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Studying the gestational diabetes risk associated with endocrine-disrupting chemicals
Pregnancy presents a unique opportunity for ob.gyns. to counsel their patients on the benefits of adopting healthy lifestyle habits. Women routinely seek care from a practitioner on a regular basis. Expectant mothers are highly motivated to take care of themselves for the sake of their developing babies. Patients can be much more receptive to recommendations from their health care teams during pregnancy than they might be outside of pregnancy. Frequent biometric analyses allow ob.gyns. to monitor patients’ progress and let them know, in a supportive manner, where they might be “falling short” of their health goals.
There are a number of chemicals with which we come in contact every day, sometimes multiple times in a day, which may deeply affect our health. This month’s Master Class highlights one such group of compounds, endocrine-disrupting chemicals, the most widely known of which is bisphenol A (BPA).
Several years ago, our guest author, Dr. Shelley Ehrlich of the University of Cincinnati, spoke at a diabetes in pregnancy meeting about her research on BPA and its potential association with the development of gestational diabetes mellitus (GDM). As a perinatologist who worked for many years with patients who had diabetes in pregnancy, I was particularly struck by her preliminary findings which indicated that BPA might be altering gene expression, thereby leading to pregnancy-related disorders. At the time, Dr. Ehrlich’s research was still in the very early stages. However, her results were a new way of answering the age-old question of why some women, including those without other overt risk factors, might develop GDM.
Therefore, I’m delighted that Dr. Ehrlich agreed to author this month’s class to provide an overview of where her last few years of research has taken her.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Pregnancy presents a unique opportunity for ob.gyns. to counsel their patients on the benefits of adopting healthy lifestyle habits. Women routinely seek care from a practitioner on a regular basis. Expectant mothers are highly motivated to take care of themselves for the sake of their developing babies. Patients can be much more receptive to recommendations from their health care teams during pregnancy than they might be outside of pregnancy. Frequent biometric analyses allow ob.gyns. to monitor patients’ progress and let them know, in a supportive manner, where they might be “falling short” of their health goals.
There are a number of chemicals with which we come in contact every day, sometimes multiple times in a day, which may deeply affect our health. This month’s Master Class highlights one such group of compounds, endocrine-disrupting chemicals, the most widely known of which is bisphenol A (BPA).
Several years ago, our guest author, Dr. Shelley Ehrlich of the University of Cincinnati, spoke at a diabetes in pregnancy meeting about her research on BPA and its potential association with the development of gestational diabetes mellitus (GDM). As a perinatologist who worked for many years with patients who had diabetes in pregnancy, I was particularly struck by her preliminary findings which indicated that BPA might be altering gene expression, thereby leading to pregnancy-related disorders. At the time, Dr. Ehrlich’s research was still in the very early stages. However, her results were a new way of answering the age-old question of why some women, including those without other overt risk factors, might develop GDM.
Therefore, I’m delighted that Dr. Ehrlich agreed to author this month’s class to provide an overview of where her last few years of research has taken her.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Pregnancy presents a unique opportunity for ob.gyns. to counsel their patients on the benefits of adopting healthy lifestyle habits. Women routinely seek care from a practitioner on a regular basis. Expectant mothers are highly motivated to take care of themselves for the sake of their developing babies. Patients can be much more receptive to recommendations from their health care teams during pregnancy than they might be outside of pregnancy. Frequent biometric analyses allow ob.gyns. to monitor patients’ progress and let them know, in a supportive manner, where they might be “falling short” of their health goals.
There are a number of chemicals with which we come in contact every day, sometimes multiple times in a day, which may deeply affect our health. This month’s Master Class highlights one such group of compounds, endocrine-disrupting chemicals, the most widely known of which is bisphenol A (BPA).
Several years ago, our guest author, Dr. Shelley Ehrlich of the University of Cincinnati, spoke at a diabetes in pregnancy meeting about her research on BPA and its potential association with the development of gestational diabetes mellitus (GDM). As a perinatologist who worked for many years with patients who had diabetes in pregnancy, I was particularly struck by her preliminary findings which indicated that BPA might be altering gene expression, thereby leading to pregnancy-related disorders. At the time, Dr. Ehrlich’s research was still in the very early stages. However, her results were a new way of answering the age-old question of why some women, including those without other overt risk factors, might develop GDM.
Therefore, I’m delighted that Dr. Ehrlich agreed to author this month’s class to provide an overview of where her last few years of research has taken her.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
CVD risk high in individuals who once had metabolically healthy obesity
Nearly half of the individuals with MHO developed metabolic syndrome over time, according to the analysis of 6,809 participants followed since the year 2000 in the Multi-Ethnic Study of Atherosclerosis.
Those who developed metabolic syndrome had an increased risk of CVD, compared with those who did not, according to results published in the Journal of the American College of Cardiology.
The results provide new evidence that MHO alone is not a stable or reliable characterization of lower CVD risk, according to Morgana Mongraw-Chaffin, PhD, of the department of epidemiology and prevention at Wake Forest University, Winston-Salem, N.C., and her coauthors.
“Instead, MHO signals an opportunity for weight reduction, and prevention and management of existing metabolic syndrome components should be prioritized,” Dr. Mongraw-Chaffin and her colleagues wrote.
Individuals with MHO, defined in this study as a body mass index of 30 kg/m2 or greater without metabolic syndrome, have a relatively favorable metabolic profile. However, their precise level of CVD risk remains contentious, the investigators noted.
“Although the accumulating evidence is leaning toward the consensus that MHO is not a low-risk state compared with metabolically healthy normal weight, many questions remain about the risk stratification for this group and what causes the heterogeneity seen in the literature,” they wrote.
In this study, 501 out of 1,051 individuals with MHO at baseline (48%) developed metabolic syndrome over a median follow-up of 12.2 years. Moreover, they then had increased odds of CVD (odds ratio, 1.60; 95% confidence interval, 1.14-2.25), compared with individuals who had stable MHO or normal weight.
Duration of metabolic syndrome was linearly associated with CVD risk, with an odds ratio of 0.41 for those with metabolic syndrome at one out of five study visits, 2.19 for metabolic syndrome at two or three visits, and 2.50 for metabolic syndrome at four or five visits, the researchers said.
The results of this study may explain why some previous meta-analyses found individuals with MHO had increased risk, but only with longer duration of follow-up.
“Both transition to metabolic syndrome and longer duration of metabolic syndrome were associated with CVD, indicating that those with MHO may experience a lag in risk while they progress to metabolic syndrome and develop the resultant cardiometabolic risk,” Dr. Mongraw-Chaffin and her coauthors wrote.
The results mean that MHO represents an opportunity for primary prevention of CVD, they added.
“Prevention of incident metabolic syndrome and resulting CVD at the population level will necessitate the prevention of obesity,” they explained in a discussion of the results.
Dr. Mongraw-Chaffin and her associates reported that they had no relevant relationships to disclose.
SOURCE: Mongraw-Chaffin M et al. J Am Coll Cardiol 2018 May 1;71(17):1857-65.
While obesity has inherent adverse effects on cardiometabolic parameters and cardiovascular disease (CVD) risk factors, metabolically healthy obesity (MHO) has emerged as a categorization of obese individuals who may not be at increased CVD risk because of relatively normal levels of lipids, blood pressure, and glucose.
An increasing body of research, however, including the present study by Dr. Mongraw-Chaffin and colleagues, highlights “dangers and long-term outcomes” of the MHO phenotype, Dr. Prakash Deedwania and Dr. Carl J. Lavie wrote in an editorial.
The analysis of 6,809 individuals in the Multi-Ethic Study of Atherosclerosis found that MHO is not a stable condition, as almost one-half of individuals developed metabolic syndrome over 12.2 years of follow-up, they noted.
Moreover, CVD risk was indeed elevated in these individuals with “unstable” MHO.
“Clearly, therefore, prevention of obesity in the first place is most prudent,” Dr. Deedwania and Dr. Lavie said in their editorial. “Prevention of progressive weight gain over time among the overweight and mildly obese is also of high importance to prevent development of metabolic syndrome and subsequent risk of CVD.”
If individuals with MHO can be identified early, the authors said, there is an excellent opportunity for primary prevention through lifestyle changes, including weight loss and regular physical exercise that might prevent MHO from converting to metabolically unhealthy obesity.
“Such population-wide healthy interventions are the only hope of preventing the oncoming tsunami of metabolic syndrome, diabetes, and CVD,” the editorial authors concluded.
Prakash Deedwania, MD, is with the University of California at San Francisco School of Medicine Program at Fresno. Carl J. Lavie, MD, is with the John Ochsner Heart and Vascular Institute, New Orleans, and the University of Queensland in Brisbane, Australia. These comments are derived from their editorial in the Journal of the American College of Cardiology ( 2018 May 1;71[17]:1866-8) . Both authors reported they had no relevant relationships to disclose.
While obesity has inherent adverse effects on cardiometabolic parameters and cardiovascular disease (CVD) risk factors, metabolically healthy obesity (MHO) has emerged as a categorization of obese individuals who may not be at increased CVD risk because of relatively normal levels of lipids, blood pressure, and glucose.
An increasing body of research, however, including the present study by Dr. Mongraw-Chaffin and colleagues, highlights “dangers and long-term outcomes” of the MHO phenotype, Dr. Prakash Deedwania and Dr. Carl J. Lavie wrote in an editorial.
The analysis of 6,809 individuals in the Multi-Ethic Study of Atherosclerosis found that MHO is not a stable condition, as almost one-half of individuals developed metabolic syndrome over 12.2 years of follow-up, they noted.
Moreover, CVD risk was indeed elevated in these individuals with “unstable” MHO.
“Clearly, therefore, prevention of obesity in the first place is most prudent,” Dr. Deedwania and Dr. Lavie said in their editorial. “Prevention of progressive weight gain over time among the overweight and mildly obese is also of high importance to prevent development of metabolic syndrome and subsequent risk of CVD.”
If individuals with MHO can be identified early, the authors said, there is an excellent opportunity for primary prevention through lifestyle changes, including weight loss and regular physical exercise that might prevent MHO from converting to metabolically unhealthy obesity.
“Such population-wide healthy interventions are the only hope of preventing the oncoming tsunami of metabolic syndrome, diabetes, and CVD,” the editorial authors concluded.
Prakash Deedwania, MD, is with the University of California at San Francisco School of Medicine Program at Fresno. Carl J. Lavie, MD, is with the John Ochsner Heart and Vascular Institute, New Orleans, and the University of Queensland in Brisbane, Australia. These comments are derived from their editorial in the Journal of the American College of Cardiology ( 2018 May 1;71[17]:1866-8) . Both authors reported they had no relevant relationships to disclose.
While obesity has inherent adverse effects on cardiometabolic parameters and cardiovascular disease (CVD) risk factors, metabolically healthy obesity (MHO) has emerged as a categorization of obese individuals who may not be at increased CVD risk because of relatively normal levels of lipids, blood pressure, and glucose.
An increasing body of research, however, including the present study by Dr. Mongraw-Chaffin and colleagues, highlights “dangers and long-term outcomes” of the MHO phenotype, Dr. Prakash Deedwania and Dr. Carl J. Lavie wrote in an editorial.
The analysis of 6,809 individuals in the Multi-Ethic Study of Atherosclerosis found that MHO is not a stable condition, as almost one-half of individuals developed metabolic syndrome over 12.2 years of follow-up, they noted.
Moreover, CVD risk was indeed elevated in these individuals with “unstable” MHO.
“Clearly, therefore, prevention of obesity in the first place is most prudent,” Dr. Deedwania and Dr. Lavie said in their editorial. “Prevention of progressive weight gain over time among the overweight and mildly obese is also of high importance to prevent development of metabolic syndrome and subsequent risk of CVD.”
If individuals with MHO can be identified early, the authors said, there is an excellent opportunity for primary prevention through lifestyle changes, including weight loss and regular physical exercise that might prevent MHO from converting to metabolically unhealthy obesity.
“Such population-wide healthy interventions are the only hope of preventing the oncoming tsunami of metabolic syndrome, diabetes, and CVD,” the editorial authors concluded.
Prakash Deedwania, MD, is with the University of California at San Francisco School of Medicine Program at Fresno. Carl J. Lavie, MD, is with the John Ochsner Heart and Vascular Institute, New Orleans, and the University of Queensland in Brisbane, Australia. These comments are derived from their editorial in the Journal of the American College of Cardiology ( 2018 May 1;71[17]:1866-8) . Both authors reported they had no relevant relationships to disclose.
Nearly half of the individuals with MHO developed metabolic syndrome over time, according to the analysis of 6,809 participants followed since the year 2000 in the Multi-Ethnic Study of Atherosclerosis.
Those who developed metabolic syndrome had an increased risk of CVD, compared with those who did not, according to results published in the Journal of the American College of Cardiology.
The results provide new evidence that MHO alone is not a stable or reliable characterization of lower CVD risk, according to Morgana Mongraw-Chaffin, PhD, of the department of epidemiology and prevention at Wake Forest University, Winston-Salem, N.C., and her coauthors.
“Instead, MHO signals an opportunity for weight reduction, and prevention and management of existing metabolic syndrome components should be prioritized,” Dr. Mongraw-Chaffin and her colleagues wrote.
Individuals with MHO, defined in this study as a body mass index of 30 kg/m2 or greater without metabolic syndrome, have a relatively favorable metabolic profile. However, their precise level of CVD risk remains contentious, the investigators noted.
“Although the accumulating evidence is leaning toward the consensus that MHO is not a low-risk state compared with metabolically healthy normal weight, many questions remain about the risk stratification for this group and what causes the heterogeneity seen in the literature,” they wrote.
In this study, 501 out of 1,051 individuals with MHO at baseline (48%) developed metabolic syndrome over a median follow-up of 12.2 years. Moreover, they then had increased odds of CVD (odds ratio, 1.60; 95% confidence interval, 1.14-2.25), compared with individuals who had stable MHO or normal weight.
Duration of metabolic syndrome was linearly associated with CVD risk, with an odds ratio of 0.41 for those with metabolic syndrome at one out of five study visits, 2.19 for metabolic syndrome at two or three visits, and 2.50 for metabolic syndrome at four or five visits, the researchers said.
The results of this study may explain why some previous meta-analyses found individuals with MHO had increased risk, but only with longer duration of follow-up.
“Both transition to metabolic syndrome and longer duration of metabolic syndrome were associated with CVD, indicating that those with MHO may experience a lag in risk while they progress to metabolic syndrome and develop the resultant cardiometabolic risk,” Dr. Mongraw-Chaffin and her coauthors wrote.
The results mean that MHO represents an opportunity for primary prevention of CVD, they added.
“Prevention of incident metabolic syndrome and resulting CVD at the population level will necessitate the prevention of obesity,” they explained in a discussion of the results.
Dr. Mongraw-Chaffin and her associates reported that they had no relevant relationships to disclose.
SOURCE: Mongraw-Chaffin M et al. J Am Coll Cardiol 2018 May 1;71(17):1857-65.
Nearly half of the individuals with MHO developed metabolic syndrome over time, according to the analysis of 6,809 participants followed since the year 2000 in the Multi-Ethnic Study of Atherosclerosis.
Those who developed metabolic syndrome had an increased risk of CVD, compared with those who did not, according to results published in the Journal of the American College of Cardiology.
The results provide new evidence that MHO alone is not a stable or reliable characterization of lower CVD risk, according to Morgana Mongraw-Chaffin, PhD, of the department of epidemiology and prevention at Wake Forest University, Winston-Salem, N.C., and her coauthors.
“Instead, MHO signals an opportunity for weight reduction, and prevention and management of existing metabolic syndrome components should be prioritized,” Dr. Mongraw-Chaffin and her colleagues wrote.
Individuals with MHO, defined in this study as a body mass index of 30 kg/m2 or greater without metabolic syndrome, have a relatively favorable metabolic profile. However, their precise level of CVD risk remains contentious, the investigators noted.
“Although the accumulating evidence is leaning toward the consensus that MHO is not a low-risk state compared with metabolically healthy normal weight, many questions remain about the risk stratification for this group and what causes the heterogeneity seen in the literature,” they wrote.
In this study, 501 out of 1,051 individuals with MHO at baseline (48%) developed metabolic syndrome over a median follow-up of 12.2 years. Moreover, they then had increased odds of CVD (odds ratio, 1.60; 95% confidence interval, 1.14-2.25), compared with individuals who had stable MHO or normal weight.
Duration of metabolic syndrome was linearly associated with CVD risk, with an odds ratio of 0.41 for those with metabolic syndrome at one out of five study visits, 2.19 for metabolic syndrome at two or three visits, and 2.50 for metabolic syndrome at four or five visits, the researchers said.
The results of this study may explain why some previous meta-analyses found individuals with MHO had increased risk, but only with longer duration of follow-up.
“Both transition to metabolic syndrome and longer duration of metabolic syndrome were associated with CVD, indicating that those with MHO may experience a lag in risk while they progress to metabolic syndrome and develop the resultant cardiometabolic risk,” Dr. Mongraw-Chaffin and her coauthors wrote.
The results mean that MHO represents an opportunity for primary prevention of CVD, they added.
“Prevention of incident metabolic syndrome and resulting CVD at the population level will necessitate the prevention of obesity,” they explained in a discussion of the results.
Dr. Mongraw-Chaffin and her associates reported that they had no relevant relationships to disclose.
SOURCE: Mongraw-Chaffin M et al. J Am Coll Cardiol 2018 May 1;71(17):1857-65.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point: Metabolically healthy obesity (MHO) was transient and was not a reliable indicator of future risk of cardiovascular disease risk, prompting investigators to recommend weight loss and lifestyle management for any individual with obesity.
Major finding: Nearly half of patients with MHO developed metabolic syndrome over a median follow-up of 12.2 years. They had increased risk of cardiovascular disease, compared with individuals who had stable MHO or normal weight (odds ratio, 1.60, 95% CI, 1.14-2.25).
Study details: Analysis based on data for 6,809 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), a six-center U.S. population-based longitudinal cohort study started in 2000.
Disclosures: The authors reported they had no relevant relationships to disclose.
Source: Mongraw-Chaffin M et al. J Am Coll Cardiol. 2018 May 1;71(17):1857-65.
Nitrofurantoin beats fosfomycin for uncomplicated UTI
MADRID – (UTIs), a randomized study has determined.
By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.
The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).
Despite its success, nitrofurantoin did not live up to its purported 96% UTI cure rate – an established number based on study data from the 1950s-1970s.
Such efficacy was probably a false finding, she said. Studies of that era were much less rigorous than they are today, Dr. Huttner pointed out. The primary endpoint in those studies was typically defined not as complete resolution of symptoms – as it was in her study – but as resolution or improvement.
“Also, improvement was often defined microbiologically, often something like a decrease from 105 colony-forming units to 104, which is never something we would use today.”
The study was conducted in Geneva, Poland, and Israel. It randomized 512 women with an uncomplicated lower UTI to either 5 days of thrice-daily nitrofurantoin 100 mg or to a single 3-gram dose of fosfomycin. The women returned for clinical exam and urine culture at 14 and 28 days after they completed their treatment.
The primary outcome was 28-day clinical response. Success was defined as complete resolution of symptoms, a characterization that Dr. Huttner and her colleagues chose carefully. Many UTI studies include “improvement” in the clinical picture as part of a successful response. Dr. Huttner disagreed with that. “Our patients don’t want a partial response. They don’t want just an improvement. They want complete resolution of their symptoms.”
Failure was defined as the need for additional antibiotics or a change in antibiotic treatment. There was also an “indeterminate” category, for the small minority of patients who still felt some mild symptoms but were without microbiological signs of infection.
The mean age of the women was 44 years. All had an uncomplicated UTI characterized by dysuria, urgency, frequency, or suprapubic tenderness; 73% had a positive baseline urine culture. E. coli was the most common infective organism (about 60%) followed by different Klebsiella species, Proteus, and Enterococci. A few women had mixed pathogen infections. Only six patients had infective pathogens that were resistant to either of the study drugs.
After 28 days of treatment, a clinical cure was determined in 70% of those taking nitrofurantoin and 58% of those taking fosfomycin – an absolute difference of 12 points.
“The difference was obvious at 14 days,” Dr. Huttner noted. At that point, 75% of those taking nitrofurantoin and 66% of those taking fosfomycin reported resolution of their symptoms.
Pathology reflected the improving clinical picture: Microbiologic resolution occurred in 74% of the nitrofurantoin group and 63% of the fosfomycin group.
A post hoc analysis looked at results among the 214 women with confirmed E. coli infections.
The difference in clinical response was “even more pronounced” in these patients, Dr. Huttner said. Through day 28, clinical resolution occurred in 78% of those taking nitrofurantoin and 50% of those taking fosfomycin – a significant difference of 28 points.
Patients with E. coli infections were 4.48 times more likely to fail treatment if they received fosfomycin than if they received nitrofurantoin.
Adverse events were few and primarily gastrointestinal. The most common were mild to moderate nausea and diarrhea (less than 4% in each group).
Both of the antibiotics were popular from the 1950s on, but gradually fell out of favor as more powerful therapies were developed. However, as antibiotic resistance began to develop, infectious disease specialists began to support bringing nitrofurantoin and fosfomycin out of mothballs. In 2011, a panel of international experts convened by the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommended both of the medications as first-line therapy for women with acute uncomplicated cystitis and pyelonephritis.
The group recommended fosfomycin in a single 3-gram dose and a nitrofurantoin regimen of 100 mg twice daily for 5 days. The fosfomycin recommendation is clearly inadequate, Dr. Huttner said.
“Fosfomycin is not a bad drug. I just think it’s underdosed in this setting,” she said.
Dr. Huttner had no financial disclosures.
SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.
MADRID – (UTIs), a randomized study has determined.
By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.
The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).
Despite its success, nitrofurantoin did not live up to its purported 96% UTI cure rate – an established number based on study data from the 1950s-1970s.
Such efficacy was probably a false finding, she said. Studies of that era were much less rigorous than they are today, Dr. Huttner pointed out. The primary endpoint in those studies was typically defined not as complete resolution of symptoms – as it was in her study – but as resolution or improvement.
“Also, improvement was often defined microbiologically, often something like a decrease from 105 colony-forming units to 104, which is never something we would use today.”
The study was conducted in Geneva, Poland, and Israel. It randomized 512 women with an uncomplicated lower UTI to either 5 days of thrice-daily nitrofurantoin 100 mg or to a single 3-gram dose of fosfomycin. The women returned for clinical exam and urine culture at 14 and 28 days after they completed their treatment.
The primary outcome was 28-day clinical response. Success was defined as complete resolution of symptoms, a characterization that Dr. Huttner and her colleagues chose carefully. Many UTI studies include “improvement” in the clinical picture as part of a successful response. Dr. Huttner disagreed with that. “Our patients don’t want a partial response. They don’t want just an improvement. They want complete resolution of their symptoms.”
Failure was defined as the need for additional antibiotics or a change in antibiotic treatment. There was also an “indeterminate” category, for the small minority of patients who still felt some mild symptoms but were without microbiological signs of infection.
The mean age of the women was 44 years. All had an uncomplicated UTI characterized by dysuria, urgency, frequency, or suprapubic tenderness; 73% had a positive baseline urine culture. E. coli was the most common infective organism (about 60%) followed by different Klebsiella species, Proteus, and Enterococci. A few women had mixed pathogen infections. Only six patients had infective pathogens that were resistant to either of the study drugs.
After 28 days of treatment, a clinical cure was determined in 70% of those taking nitrofurantoin and 58% of those taking fosfomycin – an absolute difference of 12 points.
“The difference was obvious at 14 days,” Dr. Huttner noted. At that point, 75% of those taking nitrofurantoin and 66% of those taking fosfomycin reported resolution of their symptoms.
Pathology reflected the improving clinical picture: Microbiologic resolution occurred in 74% of the nitrofurantoin group and 63% of the fosfomycin group.
A post hoc analysis looked at results among the 214 women with confirmed E. coli infections.
The difference in clinical response was “even more pronounced” in these patients, Dr. Huttner said. Through day 28, clinical resolution occurred in 78% of those taking nitrofurantoin and 50% of those taking fosfomycin – a significant difference of 28 points.
Patients with E. coli infections were 4.48 times more likely to fail treatment if they received fosfomycin than if they received nitrofurantoin.
Adverse events were few and primarily gastrointestinal. The most common were mild to moderate nausea and diarrhea (less than 4% in each group).
Both of the antibiotics were popular from the 1950s on, but gradually fell out of favor as more powerful therapies were developed. However, as antibiotic resistance began to develop, infectious disease specialists began to support bringing nitrofurantoin and fosfomycin out of mothballs. In 2011, a panel of international experts convened by the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommended both of the medications as first-line therapy for women with acute uncomplicated cystitis and pyelonephritis.
The group recommended fosfomycin in a single 3-gram dose and a nitrofurantoin regimen of 100 mg twice daily for 5 days. The fosfomycin recommendation is clearly inadequate, Dr. Huttner said.
“Fosfomycin is not a bad drug. I just think it’s underdosed in this setting,” she said.
Dr. Huttner had no financial disclosures.
SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.
MADRID – (UTIs), a randomized study has determined.
By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.
The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).
Despite its success, nitrofurantoin did not live up to its purported 96% UTI cure rate – an established number based on study data from the 1950s-1970s.
Such efficacy was probably a false finding, she said. Studies of that era were much less rigorous than they are today, Dr. Huttner pointed out. The primary endpoint in those studies was typically defined not as complete resolution of symptoms – as it was in her study – but as resolution or improvement.
“Also, improvement was often defined microbiologically, often something like a decrease from 105 colony-forming units to 104, which is never something we would use today.”
The study was conducted in Geneva, Poland, and Israel. It randomized 512 women with an uncomplicated lower UTI to either 5 days of thrice-daily nitrofurantoin 100 mg or to a single 3-gram dose of fosfomycin. The women returned for clinical exam and urine culture at 14 and 28 days after they completed their treatment.
The primary outcome was 28-day clinical response. Success was defined as complete resolution of symptoms, a characterization that Dr. Huttner and her colleagues chose carefully. Many UTI studies include “improvement” in the clinical picture as part of a successful response. Dr. Huttner disagreed with that. “Our patients don’t want a partial response. They don’t want just an improvement. They want complete resolution of their symptoms.”
Failure was defined as the need for additional antibiotics or a change in antibiotic treatment. There was also an “indeterminate” category, for the small minority of patients who still felt some mild symptoms but were without microbiological signs of infection.
The mean age of the women was 44 years. All had an uncomplicated UTI characterized by dysuria, urgency, frequency, or suprapubic tenderness; 73% had a positive baseline urine culture. E. coli was the most common infective organism (about 60%) followed by different Klebsiella species, Proteus, and Enterococci. A few women had mixed pathogen infections. Only six patients had infective pathogens that were resistant to either of the study drugs.
After 28 days of treatment, a clinical cure was determined in 70% of those taking nitrofurantoin and 58% of those taking fosfomycin – an absolute difference of 12 points.
“The difference was obvious at 14 days,” Dr. Huttner noted. At that point, 75% of those taking nitrofurantoin and 66% of those taking fosfomycin reported resolution of their symptoms.
Pathology reflected the improving clinical picture: Microbiologic resolution occurred in 74% of the nitrofurantoin group and 63% of the fosfomycin group.
A post hoc analysis looked at results among the 214 women with confirmed E. coli infections.
The difference in clinical response was “even more pronounced” in these patients, Dr. Huttner said. Through day 28, clinical resolution occurred in 78% of those taking nitrofurantoin and 50% of those taking fosfomycin – a significant difference of 28 points.
Patients with E. coli infections were 4.48 times more likely to fail treatment if they received fosfomycin than if they received nitrofurantoin.
Adverse events were few and primarily gastrointestinal. The most common were mild to moderate nausea and diarrhea (less than 4% in each group).
Both of the antibiotics were popular from the 1950s on, but gradually fell out of favor as more powerful therapies were developed. However, as antibiotic resistance began to develop, infectious disease specialists began to support bringing nitrofurantoin and fosfomycin out of mothballs. In 2011, a panel of international experts convened by the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommended both of the medications as first-line therapy for women with acute uncomplicated cystitis and pyelonephritis.
The group recommended fosfomycin in a single 3-gram dose and a nitrofurantoin regimen of 100 mg twice daily for 5 days. The fosfomycin recommendation is clearly inadequate, Dr. Huttner said.
“Fosfomycin is not a bad drug. I just think it’s underdosed in this setting,” she said.
Dr. Huttner had no financial disclosures.
SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.
REPORTING FROM ECCMID 2018
Key clinical point: Nitrofurantoin was significantly more effective than was fosfomycin for a clinical and microbiological cure of uncomplicated UTI in women.
Major finding: By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin .
Study details: The prospective study randomized 512 women.
Disclosures: Dr. Huttner had no financial disclosures.
Source: Huttner A et al. ECCMID 2018. Abstract O0479.
Fetal exposure to depression: How does ‘dose’ figure in?
The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.
When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.
The ability to factor “dose and duration” of exposure to perinatal psychiatric illness into a model predicting risk for a number of obstetrical or neonatal outcomes allows for a more refined risk-benefit decision with respect to use of antidepressants during pregnancy. For example, there may be a threshold over which it’s even more imperative to treat depression during pregnancy than in women who do not suffer from such severe histories of psychiatric disorder.
Research along these lines has been published in a study in Nursing Research in which the question of the effect of maternal mood on infant outcomes was examined, specifically looking at stress, depression, and intimate partner violence, and not just the presence of these elements, but their duration and intensity both before and during the pregnancy (2015 Sep-Oct;64[5]:331-41).
To do this, researchers examined survey data from Utah’s Pregnancy Risk Assessment Monitoring System of 4,296 women who gave birth during 2009-2011. Stress, depression, and intimate partner violence, and the duration and severity of each, were determined by questionnaire. Those determinations were compared with the outcomes of gestational age, birth weight, neonatal ICU admission, and the symptoms and diagnosis of postpartum depression.
Results of the study included the following: Increased duration of depression was associated with a greater risk of neonatal ICU admission, particularly in women who were depressed both before and during their pregnancy (adjusted odds ratio, 2.48), compared with women who had no depression.
We’ve known for a long time that a history of depression predicts increased risk for postpartum depression. In this particular study, it was actually shown that not just a history of depression, but the duration of experienced depression influenced the risk for postpartum depression.
For example, compared with women with no depression, women who were depressed before but not during their pregnancy had an aOR of 7.67, women depressed during pregnancy but not before had an aOR of 17.65, and women depressed both before and during pregnancy had an aOR of 58.35 – an extraordinary stratification of risk, basically.
What these data begin to suggest is that there may be a continuum of risk when it comes to the effects of exposure to depression (factoring in now dose and duration of exposure) during pregnancy. If risk of adverse outcome increases with greater severity of perinatal psychiatric illness, then a mandate to treat depression during pregnancy, whether with pharmacologic or nonpharmacologic interventions (or, commonly, a combination of the two) becomes that much more imperative. Regardless of the treatment interventions that are used, Such a recommendation dovetails with the literature showing the intergenerational effects of untreated depression. Maternal depression is one of the strongest predictors of later childhood psychopathology. With current national trends moving toward mandating screening initiatives for postpartum depression, the appreciation of the extent to which depression before and during pregnancy drives risk for postpartum mood disorder broadens how we think about mitigating risk for puerperal mood disturbance. Specifically, mitigating the effects of postpartum depression on women, their children, and their families must include more effective management of depression both before and during pregnancy.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.
When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.
The ability to factor “dose and duration” of exposure to perinatal psychiatric illness into a model predicting risk for a number of obstetrical or neonatal outcomes allows for a more refined risk-benefit decision with respect to use of antidepressants during pregnancy. For example, there may be a threshold over which it’s even more imperative to treat depression during pregnancy than in women who do not suffer from such severe histories of psychiatric disorder.
Research along these lines has been published in a study in Nursing Research in which the question of the effect of maternal mood on infant outcomes was examined, specifically looking at stress, depression, and intimate partner violence, and not just the presence of these elements, but their duration and intensity both before and during the pregnancy (2015 Sep-Oct;64[5]:331-41).
To do this, researchers examined survey data from Utah’s Pregnancy Risk Assessment Monitoring System of 4,296 women who gave birth during 2009-2011. Stress, depression, and intimate partner violence, and the duration and severity of each, were determined by questionnaire. Those determinations were compared with the outcomes of gestational age, birth weight, neonatal ICU admission, and the symptoms and diagnosis of postpartum depression.
Results of the study included the following: Increased duration of depression was associated with a greater risk of neonatal ICU admission, particularly in women who were depressed both before and during their pregnancy (adjusted odds ratio, 2.48), compared with women who had no depression.
We’ve known for a long time that a history of depression predicts increased risk for postpartum depression. In this particular study, it was actually shown that not just a history of depression, but the duration of experienced depression influenced the risk for postpartum depression.
For example, compared with women with no depression, women who were depressed before but not during their pregnancy had an aOR of 7.67, women depressed during pregnancy but not before had an aOR of 17.65, and women depressed both before and during pregnancy had an aOR of 58.35 – an extraordinary stratification of risk, basically.
What these data begin to suggest is that there may be a continuum of risk when it comes to the effects of exposure to depression (factoring in now dose and duration of exposure) during pregnancy. If risk of adverse outcome increases with greater severity of perinatal psychiatric illness, then a mandate to treat depression during pregnancy, whether with pharmacologic or nonpharmacologic interventions (or, commonly, a combination of the two) becomes that much more imperative. Regardless of the treatment interventions that are used, Such a recommendation dovetails with the literature showing the intergenerational effects of untreated depression. Maternal depression is one of the strongest predictors of later childhood psychopathology. With current national trends moving toward mandating screening initiatives for postpartum depression, the appreciation of the extent to which depression before and during pregnancy drives risk for postpartum mood disorder broadens how we think about mitigating risk for puerperal mood disturbance. Specifically, mitigating the effects of postpartum depression on women, their children, and their families must include more effective management of depression both before and during pregnancy.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.
When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.
The ability to factor “dose and duration” of exposure to perinatal psychiatric illness into a model predicting risk for a number of obstetrical or neonatal outcomes allows for a more refined risk-benefit decision with respect to use of antidepressants during pregnancy. For example, there may be a threshold over which it’s even more imperative to treat depression during pregnancy than in women who do not suffer from such severe histories of psychiatric disorder.
Research along these lines has been published in a study in Nursing Research in which the question of the effect of maternal mood on infant outcomes was examined, specifically looking at stress, depression, and intimate partner violence, and not just the presence of these elements, but their duration and intensity both before and during the pregnancy (2015 Sep-Oct;64[5]:331-41).
To do this, researchers examined survey data from Utah’s Pregnancy Risk Assessment Monitoring System of 4,296 women who gave birth during 2009-2011. Stress, depression, and intimate partner violence, and the duration and severity of each, were determined by questionnaire. Those determinations were compared with the outcomes of gestational age, birth weight, neonatal ICU admission, and the symptoms and diagnosis of postpartum depression.
Results of the study included the following: Increased duration of depression was associated with a greater risk of neonatal ICU admission, particularly in women who were depressed both before and during their pregnancy (adjusted odds ratio, 2.48), compared with women who had no depression.
We’ve known for a long time that a history of depression predicts increased risk for postpartum depression. In this particular study, it was actually shown that not just a history of depression, but the duration of experienced depression influenced the risk for postpartum depression.
For example, compared with women with no depression, women who were depressed before but not during their pregnancy had an aOR of 7.67, women depressed during pregnancy but not before had an aOR of 17.65, and women depressed both before and during pregnancy had an aOR of 58.35 – an extraordinary stratification of risk, basically.
What these data begin to suggest is that there may be a continuum of risk when it comes to the effects of exposure to depression (factoring in now dose and duration of exposure) during pregnancy. If risk of adverse outcome increases with greater severity of perinatal psychiatric illness, then a mandate to treat depression during pregnancy, whether with pharmacologic or nonpharmacologic interventions (or, commonly, a combination of the two) becomes that much more imperative. Regardless of the treatment interventions that are used, Such a recommendation dovetails with the literature showing the intergenerational effects of untreated depression. Maternal depression is one of the strongest predictors of later childhood psychopathology. With current national trends moving toward mandating screening initiatives for postpartum depression, the appreciation of the extent to which depression before and during pregnancy drives risk for postpartum mood disorder broadens how we think about mitigating risk for puerperal mood disturbance. Specifically, mitigating the effects of postpartum depression on women, their children, and their families must include more effective management of depression both before and during pregnancy.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
Adolescents, young adults endorse marijuana for IBD
according to study findings.
In a cross-sectional study of 99 patients with IBD aged 13-22 years, 32% of participants reported ever having used marijuana or endorsing use in the past 6 months. Additionally, 42% of patients perceived little to no risk of harm with regular use, reported Edward J. Hoffenberg, MD, of the departments of pediatrics and psychiatry at the University of Colorado, Aurora, and his associates.
Overall, 62 patients had a diagnosis of Crohn’s disease, 27 had ulcerative colitis, and 10 had indeterminate/unknown colitis. Patients in the ever-use group were older (mean, 17 years) than those in the never-use group (mean, 15.9 years). Serum cannabinoids were detected in 50% of patients in the ever-use group. “The detection of serum cannabinoids only in the ever-users is consistent with truthful reporting,” the researchers said.
Additionally, 80% of ever-users and 25% of never users perceived low to no risk of harm with regular use. After adjustment for age, ever-users were 10.7 times more likely to perceive low to no risk of harm (odds ratio, 10.7; P less than .001), the authors reported.
Weekly and daily marijuana use was reported by 52% and 31% of ever-users, respectively; 9% reported daily or almost daily use. Medical reasons for use was endorsed by 57%, and 53% reported physical pain relief as a reason. Nonmedical recreational or psychological reasons for use were reported by 87%. Problems with use were reported by 37% of users, including cravings or strong desire to use (20%), needing to use more to achieve the same effect (17%), and using a larger amount for longer than intended (17%).
“There is a need for further understanding of the potential medical benefits of marijuana use in IBD,” Dr. Hoffenberg and his associates wrote. “Theoretically, a different study design, such as a randomized controlled trial of marijuana use or placebo, could better evaluate the safety and benefit of frequent marijuana use for induction or maintenance of remission.”
Limitations of the study include difficulty determining differences in disease activity between groups because of the large number of patients with inactive or mild disease, as well as the need to group patients with Crohn’s disease and ulcerative colitis together because of the small total number of participants who endorse marijuana use.
The study was funded by the Colorado Department of Public Health and Environment. No conflicts of interest were reported.
SOURCE: Hoffenberg EJ et al. 2018. doi: 10.1016/j.jpeds.2018.03.041.
according to study findings.
In a cross-sectional study of 99 patients with IBD aged 13-22 years, 32% of participants reported ever having used marijuana or endorsing use in the past 6 months. Additionally, 42% of patients perceived little to no risk of harm with regular use, reported Edward J. Hoffenberg, MD, of the departments of pediatrics and psychiatry at the University of Colorado, Aurora, and his associates.
Overall, 62 patients had a diagnosis of Crohn’s disease, 27 had ulcerative colitis, and 10 had indeterminate/unknown colitis. Patients in the ever-use group were older (mean, 17 years) than those in the never-use group (mean, 15.9 years). Serum cannabinoids were detected in 50% of patients in the ever-use group. “The detection of serum cannabinoids only in the ever-users is consistent with truthful reporting,” the researchers said.
Additionally, 80% of ever-users and 25% of never users perceived low to no risk of harm with regular use. After adjustment for age, ever-users were 10.7 times more likely to perceive low to no risk of harm (odds ratio, 10.7; P less than .001), the authors reported.
Weekly and daily marijuana use was reported by 52% and 31% of ever-users, respectively; 9% reported daily or almost daily use. Medical reasons for use was endorsed by 57%, and 53% reported physical pain relief as a reason. Nonmedical recreational or psychological reasons for use were reported by 87%. Problems with use were reported by 37% of users, including cravings or strong desire to use (20%), needing to use more to achieve the same effect (17%), and using a larger amount for longer than intended (17%).
“There is a need for further understanding of the potential medical benefits of marijuana use in IBD,” Dr. Hoffenberg and his associates wrote. “Theoretically, a different study design, such as a randomized controlled trial of marijuana use or placebo, could better evaluate the safety and benefit of frequent marijuana use for induction or maintenance of remission.”
Limitations of the study include difficulty determining differences in disease activity between groups because of the large number of patients with inactive or mild disease, as well as the need to group patients with Crohn’s disease and ulcerative colitis together because of the small total number of participants who endorse marijuana use.
The study was funded by the Colorado Department of Public Health and Environment. No conflicts of interest were reported.
SOURCE: Hoffenberg EJ et al. 2018. doi: 10.1016/j.jpeds.2018.03.041.
according to study findings.
In a cross-sectional study of 99 patients with IBD aged 13-22 years, 32% of participants reported ever having used marijuana or endorsing use in the past 6 months. Additionally, 42% of patients perceived little to no risk of harm with regular use, reported Edward J. Hoffenberg, MD, of the departments of pediatrics and psychiatry at the University of Colorado, Aurora, and his associates.
Overall, 62 patients had a diagnosis of Crohn’s disease, 27 had ulcerative colitis, and 10 had indeterminate/unknown colitis. Patients in the ever-use group were older (mean, 17 years) than those in the never-use group (mean, 15.9 years). Serum cannabinoids were detected in 50% of patients in the ever-use group. “The detection of serum cannabinoids only in the ever-users is consistent with truthful reporting,” the researchers said.
Additionally, 80% of ever-users and 25% of never users perceived low to no risk of harm with regular use. After adjustment for age, ever-users were 10.7 times more likely to perceive low to no risk of harm (odds ratio, 10.7; P less than .001), the authors reported.
Weekly and daily marijuana use was reported by 52% and 31% of ever-users, respectively; 9% reported daily or almost daily use. Medical reasons for use was endorsed by 57%, and 53% reported physical pain relief as a reason. Nonmedical recreational or psychological reasons for use were reported by 87%. Problems with use were reported by 37% of users, including cravings or strong desire to use (20%), needing to use more to achieve the same effect (17%), and using a larger amount for longer than intended (17%).
“There is a need for further understanding of the potential medical benefits of marijuana use in IBD,” Dr. Hoffenberg and his associates wrote. “Theoretically, a different study design, such as a randomized controlled trial of marijuana use or placebo, could better evaluate the safety and benefit of frequent marijuana use for induction or maintenance of remission.”
Limitations of the study include difficulty determining differences in disease activity between groups because of the large number of patients with inactive or mild disease, as well as the need to group patients with Crohn’s disease and ulcerative colitis together because of the small total number of participants who endorse marijuana use.
The study was funded by the Colorado Department of Public Health and Environment. No conflicts of interest were reported.
SOURCE: Hoffenberg EJ et al. 2018. doi: 10.1016/j.jpeds.2018.03.041.
FROM THE JOURNAL OF PEDIATRICS
Key clinical point: Many adolescents and young adults with IBD use marijuana and perceive little to no harm from regular use.
Major finding: Of the participants in the study, 32% reported ever having used marijuana or endorsing use in the past 6 months, and 42% perceived little to no risk of harm with regular use.
Study details: A cross-sectional study of 99 IBD patients aged 13-22 years at Children’s Hospital Colorado.
Disclosures: The study was funded by the Colorado Department of Public Health and Environment. No conflicts of interest were reported.
Source: Hoffenberg EJ et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.03.041.
Early results favorable for combo TLR9 agonist + pembro in advanced melanoma
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
REPORTING FROM THE AACR ANNUAL MEETING
Key clinical point: The combination demonstrated a manageable toxicity profile with ORR of 22%.
Major finding: Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively.
Study details: This phase 1b study comprised 69 patients (44 in escalation and 25 in expansion).
Disclosures: Dr. Milhem had no financial relationships to disclose.
Source: Milhem MD et al. AACR Annual Meeting. Abstract CT144.
Adjunct treatments assist with persistent asthma
Asthma patients who struggle with poor control despite using inhaled corticosteroids can benefit from additional treatment with long-acting muscarinic antagonists (LAMAs) or single maintenance and reliever therapy, suggest data from a pair of systematic reviews and meta-analyses.
Asthma control remains a problem for many patients despite the daily use of inhaled corticosteroids. The current preferred adjunct therapy for patients aged 12 years and older is long-acting beta-agonists (LABAs), wrote Diana M. Sobieraj, PharmD, of the University of Connecticut School of Pharmacy, Storrs, and her colleagues in a study published in JAMA. The researchers examined the efficacy of other adjunct therapies and therapeutic regimes, including the use of a LAMA, in two studies of patients with persistent asthma.
Overall, patients who took a LAMA had a lower risk of asthma exacerbation requiring systemic corticosteroids and improved spirometry measures than did the patients who took a placebo or used another controller as an adjunct therapy.
In trials that compared LAMAs with placebo as an add-on to inhaled corticosteroids, LAMA patients experienced a significantly reduced risk of exacerbation requiring systemic corticosteroids (–1.8) and a significantly reduced risk of asthma worsening (–4.8). Another benefit seen in the patients who used a LAMA rather than those who used a placebo was improved spirometry measures, but the differences between these two patient groups’ numbers did not reach statistical significance.
The analysis also included studies that compared “triple therapy” – defined as use of a LAMA as add-on therapy to inhaled corticosteroids and LABAs – to LABA plus use of inhaled corticosteroids.
Triple therapy was significantly associated with a lower risk of asthma worsening, compared with inhaled corticosteroids and LABAs, but not with a reduced risk of exacerbation. In addition, no significant differences appeared in Asthma Control Questionnaire-7 scores or overall Asthma Quality of Life Questionnaire scores between the two patient groups.
“Triple therapy was not significantly associated with improvements in rescue medication use vs. combined inhaled corticosteroids and LABA therapy,” the researchers added.
The review of LAMAs used as add-on therapy was limited by several factors, including a primary focus on tiotropium, a lack of analysis of harms or the costs of the various therapies, the lack of data for children, and an inability to perform a subgroup analysis, the researchers said. Although LAMA use was associated with a lower risk of asthma exacerbation, compared with placebo use, the review could not adequately compare LAMA with controllers other than LABA, they added.
In the second analysis, which also was published in JAMA, the researchers evaluated the use of inhaled corticosteroids and LABAs as both a controller and quick-relief treatment, a strategy known as SMART, or Single Maintenance and Reliever Therapy. The SMART protocol, which is not approved in the United States, involved taking a combination of the corticosteroid budesonide and the LABA formoterol in a dry-powder inhaler in most of the studies reviewed.
Overall, in the analysis of 22,524 patients aged 12 years and older, an absolute risk difference of –2.8% for asthma exacerbations was seen in those who used the SMART protocol versus those who used a higher dose of inhaled corticosteroids and inhaled LABA as controller therapy.
In addition, data from 341 children aged 4-11 years showed a –12% absolute difference in risk of asthma exacerbation with the SMART therapy.
In trials that compared patients using the SMART protocol with those taking only the dose of inhaled corticosteroids called for by SMART, the protocol was associated with an improvement in forced expiratory volume in 1 second (FEV1) and a reduction in the need for rescue medication.
The SMART protocol also demonstrated advantages over taking the same dose of inhaled corticosteroid called for by SMART plus a LABA controller therapy or a higher dose of inhaled corticosteroids with a LABA controller therapy. Specifically, SMART patients experienced a –6.4% risk of asthma exacerbations, versus the first comparator group; and a –2.7% risk of asthma, compared with the group who took a higher dose of inhaled corticosteroids with LABA controller therapy.
No significant associations appeared in any of the studies between the SMART protocol and outcomes that included all-cause mortality or changes in FEV1, forced vital capacity, or the percentage of predicted FEV1, when compared with those for patients who used a LABA controller therapy plus inhaled corticosteroids at either dose.
The SMART protocol review was limited by factors that included a lack of data on adverse events, a lack of subgroup analysis, and the potential for bias, because of the open label nature of some of the studies, the researchers noted.
However, despite the limitations in both reviews, the results support the SMART strategy and LAMAs as alternatives for patients with persistent asthma, and highlight the need for further research, they noted.
The reviews were supported by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.
SOURCE: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.
Asthma remains a major public health problem in the United States, but 11 years have passed since the last update to treatment guidelines, and an update to the current guidelines for asthma treatment is needed, wrote Jerry A. Krishnan, MD, and David H. Au, MD, in an accompanying editorial (JAMA. 2018;319[14]:1441-3). “It is time to connect the efforts of the FDA, the evidence presented by Sobieraj et al., and the support from the National Education and Prevention Program to update the 2007 [Expert Panel Report 3] guidelines on asthma.”
Both reviews showed effectiveness for the treatments being assessed, compared with placebo, but each had limitations, the editorialists noted.
The study findings in the report on the efficacy of inhaled long-acting muscarinic antagonists (LAMAs) in adolescents and adults with uncontrolled asthma were limited by several factors including a focus primarily on tiotropium, absence of data on potential harms and relative costs of treatment, and a lack of data on children younger than 12 years, they noted. The findings in the analysis of the strategy known as Single Maintenance and Reliever Therapy (SMART) containing formoterol, a long-acting beta2-agonist, were similarly limited by a lack of assessment of potential harm and a data on children within the same age group, they said.
However, the effectiveness of the treatments seen in both reviews suggest that the forthcoming revision of the Expert Panel Report 3 guidelines on asthma from the National Asthma Education and Prevention Program should include the option for inhaled tiotropium, a LAMA, and for the formoterol-based SMART protocol, the editorialists wrote.
“For patients and clinicians, the results from these meta-analyses suggest that dual therapy with scheduled doses of inhaled corticosteroids and LABA or inhaled corticosteroids and LAMA should help reduce the risk of future asthma exacerbations in patients with inadequate asthma control while using inhaled corticosteroids alone,” they said. The new guidelines should include evidence for the SMART therapy as well, but “studies assessing the efficacy of SMART using combination formoterol and budesonide via a metered-dose inhaler are needed,” they concluded.
Dr. Krishnan is affiliated with the division of pulmonary, critical care, sleep, and allergy at the University of Illinois, Chicago, and disclosed having received compensation from Sanofi for participation on an independent data-monitoring committee. Dr. Au is affiliated with the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, and disclosed having received compensation from Novartis for participation on a data-monitoring committee and for serving as a consultant to Gilead Sciences.
Asthma remains a major public health problem in the United States, but 11 years have passed since the last update to treatment guidelines, and an update to the current guidelines for asthma treatment is needed, wrote Jerry A. Krishnan, MD, and David H. Au, MD, in an accompanying editorial (JAMA. 2018;319[14]:1441-3). “It is time to connect the efforts of the FDA, the evidence presented by Sobieraj et al., and the support from the National Education and Prevention Program to update the 2007 [Expert Panel Report 3] guidelines on asthma.”
Both reviews showed effectiveness for the treatments being assessed, compared with placebo, but each had limitations, the editorialists noted.
The study findings in the report on the efficacy of inhaled long-acting muscarinic antagonists (LAMAs) in adolescents and adults with uncontrolled asthma were limited by several factors including a focus primarily on tiotropium, absence of data on potential harms and relative costs of treatment, and a lack of data on children younger than 12 years, they noted. The findings in the analysis of the strategy known as Single Maintenance and Reliever Therapy (SMART) containing formoterol, a long-acting beta2-agonist, were similarly limited by a lack of assessment of potential harm and a data on children within the same age group, they said.
However, the effectiveness of the treatments seen in both reviews suggest that the forthcoming revision of the Expert Panel Report 3 guidelines on asthma from the National Asthma Education and Prevention Program should include the option for inhaled tiotropium, a LAMA, and for the formoterol-based SMART protocol, the editorialists wrote.
“For patients and clinicians, the results from these meta-analyses suggest that dual therapy with scheduled doses of inhaled corticosteroids and LABA or inhaled corticosteroids and LAMA should help reduce the risk of future asthma exacerbations in patients with inadequate asthma control while using inhaled corticosteroids alone,” they said. The new guidelines should include evidence for the SMART therapy as well, but “studies assessing the efficacy of SMART using combination formoterol and budesonide via a metered-dose inhaler are needed,” they concluded.
Dr. Krishnan is affiliated with the division of pulmonary, critical care, sleep, and allergy at the University of Illinois, Chicago, and disclosed having received compensation from Sanofi for participation on an independent data-monitoring committee. Dr. Au is affiliated with the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, and disclosed having received compensation from Novartis for participation on a data-monitoring committee and for serving as a consultant to Gilead Sciences.
Asthma remains a major public health problem in the United States, but 11 years have passed since the last update to treatment guidelines, and an update to the current guidelines for asthma treatment is needed, wrote Jerry A. Krishnan, MD, and David H. Au, MD, in an accompanying editorial (JAMA. 2018;319[14]:1441-3). “It is time to connect the efforts of the FDA, the evidence presented by Sobieraj et al., and the support from the National Education and Prevention Program to update the 2007 [Expert Panel Report 3] guidelines on asthma.”
Both reviews showed effectiveness for the treatments being assessed, compared with placebo, but each had limitations, the editorialists noted.
The study findings in the report on the efficacy of inhaled long-acting muscarinic antagonists (LAMAs) in adolescents and adults with uncontrolled asthma were limited by several factors including a focus primarily on tiotropium, absence of data on potential harms and relative costs of treatment, and a lack of data on children younger than 12 years, they noted. The findings in the analysis of the strategy known as Single Maintenance and Reliever Therapy (SMART) containing formoterol, a long-acting beta2-agonist, were similarly limited by a lack of assessment of potential harm and a data on children within the same age group, they said.
However, the effectiveness of the treatments seen in both reviews suggest that the forthcoming revision of the Expert Panel Report 3 guidelines on asthma from the National Asthma Education and Prevention Program should include the option for inhaled tiotropium, a LAMA, and for the formoterol-based SMART protocol, the editorialists wrote.
“For patients and clinicians, the results from these meta-analyses suggest that dual therapy with scheduled doses of inhaled corticosteroids and LABA or inhaled corticosteroids and LAMA should help reduce the risk of future asthma exacerbations in patients with inadequate asthma control while using inhaled corticosteroids alone,” they said. The new guidelines should include evidence for the SMART therapy as well, but “studies assessing the efficacy of SMART using combination formoterol and budesonide via a metered-dose inhaler are needed,” they concluded.
Dr. Krishnan is affiliated with the division of pulmonary, critical care, sleep, and allergy at the University of Illinois, Chicago, and disclosed having received compensation from Sanofi for participation on an independent data-monitoring committee. Dr. Au is affiliated with the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, and disclosed having received compensation from Novartis for participation on a data-monitoring committee and for serving as a consultant to Gilead Sciences.
Asthma patients who struggle with poor control despite using inhaled corticosteroids can benefit from additional treatment with long-acting muscarinic antagonists (LAMAs) or single maintenance and reliever therapy, suggest data from a pair of systematic reviews and meta-analyses.
Asthma control remains a problem for many patients despite the daily use of inhaled corticosteroids. The current preferred adjunct therapy for patients aged 12 years and older is long-acting beta-agonists (LABAs), wrote Diana M. Sobieraj, PharmD, of the University of Connecticut School of Pharmacy, Storrs, and her colleagues in a study published in JAMA. The researchers examined the efficacy of other adjunct therapies and therapeutic regimes, including the use of a LAMA, in two studies of patients with persistent asthma.
Overall, patients who took a LAMA had a lower risk of asthma exacerbation requiring systemic corticosteroids and improved spirometry measures than did the patients who took a placebo or used another controller as an adjunct therapy.
In trials that compared LAMAs with placebo as an add-on to inhaled corticosteroids, LAMA patients experienced a significantly reduced risk of exacerbation requiring systemic corticosteroids (–1.8) and a significantly reduced risk of asthma worsening (–4.8). Another benefit seen in the patients who used a LAMA rather than those who used a placebo was improved spirometry measures, but the differences between these two patient groups’ numbers did not reach statistical significance.
The analysis also included studies that compared “triple therapy” – defined as use of a LAMA as add-on therapy to inhaled corticosteroids and LABAs – to LABA plus use of inhaled corticosteroids.
Triple therapy was significantly associated with a lower risk of asthma worsening, compared with inhaled corticosteroids and LABAs, but not with a reduced risk of exacerbation. In addition, no significant differences appeared in Asthma Control Questionnaire-7 scores or overall Asthma Quality of Life Questionnaire scores between the two patient groups.
“Triple therapy was not significantly associated with improvements in rescue medication use vs. combined inhaled corticosteroids and LABA therapy,” the researchers added.
The review of LAMAs used as add-on therapy was limited by several factors, including a primary focus on tiotropium, a lack of analysis of harms or the costs of the various therapies, the lack of data for children, and an inability to perform a subgroup analysis, the researchers said. Although LAMA use was associated with a lower risk of asthma exacerbation, compared with placebo use, the review could not adequately compare LAMA with controllers other than LABA, they added.
In the second analysis, which also was published in JAMA, the researchers evaluated the use of inhaled corticosteroids and LABAs as both a controller and quick-relief treatment, a strategy known as SMART, or Single Maintenance and Reliever Therapy. The SMART protocol, which is not approved in the United States, involved taking a combination of the corticosteroid budesonide and the LABA formoterol in a dry-powder inhaler in most of the studies reviewed.
Overall, in the analysis of 22,524 patients aged 12 years and older, an absolute risk difference of –2.8% for asthma exacerbations was seen in those who used the SMART protocol versus those who used a higher dose of inhaled corticosteroids and inhaled LABA as controller therapy.
In addition, data from 341 children aged 4-11 years showed a –12% absolute difference in risk of asthma exacerbation with the SMART therapy.
In trials that compared patients using the SMART protocol with those taking only the dose of inhaled corticosteroids called for by SMART, the protocol was associated with an improvement in forced expiratory volume in 1 second (FEV1) and a reduction in the need for rescue medication.
The SMART protocol also demonstrated advantages over taking the same dose of inhaled corticosteroid called for by SMART plus a LABA controller therapy or a higher dose of inhaled corticosteroids with a LABA controller therapy. Specifically, SMART patients experienced a –6.4% risk of asthma exacerbations, versus the first comparator group; and a –2.7% risk of asthma, compared with the group who took a higher dose of inhaled corticosteroids with LABA controller therapy.
No significant associations appeared in any of the studies between the SMART protocol and outcomes that included all-cause mortality or changes in FEV1, forced vital capacity, or the percentage of predicted FEV1, when compared with those for patients who used a LABA controller therapy plus inhaled corticosteroids at either dose.
The SMART protocol review was limited by factors that included a lack of data on adverse events, a lack of subgroup analysis, and the potential for bias, because of the open label nature of some of the studies, the researchers noted.
However, despite the limitations in both reviews, the results support the SMART strategy and LAMAs as alternatives for patients with persistent asthma, and highlight the need for further research, they noted.
The reviews were supported by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.
SOURCE: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.
Asthma patients who struggle with poor control despite using inhaled corticosteroids can benefit from additional treatment with long-acting muscarinic antagonists (LAMAs) or single maintenance and reliever therapy, suggest data from a pair of systematic reviews and meta-analyses.
Asthma control remains a problem for many patients despite the daily use of inhaled corticosteroids. The current preferred adjunct therapy for patients aged 12 years and older is long-acting beta-agonists (LABAs), wrote Diana M. Sobieraj, PharmD, of the University of Connecticut School of Pharmacy, Storrs, and her colleagues in a study published in JAMA. The researchers examined the efficacy of other adjunct therapies and therapeutic regimes, including the use of a LAMA, in two studies of patients with persistent asthma.
Overall, patients who took a LAMA had a lower risk of asthma exacerbation requiring systemic corticosteroids and improved spirometry measures than did the patients who took a placebo or used another controller as an adjunct therapy.
In trials that compared LAMAs with placebo as an add-on to inhaled corticosteroids, LAMA patients experienced a significantly reduced risk of exacerbation requiring systemic corticosteroids (–1.8) and a significantly reduced risk of asthma worsening (–4.8). Another benefit seen in the patients who used a LAMA rather than those who used a placebo was improved spirometry measures, but the differences between these two patient groups’ numbers did not reach statistical significance.
The analysis also included studies that compared “triple therapy” – defined as use of a LAMA as add-on therapy to inhaled corticosteroids and LABAs – to LABA plus use of inhaled corticosteroids.
Triple therapy was significantly associated with a lower risk of asthma worsening, compared with inhaled corticosteroids and LABAs, but not with a reduced risk of exacerbation. In addition, no significant differences appeared in Asthma Control Questionnaire-7 scores or overall Asthma Quality of Life Questionnaire scores between the two patient groups.
“Triple therapy was not significantly associated with improvements in rescue medication use vs. combined inhaled corticosteroids and LABA therapy,” the researchers added.
The review of LAMAs used as add-on therapy was limited by several factors, including a primary focus on tiotropium, a lack of analysis of harms or the costs of the various therapies, the lack of data for children, and an inability to perform a subgroup analysis, the researchers said. Although LAMA use was associated with a lower risk of asthma exacerbation, compared with placebo use, the review could not adequately compare LAMA with controllers other than LABA, they added.
In the second analysis, which also was published in JAMA, the researchers evaluated the use of inhaled corticosteroids and LABAs as both a controller and quick-relief treatment, a strategy known as SMART, or Single Maintenance and Reliever Therapy. The SMART protocol, which is not approved in the United States, involved taking a combination of the corticosteroid budesonide and the LABA formoterol in a dry-powder inhaler in most of the studies reviewed.
Overall, in the analysis of 22,524 patients aged 12 years and older, an absolute risk difference of –2.8% for asthma exacerbations was seen in those who used the SMART protocol versus those who used a higher dose of inhaled corticosteroids and inhaled LABA as controller therapy.
In addition, data from 341 children aged 4-11 years showed a –12% absolute difference in risk of asthma exacerbation with the SMART therapy.
In trials that compared patients using the SMART protocol with those taking only the dose of inhaled corticosteroids called for by SMART, the protocol was associated with an improvement in forced expiratory volume in 1 second (FEV1) and a reduction in the need for rescue medication.
The SMART protocol also demonstrated advantages over taking the same dose of inhaled corticosteroid called for by SMART plus a LABA controller therapy or a higher dose of inhaled corticosteroids with a LABA controller therapy. Specifically, SMART patients experienced a –6.4% risk of asthma exacerbations, versus the first comparator group; and a –2.7% risk of asthma, compared with the group who took a higher dose of inhaled corticosteroids with LABA controller therapy.
No significant associations appeared in any of the studies between the SMART protocol and outcomes that included all-cause mortality or changes in FEV1, forced vital capacity, or the percentage of predicted FEV1, when compared with those for patients who used a LABA controller therapy plus inhaled corticosteroids at either dose.
The SMART protocol review was limited by factors that included a lack of data on adverse events, a lack of subgroup analysis, and the potential for bias, because of the open label nature of some of the studies, the researchers noted.
However, despite the limitations in both reviews, the results support the SMART strategy and LAMAs as alternatives for patients with persistent asthma, and highlight the need for further research, they noted.
The reviews were supported by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.
SOURCE: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.
FROM JAMA
Key clinical point:
Major finding: LAMA patients had a risk difference of –1.8 for asthma exacerbations, compared with placebo users, while patients using the SMART protocol had an absolute risk difference of –2.8%, compared with those taking a higher dose of inhaled corticosteroids plus LABAs as a controller.
Study details: The data came from two reviews of randomized clinical trials; the first included 7,122 patients and the second included 22,524 patients.
Disclosures: The reviews were supported in part by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.
Source: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.
Anti-TNF drugs appear to lessen PD risk in IBD patients
Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.
But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.
The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.
A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).
Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).
“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”
Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.
SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.
The research provides “a glimpse of the promise and beauty of big data for Parkinson’s disease (PD) and for neurology in general,” experts wrote in an editorial accompanying the study.
“Every physician knows how much can be learned by listening to a patient,” wrote Abby L. Olsen, MD, PhD, Trond Riise, PhD, and Clemens R. Scherzer, MD. “Imagine how much might be learned by scaling this singular experience to torrents of digital health data from millions of patients.”
If inflammatory bowel disease and PD share a common inflammatory etiology, anti–tumor necrosis factor therapy might well help prevent PD, they wrote. But a clinical trial testing that hypothesis would be “incredibly difficult and expensive” because PD has a fairly low incidence, even among people at increased risk.
To surmount this obstacle, the researchers created a “virtual” trial that repurposed old drugs for new potential benefit, the experts continued. Although the study fell short on follow-up time and certain clinical data (such as smoking status), it offered “exciting evidence” in support of this concept.
The editorialists are with Precision Neurology Program, Brigham and Women’s Hospital, Boston. These comments paraphrase their editorial (JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0345 ).
The research provides “a glimpse of the promise and beauty of big data for Parkinson’s disease (PD) and for neurology in general,” experts wrote in an editorial accompanying the study.
“Every physician knows how much can be learned by listening to a patient,” wrote Abby L. Olsen, MD, PhD, Trond Riise, PhD, and Clemens R. Scherzer, MD. “Imagine how much might be learned by scaling this singular experience to torrents of digital health data from millions of patients.”
If inflammatory bowel disease and PD share a common inflammatory etiology, anti–tumor necrosis factor therapy might well help prevent PD, they wrote. But a clinical trial testing that hypothesis would be “incredibly difficult and expensive” because PD has a fairly low incidence, even among people at increased risk.
To surmount this obstacle, the researchers created a “virtual” trial that repurposed old drugs for new potential benefit, the experts continued. Although the study fell short on follow-up time and certain clinical data (such as smoking status), it offered “exciting evidence” in support of this concept.
The editorialists are with Precision Neurology Program, Brigham and Women’s Hospital, Boston. These comments paraphrase their editorial (JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0345 ).
The research provides “a glimpse of the promise and beauty of big data for Parkinson’s disease (PD) and for neurology in general,” experts wrote in an editorial accompanying the study.
“Every physician knows how much can be learned by listening to a patient,” wrote Abby L. Olsen, MD, PhD, Trond Riise, PhD, and Clemens R. Scherzer, MD. “Imagine how much might be learned by scaling this singular experience to torrents of digital health data from millions of patients.”
If inflammatory bowel disease and PD share a common inflammatory etiology, anti–tumor necrosis factor therapy might well help prevent PD, they wrote. But a clinical trial testing that hypothesis would be “incredibly difficult and expensive” because PD has a fairly low incidence, even among people at increased risk.
To surmount this obstacle, the researchers created a “virtual” trial that repurposed old drugs for new potential benefit, the experts continued. Although the study fell short on follow-up time and certain clinical data (such as smoking status), it offered “exciting evidence” in support of this concept.
The editorialists are with Precision Neurology Program, Brigham and Women’s Hospital, Boston. These comments paraphrase their editorial (JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0345 ).
Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.
But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.
The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.
A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).
Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).
“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”
Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.
SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.
Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.
But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.
The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.
A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).
Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).
“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”
Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.
SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.
FROM JAMA NEUROLOGY
Key clinical point: Inflammatory bowel disease was associated with a significantly increased risk of Parkinson’s disease. Anti–tumor necrosis factor therapy appeared to lessen this risk.
Major finding: Patients with IBD had a 28% higher PD incidence than that of matched controls (adjusted IRR, 1.28; P less than .001). Patients with IBD who received anti-TNF therapy had a 78% lower incidence of PD compared with those who did not (adjusted IRR, 0.22; P = .03).
Study details: Administrative data claims analysis of 144,018 patients with IBD and 720,090 patients without IBD.
Disclosures: Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.
Source: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.
Meta-analysis finds no link between stroke and sickle cell trait
Those findings contrast with an earlier longitudinal study that found a 1.4-fold risk of ischemic stroke in SCT carriers, the authors noted.
In their study, neither crude stroke incidence rates nor regression analysis indicated a link between SCT and stroke, said first author Hyacinth I. Hyacinth, MD, PhD, MPH, of the Aflac Cancer and Blood Disorder Center, Emory University, Atlanta, and his coauthors.
“The absence of an association between SCT and risk of ischemic stroke was consistent among the cohorts, and suggests that SCT is not an independent genetic risk factor for ischemic stroke among African Americans,” Dr. Hyacinth and his coauthors wrote.
The results may have implications for patient care. In particular, a more thorough evaluation of stroke in a patient with SCT may be warranted, instead of assuming that the SCT is an underlying cause of the stroke, they said.
The meta-analysis included a total of 19,464 subjects from four large, prospective, population-based studies with African American cohorts.
Results of the meta-analysis show that crude incidence of stroke was similar for individuals with SCT, at 2.9 per 1,000 person-years (95% confidence interval, 2.2-4.0), and for those with no SCT, at 3.2 per 1,000 person-years (95% CI, 2.7-3.8).
After adjusting for stroke risk factors, the hazard ratio of stroke independently associated with SCT was 0.80 (95% CI, 0.47-1.35; P = 0.82), results further show.
It’s unclear why this study found no association between SCT and stroke when the earlier population-based study suggested a link between the two. Dr. Hyacinth and his coauthors suggested differences in study methods or proportion of individuals at risk for stroke may account for the divergent findings. They also controlled for left ventricular hypertrophy, while the previous study did not.
“However, in our analysis, adjusting for left ventricular hypertrophy did not change the direction of estimate effects,” they said in the report.
Further study is needed to determine whether or not SCT may be linked to a particular type of stroke. “We were unable to test the association of SCT with ischemic stroke subtypes,” the authors noted.
Dr. Hyacinth and his coauthors reported no conflicts of interest related to the study.
SOURCE: Hyacinth HI et al. JAMA Neurol. 2018 Apr 23. doi:10.1001/jamaneurol.2018.0571
Those findings contrast with an earlier longitudinal study that found a 1.4-fold risk of ischemic stroke in SCT carriers, the authors noted.
In their study, neither crude stroke incidence rates nor regression analysis indicated a link between SCT and stroke, said first author Hyacinth I. Hyacinth, MD, PhD, MPH, of the Aflac Cancer and Blood Disorder Center, Emory University, Atlanta, and his coauthors.
“The absence of an association between SCT and risk of ischemic stroke was consistent among the cohorts, and suggests that SCT is not an independent genetic risk factor for ischemic stroke among African Americans,” Dr. Hyacinth and his coauthors wrote.
The results may have implications for patient care. In particular, a more thorough evaluation of stroke in a patient with SCT may be warranted, instead of assuming that the SCT is an underlying cause of the stroke, they said.
The meta-analysis included a total of 19,464 subjects from four large, prospective, population-based studies with African American cohorts.
Results of the meta-analysis show that crude incidence of stroke was similar for individuals with SCT, at 2.9 per 1,000 person-years (95% confidence interval, 2.2-4.0), and for those with no SCT, at 3.2 per 1,000 person-years (95% CI, 2.7-3.8).
After adjusting for stroke risk factors, the hazard ratio of stroke independently associated with SCT was 0.80 (95% CI, 0.47-1.35; P = 0.82), results further show.
It’s unclear why this study found no association between SCT and stroke when the earlier population-based study suggested a link between the two. Dr. Hyacinth and his coauthors suggested differences in study methods or proportion of individuals at risk for stroke may account for the divergent findings. They also controlled for left ventricular hypertrophy, while the previous study did not.
“However, in our analysis, adjusting for left ventricular hypertrophy did not change the direction of estimate effects,” they said in the report.
Further study is needed to determine whether or not SCT may be linked to a particular type of stroke. “We were unable to test the association of SCT with ischemic stroke subtypes,” the authors noted.
Dr. Hyacinth and his coauthors reported no conflicts of interest related to the study.
SOURCE: Hyacinth HI et al. JAMA Neurol. 2018 Apr 23. doi:10.1001/jamaneurol.2018.0571
Those findings contrast with an earlier longitudinal study that found a 1.4-fold risk of ischemic stroke in SCT carriers, the authors noted.
In their study, neither crude stroke incidence rates nor regression analysis indicated a link between SCT and stroke, said first author Hyacinth I. Hyacinth, MD, PhD, MPH, of the Aflac Cancer and Blood Disorder Center, Emory University, Atlanta, and his coauthors.
“The absence of an association between SCT and risk of ischemic stroke was consistent among the cohorts, and suggests that SCT is not an independent genetic risk factor for ischemic stroke among African Americans,” Dr. Hyacinth and his coauthors wrote.
The results may have implications for patient care. In particular, a more thorough evaluation of stroke in a patient with SCT may be warranted, instead of assuming that the SCT is an underlying cause of the stroke, they said.
The meta-analysis included a total of 19,464 subjects from four large, prospective, population-based studies with African American cohorts.
Results of the meta-analysis show that crude incidence of stroke was similar for individuals with SCT, at 2.9 per 1,000 person-years (95% confidence interval, 2.2-4.0), and for those with no SCT, at 3.2 per 1,000 person-years (95% CI, 2.7-3.8).
After adjusting for stroke risk factors, the hazard ratio of stroke independently associated with SCT was 0.80 (95% CI, 0.47-1.35; P = 0.82), results further show.
It’s unclear why this study found no association between SCT and stroke when the earlier population-based study suggested a link between the two. Dr. Hyacinth and his coauthors suggested differences in study methods or proportion of individuals at risk for stroke may account for the divergent findings. They also controlled for left ventricular hypertrophy, while the previous study did not.
“However, in our analysis, adjusting for left ventricular hypertrophy did not change the direction of estimate effects,” they said in the report.
Further study is needed to determine whether or not SCT may be linked to a particular type of stroke. “We were unable to test the association of SCT with ischemic stroke subtypes,” the authors noted.
Dr. Hyacinth and his coauthors reported no conflicts of interest related to the study.
SOURCE: Hyacinth HI et al. JAMA Neurol. 2018 Apr 23. doi:10.1001/jamaneurol.2018.0571
FROM JAMA NEUROLOGY
Key clinical point: In contrast to results of a previous study, a meta-analysis has found no evidence linking sickle cell trait (SCT) and risk of incident ischemic stroke in African Americans.
Major finding: Crude stroke incidence was not different for SCT versus no SCT. After adjusting for stroke risk factors, the hazard ratio of stroke independently associated with SCT was 0.80 (95% CI, 0.47-1.35; P = .82).
Study details: A meta-analysis of the association between SCT and risk of incident ischemic stroke in four large prospective, population-based studies with African American cohorts (19,464 total subjects).
Disclosures: Authors reported no conflicts of interest related to the study.
Source: Hyacinth HI et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0571.
Long-Term Perampanel Treatment Is Safe and Effective for Adolescents
LOS ANGELES—Treatment for as long as four years with adjunctive perampanel is safe and effective for adolescents with secondarily generalized seizures or primary generalized tonic-clonic seizures, according to a post hoc study presented at the 70th Annual Meeting of the American Academy of Neurology. “These post hoc results are encouraging, given the refractory nature of these seizure types,” said the investigators.
Perampanel has regulatory approval for the treatment of partial seizures with or without secondarily generalized seizures, and for the adjunctive treatment of primary generalized tonic-clonic seizures in patients age 12 and younger with epilepsy. Phase II and III randomized, double-blind, placebo-controlled trials indicated that adjunctive perampanel (at doses of 12 mg/day or less) was effective and tolerable in patients with these types of seizures in idiopathic generalized epilepsy. The participants who completed these studies were eligible to enter one of four open-label extension studies.
Jesus Eric Piña-Garza, MD, a pediatric neurologist at the Children’s Hospital at TriStar Centennial in Nashville, and colleagues used data from these open-label extension studies to assess the long-term efficacy and safety of adjunctive perampanel in patients from ages 12 to 17 with secondarily generalized seizures or primary generalized tonic-clonic seizures.
The extension studies incorporated a blinded conversion period that lasted for six to 16 weeks, during which perampanel dose was optimized (at 12 mg/day or less), and a maintenance phase that lasted for 27 to 256 weeks. Total drug exposure was as long as five years. All patients received perampanel during these studies. Efficacy and safety assessments, which were performed for as long as four years, included median percent change in seizure frequency per 28 days and 50% and 75% responder and seizure-freedom rates. Investigators also monitored treatment-emergent adverse events.
The investigators included 129 adolescent patients in the safety analysis set, including 109 with secondarily generalized seizures and 19 with primary generalized tonic-clonic seizures. During the first year, median percent reductions in seizure frequency per 28 days were 62.8% for patients with secondarily generalized seizures and 84.0% for patients with primary generalized tonic-clonic seizures. During year four, median percent reductions in seizure frequency per 28 days were 73.2% for patients with secondarily generalized seizures and 100.0% for patients with primary generalized tonic-clonic seizures. The 50% responder rates were 56.9% for patients with secondarily generalized seizures and 63.2% for patients with primary generalized tonic-clonic seizures in year one, and 65.2% for patients with secondarily generalized seizures and 100.0% for patients with primary generalized tonic-clonic seizures in year four.
For each seizure type, the incidence of treatment-emergent adverse events was highest during the first year of perampanel exposure. The most common treatment-emergent adverse events were dizziness, somnolence, and nasopharyngitis.
The study was supported by Eisai.
LOS ANGELES—Treatment for as long as four years with adjunctive perampanel is safe and effective for adolescents with secondarily generalized seizures or primary generalized tonic-clonic seizures, according to a post hoc study presented at the 70th Annual Meeting of the American Academy of Neurology. “These post hoc results are encouraging, given the refractory nature of these seizure types,” said the investigators.
Perampanel has regulatory approval for the treatment of partial seizures with or without secondarily generalized seizures, and for the adjunctive treatment of primary generalized tonic-clonic seizures in patients age 12 and younger with epilepsy. Phase II and III randomized, double-blind, placebo-controlled trials indicated that adjunctive perampanel (at doses of 12 mg/day or less) was effective and tolerable in patients with these types of seizures in idiopathic generalized epilepsy. The participants who completed these studies were eligible to enter one of four open-label extension studies.
Jesus Eric Piña-Garza, MD, a pediatric neurologist at the Children’s Hospital at TriStar Centennial in Nashville, and colleagues used data from these open-label extension studies to assess the long-term efficacy and safety of adjunctive perampanel in patients from ages 12 to 17 with secondarily generalized seizures or primary generalized tonic-clonic seizures.
The extension studies incorporated a blinded conversion period that lasted for six to 16 weeks, during which perampanel dose was optimized (at 12 mg/day or less), and a maintenance phase that lasted for 27 to 256 weeks. Total drug exposure was as long as five years. All patients received perampanel during these studies. Efficacy and safety assessments, which were performed for as long as four years, included median percent change in seizure frequency per 28 days and 50% and 75% responder and seizure-freedom rates. Investigators also monitored treatment-emergent adverse events.
The investigators included 129 adolescent patients in the safety analysis set, including 109 with secondarily generalized seizures and 19 with primary generalized tonic-clonic seizures. During the first year, median percent reductions in seizure frequency per 28 days were 62.8% for patients with secondarily generalized seizures and 84.0% for patients with primary generalized tonic-clonic seizures. During year four, median percent reductions in seizure frequency per 28 days were 73.2% for patients with secondarily generalized seizures and 100.0% for patients with primary generalized tonic-clonic seizures. The 50% responder rates were 56.9% for patients with secondarily generalized seizures and 63.2% for patients with primary generalized tonic-clonic seizures in year one, and 65.2% for patients with secondarily generalized seizures and 100.0% for patients with primary generalized tonic-clonic seizures in year four.
For each seizure type, the incidence of treatment-emergent adverse events was highest during the first year of perampanel exposure. The most common treatment-emergent adverse events were dizziness, somnolence, and nasopharyngitis.
The study was supported by Eisai.
LOS ANGELES—Treatment for as long as four years with adjunctive perampanel is safe and effective for adolescents with secondarily generalized seizures or primary generalized tonic-clonic seizures, according to a post hoc study presented at the 70th Annual Meeting of the American Academy of Neurology. “These post hoc results are encouraging, given the refractory nature of these seizure types,” said the investigators.
Perampanel has regulatory approval for the treatment of partial seizures with or without secondarily generalized seizures, and for the adjunctive treatment of primary generalized tonic-clonic seizures in patients age 12 and younger with epilepsy. Phase II and III randomized, double-blind, placebo-controlled trials indicated that adjunctive perampanel (at doses of 12 mg/day or less) was effective and tolerable in patients with these types of seizures in idiopathic generalized epilepsy. The participants who completed these studies were eligible to enter one of four open-label extension studies.
Jesus Eric Piña-Garza, MD, a pediatric neurologist at the Children’s Hospital at TriStar Centennial in Nashville, and colleagues used data from these open-label extension studies to assess the long-term efficacy and safety of adjunctive perampanel in patients from ages 12 to 17 with secondarily generalized seizures or primary generalized tonic-clonic seizures.
The extension studies incorporated a blinded conversion period that lasted for six to 16 weeks, during which perampanel dose was optimized (at 12 mg/day or less), and a maintenance phase that lasted for 27 to 256 weeks. Total drug exposure was as long as five years. All patients received perampanel during these studies. Efficacy and safety assessments, which were performed for as long as four years, included median percent change in seizure frequency per 28 days and 50% and 75% responder and seizure-freedom rates. Investigators also monitored treatment-emergent adverse events.
The investigators included 129 adolescent patients in the safety analysis set, including 109 with secondarily generalized seizures and 19 with primary generalized tonic-clonic seizures. During the first year, median percent reductions in seizure frequency per 28 days were 62.8% for patients with secondarily generalized seizures and 84.0% for patients with primary generalized tonic-clonic seizures. During year four, median percent reductions in seizure frequency per 28 days were 73.2% for patients with secondarily generalized seizures and 100.0% for patients with primary generalized tonic-clonic seizures. The 50% responder rates were 56.9% for patients with secondarily generalized seizures and 63.2% for patients with primary generalized tonic-clonic seizures in year one, and 65.2% for patients with secondarily generalized seizures and 100.0% for patients with primary generalized tonic-clonic seizures in year four.
For each seizure type, the incidence of treatment-emergent adverse events was highest during the first year of perampanel exposure. The most common treatment-emergent adverse events were dizziness, somnolence, and nasopharyngitis.
The study was supported by Eisai.