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Release nears for revised U.S. hypertension guidelines
Authoritative U.S. guidelines for managing high blood pressure have traveled a rocky and serpentine path ever since the expert group originally constituted as the Eighth Joint National Committee (JNC 8) released its controversial report in early 2014, when it relaxed the target blood pressure for most adults aged 60-79 years from less than 140 mm Hg to under 150/90 mm Hg (JAMA. 2014 Feb 5;3311[5]:507-20). A few months before those recommendations came out, the National Heart, Lung, and Blood Institute, which since 1977 had organized seven preceding iterations of U.S. blood pressure guidelines, handed off oversight of the project and any future updates to the American Heart Association, the American College of Cardiology, and the American Society of Hypertension. A year later, an expert panel organized by those three groups reset the blood pressure target for most U.S. adults with coronary artery disease back to a pressure of less than 140/90 mm Hg (Hypertension. 2015 Jun;65[6]:1372-1407), and that has been the prevailing U.S. standard in the 2-plus years since.
A few months later, in September 2015, data from the SPRINT trial in more than 9,000 patients with high cardiovascular risk first came out and showed that treating to a target systolic blood pressure of less than 120 mm Hg led to a significant 25% reduction in cardiovascular disease events, compared with controls treated to a systolic pressure of less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16). Ever since, the big question surrounding blood pressure targets in U.S. practice has been, when would new official guidelines emerge that took the SPRINT findings into consideration? It now looks like it will finally happen in September 2017.
That’s when the ASH and the AHA’s Hypertension Council will for the first time hold a joint annual meeting, after many years when each organization had its own, individual annual meeting. The ASH’s traditional spring meeting didn’t happen this year; early fall has traditionally been when the AHA’s Hypertension Council meets.
The Council’s posted preliminary program for the September meeting showed, as of late July, an opening session the morning of September 14 called a “Review of AHA Scientific Statement 2017.” On the ASH’s website is a virtual flier for a session the afternoon of September 15 on the “2017 Guidelines for Adult and Pediatric Hypertension.”
“I know that something will be discussed on September 14,” he told me recently. “I am not sure the full report will be ready then, but I think something will be presented that will at least describe the ‘attitude’ of the guidelines, if not the whole report. There will be more presented at the AHA Sessions in November.” Of course, there will also be “an accompanying evidence document describing the studies and evidence that generated the report, but I don’t know the release date,” he added.
Some of the suspense is already gone from the new guidelines, because the punch line – the new target blood pressure to treat toward for most U.S. adults with hypertension – is already known to be less than 130/80 mm Hg. That was the treatment goal set in April in updated guidelines for treating patients with heart failure by a panel of the ACC, the AHA, and the Heart Failure Society of America (J Am Coll Cardiol. 2017 Apr 30. doi: 10.1016/j.jacc.2017.04.025). Among the heart failure patients subject to this blood pressure target are adults with stage A heart failure, which the panel defined as any adult diagnosed with hypertension, as well as those with diabetes, coronary artery disease, or other risk factors that clearly predispose patients to develop heart failure.
Last April, the heart failure panel’s vice-chair, Mariell Jessup, MD, told me that the group chose a treatment target of less than 130/80 mm Hg to “harmonize” with the target that the hypertension guideline group had already selected.
So, in truth, an official U.S. hypertension treatment target of less than 130/80 mm Hg is already on the books for clinicians to follow that’s endorsed by the ACC and AHA. Unless the hypertension group throws a real curve ball its target will be identical.
But just knowing this lower target leaves important questions unanswered that presumably the hypertension panel will address. Questions like the best drug combinations to use to get blood pressures this low, and how aggressively to treat older patients with comorbidities who may need upward of four drugs to achieve a systolic blood pressure in this target range.
“I suspect some will say that the heart failure guidelines are for patients with heart failure, and thus the hypertension guidelines will complement them,” said Dr. Lackland. On the other hand, the SPRINT evidence is so persuasive that at least “some physicians will move to 130/80 mm Hg” readily, he predicted. “Others will probably wait and see, and some will wait even longer for follow-up comments” to come out.
Dr. Lackland also stressed the usual caveat about any medical guideline, that both the heart failure and hypertension statements simply give clinicians the recommended approach but “should not override clinical judgment for specific patients.”
But before the medical community can embrace or question the new hypertension guidelines it needs to at least see them. That finally seems ready to happen in September, and perhaps in November too.
[email protected]
On Twitter @mitchelzoler
Authoritative U.S. guidelines for managing high blood pressure have traveled a rocky and serpentine path ever since the expert group originally constituted as the Eighth Joint National Committee (JNC 8) released its controversial report in early 2014, when it relaxed the target blood pressure for most adults aged 60-79 years from less than 140 mm Hg to under 150/90 mm Hg (JAMA. 2014 Feb 5;3311[5]:507-20). A few months before those recommendations came out, the National Heart, Lung, and Blood Institute, which since 1977 had organized seven preceding iterations of U.S. blood pressure guidelines, handed off oversight of the project and any future updates to the American Heart Association, the American College of Cardiology, and the American Society of Hypertension. A year later, an expert panel organized by those three groups reset the blood pressure target for most U.S. adults with coronary artery disease back to a pressure of less than 140/90 mm Hg (Hypertension. 2015 Jun;65[6]:1372-1407), and that has been the prevailing U.S. standard in the 2-plus years since.
A few months later, in September 2015, data from the SPRINT trial in more than 9,000 patients with high cardiovascular risk first came out and showed that treating to a target systolic blood pressure of less than 120 mm Hg led to a significant 25% reduction in cardiovascular disease events, compared with controls treated to a systolic pressure of less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16). Ever since, the big question surrounding blood pressure targets in U.S. practice has been, when would new official guidelines emerge that took the SPRINT findings into consideration? It now looks like it will finally happen in September 2017.
That’s when the ASH and the AHA’s Hypertension Council will for the first time hold a joint annual meeting, after many years when each organization had its own, individual annual meeting. The ASH’s traditional spring meeting didn’t happen this year; early fall has traditionally been when the AHA’s Hypertension Council meets.
The Council’s posted preliminary program for the September meeting showed, as of late July, an opening session the morning of September 14 called a “Review of AHA Scientific Statement 2017.” On the ASH’s website is a virtual flier for a session the afternoon of September 15 on the “2017 Guidelines for Adult and Pediatric Hypertension.”
“I know that something will be discussed on September 14,” he told me recently. “I am not sure the full report will be ready then, but I think something will be presented that will at least describe the ‘attitude’ of the guidelines, if not the whole report. There will be more presented at the AHA Sessions in November.” Of course, there will also be “an accompanying evidence document describing the studies and evidence that generated the report, but I don’t know the release date,” he added.
Some of the suspense is already gone from the new guidelines, because the punch line – the new target blood pressure to treat toward for most U.S. adults with hypertension – is already known to be less than 130/80 mm Hg. That was the treatment goal set in April in updated guidelines for treating patients with heart failure by a panel of the ACC, the AHA, and the Heart Failure Society of America (J Am Coll Cardiol. 2017 Apr 30. doi: 10.1016/j.jacc.2017.04.025). Among the heart failure patients subject to this blood pressure target are adults with stage A heart failure, which the panel defined as any adult diagnosed with hypertension, as well as those with diabetes, coronary artery disease, or other risk factors that clearly predispose patients to develop heart failure.
Last April, the heart failure panel’s vice-chair, Mariell Jessup, MD, told me that the group chose a treatment target of less than 130/80 mm Hg to “harmonize” with the target that the hypertension guideline group had already selected.
So, in truth, an official U.S. hypertension treatment target of less than 130/80 mm Hg is already on the books for clinicians to follow that’s endorsed by the ACC and AHA. Unless the hypertension group throws a real curve ball its target will be identical.
But just knowing this lower target leaves important questions unanswered that presumably the hypertension panel will address. Questions like the best drug combinations to use to get blood pressures this low, and how aggressively to treat older patients with comorbidities who may need upward of four drugs to achieve a systolic blood pressure in this target range.
“I suspect some will say that the heart failure guidelines are for patients with heart failure, and thus the hypertension guidelines will complement them,” said Dr. Lackland. On the other hand, the SPRINT evidence is so persuasive that at least “some physicians will move to 130/80 mm Hg” readily, he predicted. “Others will probably wait and see, and some will wait even longer for follow-up comments” to come out.
Dr. Lackland also stressed the usual caveat about any medical guideline, that both the heart failure and hypertension statements simply give clinicians the recommended approach but “should not override clinical judgment for specific patients.”
But before the medical community can embrace or question the new hypertension guidelines it needs to at least see them. That finally seems ready to happen in September, and perhaps in November too.
[email protected]
On Twitter @mitchelzoler
Authoritative U.S. guidelines for managing high blood pressure have traveled a rocky and serpentine path ever since the expert group originally constituted as the Eighth Joint National Committee (JNC 8) released its controversial report in early 2014, when it relaxed the target blood pressure for most adults aged 60-79 years from less than 140 mm Hg to under 150/90 mm Hg (JAMA. 2014 Feb 5;3311[5]:507-20). A few months before those recommendations came out, the National Heart, Lung, and Blood Institute, which since 1977 had organized seven preceding iterations of U.S. blood pressure guidelines, handed off oversight of the project and any future updates to the American Heart Association, the American College of Cardiology, and the American Society of Hypertension. A year later, an expert panel organized by those three groups reset the blood pressure target for most U.S. adults with coronary artery disease back to a pressure of less than 140/90 mm Hg (Hypertension. 2015 Jun;65[6]:1372-1407), and that has been the prevailing U.S. standard in the 2-plus years since.
A few months later, in September 2015, data from the SPRINT trial in more than 9,000 patients with high cardiovascular risk first came out and showed that treating to a target systolic blood pressure of less than 120 mm Hg led to a significant 25% reduction in cardiovascular disease events, compared with controls treated to a systolic pressure of less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16). Ever since, the big question surrounding blood pressure targets in U.S. practice has been, when would new official guidelines emerge that took the SPRINT findings into consideration? It now looks like it will finally happen in September 2017.
That’s when the ASH and the AHA’s Hypertension Council will for the first time hold a joint annual meeting, after many years when each organization had its own, individual annual meeting. The ASH’s traditional spring meeting didn’t happen this year; early fall has traditionally been when the AHA’s Hypertension Council meets.
The Council’s posted preliminary program for the September meeting showed, as of late July, an opening session the morning of September 14 called a “Review of AHA Scientific Statement 2017.” On the ASH’s website is a virtual flier for a session the afternoon of September 15 on the “2017 Guidelines for Adult and Pediatric Hypertension.”
“I know that something will be discussed on September 14,” he told me recently. “I am not sure the full report will be ready then, but I think something will be presented that will at least describe the ‘attitude’ of the guidelines, if not the whole report. There will be more presented at the AHA Sessions in November.” Of course, there will also be “an accompanying evidence document describing the studies and evidence that generated the report, but I don’t know the release date,” he added.
Some of the suspense is already gone from the new guidelines, because the punch line – the new target blood pressure to treat toward for most U.S. adults with hypertension – is already known to be less than 130/80 mm Hg. That was the treatment goal set in April in updated guidelines for treating patients with heart failure by a panel of the ACC, the AHA, and the Heart Failure Society of America (J Am Coll Cardiol. 2017 Apr 30. doi: 10.1016/j.jacc.2017.04.025). Among the heart failure patients subject to this blood pressure target are adults with stage A heart failure, which the panel defined as any adult diagnosed with hypertension, as well as those with diabetes, coronary artery disease, or other risk factors that clearly predispose patients to develop heart failure.
Last April, the heart failure panel’s vice-chair, Mariell Jessup, MD, told me that the group chose a treatment target of less than 130/80 mm Hg to “harmonize” with the target that the hypertension guideline group had already selected.
So, in truth, an official U.S. hypertension treatment target of less than 130/80 mm Hg is already on the books for clinicians to follow that’s endorsed by the ACC and AHA. Unless the hypertension group throws a real curve ball its target will be identical.
But just knowing this lower target leaves important questions unanswered that presumably the hypertension panel will address. Questions like the best drug combinations to use to get blood pressures this low, and how aggressively to treat older patients with comorbidities who may need upward of four drugs to achieve a systolic blood pressure in this target range.
“I suspect some will say that the heart failure guidelines are for patients with heart failure, and thus the hypertension guidelines will complement them,” said Dr. Lackland. On the other hand, the SPRINT evidence is so persuasive that at least “some physicians will move to 130/80 mm Hg” readily, he predicted. “Others will probably wait and see, and some will wait even longer for follow-up comments” to come out.
Dr. Lackland also stressed the usual caveat about any medical guideline, that both the heart failure and hypertension statements simply give clinicians the recommended approach but “should not override clinical judgment for specific patients.”
But before the medical community can embrace or question the new hypertension guidelines it needs to at least see them. That finally seems ready to happen in September, and perhaps in November too.
[email protected]
On Twitter @mitchelzoler
Minor measles vaccination decline could triple childhood cases
, based on data from a mathematical model published in JAMA Pediatrics.
Increased reluctance among parents to vaccinate children has led to calls for a government commission on vaccine safety, wrote Nathan C. Lo of Stanford (Calif.) University, and Peter J. Hotez, MD, PhD, of Baylor College of Medicine, Houston (JAMA Pediatr. 2017 Jul 24. doi: 10.1001/jamapediatrics.2017.1695).
The researchers sought to estimate the potential impact of reduced vaccination on public health and the economy, using the MMR vaccine as an example. They collected vaccination data from the Centers for Disease Control and Prevention, created a mathematical model, and estimated $20,000 per case of measles from a public health perspective. They simulated a measles outbreak following the importation of measles into a county in the United States, and estimated the size of an outbreak based on local vaccine coverage.
In the model population, the average baseline coverage for MMR vaccination was 93% prevalence (varying by state from 87% to 97%). The average prevalence of nonmedical exemptions was 2%; state prevalence ranged from 0.4% to 6.2%. The annual number of measles cases was 48.
Using the model, a drop in MMR vaccination as little as 5% “would result in a threefold increase in national measles cases in this age group, for a total of 150 cases and an additional $2.1 million in economic costs to the public sector,” the researchers said. By contrast, increasing national MMR coverage to 95% would reduce the number of cases by 20%, they predicted.
“These estimates would be substantially higher if unvaccinated infants, adolescents, and adult populations are also considered,” Mr. Lo and Dr. Hotez said.
The study findings were limited by the use of a model and simulation of vaccine coverage, and by restricting the study to children aged 2-11 years.
However, the results “directly confront the notion that measles is no longer a threat in the United States,” and suggest “substantial public health and economic consequences with even minor reductions in MMR coverage due to vaccine hesitancy,” they emphasized. “Removal of the nonmedical personal belief exemptions for childhood vaccination may mitigate these consequences.”
Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.
, based on data from a mathematical model published in JAMA Pediatrics.
Increased reluctance among parents to vaccinate children has led to calls for a government commission on vaccine safety, wrote Nathan C. Lo of Stanford (Calif.) University, and Peter J. Hotez, MD, PhD, of Baylor College of Medicine, Houston (JAMA Pediatr. 2017 Jul 24. doi: 10.1001/jamapediatrics.2017.1695).
The researchers sought to estimate the potential impact of reduced vaccination on public health and the economy, using the MMR vaccine as an example. They collected vaccination data from the Centers for Disease Control and Prevention, created a mathematical model, and estimated $20,000 per case of measles from a public health perspective. They simulated a measles outbreak following the importation of measles into a county in the United States, and estimated the size of an outbreak based on local vaccine coverage.
In the model population, the average baseline coverage for MMR vaccination was 93% prevalence (varying by state from 87% to 97%). The average prevalence of nonmedical exemptions was 2%; state prevalence ranged from 0.4% to 6.2%. The annual number of measles cases was 48.
Using the model, a drop in MMR vaccination as little as 5% “would result in a threefold increase in national measles cases in this age group, for a total of 150 cases and an additional $2.1 million in economic costs to the public sector,” the researchers said. By contrast, increasing national MMR coverage to 95% would reduce the number of cases by 20%, they predicted.
“These estimates would be substantially higher if unvaccinated infants, adolescents, and adult populations are also considered,” Mr. Lo and Dr. Hotez said.
The study findings were limited by the use of a model and simulation of vaccine coverage, and by restricting the study to children aged 2-11 years.
However, the results “directly confront the notion that measles is no longer a threat in the United States,” and suggest “substantial public health and economic consequences with even minor reductions in MMR coverage due to vaccine hesitancy,” they emphasized. “Removal of the nonmedical personal belief exemptions for childhood vaccination may mitigate these consequences.”
Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.
, based on data from a mathematical model published in JAMA Pediatrics.
Increased reluctance among parents to vaccinate children has led to calls for a government commission on vaccine safety, wrote Nathan C. Lo of Stanford (Calif.) University, and Peter J. Hotez, MD, PhD, of Baylor College of Medicine, Houston (JAMA Pediatr. 2017 Jul 24. doi: 10.1001/jamapediatrics.2017.1695).
The researchers sought to estimate the potential impact of reduced vaccination on public health and the economy, using the MMR vaccine as an example. They collected vaccination data from the Centers for Disease Control and Prevention, created a mathematical model, and estimated $20,000 per case of measles from a public health perspective. They simulated a measles outbreak following the importation of measles into a county in the United States, and estimated the size of an outbreak based on local vaccine coverage.
In the model population, the average baseline coverage for MMR vaccination was 93% prevalence (varying by state from 87% to 97%). The average prevalence of nonmedical exemptions was 2%; state prevalence ranged from 0.4% to 6.2%. The annual number of measles cases was 48.
Using the model, a drop in MMR vaccination as little as 5% “would result in a threefold increase in national measles cases in this age group, for a total of 150 cases and an additional $2.1 million in economic costs to the public sector,” the researchers said. By contrast, increasing national MMR coverage to 95% would reduce the number of cases by 20%, they predicted.
“These estimates would be substantially higher if unvaccinated infants, adolescents, and adult populations are also considered,” Mr. Lo and Dr. Hotez said.
The study findings were limited by the use of a model and simulation of vaccine coverage, and by restricting the study to children aged 2-11 years.
However, the results “directly confront the notion that measles is no longer a threat in the United States,” and suggest “substantial public health and economic consequences with even minor reductions in MMR coverage due to vaccine hesitancy,” they emphasized. “Removal of the nonmedical personal belief exemptions for childhood vaccination may mitigate these consequences.”
Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.
FROM JAMA PEDIATRICS
Key clinical point: Even a small reduction in vaccination rates has significant public health and economic implications.
Major finding: A 5% decline in MMR vaccine coverage among children aged 2-11 years in the United States would yield an additional 150 measles cases at an economic cost of $2.1 million.
Data source: The data come from an analysis of children aged 2-11 years based on a mathematical model of MMR vaccination.
Disclosures: Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.
Extreme caffeine use in early pregnancy risks offspring behavioral disorders
, Susanne Hvolgaard Mikkelsen, PhD, of Aarhus (Denmark) University and her associates said.
“Caffeine metabolism is delayed during pregnancy, allowing longer opportunities for absorption. Caffeine increases dopamine levels by slowing down the rate of dopamine reabsorption, and this dysfunction of the dopaminergic system is thought to explain part of the association between caffeine consumption and offspring behavioral disorders,” the investigators said.
From 1996 to 2002, Danish physicians recruited women during their first pregnancy visit to participate in a study evaluating daily coffee and tea consumption during pregnancy, with follow-up of the children at age 11 years using the Danish National Birth Cohort. A follow-up questionnaire, including the Strength and Difficulties Questionnaire, was completed by the children, their parents, and their teachers; the results were paired with data on coffee and tea consumption by the mothers of 47,491 children. At 15 weeks’ gestation, 12% of the women had consumed more than three cups/day of coffee, and 3% ingested eight or more cups/day of coffee; 19% of the women drank more than three cups/day of tea, and 4% drank eight or more cups/day of tea. The amount of coffee and tea consumed at 30 weeks’ gestation was only slightly less.
The percentage of children predicted to have “possible/probable” ADHD was 5%, conduct-oppositional disorders was 7%, anxiety-depressive disorders was 7%, and any psychiatric disorder was 14%.
A statistically significant association was found between maternal consumption of eight or more cups of coffee at 15 weeks’ gestation and greater risk of ADHD (a risk ratio [RR] of 1.47), conduct-oppositional disorder (RR, 1.22), and any psychiatric disorder (RR, 1.23). A statistically significant link was found between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and greater risk of conduct-oppositional disorder (RR, 1.21). There was a statistically significant association between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and a higher risk of anxiety-depressive disorder (RR, 1.28), but not for coffee. These significant relationships were not found again at 30 weeks’ gestation.
“The period of greatest prenatal brain development is 10-26 weeks after conception,which may explain our results suggesting the fetus to be more vulnerable to caffeine in first and second trimester, compared with the third trimester,” the researchers said.
There was no information available about caffeine consumption by chocolate, energy drinks, or medication; the measure of cola consumption also was not taken into account. Confounding by genetics or socioeconomic factors may affect these findings, Dr. Mikkelsen and her associates said.
Read more at (J Pediatr. 2017 Jul 18. doi: 10.1016/j.jpeds.2017.06.051).
, Susanne Hvolgaard Mikkelsen, PhD, of Aarhus (Denmark) University and her associates said.
“Caffeine metabolism is delayed during pregnancy, allowing longer opportunities for absorption. Caffeine increases dopamine levels by slowing down the rate of dopamine reabsorption, and this dysfunction of the dopaminergic system is thought to explain part of the association between caffeine consumption and offspring behavioral disorders,” the investigators said.
From 1996 to 2002, Danish physicians recruited women during their first pregnancy visit to participate in a study evaluating daily coffee and tea consumption during pregnancy, with follow-up of the children at age 11 years using the Danish National Birth Cohort. A follow-up questionnaire, including the Strength and Difficulties Questionnaire, was completed by the children, their parents, and their teachers; the results were paired with data on coffee and tea consumption by the mothers of 47,491 children. At 15 weeks’ gestation, 12% of the women had consumed more than three cups/day of coffee, and 3% ingested eight or more cups/day of coffee; 19% of the women drank more than three cups/day of tea, and 4% drank eight or more cups/day of tea. The amount of coffee and tea consumed at 30 weeks’ gestation was only slightly less.
The percentage of children predicted to have “possible/probable” ADHD was 5%, conduct-oppositional disorders was 7%, anxiety-depressive disorders was 7%, and any psychiatric disorder was 14%.
A statistically significant association was found between maternal consumption of eight or more cups of coffee at 15 weeks’ gestation and greater risk of ADHD (a risk ratio [RR] of 1.47), conduct-oppositional disorder (RR, 1.22), and any psychiatric disorder (RR, 1.23). A statistically significant link was found between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and greater risk of conduct-oppositional disorder (RR, 1.21). There was a statistically significant association between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and a higher risk of anxiety-depressive disorder (RR, 1.28), but not for coffee. These significant relationships were not found again at 30 weeks’ gestation.
“The period of greatest prenatal brain development is 10-26 weeks after conception,which may explain our results suggesting the fetus to be more vulnerable to caffeine in first and second trimester, compared with the third trimester,” the researchers said.
There was no information available about caffeine consumption by chocolate, energy drinks, or medication; the measure of cola consumption also was not taken into account. Confounding by genetics or socioeconomic factors may affect these findings, Dr. Mikkelsen and her associates said.
Read more at (J Pediatr. 2017 Jul 18. doi: 10.1016/j.jpeds.2017.06.051).
, Susanne Hvolgaard Mikkelsen, PhD, of Aarhus (Denmark) University and her associates said.
“Caffeine metabolism is delayed during pregnancy, allowing longer opportunities for absorption. Caffeine increases dopamine levels by slowing down the rate of dopamine reabsorption, and this dysfunction of the dopaminergic system is thought to explain part of the association between caffeine consumption and offspring behavioral disorders,” the investigators said.
From 1996 to 2002, Danish physicians recruited women during their first pregnancy visit to participate in a study evaluating daily coffee and tea consumption during pregnancy, with follow-up of the children at age 11 years using the Danish National Birth Cohort. A follow-up questionnaire, including the Strength and Difficulties Questionnaire, was completed by the children, their parents, and their teachers; the results were paired with data on coffee and tea consumption by the mothers of 47,491 children. At 15 weeks’ gestation, 12% of the women had consumed more than three cups/day of coffee, and 3% ingested eight or more cups/day of coffee; 19% of the women drank more than three cups/day of tea, and 4% drank eight or more cups/day of tea. The amount of coffee and tea consumed at 30 weeks’ gestation was only slightly less.
The percentage of children predicted to have “possible/probable” ADHD was 5%, conduct-oppositional disorders was 7%, anxiety-depressive disorders was 7%, and any psychiatric disorder was 14%.
A statistically significant association was found between maternal consumption of eight or more cups of coffee at 15 weeks’ gestation and greater risk of ADHD (a risk ratio [RR] of 1.47), conduct-oppositional disorder (RR, 1.22), and any psychiatric disorder (RR, 1.23). A statistically significant link was found between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and greater risk of conduct-oppositional disorder (RR, 1.21). There was a statistically significant association between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and a higher risk of anxiety-depressive disorder (RR, 1.28), but not for coffee. These significant relationships were not found again at 30 weeks’ gestation.
“The period of greatest prenatal brain development is 10-26 weeks after conception,which may explain our results suggesting the fetus to be more vulnerable to caffeine in first and second trimester, compared with the third trimester,” the researchers said.
There was no information available about caffeine consumption by chocolate, energy drinks, or medication; the measure of cola consumption also was not taken into account. Confounding by genetics or socioeconomic factors may affect these findings, Dr. Mikkelsen and her associates said.
Read more at (J Pediatr. 2017 Jul 18. doi: 10.1016/j.jpeds.2017.06.051).
FROM THE JOURNAL OF PEDIATRICS
Long-acting injectable antiretroviral combo as good as HIV oral therapy
A long-acting injectable formulation combining two antiretroviral drugs – cabotegravir and rilpivirine – is as effective as a daily oral regimen of cabotegravir plus abacavir and lamivudine, according to interim results from the LATTE-2 trial.
Writing in the July 24 online edition of The Lancet, researchers have reported the 96-week results of the ongoing open-label phase 2b trial involving 286 treatment-naive adults infected with HIV-1.
At 32 weeks, 95% of patients in 8-week group, 94% of patients in the 4-week group, and 91% of patients in the oral therapy group had maintained viral suppression, defined as plasma HIV-1 RNA less than 50 copies per mL (Lancet. 2017 Jul 24. doi: 10.1016/S0140-6736[17]31917-7).
By week 96, viral suppression was seen in 94% of patients in the 8-week group, 87% of patients in the 4-week group and 84% of patients on oral treatment.
A nonresponse at 96 weeks was seen in five patients in the 8-week group and one patient in the oral therapy group. There were also two patients in the 8-week group and one in the oral treatment group who met the criteria for virologic failure.
“Viral genotyping analysis for the patient in the oral treatment group had no treatment-emergent resistance mutations in the genes encoding viral reverse transcriptase, protease, or integrase,” wrote David A. Margolis, MD, from ViiV Healthcare, and his coauthors.
Injection-site pain was the most common adverse event in the injectable groups, experienced by 96%-97% of patients, but most reactions were mild or moderate and lasted a median of 3 days.
There was only one drug-related serious adverse event, which was a migraine that occurred in one patient during the oral induction period. None of the other serious adverse events were deemed to be drug-related.
Patients reported high levels of treatment satisfaction across all study groups, and more than 99% of patients in the injectable treatment arms said they would be highly satisfied to continue with the regimen, compared with 78% of patients in the oral treatment arm.
“The acceptability and tolerability of injectable dosing options will be an important component of long-term treatment success, and a high degree of treatment satisfaction will avail this option for patients burdened by life-long daily oral medication compliance,” the authors wrote.
However they did note that the study population was mostly white men with a CD4+ cell count at entry of at least 200 cells per mm.
“Therefore, the efficacy, safety, and pharmacokinetic outcomes of long-acting cabotegravir plus rilpivirine in different subpopulations infected with HIV-1 needs further evaluation,” the investigators concluded.
The study was funded by ViiV Healthcare and Janssen R&D. Nine authors are employees of ViiV Healthcare and shareholders in GlaxoSmithKline. Nine authors declared funding, grants, and honoraria from a range of pharmaceutical companies including ViiV Healthcare. Two authors are employees and shareholders of GlaxoSmithKline. Two authors are employees of Janssen, and stockholders of Johnson & Johnson, AstraZeneca, or GlaxoSmithKline. One author had no conflicts to disclose.
A long-acting injectable formulation combining two antiretroviral drugs – cabotegravir and rilpivirine – is as effective as a daily oral regimen of cabotegravir plus abacavir and lamivudine, according to interim results from the LATTE-2 trial.
Writing in the July 24 online edition of The Lancet, researchers have reported the 96-week results of the ongoing open-label phase 2b trial involving 286 treatment-naive adults infected with HIV-1.
At 32 weeks, 95% of patients in 8-week group, 94% of patients in the 4-week group, and 91% of patients in the oral therapy group had maintained viral suppression, defined as plasma HIV-1 RNA less than 50 copies per mL (Lancet. 2017 Jul 24. doi: 10.1016/S0140-6736[17]31917-7).
By week 96, viral suppression was seen in 94% of patients in the 8-week group, 87% of patients in the 4-week group and 84% of patients on oral treatment.
A nonresponse at 96 weeks was seen in five patients in the 8-week group and one patient in the oral therapy group. There were also two patients in the 8-week group and one in the oral treatment group who met the criteria for virologic failure.
“Viral genotyping analysis for the patient in the oral treatment group had no treatment-emergent resistance mutations in the genes encoding viral reverse transcriptase, protease, or integrase,” wrote David A. Margolis, MD, from ViiV Healthcare, and his coauthors.
Injection-site pain was the most common adverse event in the injectable groups, experienced by 96%-97% of patients, but most reactions were mild or moderate and lasted a median of 3 days.
There was only one drug-related serious adverse event, which was a migraine that occurred in one patient during the oral induction period. None of the other serious adverse events were deemed to be drug-related.
Patients reported high levels of treatment satisfaction across all study groups, and more than 99% of patients in the injectable treatment arms said they would be highly satisfied to continue with the regimen, compared with 78% of patients in the oral treatment arm.
“The acceptability and tolerability of injectable dosing options will be an important component of long-term treatment success, and a high degree of treatment satisfaction will avail this option for patients burdened by life-long daily oral medication compliance,” the authors wrote.
However they did note that the study population was mostly white men with a CD4+ cell count at entry of at least 200 cells per mm.
“Therefore, the efficacy, safety, and pharmacokinetic outcomes of long-acting cabotegravir plus rilpivirine in different subpopulations infected with HIV-1 needs further evaluation,” the investigators concluded.
The study was funded by ViiV Healthcare and Janssen R&D. Nine authors are employees of ViiV Healthcare and shareholders in GlaxoSmithKline. Nine authors declared funding, grants, and honoraria from a range of pharmaceutical companies including ViiV Healthcare. Two authors are employees and shareholders of GlaxoSmithKline. Two authors are employees of Janssen, and stockholders of Johnson & Johnson, AstraZeneca, or GlaxoSmithKline. One author had no conflicts to disclose.
A long-acting injectable formulation combining two antiretroviral drugs – cabotegravir and rilpivirine – is as effective as a daily oral regimen of cabotegravir plus abacavir and lamivudine, according to interim results from the LATTE-2 trial.
Writing in the July 24 online edition of The Lancet, researchers have reported the 96-week results of the ongoing open-label phase 2b trial involving 286 treatment-naive adults infected with HIV-1.
At 32 weeks, 95% of patients in 8-week group, 94% of patients in the 4-week group, and 91% of patients in the oral therapy group had maintained viral suppression, defined as plasma HIV-1 RNA less than 50 copies per mL (Lancet. 2017 Jul 24. doi: 10.1016/S0140-6736[17]31917-7).
By week 96, viral suppression was seen in 94% of patients in the 8-week group, 87% of patients in the 4-week group and 84% of patients on oral treatment.
A nonresponse at 96 weeks was seen in five patients in the 8-week group and one patient in the oral therapy group. There were also two patients in the 8-week group and one in the oral treatment group who met the criteria for virologic failure.
“Viral genotyping analysis for the patient in the oral treatment group had no treatment-emergent resistance mutations in the genes encoding viral reverse transcriptase, protease, or integrase,” wrote David A. Margolis, MD, from ViiV Healthcare, and his coauthors.
Injection-site pain was the most common adverse event in the injectable groups, experienced by 96%-97% of patients, but most reactions were mild or moderate and lasted a median of 3 days.
There was only one drug-related serious adverse event, which was a migraine that occurred in one patient during the oral induction period. None of the other serious adverse events were deemed to be drug-related.
Patients reported high levels of treatment satisfaction across all study groups, and more than 99% of patients in the injectable treatment arms said they would be highly satisfied to continue with the regimen, compared with 78% of patients in the oral treatment arm.
“The acceptability and tolerability of injectable dosing options will be an important component of long-term treatment success, and a high degree of treatment satisfaction will avail this option for patients burdened by life-long daily oral medication compliance,” the authors wrote.
However they did note that the study population was mostly white men with a CD4+ cell count at entry of at least 200 cells per mm.
“Therefore, the efficacy, safety, and pharmacokinetic outcomes of long-acting cabotegravir plus rilpivirine in different subpopulations infected with HIV-1 needs further evaluation,” the investigators concluded.
The study was funded by ViiV Healthcare and Janssen R&D. Nine authors are employees of ViiV Healthcare and shareholders in GlaxoSmithKline. Nine authors declared funding, grants, and honoraria from a range of pharmaceutical companies including ViiV Healthcare. Two authors are employees and shareholders of GlaxoSmithKline. Two authors are employees of Janssen, and stockholders of Johnson & Johnson, AstraZeneca, or GlaxoSmithKline. One author had no conflicts to disclose.
FROM THE LANCET
Key clinical point: The long-acting injectable formulation of cabotegravir and rilpivirine is as effective as a daily oral regimen of cabotegravir plus abacavir and lamivudine.
Major finding: A long-acting injectable formulation of cabotegravir and rilpivirine, given either every 4 or 8 weeks, achieved similar levels of viral suppression to daily oral therapy with cabotegravir plus abacavir and lamivudine.
Data source: Randomized, open-label phase 2b study in 286 adults with HIV-1 infection.
Disclosures: This study was funded by ViiV Healthcare and Janssen R&D. Nine authors are employees of ViiV Healthcare and shareholders in GlaxoSmithKline. Nine authors declared funding, grants, and honoraria from a range of pharmaceutical companies including ViiV Healthcare. Two authors are employees and shareholders of GlaxoSmithKline. Two authors are employees of Janssen, and stockholders of Johnson & Johnson, AstraZeneca, or GlaxoSmithKline. One author had no conflicts to disclose.
Procalcitonin-guided decision making found best in neonatal suspected sepsis
, according to an investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study.
In the Neonatal Procalcitonin Intervention Study (NeoPInS) study aimed to reduce the duration of antibiotic treatment, 1,710 neonates who were already receiving antibiotic therapy were enrolled in 18 hospitals in Canada, the Czech Republic, the Netherlands, and Switzerland, and randomized to procalcitonin-guided decision making or standard care. Some patients were excluded from the larger initial population because of congenital malformation, surgery in the first week of life, or a lack of parental consent, among other reasons.
The intention-to-treat population included 866 neonates in the procalcitonin group whose median treatment duration was 55 hours (95% confidence interval [CI], 50.5-60.0) and 844 in the standard group whose median treatment duration was 65 hours (95% CI, 63.0-69.0; P less than .0001), with a median difference of –9.9. The per-protocol population saw an even greater median difference of –12.2, with a treatment duration of 52 hours in 745 neonates assigned to procalcitonin-guided decision making (95% CI, 48.2-56.0) and a duration of 64 hours in 663 neonates assigned to standard care (95% CI, 61.0-68.1; P less than .0001).
Length of hospital stay also was significantly shorter in both procalcitonin groups, according to the researchers.
One neonate in the standard group died from the consequences of severe perinatal asphyxia. In each procalcitonin group, five (0.6% and 0.7%, respectively) had a suspected reinfection, compared with three in each of the standard groups (0.5% and 0.6%, respectively). None of the neonates suspected of reinfection had a culture-proven bacteria infection.
“In this era of globally increasing antibiotic resistance rates ... every dose of antimicrobial therapy counts in the emergence of antimicrobial resistance and in changing the human microbiome,” the investigators wrote, “and other evidence suggests that changes in the microbiome in early life are particularly important in shaping the individual’s immune system and future health.”
The primary outcomes of the study were duration of treatment and reinfection or death in the first month of life, with a secondary outcome of length of hospital stay. Noninferiority for reinfection and death could not be shown because there were too few of these events.
“Procalcitonin-guided decision making led to a significant reduction in duration of empirical antibiotic therapy and hospital stay in term and near-term neonates with suspected early-onset sepsis, with a low rate of reinfections and with no study-related mortality. Combining serial procalcitonin measurements with initial assessment based on perinatal risk factors, the neonate’s clinical signs and symptoms, and conventional laboratory variables support antimicrobial stewardship and help physicians to decide to discontinue antibiotic treatment sooner in neonates classified as having low or moderate risk of infection,” Dr. Stocker, Dr. van Herk, and their associates said.
A limitation was that results cannot be extrapolated to other populations. The neonates in this study all had easy and low-threshold access to care, so the results may not apply to low-income or low-access areas, they said.
Length of hospital stay results may be affected by other conditions developed by the neonates. “It would be interesting to analyze duration of hospital stay separately for neonates with or without other reasons for hospital admission, but this was not possible in our study design,” the investigators said.
The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
Dr. Stocker, Dr. Herk, and their coauthors “are to be commended for conducting this pragmatic and international, multicenter trial.” When withholding antibiotics, especially from neonates who are susceptible to infection, safety is key. In this “landmark study done in neonates,” the authors determined that procalcitonin can be safely used to guide decision making in neonates at low risk of sepsis. Using procalcitonin in a clinical algorithm also was effective, reducing the duration of antibiotic therapy by around 20% and the length of hospital stay by around 5%.
Although the biomarker is the most accurate diagnostic tool currently available, it should be used with caution. On its own, it is not enough to determine if a neonate is in need of continued antibiotic therapy. It should be used in conjunction with clinical examination and reasoning on the part of the physician. In addition, the cutoffs that have been determined for adults are too low for neonates. “Nevertheless, if the cutoff is adapted accordingly and embedded in a reasonable clinical algorithm – as done in the NeoPInS study – procalcitonin can and should be used to improve antibiotic stewardship.
“Procalcitonin-guided antibiotic de-escalation therapy is evidence based and state of the art for antibiotic therapy for suspected and proven bacterial infection in different clinical settings and different acuity of infections.”
Philipp Schuetz, MD, and Beat Mueller, MD, are of the University of Basel, Aarau, Switzerland. Dr. Schuetz received support from BRAHMS/Thermofisher and bioMérieux to attend meetings, fulfill speaking engagements, and for unrestricted research grants related to procalcitonin. Dr. Mueller has received research support, as well as consulting fees and speakers’ honoraria, from BRAHMS/Thermofisher and bioMérieux, related to procalcitonin. They made these remarks in a commentary accompanying Dr. Stocker’s and Dr. van Herk’s report (Lancet. 2017 Jul 12. doi: 10.1016/S0140-6736[17]31628-8).
Dr. Stocker, Dr. Herk, and their coauthors “are to be commended for conducting this pragmatic and international, multicenter trial.” When withholding antibiotics, especially from neonates who are susceptible to infection, safety is key. In this “landmark study done in neonates,” the authors determined that procalcitonin can be safely used to guide decision making in neonates at low risk of sepsis. Using procalcitonin in a clinical algorithm also was effective, reducing the duration of antibiotic therapy by around 20% and the length of hospital stay by around 5%.
Although the biomarker is the most accurate diagnostic tool currently available, it should be used with caution. On its own, it is not enough to determine if a neonate is in need of continued antibiotic therapy. It should be used in conjunction with clinical examination and reasoning on the part of the physician. In addition, the cutoffs that have been determined for adults are too low for neonates. “Nevertheless, if the cutoff is adapted accordingly and embedded in a reasonable clinical algorithm – as done in the NeoPInS study – procalcitonin can and should be used to improve antibiotic stewardship.
“Procalcitonin-guided antibiotic de-escalation therapy is evidence based and state of the art for antibiotic therapy for suspected and proven bacterial infection in different clinical settings and different acuity of infections.”
Philipp Schuetz, MD, and Beat Mueller, MD, are of the University of Basel, Aarau, Switzerland. Dr. Schuetz received support from BRAHMS/Thermofisher and bioMérieux to attend meetings, fulfill speaking engagements, and for unrestricted research grants related to procalcitonin. Dr. Mueller has received research support, as well as consulting fees and speakers’ honoraria, from BRAHMS/Thermofisher and bioMérieux, related to procalcitonin. They made these remarks in a commentary accompanying Dr. Stocker’s and Dr. van Herk’s report (Lancet. 2017 Jul 12. doi: 10.1016/S0140-6736[17]31628-8).
Dr. Stocker, Dr. Herk, and their coauthors “are to be commended for conducting this pragmatic and international, multicenter trial.” When withholding antibiotics, especially from neonates who are susceptible to infection, safety is key. In this “landmark study done in neonates,” the authors determined that procalcitonin can be safely used to guide decision making in neonates at low risk of sepsis. Using procalcitonin in a clinical algorithm also was effective, reducing the duration of antibiotic therapy by around 20% and the length of hospital stay by around 5%.
Although the biomarker is the most accurate diagnostic tool currently available, it should be used with caution. On its own, it is not enough to determine if a neonate is in need of continued antibiotic therapy. It should be used in conjunction with clinical examination and reasoning on the part of the physician. In addition, the cutoffs that have been determined for adults are too low for neonates. “Nevertheless, if the cutoff is adapted accordingly and embedded in a reasonable clinical algorithm – as done in the NeoPInS study – procalcitonin can and should be used to improve antibiotic stewardship.
“Procalcitonin-guided antibiotic de-escalation therapy is evidence based and state of the art for antibiotic therapy for suspected and proven bacterial infection in different clinical settings and different acuity of infections.”
Philipp Schuetz, MD, and Beat Mueller, MD, are of the University of Basel, Aarau, Switzerland. Dr. Schuetz received support from BRAHMS/Thermofisher and bioMérieux to attend meetings, fulfill speaking engagements, and for unrestricted research grants related to procalcitonin. Dr. Mueller has received research support, as well as consulting fees and speakers’ honoraria, from BRAHMS/Thermofisher and bioMérieux, related to procalcitonin. They made these remarks in a commentary accompanying Dr. Stocker’s and Dr. van Herk’s report (Lancet. 2017 Jul 12. doi: 10.1016/S0140-6736[17]31628-8).
, according to an investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study.
In the Neonatal Procalcitonin Intervention Study (NeoPInS) study aimed to reduce the duration of antibiotic treatment, 1,710 neonates who were already receiving antibiotic therapy were enrolled in 18 hospitals in Canada, the Czech Republic, the Netherlands, and Switzerland, and randomized to procalcitonin-guided decision making or standard care. Some patients were excluded from the larger initial population because of congenital malformation, surgery in the first week of life, or a lack of parental consent, among other reasons.
The intention-to-treat population included 866 neonates in the procalcitonin group whose median treatment duration was 55 hours (95% confidence interval [CI], 50.5-60.0) and 844 in the standard group whose median treatment duration was 65 hours (95% CI, 63.0-69.0; P less than .0001), with a median difference of –9.9. The per-protocol population saw an even greater median difference of –12.2, with a treatment duration of 52 hours in 745 neonates assigned to procalcitonin-guided decision making (95% CI, 48.2-56.0) and a duration of 64 hours in 663 neonates assigned to standard care (95% CI, 61.0-68.1; P less than .0001).
Length of hospital stay also was significantly shorter in both procalcitonin groups, according to the researchers.
One neonate in the standard group died from the consequences of severe perinatal asphyxia. In each procalcitonin group, five (0.6% and 0.7%, respectively) had a suspected reinfection, compared with three in each of the standard groups (0.5% and 0.6%, respectively). None of the neonates suspected of reinfection had a culture-proven bacteria infection.
“In this era of globally increasing antibiotic resistance rates ... every dose of antimicrobial therapy counts in the emergence of antimicrobial resistance and in changing the human microbiome,” the investigators wrote, “and other evidence suggests that changes in the microbiome in early life are particularly important in shaping the individual’s immune system and future health.”
The primary outcomes of the study were duration of treatment and reinfection or death in the first month of life, with a secondary outcome of length of hospital stay. Noninferiority for reinfection and death could not be shown because there were too few of these events.
“Procalcitonin-guided decision making led to a significant reduction in duration of empirical antibiotic therapy and hospital stay in term and near-term neonates with suspected early-onset sepsis, with a low rate of reinfections and with no study-related mortality. Combining serial procalcitonin measurements with initial assessment based on perinatal risk factors, the neonate’s clinical signs and symptoms, and conventional laboratory variables support antimicrobial stewardship and help physicians to decide to discontinue antibiotic treatment sooner in neonates classified as having low or moderate risk of infection,” Dr. Stocker, Dr. van Herk, and their associates said.
A limitation was that results cannot be extrapolated to other populations. The neonates in this study all had easy and low-threshold access to care, so the results may not apply to low-income or low-access areas, they said.
Length of hospital stay results may be affected by other conditions developed by the neonates. “It would be interesting to analyze duration of hospital stay separately for neonates with or without other reasons for hospital admission, but this was not possible in our study design,” the investigators said.
The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
, according to an investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study.
In the Neonatal Procalcitonin Intervention Study (NeoPInS) study aimed to reduce the duration of antibiotic treatment, 1,710 neonates who were already receiving antibiotic therapy were enrolled in 18 hospitals in Canada, the Czech Republic, the Netherlands, and Switzerland, and randomized to procalcitonin-guided decision making or standard care. Some patients were excluded from the larger initial population because of congenital malformation, surgery in the first week of life, or a lack of parental consent, among other reasons.
The intention-to-treat population included 866 neonates in the procalcitonin group whose median treatment duration was 55 hours (95% confidence interval [CI], 50.5-60.0) and 844 in the standard group whose median treatment duration was 65 hours (95% CI, 63.0-69.0; P less than .0001), with a median difference of –9.9. The per-protocol population saw an even greater median difference of –12.2, with a treatment duration of 52 hours in 745 neonates assigned to procalcitonin-guided decision making (95% CI, 48.2-56.0) and a duration of 64 hours in 663 neonates assigned to standard care (95% CI, 61.0-68.1; P less than .0001).
Length of hospital stay also was significantly shorter in both procalcitonin groups, according to the researchers.
One neonate in the standard group died from the consequences of severe perinatal asphyxia. In each procalcitonin group, five (0.6% and 0.7%, respectively) had a suspected reinfection, compared with three in each of the standard groups (0.5% and 0.6%, respectively). None of the neonates suspected of reinfection had a culture-proven bacteria infection.
“In this era of globally increasing antibiotic resistance rates ... every dose of antimicrobial therapy counts in the emergence of antimicrobial resistance and in changing the human microbiome,” the investigators wrote, “and other evidence suggests that changes in the microbiome in early life are particularly important in shaping the individual’s immune system and future health.”
The primary outcomes of the study were duration of treatment and reinfection or death in the first month of life, with a secondary outcome of length of hospital stay. Noninferiority for reinfection and death could not be shown because there were too few of these events.
“Procalcitonin-guided decision making led to a significant reduction in duration of empirical antibiotic therapy and hospital stay in term and near-term neonates with suspected early-onset sepsis, with a low rate of reinfections and with no study-related mortality. Combining serial procalcitonin measurements with initial assessment based on perinatal risk factors, the neonate’s clinical signs and symptoms, and conventional laboratory variables support antimicrobial stewardship and help physicians to decide to discontinue antibiotic treatment sooner in neonates classified as having low or moderate risk of infection,” Dr. Stocker, Dr. van Herk, and their associates said.
A limitation was that results cannot be extrapolated to other populations. The neonates in this study all had easy and low-threshold access to care, so the results may not apply to low-income or low-access areas, they said.
Length of hospital stay results may be affected by other conditions developed by the neonates. “It would be interesting to analyze duration of hospital stay separately for neonates with or without other reasons for hospital admission, but this was not possible in our study design,” the investigators said.
The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
FROM THE LANCET
Key clinical point: Procalcitonin-guided decision making had a significant impact on duration of antibiotic treatment and hospital stay in pediatric patients with suspected early-onset sepsis.
Major finding: The median differences in antibiotic treatment duration between procalcitonin groups and standard care groups were –9.9 and –12.1 hours in intention-to-treat and per protocol study populations.
Data source: An investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study (NeoPInS) of 1,710 neonates with suspected early-stage sepsis.
Disclosures: The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
CCDSSs to prevent VTE
Title: Use of computerized clinical decision support systems decreases venous thromboembolic events in surgical patients
Clinical Question: Do computerized clinical decision support systems (CCDSSs) decrease the risk of venous thromboembolism (VTE) in surgical patients?
Background: VTE remains the leading preventable cause of death in the hospital. Despite multiple tools that are available to stratify risk of VTE, they are not used uniformly or are used incorrectly. It is unclear whether CCDSSs help prevent VTE compared to standard care.
Study Design: Retrospective systematic review and meta-analysis.
Setting: 188 studies initially screened, 11 studies were included.
Synopsis: Multiple studies relevant to the topic were reviewed; only studies that used an electronic medical record (EMR)–based tool to augment the rate of appropriate prophylaxis of VTE were included. Primary outcomes assessed were rate of appropriate prophylaxis for VTE and rate of VTE events. A total of 156,366 patients were analyzed, of which 104,241 (66%) received intervention with CCDSSs and 52,125 (33%) received standard care (physician judgment and discretion). The use of CCDSSs was associated with a significant increase in the rate of appropriate ordering of prophylaxis for VTE (odds ratio, 2.35; 95% confidence interval, 1.78-3.10; P less than .001) and a significant decrease in the risk of VTE events (risk ratio, 0.78; 95% CI, 0.72-0.85; P less than .001). The major limitation of this study is that it did not evaluate the number of adverse events as a result of VTE prophylaxis, such as bleeding, which may have been significantly increased in the CCDSS group.
Bottom Line: The use of CCDSSs increases the proportion of surgical patients who are prescribed adequate prophylaxis for VTE and correlates with a reduction in VTE events.
Citation: Borab ZM, Lanni MA, Tecce MG, Pannucci CJ, Fischer JP. Use of computerized clinical decision support systems to prevent venous thromboembolism in surgical patients: A systematic review and meta-analysis. JAMA Surg. 2017; doi: 10.1001/jamasurg.2017.0131.
Dr. Mayasy is assistant professor in the department of hospital medicine at the University of New Mexico.
Title: Use of computerized clinical decision support systems decreases venous thromboembolic events in surgical patients
Clinical Question: Do computerized clinical decision support systems (CCDSSs) decrease the risk of venous thromboembolism (VTE) in surgical patients?
Background: VTE remains the leading preventable cause of death in the hospital. Despite multiple tools that are available to stratify risk of VTE, they are not used uniformly or are used incorrectly. It is unclear whether CCDSSs help prevent VTE compared to standard care.
Study Design: Retrospective systematic review and meta-analysis.
Setting: 188 studies initially screened, 11 studies were included.
Synopsis: Multiple studies relevant to the topic were reviewed; only studies that used an electronic medical record (EMR)–based tool to augment the rate of appropriate prophylaxis of VTE were included. Primary outcomes assessed were rate of appropriate prophylaxis for VTE and rate of VTE events. A total of 156,366 patients were analyzed, of which 104,241 (66%) received intervention with CCDSSs and 52,125 (33%) received standard care (physician judgment and discretion). The use of CCDSSs was associated with a significant increase in the rate of appropriate ordering of prophylaxis for VTE (odds ratio, 2.35; 95% confidence interval, 1.78-3.10; P less than .001) and a significant decrease in the risk of VTE events (risk ratio, 0.78; 95% CI, 0.72-0.85; P less than .001). The major limitation of this study is that it did not evaluate the number of adverse events as a result of VTE prophylaxis, such as bleeding, which may have been significantly increased in the CCDSS group.
Bottom Line: The use of CCDSSs increases the proportion of surgical patients who are prescribed adequate prophylaxis for VTE and correlates with a reduction in VTE events.
Citation: Borab ZM, Lanni MA, Tecce MG, Pannucci CJ, Fischer JP. Use of computerized clinical decision support systems to prevent venous thromboembolism in surgical patients: A systematic review and meta-analysis. JAMA Surg. 2017; doi: 10.1001/jamasurg.2017.0131.
Dr. Mayasy is assistant professor in the department of hospital medicine at the University of New Mexico.
Title: Use of computerized clinical decision support systems decreases venous thromboembolic events in surgical patients
Clinical Question: Do computerized clinical decision support systems (CCDSSs) decrease the risk of venous thromboembolism (VTE) in surgical patients?
Background: VTE remains the leading preventable cause of death in the hospital. Despite multiple tools that are available to stratify risk of VTE, they are not used uniformly or are used incorrectly. It is unclear whether CCDSSs help prevent VTE compared to standard care.
Study Design: Retrospective systematic review and meta-analysis.
Setting: 188 studies initially screened, 11 studies were included.
Synopsis: Multiple studies relevant to the topic were reviewed; only studies that used an electronic medical record (EMR)–based tool to augment the rate of appropriate prophylaxis of VTE were included. Primary outcomes assessed were rate of appropriate prophylaxis for VTE and rate of VTE events. A total of 156,366 patients were analyzed, of which 104,241 (66%) received intervention with CCDSSs and 52,125 (33%) received standard care (physician judgment and discretion). The use of CCDSSs was associated with a significant increase in the rate of appropriate ordering of prophylaxis for VTE (odds ratio, 2.35; 95% confidence interval, 1.78-3.10; P less than .001) and a significant decrease in the risk of VTE events (risk ratio, 0.78; 95% CI, 0.72-0.85; P less than .001). The major limitation of this study is that it did not evaluate the number of adverse events as a result of VTE prophylaxis, such as bleeding, which may have been significantly increased in the CCDSS group.
Bottom Line: The use of CCDSSs increases the proportion of surgical patients who are prescribed adequate prophylaxis for VTE and correlates with a reduction in VTE events.
Citation: Borab ZM, Lanni MA, Tecce MG, Pannucci CJ, Fischer JP. Use of computerized clinical decision support systems to prevent venous thromboembolism in surgical patients: A systematic review and meta-analysis. JAMA Surg. 2017; doi: 10.1001/jamasurg.2017.0131.
Dr. Mayasy is assistant professor in the department of hospital medicine at the University of New Mexico.
Ask PAs to Complete Survey on Joining 1st SVS ‘Section’
SVS President Dr. Clem Darling is asking all members to pass an email message – and survey – along to PAs and Nurse Practitioners with whom members work.
During the recent Vascular Annual Meeting, SVS leaders met with six physician assistants, all of whom work in vascular settings, and asked if they wish to work on establishing a home within the SVS. “Their response was a resounding and enthusiastic …YES!,” said Dr. Darling.
The group has now become the Steering Committee organizing the effort to create the historic first "Section" of the SVS.
SVS President Dr. Clem Darling is asking all members to pass an email message – and survey – along to PAs and Nurse Practitioners with whom members work.
During the recent Vascular Annual Meeting, SVS leaders met with six physician assistants, all of whom work in vascular settings, and asked if they wish to work on establishing a home within the SVS. “Their response was a resounding and enthusiastic …YES!,” said Dr. Darling.
The group has now become the Steering Committee organizing the effort to create the historic first "Section" of the SVS.
SVS President Dr. Clem Darling is asking all members to pass an email message – and survey – along to PAs and Nurse Practitioners with whom members work.
During the recent Vascular Annual Meeting, SVS leaders met with six physician assistants, all of whom work in vascular settings, and asked if they wish to work on establishing a home within the SVS. “Their response was a resounding and enthusiastic …YES!,” said Dr. Darling.
The group has now become the Steering Committee organizing the effort to create the historic first "Section" of the SVS.
Senate parliamentarian upends GOP hopes for health bill
The official rules keeper in the Senate tossed a bucket of cold water July 21 on the Senate Republican health bill by advising that major parts of the bill cannot be passed with a simple majority, but rather would require 60 votes. Republicans hold only 52 seats in the Senate.
Senate Parliamentarian Elizabeth MacDonough said that a super-majority is needed for the temporary defunding of Planned Parenthood, abortion coverage restrictions to health plans purchased with tax credits, and the requirement that people with breaks in coverage wait 6 months before they can purchase new plans.
The list was released by Democrats on the Senate Budget Committee and later confirmed by a spokesman for the committee Republicans. It is the result of what is called the “Byrd Bath,” a process in which the parliamentarian hears arguments from Democrats and Republicans and then advises on which provisions comply with the Byrd Rule. That rule requires that only matters directly pertaining to the federal budget are included. The rule is named for former Senate Majority Leader Robert Byrd (D-W.Va.), who first wrote it.
Senate Republicans were quick to point out that the document is “guidance” that they can use to try to rewrite impermissible language. The guidance “will help inform action on the legislation going forward,” said a spokesman for Senate Budget Committee Chairman Mike Enzi (R-Wyo.).
Among the other provisions that the parliamentarian has advised should require 60 votes are ones that would eliminate Medicaid requirements to provide 10 “essential health benefits.” Also on the list is a provision to repeal a requirement that insurers spend a minimum amount of each premium dollar on direct medical services, rather than administration or profits.
The determination also pertains to a part of the bill that would continue payments for “cost-sharing subsidies” to insurers for 2 more years. Those subsidies help lower-income people afford out-of-pocket costs such as deductibles. The parliamentarian said that duplicated existing law.
Ms. MacDonough also said that a provision in the House version of the bill that pertains directly to New York violates the Byrd Rule. That measure would change the way the state collects money for Medicaid. That could suggest efforts by Senate Majority Leader Mitch McConnell (R-Ky.) to offer state-specific changes to gain support for the bill might meet the same fate.
Minority Leader Chuck Schumer (D-N.Y.) said that decision could have “the greatest effect on Republicans’ ability to pass this bill.” He predicted it would “tie the majority leader’s hands as he tries to win over reluctant Republicans.”
Some of the provisions that didn’t pass muster with Ms. MacDonough were key to getting the bill through the House. And if they are dropped, it might make it difficult for the House to approve a final version of the bill.
Not all the decisions went the Democrats’ way. Ms. MacDonough found that only a simple majority is needed for language allowing states to impose work requirements for Medicaid recipients. She also said that a provision that will ban abortions if the services are paid through a new fund provided to states would be allowed. That’s because that fund will be governed by existing rules that already ban abortion in most cases.
A few provisions remain under review, according to the list. Those include allowing states to waive a long list of insurance protections, including the ACA’s essential health benefits and preexisting coverage guarantees. Also still under review is language allowing small businesses to pool together to purchase insurance as well as a provision changing requirements related to how much more insurers can charge older adults.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
The official rules keeper in the Senate tossed a bucket of cold water July 21 on the Senate Republican health bill by advising that major parts of the bill cannot be passed with a simple majority, but rather would require 60 votes. Republicans hold only 52 seats in the Senate.
Senate Parliamentarian Elizabeth MacDonough said that a super-majority is needed for the temporary defunding of Planned Parenthood, abortion coverage restrictions to health plans purchased with tax credits, and the requirement that people with breaks in coverage wait 6 months before they can purchase new plans.
The list was released by Democrats on the Senate Budget Committee and later confirmed by a spokesman for the committee Republicans. It is the result of what is called the “Byrd Bath,” a process in which the parliamentarian hears arguments from Democrats and Republicans and then advises on which provisions comply with the Byrd Rule. That rule requires that only matters directly pertaining to the federal budget are included. The rule is named for former Senate Majority Leader Robert Byrd (D-W.Va.), who first wrote it.
Senate Republicans were quick to point out that the document is “guidance” that they can use to try to rewrite impermissible language. The guidance “will help inform action on the legislation going forward,” said a spokesman for Senate Budget Committee Chairman Mike Enzi (R-Wyo.).
Among the other provisions that the parliamentarian has advised should require 60 votes are ones that would eliminate Medicaid requirements to provide 10 “essential health benefits.” Also on the list is a provision to repeal a requirement that insurers spend a minimum amount of each premium dollar on direct medical services, rather than administration or profits.
The determination also pertains to a part of the bill that would continue payments for “cost-sharing subsidies” to insurers for 2 more years. Those subsidies help lower-income people afford out-of-pocket costs such as deductibles. The parliamentarian said that duplicated existing law.
Ms. MacDonough also said that a provision in the House version of the bill that pertains directly to New York violates the Byrd Rule. That measure would change the way the state collects money for Medicaid. That could suggest efforts by Senate Majority Leader Mitch McConnell (R-Ky.) to offer state-specific changes to gain support for the bill might meet the same fate.
Minority Leader Chuck Schumer (D-N.Y.) said that decision could have “the greatest effect on Republicans’ ability to pass this bill.” He predicted it would “tie the majority leader’s hands as he tries to win over reluctant Republicans.”
Some of the provisions that didn’t pass muster with Ms. MacDonough were key to getting the bill through the House. And if they are dropped, it might make it difficult for the House to approve a final version of the bill.
Not all the decisions went the Democrats’ way. Ms. MacDonough found that only a simple majority is needed for language allowing states to impose work requirements for Medicaid recipients. She also said that a provision that will ban abortions if the services are paid through a new fund provided to states would be allowed. That’s because that fund will be governed by existing rules that already ban abortion in most cases.
A few provisions remain under review, according to the list. Those include allowing states to waive a long list of insurance protections, including the ACA’s essential health benefits and preexisting coverage guarantees. Also still under review is language allowing small businesses to pool together to purchase insurance as well as a provision changing requirements related to how much more insurers can charge older adults.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
The official rules keeper in the Senate tossed a bucket of cold water July 21 on the Senate Republican health bill by advising that major parts of the bill cannot be passed with a simple majority, but rather would require 60 votes. Republicans hold only 52 seats in the Senate.
Senate Parliamentarian Elizabeth MacDonough said that a super-majority is needed for the temporary defunding of Planned Parenthood, abortion coverage restrictions to health plans purchased with tax credits, and the requirement that people with breaks in coverage wait 6 months before they can purchase new plans.
The list was released by Democrats on the Senate Budget Committee and later confirmed by a spokesman for the committee Republicans. It is the result of what is called the “Byrd Bath,” a process in which the parliamentarian hears arguments from Democrats and Republicans and then advises on which provisions comply with the Byrd Rule. That rule requires that only matters directly pertaining to the federal budget are included. The rule is named for former Senate Majority Leader Robert Byrd (D-W.Va.), who first wrote it.
Senate Republicans were quick to point out that the document is “guidance” that they can use to try to rewrite impermissible language. The guidance “will help inform action on the legislation going forward,” said a spokesman for Senate Budget Committee Chairman Mike Enzi (R-Wyo.).
Among the other provisions that the parliamentarian has advised should require 60 votes are ones that would eliminate Medicaid requirements to provide 10 “essential health benefits.” Also on the list is a provision to repeal a requirement that insurers spend a minimum amount of each premium dollar on direct medical services, rather than administration or profits.
The determination also pertains to a part of the bill that would continue payments for “cost-sharing subsidies” to insurers for 2 more years. Those subsidies help lower-income people afford out-of-pocket costs such as deductibles. The parliamentarian said that duplicated existing law.
Ms. MacDonough also said that a provision in the House version of the bill that pertains directly to New York violates the Byrd Rule. That measure would change the way the state collects money for Medicaid. That could suggest efforts by Senate Majority Leader Mitch McConnell (R-Ky.) to offer state-specific changes to gain support for the bill might meet the same fate.
Minority Leader Chuck Schumer (D-N.Y.) said that decision could have “the greatest effect on Republicans’ ability to pass this bill.” He predicted it would “tie the majority leader’s hands as he tries to win over reluctant Republicans.”
Some of the provisions that didn’t pass muster with Ms. MacDonough were key to getting the bill through the House. And if they are dropped, it might make it difficult for the House to approve a final version of the bill.
Not all the decisions went the Democrats’ way. Ms. MacDonough found that only a simple majority is needed for language allowing states to impose work requirements for Medicaid recipients. She also said that a provision that will ban abortions if the services are paid through a new fund provided to states would be allowed. That’s because that fund will be governed by existing rules that already ban abortion in most cases.
A few provisions remain under review, according to the list. Those include allowing states to waive a long list of insurance protections, including the ACA’s essential health benefits and preexisting coverage guarantees. Also still under review is language allowing small businesses to pool together to purchase insurance as well as a provision changing requirements related to how much more insurers can charge older adults.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Novel knee osteoarthritis drugs target pain, joint space narrowing
MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.
In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.
These findings suggest that both could be future alternatives to using nonsteroidal anti-inflammatory drugs (NSAIDs), injected corticosteroids, and opioid analgesics, which are currently used to help manage knee OA.
Synthetic trans-capsaicin CNTX-4975
“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.
CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.
The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m2, and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.
The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.
The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).
“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.
The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.
A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).
“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.
Wnt inhibitor SM04690
Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.
Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.
SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.
Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.
In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.
Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.
A total of 455 subjects, mean age 60 years, were randomized into the trial.
Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.
An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.
The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).
However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.
Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.
“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.
The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.
MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.
In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.
These findings suggest that both could be future alternatives to using nonsteroidal anti-inflammatory drugs (NSAIDs), injected corticosteroids, and opioid analgesics, which are currently used to help manage knee OA.
Synthetic trans-capsaicin CNTX-4975
“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.
CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.
The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m2, and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.
The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.
The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).
“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.
The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.
A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).
“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.
Wnt inhibitor SM04690
Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.
Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.
SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.
Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.
In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.
Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.
A total of 455 subjects, mean age 60 years, were randomized into the trial.
Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.
An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.
The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).
However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.
Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.
“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.
The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.
MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.
In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.
These findings suggest that both could be future alternatives to using nonsteroidal anti-inflammatory drugs (NSAIDs), injected corticosteroids, and opioid analgesics, which are currently used to help manage knee OA.
Synthetic trans-capsaicin CNTX-4975
“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.
CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.
The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m2, and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.
The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.
The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).
“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.
The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.
A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).
“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.
Wnt inhibitor SM04690
Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.
Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.
SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.
Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.
In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.
Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.
A total of 455 subjects, mean age 60 years, were randomized into the trial.
Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.
An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.
The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).
However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.
Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.
“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.
The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Radiographic joint space narrowing was no worse or improved after treatment with the Wnt pathway inhibitor SM04690. Treatment with the synthetic trans-capsaicin CNTX-4975 improved pain when walking, knee stiffness, and physical function.
Data source: Two independently conducted randomized, phase 2 trials of patients with moderate to severe knee OA: a 52-week trial with SM04690 in 455 patients and a 24-week trial of CNTX-4975 in 175 patients.
Disclosures: Samumed and Centrexion Therapeutics sponsored the two separate studies. The presenting authors were employees and shareholders of their respective companies.
Meta-analysis shows correlation between diabetes and erectile dysfunction
WASHINGTON – More than half of men with type 1 or type 2 diabetes develop erectile dysfunction, making them more than three times as likely to develop ED, compared with healthy men, according to a systematic review of diabetes studies.
Data on the exact prevalence of erectile dysfunction in this population has been lacking until now. More precise figures are available from a meta-analysis of 145 studies taken from international diabetes databases.
In terms of risk, men with diabetes were 3.62 (95% CI, 2.53-5.16; P less than .0001) times more likely to develop ED, compared with healthy controls, according to investigators (Diabet Med. 2017 Jul 18. doi: 10.1111/dme.13403).
“Regarding sexual activity and the psychological impact of erectile dysfunction in men with diabetes mellitus, significant and positive associations have been found between depressive symptoms and erectile dysfunction,” said Youssef Kouidrat, MD, PhD, of the department of psychosis studies, Institute of Psychiatry, King’s College London, and his fellow researchers. “Therefore, early detection of erectile dysfunction is essential to improve the psychological health and men’s quality of life.”
Given ED’s serious effects on patients’ physical and emotional well being, it is essential for physicians to have a better understanding of the root causes of the condition in order to help patients as soon as possible, wrote the investigators.
The studies included in the meta-analysis represented a population of 88.755 men with an average age of 56 years, with dates of the studies ranging from the inception of the databases they were taken from up until November 2016.
A majority of the studies included were conducted in Asia (61), followed by Europe (48), North America (17), Africa (15), and Oceania, South America, and multiple continents (4 in total).
South America reported the highest prevalence of ED (74.6%), while the lowest prevalence reported was among studies in North America (34.5%).
Patients who were assessed using the Sexual Health Inventory for Men (SHIM) score reported a higher ED prevalence (82.2%), as did men above the age of 60 years old (62.2%).
With ED correlated to cardiovascular health and mortality, investigators advise physicians to keep testing in mind when assessing patients’ cardiovascular risk.
This study was limited by incomplete data from studies included, which made it difficult to determine prevalence by certain categories.
Other limitations included the lack of separation between type 1 and type 2 diabetes among many of the studies analyzed, as well as a lack of information from the studies analyzed on other risk factors concerning diabetes-related erectile dysfunction.
Investigators reported no relevant financial disclosures.
[email protected]
On Twitter @eaztweets
WASHINGTON – More than half of men with type 1 or type 2 diabetes develop erectile dysfunction, making them more than three times as likely to develop ED, compared with healthy men, according to a systematic review of diabetes studies.
Data on the exact prevalence of erectile dysfunction in this population has been lacking until now. More precise figures are available from a meta-analysis of 145 studies taken from international diabetes databases.
In terms of risk, men with diabetes were 3.62 (95% CI, 2.53-5.16; P less than .0001) times more likely to develop ED, compared with healthy controls, according to investigators (Diabet Med. 2017 Jul 18. doi: 10.1111/dme.13403).
“Regarding sexual activity and the psychological impact of erectile dysfunction in men with diabetes mellitus, significant and positive associations have been found between depressive symptoms and erectile dysfunction,” said Youssef Kouidrat, MD, PhD, of the department of psychosis studies, Institute of Psychiatry, King’s College London, and his fellow researchers. “Therefore, early detection of erectile dysfunction is essential to improve the psychological health and men’s quality of life.”
Given ED’s serious effects on patients’ physical and emotional well being, it is essential for physicians to have a better understanding of the root causes of the condition in order to help patients as soon as possible, wrote the investigators.
The studies included in the meta-analysis represented a population of 88.755 men with an average age of 56 years, with dates of the studies ranging from the inception of the databases they were taken from up until November 2016.
A majority of the studies included were conducted in Asia (61), followed by Europe (48), North America (17), Africa (15), and Oceania, South America, and multiple continents (4 in total).
South America reported the highest prevalence of ED (74.6%), while the lowest prevalence reported was among studies in North America (34.5%).
Patients who were assessed using the Sexual Health Inventory for Men (SHIM) score reported a higher ED prevalence (82.2%), as did men above the age of 60 years old (62.2%).
With ED correlated to cardiovascular health and mortality, investigators advise physicians to keep testing in mind when assessing patients’ cardiovascular risk.
This study was limited by incomplete data from studies included, which made it difficult to determine prevalence by certain categories.
Other limitations included the lack of separation between type 1 and type 2 diabetes among many of the studies analyzed, as well as a lack of information from the studies analyzed on other risk factors concerning diabetes-related erectile dysfunction.
Investigators reported no relevant financial disclosures.
[email protected]
On Twitter @eaztweets
WASHINGTON – More than half of men with type 1 or type 2 diabetes develop erectile dysfunction, making them more than three times as likely to develop ED, compared with healthy men, according to a systematic review of diabetes studies.
Data on the exact prevalence of erectile dysfunction in this population has been lacking until now. More precise figures are available from a meta-analysis of 145 studies taken from international diabetes databases.
In terms of risk, men with diabetes were 3.62 (95% CI, 2.53-5.16; P less than .0001) times more likely to develop ED, compared with healthy controls, according to investigators (Diabet Med. 2017 Jul 18. doi: 10.1111/dme.13403).
“Regarding sexual activity and the psychological impact of erectile dysfunction in men with diabetes mellitus, significant and positive associations have been found between depressive symptoms and erectile dysfunction,” said Youssef Kouidrat, MD, PhD, of the department of psychosis studies, Institute of Psychiatry, King’s College London, and his fellow researchers. “Therefore, early detection of erectile dysfunction is essential to improve the psychological health and men’s quality of life.”
Given ED’s serious effects on patients’ physical and emotional well being, it is essential for physicians to have a better understanding of the root causes of the condition in order to help patients as soon as possible, wrote the investigators.
The studies included in the meta-analysis represented a population of 88.755 men with an average age of 56 years, with dates of the studies ranging from the inception of the databases they were taken from up until November 2016.
A majority of the studies included were conducted in Asia (61), followed by Europe (48), North America (17), Africa (15), and Oceania, South America, and multiple continents (4 in total).
South America reported the highest prevalence of ED (74.6%), while the lowest prevalence reported was among studies in North America (34.5%).
Patients who were assessed using the Sexual Health Inventory for Men (SHIM) score reported a higher ED prevalence (82.2%), as did men above the age of 60 years old (62.2%).
With ED correlated to cardiovascular health and mortality, investigators advise physicians to keep testing in mind when assessing patients’ cardiovascular risk.
This study was limited by incomplete data from studies included, which made it difficult to determine prevalence by certain categories.
Other limitations included the lack of separation between type 1 and type 2 diabetes among many of the studies analyzed, as well as a lack of information from the studies analyzed on other risk factors concerning diabetes-related erectile dysfunction.
Investigators reported no relevant financial disclosures.
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FROM DIABETIC MEDICINE
Key clinical point:
Major finding: Men with diabetes showed an odds ratio of 3.62 (95% CI, 2.53-5.16; P less than .0001) of developing erectile dysfunction, compared with healthy controls.
Data source: An analysis of 145 studies representing 88,577 men from international databases spanning from creation of the database to November 2016.
Disclosures: Investigators report no relevant financial disclosures.