropriate therapies, and decreases in use of inappropriate or ineffective treatments,” Dr. Hales and his coauthors said.
They found significant linear trends in 14 therapeutic classes or subclasses, including six decreases and eight increases, when looking at combined survey data for reported use of any prescription medication and reported use of two or more prescription medications in the prior 30 days.
Of note, antibiotic usage decreased significantly from 8% during 1999-2002 to 5% during 2011-2014, including decreases in amoxicillin, amoxicillin/clavulanate, and cephalosporins. Likewise, antihistamine use was down over time, from 4% to 2%, as was use of upper respiratory combination medications, which decreased from 2% to 0.5%.
Conversely, they found prevalence of ADHD medication usage increased significantly from 3% during 1999-2002 to 4% during 2011-2014, including significant increases for both amphetamines and centrally acting adrenergic agents.
Asthma medication also increased, from 4% to 6%, including significant increases in inhaled corticosteroids and montelukast. Likewise, a significant increase in proton pump inhibitors was reported from 0.2% to 0.7%, while contraceptive use in girls increased significantly in prevalence, from 1% to 2%.
Taken together, these findings suggest an overall decrease in medication prescribing among children and adolescents, despite significantly increased prevalence of prescribing for certain drug classes, the investigators said.
They noted that the study had limitations. For example, NHANES does not include data on most over-the-counter medications, and for the drugs it does include, there are no data on dosages, frequency of use, or specific formulations, they said.
Dr. Hales and his coauthors had no conflicts of interest.
SOURCE: Hales CM et al. JAMA. 2018;319(19):2009-20.
These thorough analyses of medication prescribing for children and adolescents are much needed, but are “frustrating” because definitive conclusions cannot be drawn because of inherent limitations of the serial, cross-sectional study design, Gary L. Freed, MD, MPH, said in an editorial.
The study by Hales et al. shows an overall decrease in prescription medication use in children and adolescents based on data from the 1999-2014 National Health and Examination Survey (NHANES). The study shows increased use of medications for asthma, ADHD, and contraception, and decreased use of antibiotics, antihistamines, and upper respiratory combination medications.
“Some of these trends likely signal potential improvements in the care of children, others may suggest little progress has been made, and yet others are difficult to interpret with certainty,” Dr. Freed wrote.
One finding that seems clear in the data, according to Dr. Freed, is a decrease in antibiotic use among children and adolescents, from 8% to 5% from the 1999-2002 to 2011-2014 time period. That likely reflects the success of efforts to decrease overuse of these agents in community settings.
On the other hand, the decreased use of antihistamines documented in this study may reflect the success of efforts to reduce overuse, or the fact that several prescription medications became approved for OTC use over the course of the study. NHANES does not include OTC drug data in its survey.
“It is unclear whether there was simply a substitution effect and the actual overall rate of utilization of these medications was unchanged,” Dr. Freed wrote.
Increased amphetamine use for the treatment of children aged 6-11 years with ADHD is “vexing” to see, but again, caution must be exercised in interpreting the results, he said, because they do not clearly demonstrate whether these agents are being overused or underused.
“The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children,” Dr. Freed wrote.
Dr. Freed is a pediatrician with the Child Health Evaluation and Research Center, University of Michigan, Ann Arbor. These comments are derived from his editorial accompanying the study by Hales et al. (JAMA. 2018;319[19]:1988-9). Dr. Freed had no conflicts of interest.
These thorough analyses of medication prescribing for children and adolescents are much needed, but are “frustrating” because definitive conclusions cannot be drawn because of inherent limitations of the serial, cross-sectional study design, Gary L. Freed, MD, MPH, said in an editorial.
The study by Hales et al. shows an overall decrease in prescription medication use in children and adolescents based on data from the 1999-2014 National Health and Examination Survey (NHANES). The study shows increased use of medications for asthma, ADHD, and contraception, and decreased use of antibiotics, antihistamines, and upper respiratory combination medications.
“Some of these trends likely signal potential improvements in the care of children, others may suggest little progress has been made, and yet others are difficult to interpret with certainty,” Dr. Freed wrote.
One finding that seems clear in the data, according to Dr. Freed, is a decrease in antibiotic use among children and adolescents, from 8% to 5% from the 1999-2002 to 2011-2014 time period. That likely reflects the success of efforts to decrease overuse of these agents in community settings.
On the other hand, the decreased use of antihistamines documented in this study may reflect the success of efforts to reduce overuse, or the fact that several prescription medications became approved for OTC use over the course of the study. NHANES does not include OTC drug data in its survey.
“It is unclear whether there was simply a substitution effect and the actual overall rate of utilization of these medications was unchanged,” Dr. Freed wrote.
Increased amphetamine use for the treatment of children aged 6-11 years with ADHD is “vexing” to see, but again, caution must be exercised in interpreting the results, he said, because they do not clearly demonstrate whether these agents are being overused or underused.
“The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children,” Dr. Freed wrote.
Dr. Freed is a pediatrician with the Child Health Evaluation and Research Center, University of Michigan, Ann Arbor. These comments are derived from his editorial accompanying the study by Hales et al. (JAMA. 2018;319[19]:1988-9). Dr. Freed had no conflicts of interest.
These thorough analyses of medication prescribing for children and adolescents are much needed, but are “frustrating” because definitive conclusions cannot be drawn because of inherent limitations of the serial, cross-sectional study design, Gary L. Freed, MD, MPH, said in an editorial.
The study by Hales et al. shows an overall decrease in prescription medication use in children and adolescents based on data from the 1999-2014 National Health and Examination Survey (NHANES). The study shows increased use of medications for asthma, ADHD, and contraception, and decreased use of antibiotics, antihistamines, and upper respiratory combination medications.
“Some of these trends likely signal potential improvements in the care of children, others may suggest little progress has been made, and yet others are difficult to interpret with certainty,” Dr. Freed wrote.
One finding that seems clear in the data, according to Dr. Freed, is a decrease in antibiotic use among children and adolescents, from 8% to 5% from the 1999-2002 to 2011-2014 time period. That likely reflects the success of efforts to decrease overuse of these agents in community settings.
On the other hand, the decreased use of antihistamines documented in this study may reflect the success of efforts to reduce overuse, or the fact that several prescription medications became approved for OTC use over the course of the study. NHANES does not include OTC drug data in its survey.
“It is unclear whether there was simply a substitution effect and the actual overall rate of utilization of these medications was unchanged,” Dr. Freed wrote.
Increased amphetamine use for the treatment of children aged 6-11 years with ADHD is “vexing” to see, but again, caution must be exercised in interpreting the results, he said, because they do not clearly demonstrate whether these agents are being overused or underused.
“The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children,” Dr. Freed wrote.
Dr. Freed is a pediatrician with the Child Health Evaluation and Research Center, University of Michigan, Ann Arbor. These comments are derived from his editorial accompanying the study by Hales et al. (JAMA. 2018;319[19]:1988-9). Dr. Freed had no conflicts of interest.
Use of prescription medication overall decreased in children and adolescents over the past 15 years, but certain medication classes saw increases over that time period, according to a comprehensive analysis of cross-sectional, nationally representative survey data.
Reported use of any prescription medication in the past 30 days decreased from 25% during 1999-2002 to 22% during 2011-2014 (P = .04), according to the analysis based on data from 38,277 children and adolescents aged 0-19 years in the National Health and Nutrition Examination Survey (NHANES).
However, the study showed increases over time in prescribing of medications for asthma, ADHD, and contraception, according to Craig M. Hales, MD, of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and his coinvestigators.
“Monitoring trends in use of prescription medications among children and adolescents provides insights on several important public health concerns, such as shifting disease burden, changes in access to health care and medicines, increases in the adoption of appropriate therapies, and decreases in use of inappropriate or ineffective treatments,” Dr. Hales and his coauthors said.
They found significant linear trends in 14 therapeutic classes or subclasses, including six decreases and eight increases, when looking at combined survey data for reported use of any prescription medication and reported use of two or more prescription medications in the prior 30 days.
Of note, antibiotic usage decreased significantly from 8% during 1999-2002 to 5% during 2011-2014, including decreases in amoxicillin, amoxicillin/clavulanate, and cephalosporins. Likewise, antihistamine use was down over time, from 4% to 2%, as was use of upper respiratory combination medications, which decreased from 2% to 0.5%.
Conversely, they found prevalence of ADHD medication usage increased significantly from 3% during 1999-2002 to 4% during 2011-2014, including significant increases for both amphetamines and centrally acting adrenergic agents.
Asthma medication also increased, from 4% to 6%, including significant increases in inhaled corticosteroids and montelukast. Likewise, a significant increase in proton pump inhibitors was reported from 0.2% to 0.7%, while contraceptive use in girls increased significantly in prevalence, from 1% to 2%.
Taken together, these findings suggest an overall decrease in medication prescribing among children and adolescents, despite significantly increased prevalence of prescribing for certain drug classes, the investigators said.
They noted that the study had limitations. For example, NHANES does not include data on most over-the-counter medications, and for the drugs it does include, there are no data on dosages, frequency of use, or specific formulations, they said.
Dr. Hales and his coauthors had no conflicts of interest.
SOURCE: Hales CM et al. JAMA. 2018;319(19):2009-20.
Use of prescription medication overall decreased in children and adolescents over the past 15 years, but certain medication classes saw increases over that time period, according to a comprehensive analysis of cross-sectional, nationally representative survey data.
Reported use of any prescription medication in the past 30 days decreased from 25% during 1999-2002 to 22% during 2011-2014 (P = .04), according to the analysis based on data from 38,277 children and adolescents aged 0-19 years in the National Health and Nutrition Examination Survey (NHANES).
However, the study showed increases over time in prescribing of medications for asthma, ADHD, and contraception, according to Craig M. Hales, MD, of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and his coinvestigators.
“Monitoring trends in use of prescription medications among children and adolescents provides insights on several important public health concerns, such as shifting disease burden, changes in access to health care and medicines, increases in the adoption of appropriate therapies, and decreases in use of inappropriate or ineffective treatments,” Dr. Hales and his coauthors said.
They found significant linear trends in 14 therapeutic classes or subclasses, including six decreases and eight increases, when looking at combined survey data for reported use of any prescription medication and reported use of two or more prescription medications in the prior 30 days.
Of note, antibiotic usage decreased significantly from 8% during 1999-2002 to 5% during 2011-2014, including decreases in amoxicillin, amoxicillin/clavulanate, and cephalosporins. Likewise, antihistamine use was down over time, from 4% to 2%, as was use of upper respiratory combination medications, which decreased from 2% to 0.5%.
Conversely, they found prevalence of ADHD medication usage increased significantly from 3% during 1999-2002 to 4% during 2011-2014, including significant increases for both amphetamines and centrally acting adrenergic agents.
Asthma medication also increased, from 4% to 6%, including significant increases in inhaled corticosteroids and montelukast. Likewise, a significant increase in proton pump inhibitors was reported from 0.2% to 0.7%, while contraceptive use in girls increased significantly in prevalence, from 1% to 2%.
Taken together, these findings suggest an overall decrease in medication prescribing among children and adolescents, despite significantly increased prevalence of prescribing for certain drug classes, the investigators said.
They noted that the study had limitations. For example, NHANES does not include data on most over-the-counter medications, and for the drugs it does include, there are no data on dosages, frequency of use, or specific formulations, they said.
Dr. Hales and his coauthors had no conflicts of interest.
SOURCE: Hales CM et al. JAMA. 2018;319(19):2009-20.
FROM JAMA
Key clinical point: Nationally representative survey data demonstrate an overall decrease in use of any medication among children and adolescents, although use of certain medications increased.
Major finding: (P = 0.04).
Study details: Analysis of survey data for U.S. children and adolescents aged 0-19 years in the 1999-2014 NHANES.
Disclosures: Dr. Hales and his coauthors had no conflicts of interest.
Source: Hales CM et al. JAMA. 2018;319(19):2009-20.
When and how to suspect asthma misdiagnosis
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
NEW ORLEANS – Kyle I. Happel, MD, said at the annual meeting of the American College of Physicians.
“Asthma is a disease whose symptoms are caused by variable airflow obstruction. It varies throughout the day, usually, and certainly by the week or by the month. I want you to think about the variability of a patient’s disease symptoms in forming your index of suspicion for this disease,” urged Dr. Happel, of the section of pulmonary, critical care, and allergy/immunology at Louisiana State University Medical Center in New Orleans.
These phenomena occur often. In a Canadian multicenter study of more than 700 patients with a history of physician-diagnosed asthma within the past 5 years, current asthma was ruled out in fully 33% of them on the basis of no deterioration of asthma symptoms, no evidence of reversible airway obstruction, and no bronchial hyperresponsiveness after all asthma drugs were tapered off (JAMA. 2017 Jan 17;317[3]:269-79).
Wheezing is the most specific symptom of asthma, although it is not, in fact, terribly specific. In descending order, the next most specific symptoms are breathlessness, chest tightness, and cough.
The top seven diseases that mimic asthma symptoms are chronic obstructive pulmonary disease, rhinosinusitis, heart failure with preserved or reduced ejection fraction, gastroesophageal reflux disease, angina, anxiety, and vocal cord dysfunction syndrome.
Strike two for an asthma diagnosis is a patient’s report that albuterol doesn’t improve the symptoms. That definitely raises questions about the diagnosis.
“Most asthmatics get symptomatic relief from their disease,” Dr. Happel observed.
And, if there is no indication in the patient’s chart that the asthma diagnosis was based upon demonstration of airflow obstruction on spirometry, the diagnosis is thrown further into doubt. In the recent Canadian study, patients who didn’t undergo pulmonary function testing (PFT) to establish airflow limitation at their time of diagnosis were significantly less likely to have current asthma.
“I would strongly suggest everyone with the diagnosis of asthma get spirometry with bronchodilator testing,” Dr. Happel said. “Good-quality PFTs are critical in forming a solid diagnosis of asthma.”
In a patient who has symptoms consistent with asthma, a 200-cc and 12% or more improvement in forced expiratory volume in 1 second (FEV1) in response to bronchodilator challenge is supportive of the diagnosis. However, absence of reversible airway obstruction doesn’t exclude the possibility of asthma.
In the setting of low to-moderate clinical suspicion of asthma plus no demonstrable obstruction on spirometry, Dr. Happel recommends moving on to bronchial hyperreactivity testing via a methacholine challenge.
“The beauty of a methacholine challenge is that is has a high negative predictive value to help exclude the diagnosis of asthma, particularly in people who are having symptoms suggestive of asthma,” Dr. Happel explained. “If it takes more than 8 mg/mL of methacholine to elicit a 20% or greater decrease in FEV1, it’s probably something else. It’s not a particularly specific test, though; you can get false positives from a methacholine challenge.”
REPORTING FROM ACP INTERNAL MEDICINE