Mary Ann Moon

Continuous chest compressions during CPR failed to improve survival or neurologic function compared with standard chest compressions that are briefly interrupted for ventilation, based on findings in the first large randomized trial to compare the two strategies for out-of-hospital, nontraumatic cardiac arrest.

In a presentation at the American Heart Association scientific sessions, simultaneously published online Nov. 9 in the New England Journal of Medicine, Dr. Graham Nichol and his associates analyzed data from the Resuscitation Outcomes Consortium, a network of clinical centers and EMS agencies that have expertise in conducting research on out-of-hospital cardiac arrest.

Data were analyzed for 23,711 adults treated by 114 EMS agencies affiliated with eight clinical centers across the United States and Canada. These agencies were grouped into 47 clusters that were randomly assigned to perform CPR using either continuous chest compressions (100 per minute) with asynchronous positive-pressure ventilations (10 per minute) or standard chest compressions interrupted for ventilations (at a rate of 30 compressions per two ventilations) at every response to an out-of-hospital cardiac arrest. Twice per year, each cluster crossed over to the other resuscitation strategy, said Dr. Nichol of the University of Washington–Harborview Center for Prehospital Emergency Care and Clinical Trial Center in Seattle.

A total of 12,653 patients were assigned to continuous chest compressions (the intervention group) and 11,058 to interrupted chest compressions (the control group). The primary outcome – the rate of survival to hospital discharge – was 9.0% in the intervention group and 9.7% in the control group, a nonsignificant difference. Similarly, the rate of survival with favorable neurologic function did not differ significantly, at 7.0% and 7.7%, respectively, the investigators said (N Engl J Med. 2015 Nov 9. doi:10.1056/NEJMoa1509139).

The reason for these unexpected findings is not yet known. It is plausible that continuous chest compressions really don’t improve outcomes and that the previous positive results were actually due to improvements in the CPR process, such as more consistent rate and depth of compressions; concurrent improvements in the system of care; or Hawthorne effects, in which CPR providers altered their behavior during the studies because they were aware they were being observed.

However, it is also possible that three important limitations of this trial unduly influenced the results.

First, the per-protocol analysis, which used an automated algorithm to assess adherence to the compression assignments, could not classify many patients as having received either continuous or interrupted chest compressions. Second, the quality of postresuscitation care, which certainly influences outcomes, was not monitored. And third, actual oxygenation levels were not measured, nor were minutes of ventilation delivered. Thus, “we do not know whether there were important differences in oxygenation or ventilation between the two treatment strategies,” he said.

Continuous chest compressions during CPR failed to improve survival or neurologic function compared with standard chest compressions that are briefly interrupted for ventilation, based on findings in the first large randomized trial to compare the two strategies for out-of-hospital, nontraumatic cardiac arrest.

In a presentation at the American Heart Association scientific sessions, simultaneously published online Nov. 9 in the New England Journal of Medicine, Dr. Graham Nichol and his associates analyzed data from the Resuscitation Outcomes Consortium, a network of clinical centers and EMS agencies that have expertise in conducting research on out-of-hospital cardiac arrest.

Data were analyzed for 23,711 adults treated by 114 EMS agencies affiliated with eight clinical centers across the United States and Canada. These agencies were grouped into 47 clusters that were randomly assigned to perform CPR using either continuous chest compressions (100 per minute) with asynchronous positive-pressure ventilations (10 per minute) or standard chest compressions interrupted for ventilations (at a rate of 30 compressions per two ventilations) at every response to an out-of-hospital cardiac arrest. Twice per year, each cluster crossed over to the other resuscitation strategy, said Dr. Nichol of the University of Washington–Harborview Center for Prehospital Emergency Care and Clinical Trial Center in Seattle.

A total of 12,653 patients were assigned to continuous chest compressions (the intervention group) and 11,058 to interrupted chest compressions (the control group). The primary outcome – the rate of survival to hospital discharge – was 9.0% in the intervention group and 9.7% in the control group, a nonsignificant difference. Similarly, the rate of survival with favorable neurologic function did not differ significantly, at 7.0% and 7.7%, respectively, the investigators said (N Engl J Med. 2015 Nov 9. doi:10.1056/NEJMoa1509139).

The reason for these unexpected findings is not yet known. It is plausible that continuous chest compressions really don’t improve outcomes and that the previous positive results were actually due to improvements in the CPR process, such as more consistent rate and depth of compressions; concurrent improvements in the system of care; or Hawthorne effects, in which CPR providers altered their behavior during the studies because they were aware they were being observed.

However, it is also possible that three important limitations of this trial unduly influenced the results.

First, the per-protocol analysis, which used an automated algorithm to assess adherence to the compression assignments, could not classify many patients as having received either continuous or interrupted chest compressions. Second, the quality of postresuscitation care, which certainly influences outcomes, was not monitored. And third, actual oxygenation levels were not measured, nor were minutes of ventilation delivered. Thus, “we do not know whether there were important differences in oxygenation or ventilation between the two treatment strategies,” he said.

Continuous chest compressions during CPR failed to improve survival or neurologic function compared with standard chest compressions that are briefly interrupted for ventilation, based on findings in the first large randomized trial to compare the two strategies for out-of-hospital, nontraumatic cardiac arrest.

In a presentation at the American Heart Association scientific sessions, simultaneously published online Nov. 9 in the New England Journal of Medicine, Dr. Graham Nichol and his associates analyzed data from the Resuscitation Outcomes Consortium, a network of clinical centers and EMS agencies that have expertise in conducting research on out-of-hospital cardiac arrest.

Data were analyzed for 23,711 adults treated by 114 EMS agencies affiliated with eight clinical centers across the United States and Canada. These agencies were grouped into 47 clusters that were randomly assigned to perform CPR using either continuous chest compressions (100 per minute) with asynchronous positive-pressure ventilations (10 per minute) or standard chest compressions interrupted for ventilations (at a rate of 30 compressions per two ventilations) at every response to an out-of-hospital cardiac arrest. Twice per year, each cluster crossed over to the other resuscitation strategy, said Dr. Nichol of the University of Washington–Harborview Center for Prehospital Emergency Care and Clinical Trial Center in Seattle.

A total of 12,653 patients were assigned to continuous chest compressions (the intervention group) and 11,058 to interrupted chest compressions (the control group). The primary outcome – the rate of survival to hospital discharge – was 9.0% in the intervention group and 9.7% in the control group, a nonsignificant difference. Similarly, the rate of survival with favorable neurologic function did not differ significantly, at 7.0% and 7.7%, respectively, the investigators said (N Engl J Med. 2015 Nov 9. doi:10.1056/NEJMoa1509139).

The reason for these unexpected findings is not yet known. It is plausible that continuous chest compressions really don’t improve outcomes and that the previous positive results were actually due to improvements in the CPR process, such as more consistent rate and depth of compressions; concurrent improvements in the system of care; or Hawthorne effects, in which CPR providers altered their behavior during the studies because they were aware they were being observed.

However, it is also possible that three important limitations of this trial unduly influenced the results.

First, the per-protocol analysis, which used an automated algorithm to assess adherence to the compression assignments, could not classify many patients as having received either continuous or interrupted chest compressions. Second, the quality of postresuscitation care, which certainly influences outcomes, was not monitored. And third, actual oxygenation levels were not measured, nor were minutes of ventilation delivered. Thus, “we do not know whether there were important differences in oxygenation or ventilation between the two treatment strategies,” he said.

Rates of both nonacute and inappropriate PCI dropped substantially in response to a concerted nationwide effort to curb overuse of the procedure, including the introduction of appropriate use criteria, Dr. Nihar R. Desai said in a presentation at the American Heart Association scientific sessions, which was simultaneously published online Nov. 9 in JAMA.

The American College of Cardiology and the American Heart Association, in conjunction with other professional societies, released appropriate use criteria for coronary revascularization in 2009 and revised them in 2011. Research indicated that the risks of the procedure outweighed the benefits in as many as 17% of patients, and that the proportion of inappropriate PCIs varied markedly across hospitals.

In what he described as the first comprehensive assessment of PCI appropriateness since that time, Dr. Desai and his associates examined national trends using information from the National Cardiovascular Data Registry’s CathPCI registry.

They focused on 2,685,683 PCIs performed at 766 U.S. hospitals during a 5-year period. A total of 76.3% of these were done for acute indications, and 14.8% were for nonacute indications. The indications could not be determined for the remaining 8.9%, usually because data were missing from the records, said Dr. Desai of the center for outcomes research and evaluation, Yale–New Haven (Conn.) Hospital (JAMA 2015 Nov 9. doi: 10.1001/jama.2015.13764).

Over time, substantial declines occurred in the number of nonacute PCIs (from 89,704 in 2010 to 59,375 in 2014) and of indeterminate PCIs (from 70,832 in 2010 to 22,589 in 2014), while the number of acute PCIs remained relatively stable (from 377,540 in 2010 to 374,543 in 2014). As a result, the percentage of PCIs performed for acute indications rose from 69.1% in 2009 to 82.0% in 2014.

Similarly, the number of nonacute PCIs classified as inappropriate dropped from 21,781 in 2010 to 7,921 in 2014. Accordingly, the percentage of nonacute PCIs deemed to be inappropriate was halved, decreasing from 26.2% in 2009 to 13.3% in 2014 of all nonacute PCIs.

The results reflect improvement in patient selection and clinical decision making, Dr. Desai said, and suggest that clinicians are doing a better job of identifying patients most likely to benefit from PCI.

In particular, “we observed significant declines in the proportions of patients undergoing nonacute PCI who were asymptomatic or had minimal symptoms, who were not receiving or were receiving only minimal antianginal therapy, and who had low- or intermediate-risk findings on noninvasive testing,” he noted.

“Collectively, these findings suggest that the practice of interventional cardiology has evolved since the introduction of appropriate use criteria,” Dr. Desai added.

The wide variation in inappropriate PCI across hospitals remains, however.

In the best-performing hospitals (those in the lowest quartile for inappropriate procedures), less than 6% of nonacute PCIs were classified as inappropriate in 2014, the most recent year for which data are available.

Conversely, in the worst-performing hospitals (those in the highest quartile for inappropriate procedures), more than 22% of nonacute PCIs were deemed inappropriate. This “suggests the need for ongoing performance improvement initiatives and hospital benchmarking,” Dr. Desai noted

It was encouraging that many of the worst-performing hospitals at baseline demonstrated immediate and steady improvement after the introduction of appropriate use criteria, he added, with a dramatic reduction in inappropriate PCIs from 70.6% in 2009-2010 to 9.4% in 2014.

However, a subset of 18 of the worst-performing hospitals showed minimal change during the first 2 years of the study. They have subsequently shown lower rates of inappropriate PCI during the final 2 years.

This study was supported by the National Cardiovascular Data Registry’s CathPCI registry, the Yale Center for Outcomes Research and Evaluation Data Analytic Center, the American College of Cardiology, the Agency for Healthcare Research and Quality, Veterans Affairs Health Services Research and Development, and the National Heart, Lung, and Blood Institute. Dr. Desai reported ties to Johnson & Johnson, and his associates reported ties to several industry sources.

Rates of both nonacute and inappropriate PCI dropped substantially in response to a concerted nationwide effort to curb overuse of the procedure, including the introduction of appropriate use criteria, Dr. Nihar R. Desai said in a presentation at the American Heart Association scientific sessions, which was simultaneously published online Nov. 9 in JAMA.

The American College of Cardiology and the American Heart Association, in conjunction with other professional societies, released appropriate use criteria for coronary revascularization in 2009 and revised them in 2011. Research indicated that the risks of the procedure outweighed the benefits in as many as 17% of patients, and that the proportion of inappropriate PCIs varied markedly across hospitals.

In what he described as the first comprehensive assessment of PCI appropriateness since that time, Dr. Desai and his associates examined national trends using information from the National Cardiovascular Data Registry’s CathPCI registry.

They focused on 2,685,683 PCIs performed at 766 U.S. hospitals during a 5-year period. A total of 76.3% of these were done for acute indications, and 14.8% were for nonacute indications. The indications could not be determined for the remaining 8.9%, usually because data were missing from the records, said Dr. Desai of the center for outcomes research and evaluation, Yale–New Haven (Conn.) Hospital (JAMA 2015 Nov 9. doi: 10.1001/jama.2015.13764).

Over time, substantial declines occurred in the number of nonacute PCIs (from 89,704 in 2010 to 59,375 in 2014) and of indeterminate PCIs (from 70,832 in 2010 to 22,589 in 2014), while the number of acute PCIs remained relatively stable (from 377,540 in 2010 to 374,543 in 2014). As a result, the percentage of PCIs performed for acute indications rose from 69.1% in 2009 to 82.0% in 2014.

Similarly, the number of nonacute PCIs classified as inappropriate dropped from 21,781 in 2010 to 7,921 in 2014. Accordingly, the percentage of nonacute PCIs deemed to be inappropriate was halved, decreasing from 26.2% in 2009 to 13.3% in 2014 of all nonacute PCIs.

The results reflect improvement in patient selection and clinical decision making, Dr. Desai said, and suggest that clinicians are doing a better job of identifying patients most likely to benefit from PCI.

In particular, “we observed significant declines in the proportions of patients undergoing nonacute PCI who were asymptomatic or had minimal symptoms, who were not receiving or were receiving only minimal antianginal therapy, and who had low- or intermediate-risk findings on noninvasive testing,” he noted.

“Collectively, these findings suggest that the practice of interventional cardiology has evolved since the introduction of appropriate use criteria,” Dr. Desai added.

The wide variation in inappropriate PCI across hospitals remains, however.

In the best-performing hospitals (those in the lowest quartile for inappropriate procedures), less than 6% of nonacute PCIs were classified as inappropriate in 2014, the most recent year for which data are available.

Conversely, in the worst-performing hospitals (those in the highest quartile for inappropriate procedures), more than 22% of nonacute PCIs were deemed inappropriate. This “suggests the need for ongoing performance improvement initiatives and hospital benchmarking,” Dr. Desai noted

It was encouraging that many of the worst-performing hospitals at baseline demonstrated immediate and steady improvement after the introduction of appropriate use criteria, he added, with a dramatic reduction in inappropriate PCIs from 70.6% in 2009-2010 to 9.4% in 2014.

However, a subset of 18 of the worst-performing hospitals showed minimal change during the first 2 years of the study. They have subsequently shown lower rates of inappropriate PCI during the final 2 years.

This study was supported by the National Cardiovascular Data Registry’s CathPCI registry, the Yale Center for Outcomes Research and Evaluation Data Analytic Center, the American College of Cardiology, the Agency for Healthcare Research and Quality, Veterans Affairs Health Services Research and Development, and the National Heart, Lung, and Blood Institute. Dr. Desai reported ties to Johnson & Johnson, and his associates reported ties to several industry sources.

Rates of both nonacute and inappropriate PCI dropped substantially in response to a concerted nationwide effort to curb overuse of the procedure, including the introduction of appropriate use criteria, Dr. Nihar R. Desai said in a presentation at the American Heart Association scientific sessions, which was simultaneously published online Nov. 9 in JAMA.

The American College of Cardiology and the American Heart Association, in conjunction with other professional societies, released appropriate use criteria for coronary revascularization in 2009 and revised them in 2011. Research indicated that the risks of the procedure outweighed the benefits in as many as 17% of patients, and that the proportion of inappropriate PCIs varied markedly across hospitals.

In what he described as the first comprehensive assessment of PCI appropriateness since that time, Dr. Desai and his associates examined national trends using information from the National Cardiovascular Data Registry’s CathPCI registry.

They focused on 2,685,683 PCIs performed at 766 U.S. hospitals during a 5-year period. A total of 76.3% of these were done for acute indications, and 14.8% were for nonacute indications. The indications could not be determined for the remaining 8.9%, usually because data were missing from the records, said Dr. Desai of the center for outcomes research and evaluation, Yale–New Haven (Conn.) Hospital (JAMA 2015 Nov 9. doi: 10.1001/jama.2015.13764).

Over time, substantial declines occurred in the number of nonacute PCIs (from 89,704 in 2010 to 59,375 in 2014) and of indeterminate PCIs (from 70,832 in 2010 to 22,589 in 2014), while the number of acute PCIs remained relatively stable (from 377,540 in 2010 to 374,543 in 2014). As a result, the percentage of PCIs performed for acute indications rose from 69.1% in 2009 to 82.0% in 2014.

Similarly, the number of nonacute PCIs classified as inappropriate dropped from 21,781 in 2010 to 7,921 in 2014. Accordingly, the percentage of nonacute PCIs deemed to be inappropriate was halved, decreasing from 26.2% in 2009 to 13.3% in 2014 of all nonacute PCIs.

The results reflect improvement in patient selection and clinical decision making, Dr. Desai said, and suggest that clinicians are doing a better job of identifying patients most likely to benefit from PCI.

In particular, “we observed significant declines in the proportions of patients undergoing nonacute PCI who were asymptomatic or had minimal symptoms, who were not receiving or were receiving only minimal antianginal therapy, and who had low- or intermediate-risk findings on noninvasive testing,” he noted.

“Collectively, these findings suggest that the practice of interventional cardiology has evolved since the introduction of appropriate use criteria,” Dr. Desai added.

The wide variation in inappropriate PCI across hospitals remains, however.

In the best-performing hospitals (those in the lowest quartile for inappropriate procedures), less than 6% of nonacute PCIs were classified as inappropriate in 2014, the most recent year for which data are available.

Conversely, in the worst-performing hospitals (those in the highest quartile for inappropriate procedures), more than 22% of nonacute PCIs were deemed inappropriate. This “suggests the need for ongoing performance improvement initiatives and hospital benchmarking,” Dr. Desai noted

It was encouraging that many of the worst-performing hospitals at baseline demonstrated immediate and steady improvement after the introduction of appropriate use criteria, he added, with a dramatic reduction in inappropriate PCIs from 70.6% in 2009-2010 to 9.4% in 2014.

However, a subset of 18 of the worst-performing hospitals showed minimal change during the first 2 years of the study. They have subsequently shown lower rates of inappropriate PCI during the final 2 years.

This study was supported by the National Cardiovascular Data Registry’s CathPCI registry, the Yale Center for Outcomes Research and Evaluation Data Analytic Center, the American College of Cardiology, the Agency for Healthcare Research and Quality, Veterans Affairs Health Services Research and Development, and the National Heart, Lung, and Blood Institute. Dr. Desai reported ties to Johnson & Johnson, and his associates reported ties to several industry sources.

The American Heart Association and the American Thoracic Society jointly released the first-ever clinical practice guideline for assessing and managing pulmonary hypertension (PH) in the pediatric population, which was published online Nov. 3 in Circulation.

The two organizations developed this guideline because the causes and treatments of PH in neonates, infants, and children are often different from those in adults. The literature for adult PH is “robust,” and there are several treatment guidelines available, whereas pediatric PH has not been well studied, “and little is understood about the natural history, fundamental mechanisms, and treatment of childhood PH,” said Dr. Steven H. Abman, cochair of the guideline committee and a pediatric pulmonologist at the University of Colorado and Children’s Hospital, both in Denver.

“It’s important to note that, although these guidelines provide a foundation for taking care of children with pulmonary hypertension, we still have a huge need for more specific data and research to further improve outcomes,” he said in a statement accompanying the guideline.

This guideline was developed by a working group of 27 clinicians and researchers with expertise in pediatric pulmonology, pediatric and adult cardiology, pediatric intensivism, neonatology, and translational science. They reviewed more than 600 articles in the literature, but given the paucity of high-quality data regarding pediatric PH, the guideline relies heavily on expert opinion and primarily describes “generally acceptable approaches” to diagnosis and management; more specific and detailed recommendations await the findings of future research, Dr. Abman and his associates said (Circulation. 2015 Oct 26. doi:10.1161/CIR.0000000000000329).

In the pediatric population, PH is defined as a resting mean pulmonary artery pressure greater than 25 mm Hg after the first few months of life and is usually related to cardiac, lung, or systemic diseases. Idiopathic PH, a pulmonary vasculopathy, is a diagnosis of exclusion after diseases of the left side of the heart, lung parenchyma, heart valves, thromboembolism, and other miscellaneous causes have been ruled out.

The guideline emphasizes that children thought to have PH should be evaluated and treated at comprehensive, multidisciplinary clinics at specialized pediatric centers. “When children are diagnosed, parents often feel helpless. However, it’s important that parents seek doctors and centers that see these children on a regular basis and can offer them access to new molecular diagnostics, new drug therapies, and new devices, as well as surgeries that have recently been developed,” Dr. Stephen L. Archer, cochair of the guideline committee and head of medicine at Queen’s University, Kingston, Ont., said in the statement.

“These children suffer with health issues throughout their lives or die prematurely, particularly if they’re not properly diagnosed and managed. But with the proper diagnosis and treatment at a specialized center for PH, the prognosis for many of these children is excellent,” he noted.

Properly classifying the type of PH is a key first step in determining treatment. The guideline addresses numerous methods for diagnosing and monitoring PH, including imaging studies, echocardiograms, cardiac catheterization, brain natriuretic peptide and other laboratory testing, 6-minute walk distance (at appropriate ages), sleep studies, and genetic testing. It specifically deals with persistent PH of the newborn and PH arising from congenital diaphragmatic hernia; bronchopulmonary dysplasia or other lung diseases; heart disease such as atrial-septal defect or patent ductus arteriosus; and systemic diseases such as hemolytic hemoglobinopathies and hepatic, renal, or metabolic illness; as well as idiopathic PH and PH related to high-altitude pulmonary edema.

Regarding ongoing outpatient care, the guideline recommends that children with PH receive influenza and pneumococcal vaccinations and prophylaxis for respiratory syncytial virus (if they are eligible), as well as antibiotic prophylaxis to prevent subacute bacterial endocarditis in those who are cyanotic or have indwelling central lines. Growth must be monitored rigorously, and infections and respiratory illnesses must be recognized and treated promptly. Any surgeries require careful preoperative planning and should be performed at hospitals with expertise in PH.

The guideline includes an extensive section on pharmacotherapy for childhood PH, including the use of digitalis, diuretics, long-term anticoagulation, oxygen therapy, calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, intravenous and subcutaneous prostacyclin therapy, and the transition from parenteral to oral or inhaled treatment.

In addition, the guideline addresses exercise and sports participation, travel restrictions, and contraceptive counseling for adolescent patients. Finally, “given the impact of childhood PH on the entire family, [patients], siblings, and caregivers should be assessed for psychosocial stress and be readily provided support and referral as needed,” the guideline recommends.

A copy of the guideline is available at http://my.americanheart.org/statements.

The American Heart Association and the American Thoracic Society jointly released the first-ever clinical practice guideline for assessing and managing pulmonary hypertension (PH) in the pediatric population, which was published online Nov. 3 in Circulation.

The two organizations developed this guideline because the causes and treatments of PH in neonates, infants, and children are often different from those in adults. The literature for adult PH is “robust,” and there are several treatment guidelines available, whereas pediatric PH has not been well studied, “and little is understood about the natural history, fundamental mechanisms, and treatment of childhood PH,” said Dr. Steven H. Abman, cochair of the guideline committee and a pediatric pulmonologist at the University of Colorado and Children’s Hospital, both in Denver.

“It’s important to note that, although these guidelines provide a foundation for taking care of children with pulmonary hypertension, we still have a huge need for more specific data and research to further improve outcomes,” he said in a statement accompanying the guideline.

This guideline was developed by a working group of 27 clinicians and researchers with expertise in pediatric pulmonology, pediatric and adult cardiology, pediatric intensivism, neonatology, and translational science. They reviewed more than 600 articles in the literature, but given the paucity of high-quality data regarding pediatric PH, the guideline relies heavily on expert opinion and primarily describes “generally acceptable approaches” to diagnosis and management; more specific and detailed recommendations await the findings of future research, Dr. Abman and his associates said (Circulation. 2015 Oct 26. doi:10.1161/CIR.0000000000000329).

In the pediatric population, PH is defined as a resting mean pulmonary artery pressure greater than 25 mm Hg after the first few months of life and is usually related to cardiac, lung, or systemic diseases. Idiopathic PH, a pulmonary vasculopathy, is a diagnosis of exclusion after diseases of the left side of the heart, lung parenchyma, heart valves, thromboembolism, and other miscellaneous causes have been ruled out.

The guideline emphasizes that children thought to have PH should be evaluated and treated at comprehensive, multidisciplinary clinics at specialized pediatric centers. “When children are diagnosed, parents often feel helpless. However, it’s important that parents seek doctors and centers that see these children on a regular basis and can offer them access to new molecular diagnostics, new drug therapies, and new devices, as well as surgeries that have recently been developed,” Dr. Stephen L. Archer, cochair of the guideline committee and head of medicine at Queen’s University, Kingston, Ont., said in the statement.

“These children suffer with health issues throughout their lives or die prematurely, particularly if they’re not properly diagnosed and managed. But with the proper diagnosis and treatment at a specialized center for PH, the prognosis for many of these children is excellent,” he noted.

Properly classifying the type of PH is a key first step in determining treatment. The guideline addresses numerous methods for diagnosing and monitoring PH, including imaging studies, echocardiograms, cardiac catheterization, brain natriuretic peptide and other laboratory testing, 6-minute walk distance (at appropriate ages), sleep studies, and genetic testing. It specifically deals with persistent PH of the newborn and PH arising from congenital diaphragmatic hernia; bronchopulmonary dysplasia or other lung diseases; heart disease such as atrial-septal defect or patent ductus arteriosus; and systemic diseases such as hemolytic hemoglobinopathies and hepatic, renal, or metabolic illness; as well as idiopathic PH and PH related to high-altitude pulmonary edema.

Regarding ongoing outpatient care, the guideline recommends that children with PH receive influenza and pneumococcal vaccinations and prophylaxis for respiratory syncytial virus (if they are eligible), as well as antibiotic prophylaxis to prevent subacute bacterial endocarditis in those who are cyanotic or have indwelling central lines. Growth must be monitored rigorously, and infections and respiratory illnesses must be recognized and treated promptly. Any surgeries require careful preoperative planning and should be performed at hospitals with expertise in PH.

The guideline includes an extensive section on pharmacotherapy for childhood PH, including the use of digitalis, diuretics, long-term anticoagulation, oxygen therapy, calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, intravenous and subcutaneous prostacyclin therapy, and the transition from parenteral to oral or inhaled treatment.

In addition, the guideline addresses exercise and sports participation, travel restrictions, and contraceptive counseling for adolescent patients. Finally, “given the impact of childhood PH on the entire family, [patients], siblings, and caregivers should be assessed for psychosocial stress and be readily provided support and referral as needed,” the guideline recommends.

A copy of the guideline is available at http://my.americanheart.org/statements.

The American Heart Association and the American Thoracic Society jointly released the first-ever clinical practice guideline for assessing and managing pulmonary hypertension (PH) in the pediatric population, which was published online Nov. 3 in Circulation.

The two organizations developed this guideline because the causes and treatments of PH in neonates, infants, and children are often different from those in adults. The literature for adult PH is “robust,” and there are several treatment guidelines available, whereas pediatric PH has not been well studied, “and little is understood about the natural history, fundamental mechanisms, and treatment of childhood PH,” said Dr. Steven H. Abman, cochair of the guideline committee and a pediatric pulmonologist at the University of Colorado and Children’s Hospital, both in Denver.

“It’s important to note that, although these guidelines provide a foundation for taking care of children with pulmonary hypertension, we still have a huge need for more specific data and research to further improve outcomes,” he said in a statement accompanying the guideline.

This guideline was developed by a working group of 27 clinicians and researchers with expertise in pediatric pulmonology, pediatric and adult cardiology, pediatric intensivism, neonatology, and translational science. They reviewed more than 600 articles in the literature, but given the paucity of high-quality data regarding pediatric PH, the guideline relies heavily on expert opinion and primarily describes “generally acceptable approaches” to diagnosis and management; more specific and detailed recommendations await the findings of future research, Dr. Abman and his associates said (Circulation. 2015 Oct 26. doi:10.1161/CIR.0000000000000329).

In the pediatric population, PH is defined as a resting mean pulmonary artery pressure greater than 25 mm Hg after the first few months of life and is usually related to cardiac, lung, or systemic diseases. Idiopathic PH, a pulmonary vasculopathy, is a diagnosis of exclusion after diseases of the left side of the heart, lung parenchyma, heart valves, thromboembolism, and other miscellaneous causes have been ruled out.

The guideline emphasizes that children thought to have PH should be evaluated and treated at comprehensive, multidisciplinary clinics at specialized pediatric centers. “When children are diagnosed, parents often feel helpless. However, it’s important that parents seek doctors and centers that see these children on a regular basis and can offer them access to new molecular diagnostics, new drug therapies, and new devices, as well as surgeries that have recently been developed,” Dr. Stephen L. Archer, cochair of the guideline committee and head of medicine at Queen’s University, Kingston, Ont., said in the statement.

“These children suffer with health issues throughout their lives or die prematurely, particularly if they’re not properly diagnosed and managed. But with the proper diagnosis and treatment at a specialized center for PH, the prognosis for many of these children is excellent,” he noted.

Properly classifying the type of PH is a key first step in determining treatment. The guideline addresses numerous methods for diagnosing and monitoring PH, including imaging studies, echocardiograms, cardiac catheterization, brain natriuretic peptide and other laboratory testing, 6-minute walk distance (at appropriate ages), sleep studies, and genetic testing. It specifically deals with persistent PH of the newborn and PH arising from congenital diaphragmatic hernia; bronchopulmonary dysplasia or other lung diseases; heart disease such as atrial-septal defect or patent ductus arteriosus; and systemic diseases such as hemolytic hemoglobinopathies and hepatic, renal, or metabolic illness; as well as idiopathic PH and PH related to high-altitude pulmonary edema.

Regarding ongoing outpatient care, the guideline recommends that children with PH receive influenza and pneumococcal vaccinations and prophylaxis for respiratory syncytial virus (if they are eligible), as well as antibiotic prophylaxis to prevent subacute bacterial endocarditis in those who are cyanotic or have indwelling central lines. Growth must be monitored rigorously, and infections and respiratory illnesses must be recognized and treated promptly. Any surgeries require careful preoperative planning and should be performed at hospitals with expertise in PH.

The guideline includes an extensive section on pharmacotherapy for childhood PH, including the use of digitalis, diuretics, long-term anticoagulation, oxygen therapy, calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, intravenous and subcutaneous prostacyclin therapy, and the transition from parenteral to oral or inhaled treatment.

In addition, the guideline addresses exercise and sports participation, travel restrictions, and contraceptive counseling for adolescent patients. Finally, “given the impact of childhood PH on the entire family, [patients], siblings, and caregivers should be assessed for psychosocial stress and be readily provided support and referral as needed,” the guideline recommends.

A copy of the guideline is available at http://my.americanheart.org/statements.

The American Heart Association and the American Thoracic Society jointly released the first-ever clinical practice guideline for assessing and managing pulmonary hypertension (PH) in the pediatric population, which was published online Nov. 3 in Circulation.

The two organizations developed this guideline because the causes and treatments of PH in neonates, infants, and children are often different from those in adults. The literature for adult PH is “robust,” and there are several treatment guidelines available, whereas pediatric PH has not been well studied, “and little is understood about the natural history, fundamental mechanisms, and treatment of childhood PH,” said Dr. Steven H. Abman, cochair of the guideline committee and a pediatric pulmonologist at the University of Colorado and Children’s Hospital, both in Denver.

“It’s important to note that, although these guidelines provide a foundation for taking care of children with pulmonary hypertension, we still have a huge need for more specific data and research to further improve outcomes,” he said in a statement accompanying the guideline.

This guideline was developed by a working group of 27 clinicians and researchers with expertise in pediatric pulmonology, pediatric and adult cardiology, pediatric intensivism, neonatology, and translational science. They reviewed more than 600 articles in the literature, but given the paucity of high-quality data regarding pediatric PH, the guideline relies heavily on expert opinion and primarily describes “generally acceptable approaches” to diagnosis and management; more specific and detailed recommendations await the findings of future research, Dr. Abman and his associates said (Circulation. 2015 Oct 26. doi:10.1161/CIR.0000000000000329).

In the pediatric population, PH is defined as a resting mean pulmonary artery pressure greater than 25 mm Hg after the first few months of life and is usually related to cardiac, lung, or systemic diseases. Idiopathic PH, a pulmonary vasculopathy, is a diagnosis of exclusion after diseases of the left side of the heart, lung parenchyma, heart valves, thromboembolism, and other miscellaneous causes have been ruled out.

The guideline emphasizes that children thought to have PH should be evaluated and treated at comprehensive, multidisciplinary clinics at specialized pediatric centers. “When children are diagnosed, parents often feel helpless. However, it’s important that parents seek doctors and centers that see these children on a regular basis and can offer them access to new molecular diagnostics, new drug therapies, and new devices, as well as surgeries that have recently been developed,” Dr. Stephen L. Archer, cochair of the guideline committee and head of medicine at Queen’s University, Kingston, Ont., said in the statement.

“These children suffer with health issues throughout their lives or die prematurely, particularly if they’re not properly diagnosed and managed. But with the proper diagnosis and treatment at a specialized center for PH, the prognosis for many of these children is excellent,” he noted.

Properly classifying the type of PH is a key first step in determining treatment. The guideline addresses numerous methods for diagnosing and monitoring PH, including imaging studies, echocardiograms, cardiac catheterization, brain natriuretic peptide and other laboratory testing, 6-minute walk distance (at appropriate ages), sleep studies, and genetic testing. It specifically deals with persistent PH of the newborn and PH arising from congenital diaphragmatic hernia; bronchopulmonary dysplasia or other lung diseases; heart disease such as atrial-septal defect or patent ductus arteriosus; and systemic diseases such as hemolytic hemoglobinopathies and hepatic, renal, or metabolic illness; as well as idiopathic PH and PH related to high-altitude pulmonary edema.

Regarding ongoing outpatient care, the guideline recommends that children with PH receive influenza and pneumococcal vaccinations and prophylaxis for respiratory syncytial virus (if they are eligible), as well as antibiotic prophylaxis to prevent subacute bacterial endocarditis in those who are cyanotic or have indwelling central lines. Growth must be monitored rigorously, and infections and respiratory illnesses must be recognized and treated promptly. Any surgeries require careful preoperative planning and should be performed at hospitals with expertise in PH.

The guideline includes an extensive section on pharmacotherapy for childhood PH, including the use of digitalis, diuretics, long-term anticoagulation, oxygen therapy, calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, intravenous and subcutaneous prostacyclin therapy, and the transition from parenteral to oral or inhaled treatment.

In addition, the guideline addresses exercise and sports participation, travel restrictions, and contraceptive counseling for adolescent patients. Finally, “given the impact of childhood PH on the entire family, [patients], siblings, and caregivers should be assessed for psychosocial stress and be readily provided support and referral as needed,” the guideline recommends.

A copy of the guideline is available at http://my.americanheart.org/statements.

The American Heart Association and the American Thoracic Society jointly released the first-ever clinical practice guideline for assessing and managing pulmonary hypertension (PH) in the pediatric population, which was published online Nov. 3 in Circulation.

The two organizations developed this guideline because the causes and treatments of PH in neonates, infants, and children are often different from those in adults. The literature for adult PH is “robust,” and there are several treatment guidelines available, whereas pediatric PH has not been well studied, “and little is understood about the natural history, fundamental mechanisms, and treatment of childhood PH,” said Dr. Steven H. Abman, cochair of the guideline committee and a pediatric pulmonologist at the University of Colorado and Children’s Hospital, both in Denver.

“It’s important to note that, although these guidelines provide a foundation for taking care of children with pulmonary hypertension, we still have a huge need for more specific data and research to further improve outcomes,” he said in a statement accompanying the guideline.

This guideline was developed by a working group of 27 clinicians and researchers with expertise in pediatric pulmonology, pediatric and adult cardiology, pediatric intensivism, neonatology, and translational science. They reviewed more than 600 articles in the literature, but given the paucity of high-quality data regarding pediatric PH, the guideline relies heavily on expert opinion and primarily describes “generally acceptable approaches” to diagnosis and management; more specific and detailed recommendations await the findings of future research, Dr. Abman and his associates said (Circulation. 2015 Oct 26. doi:10.1161/CIR.0000000000000329).

In the pediatric population, PH is defined as a resting mean pulmonary artery pressure greater than 25 mm Hg after the first few months of life and is usually related to cardiac, lung, or systemic diseases. Idiopathic PH, a pulmonary vasculopathy, is a diagnosis of exclusion after diseases of the left side of the heart, lung parenchyma, heart valves, thromboembolism, and other miscellaneous causes have been ruled out.

The guideline emphasizes that children thought to have PH should be evaluated and treated at comprehensive, multidisciplinary clinics at specialized pediatric centers. “When children are diagnosed, parents often feel helpless. However, it’s important that parents seek doctors and centers that see these children on a regular basis and can offer them access to new molecular diagnostics, new drug therapies, and new devices, as well as surgeries that have recently been developed,” Dr. Stephen L. Archer, cochair of the guideline committee and head of medicine at Queen’s University, Kingston, Ont., said in the statement.

“These children suffer with health issues throughout their lives or die prematurely, particularly if they’re not properly diagnosed and managed. But with the proper diagnosis and treatment at a specialized center for PH, the prognosis for many of these children is excellent,” he noted.

Properly classifying the type of PH is a key first step in determining treatment. The guideline addresses numerous methods for diagnosing and monitoring PH, including imaging studies, echocardiograms, cardiac catheterization, brain natriuretic peptide and other laboratory testing, 6-minute walk distance (at appropriate ages), sleep studies, and genetic testing. It specifically deals with persistent PH of the newborn and PH arising from congenital diaphragmatic hernia; bronchopulmonary dysplasia or other lung diseases; heart disease such as atrial-septal defect or patent ductus arteriosus; and systemic diseases such as hemolytic hemoglobinopathies and hepatic, renal, or metabolic illness; as well as idiopathic PH and PH related to high-altitude pulmonary edema.

Regarding ongoing outpatient care, the guideline recommends that children with PH receive influenza and pneumococcal vaccinations and prophylaxis for respiratory syncytial virus (if they are eligible), as well as antibiotic prophylaxis to prevent subacute bacterial endocarditis in those who are cyanotic or have indwelling central lines. Growth must be monitored rigorously, and infections and respiratory illnesses must be recognized and treated promptly. Any surgeries require careful preoperative planning and should be performed at hospitals with expertise in PH.

The guideline includes an extensive section on pharmacotherapy for childhood PH, including the use of digitalis, diuretics, long-term anticoagulation, oxygen therapy, calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, intravenous and subcutaneous prostacyclin therapy, and the transition from parenteral to oral or inhaled treatment.

In addition, the guideline addresses exercise and sports participation, travel restrictions, and contraceptive counseling for adolescent patients. Finally, “given the impact of childhood PH on the entire family, [patients], siblings, and caregivers should be assessed for psychosocial stress and be readily provided support and referral as needed,” the guideline recommends.

A copy of the guideline is available at http://my.americanheart.org/statements.

The American Heart Association and the American Thoracic Society jointly released the first-ever clinical practice guideline for assessing and managing pulmonary hypertension (PH) in the pediatric population, which was published online Nov. 3 in Circulation.

The two organizations developed this guideline because the causes and treatments of PH in neonates, infants, and children are often different from those in adults. The literature for adult PH is “robust,” and there are several treatment guidelines available, whereas pediatric PH has not been well studied, “and little is understood about the natural history, fundamental mechanisms, and treatment of childhood PH,” said Dr. Steven H. Abman, cochair of the guideline committee and a pediatric pulmonologist at the University of Colorado and Children’s Hospital, both in Denver.

“It’s important to note that, although these guidelines provide a foundation for taking care of children with pulmonary hypertension, we still have a huge need for more specific data and research to further improve outcomes,” he said in a statement accompanying the guideline.

This guideline was developed by a working group of 27 clinicians and researchers with expertise in pediatric pulmonology, pediatric and adult cardiology, pediatric intensivism, neonatology, and translational science. They reviewed more than 600 articles in the literature, but given the paucity of high-quality data regarding pediatric PH, the guideline relies heavily on expert opinion and primarily describes “generally acceptable approaches” to diagnosis and management; more specific and detailed recommendations await the findings of future research, Dr. Abman and his associates said (Circulation. 2015 Oct 26. doi:10.1161/CIR.0000000000000329).

In the pediatric population, PH is defined as a resting mean pulmonary artery pressure greater than 25 mm Hg after the first few months of life and is usually related to cardiac, lung, or systemic diseases. Idiopathic PH, a pulmonary vasculopathy, is a diagnosis of exclusion after diseases of the left side of the heart, lung parenchyma, heart valves, thromboembolism, and other miscellaneous causes have been ruled out.

The guideline emphasizes that children thought to have PH should be evaluated and treated at comprehensive, multidisciplinary clinics at specialized pediatric centers. “When children are diagnosed, parents often feel helpless. However, it’s important that parents seek doctors and centers that see these children on a regular basis and can offer them access to new molecular diagnostics, new drug therapies, and new devices, as well as surgeries that have recently been developed,” Dr. Stephen L. Archer, cochair of the guideline committee and head of medicine at Queen’s University, Kingston, Ont., said in the statement.

“These children suffer with health issues throughout their lives or die prematurely, particularly if they’re not properly diagnosed and managed. But with the proper diagnosis and treatment at a specialized center for PH, the prognosis for many of these children is excellent,” he noted.

Properly classifying the type of PH is a key first step in determining treatment. The guideline addresses numerous methods for diagnosing and monitoring PH, including imaging studies, echocardiograms, cardiac catheterization, brain natriuretic peptide and other laboratory testing, 6-minute walk distance (at appropriate ages), sleep studies, and genetic testing. It specifically deals with persistent PH of the newborn and PH arising from congenital diaphragmatic hernia; bronchopulmonary dysplasia or other lung diseases; heart disease such as atrial-septal defect or patent ductus arteriosus; and systemic diseases such as hemolytic hemoglobinopathies and hepatic, renal, or metabolic illness; as well as idiopathic PH and PH related to high-altitude pulmonary edema.

Regarding ongoing outpatient care, the guideline recommends that children with PH receive influenza and pneumococcal vaccinations and prophylaxis for respiratory syncytial virus (if they are eligible), as well as antibiotic prophylaxis to prevent subacute bacterial endocarditis in those who are cyanotic or have indwelling central lines. Growth must be monitored rigorously, and infections and respiratory illnesses must be recognized and treated promptly. Any surgeries require careful preoperative planning and should be performed at hospitals with expertise in PH.

The guideline includes an extensive section on pharmacotherapy for childhood PH, including the use of digitalis, diuretics, long-term anticoagulation, oxygen therapy, calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, intravenous and subcutaneous prostacyclin therapy, and the transition from parenteral to oral or inhaled treatment.

In addition, the guideline addresses exercise and sports participation, travel restrictions, and contraceptive counseling for adolescent patients. Finally, “given the impact of childhood PH on the entire family, [patients], siblings, and caregivers should be assessed for psychosocial stress and be readily provided support and referral as needed,” the guideline recommends.

A copy of the guideline is available at http://my.americanheart.org/statements.

Switching HIV-infected children aged 3 and older from a recommended first-line antiretroviral treatment to efavirenz-based therapy may offer advantages, according to a new study in JAMA.

The study, based on a single-center open-label trial involving 298 South African children and published online Nov. 3, found that changing the HIV treatment regimen from ritonavir-boosted lopinavir-based therapy to efavirenz-based therapy was noninferior regarding rates of viral rebound and viral failure.

© Dr. A. Harrison; Dr. P. Feorino / CDC

As a long-term maintenance treatment, efavirenz has several potential advantages over ritonavir-boosted lopinavir therapy. It requires once-daily rather than twice daily administration and doesn’t have the unpleasant taste of ritonavir-boosted lopinavir syrup, which would improve adherence and thus effectiveness. Efavirenz also may avoid some metabolic toxicities of the latter treatment and may simplify cotreatment for tuberculosis, a common coinfection among children with HIV in third-world countries. And it doesn’t require cold storage to maintain long-term stability, said Dr. Ashraf Coovadia of the University of the Witwatersrand and the Rahima Moosa Mother and Child Hospital, both in Johannesburg, and his associates.

There have been anecdotal reports of clinicians switching young pediatric patients to efavirenz, which is the recommended therapy for older children and adults, even though no data supported this practice until now. To shed light on the issue, the investigators compared the two treatment regimens in 298 children (average age, 4.3 years) who had been exposed to nevirapine for prevention of mother-to-child transmission and, after birth, had been maintained on ritonavir-boosted lopinavir-based therapy for an average of 3.5 years. A total of 148 of these children were randomly assigned to continue this recommended regimen and 150 were switched to efavirenz-based therapy; all were followed for 48 weeks.

Efavirenz-based therapy proved noninferior regarding both primary efficacy endpoints: viral rebound and viral failure. The probability of viral rebound, defined as more than 50 copies of HIV RNA per mL of plasma, was 17.6% for the efavirenz group and 28.4% for the ritonavir-boosted lopinavir group. The probability of viral failure, defined as more than 1,000 copies of HIV RNA per mL of plasma, was 2.7% and 2.0%, respectively. These data “support the safety and efficacy of switching to efavirenz,” Dr. Coovadia and his associates said (JAMA. 2015;314[17]:1808-17. doi:10.1001/jama.2015.13631).

The lipid profiles of children taking efavirenz were better, with lower levels of total cholesterol, LDL cholesterol, and triglycerides. CD4 cell counts and CD4 cell percentages remained in the normal range for both study groups, and there were no significant differences between the two in weight-for-age or height-for-age scores, rates of anemia or neutropenia, skin manifestations, or scores on a measure of emotional/behavioral problems. Alanine aminotransferase elevations were more common with efavirenz, as was nausea.

The adverse neuropsychiatric effects of efavirenz are well-known. After 4 weeks of treatment, 26% of children taking efavirenz had trouble sleeping or had nightmares, compared with no children in the other study group. However, this difference disappeared by 8 weeks. Two children developed seizure disorders presumed to be related to efavirenz. Both were found to have genetic mutations known to be associated with delayed drug clearance or abnormally high blood levels of efavirenz, and the seizures resolved after the drug was discontinued.

Switching HIV-infected children aged 3 and older from a recommended first-line antiretroviral treatment to efavirenz-based therapy may offer advantages, according to a new study in JAMA.

The study, based on a single-center open-label trial involving 298 South African children and published online Nov. 3, found that changing the HIV treatment regimen from ritonavir-boosted lopinavir-based therapy to efavirenz-based therapy was noninferior regarding rates of viral rebound and viral failure.

© Dr. A. Harrison; Dr. P. Feorino / CDC

As a long-term maintenance treatment, efavirenz has several potential advantages over ritonavir-boosted lopinavir therapy. It requires once-daily rather than twice daily administration and doesn’t have the unpleasant taste of ritonavir-boosted lopinavir syrup, which would improve adherence and thus effectiveness. Efavirenz also may avoid some metabolic toxicities of the latter treatment and may simplify cotreatment for tuberculosis, a common coinfection among children with HIV in third-world countries. And it doesn’t require cold storage to maintain long-term stability, said Dr. Ashraf Coovadia of the University of the Witwatersrand and the Rahima Moosa Mother and Child Hospital, both in Johannesburg, and his associates.

There have been anecdotal reports of clinicians switching young pediatric patients to efavirenz, which is the recommended therapy for older children and adults, even though no data supported this practice until now. To shed light on the issue, the investigators compared the two treatment regimens in 298 children (average age, 4.3 years) who had been exposed to nevirapine for prevention of mother-to-child transmission and, after birth, had been maintained on ritonavir-boosted lopinavir-based therapy for an average of 3.5 years. A total of 148 of these children were randomly assigned to continue this recommended regimen and 150 were switched to efavirenz-based therapy; all were followed for 48 weeks.

Efavirenz-based therapy proved noninferior regarding both primary efficacy endpoints: viral rebound and viral failure. The probability of viral rebound, defined as more than 50 copies of HIV RNA per mL of plasma, was 17.6% for the efavirenz group and 28.4% for the ritonavir-boosted lopinavir group. The probability of viral failure, defined as more than 1,000 copies of HIV RNA per mL of plasma, was 2.7% and 2.0%, respectively. These data “support the safety and efficacy of switching to efavirenz,” Dr. Coovadia and his associates said (JAMA. 2015;314[17]:1808-17. doi:10.1001/jama.2015.13631).

The lipid profiles of children taking efavirenz were better, with lower levels of total cholesterol, LDL cholesterol, and triglycerides. CD4 cell counts and CD4 cell percentages remained in the normal range for both study groups, and there were no significant differences between the two in weight-for-age or height-for-age scores, rates of anemia or neutropenia, skin manifestations, or scores on a measure of emotional/behavioral problems. Alanine aminotransferase elevations were more common with efavirenz, as was nausea.

The adverse neuropsychiatric effects of efavirenz are well-known. After 4 weeks of treatment, 26% of children taking efavirenz had trouble sleeping or had nightmares, compared with no children in the other study group. However, this difference disappeared by 8 weeks. Two children developed seizure disorders presumed to be related to efavirenz. Both were found to have genetic mutations known to be associated with delayed drug clearance or abnormally high blood levels of efavirenz, and the seizures resolved after the drug was discontinued.

Switching HIV-infected children aged 3 and older from a recommended first-line antiretroviral treatment to efavirenz-based therapy may offer advantages, according to a new study in JAMA.

The study, based on a single-center open-label trial involving 298 South African children and published online Nov. 3, found that changing the HIV treatment regimen from ritonavir-boosted lopinavir-based therapy to efavirenz-based therapy was noninferior regarding rates of viral rebound and viral failure.

© Dr. A. Harrison; Dr. P. Feorino / CDC

As a long-term maintenance treatment, efavirenz has several potential advantages over ritonavir-boosted lopinavir therapy. It requires once-daily rather than twice daily administration and doesn’t have the unpleasant taste of ritonavir-boosted lopinavir syrup, which would improve adherence and thus effectiveness. Efavirenz also may avoid some metabolic toxicities of the latter treatment and may simplify cotreatment for tuberculosis, a common coinfection among children with HIV in third-world countries. And it doesn’t require cold storage to maintain long-term stability, said Dr. Ashraf Coovadia of the University of the Witwatersrand and the Rahima Moosa Mother and Child Hospital, both in Johannesburg, and his associates.

There have been anecdotal reports of clinicians switching young pediatric patients to efavirenz, which is the recommended therapy for older children and adults, even though no data supported this practice until now. To shed light on the issue, the investigators compared the two treatment regimens in 298 children (average age, 4.3 years) who had been exposed to nevirapine for prevention of mother-to-child transmission and, after birth, had been maintained on ritonavir-boosted lopinavir-based therapy for an average of 3.5 years. A total of 148 of these children were randomly assigned to continue this recommended regimen and 150 were switched to efavirenz-based therapy; all were followed for 48 weeks.

Efavirenz-based therapy proved noninferior regarding both primary efficacy endpoints: viral rebound and viral failure. The probability of viral rebound, defined as more than 50 copies of HIV RNA per mL of plasma, was 17.6% for the efavirenz group and 28.4% for the ritonavir-boosted lopinavir group. The probability of viral failure, defined as more than 1,000 copies of HIV RNA per mL of plasma, was 2.7% and 2.0%, respectively. These data “support the safety and efficacy of switching to efavirenz,” Dr. Coovadia and his associates said (JAMA. 2015;314[17]:1808-17. doi:10.1001/jama.2015.13631).

The lipid profiles of children taking efavirenz were better, with lower levels of total cholesterol, LDL cholesterol, and triglycerides. CD4 cell counts and CD4 cell percentages remained in the normal range for both study groups, and there were no significant differences between the two in weight-for-age or height-for-age scores, rates of anemia or neutropenia, skin manifestations, or scores on a measure of emotional/behavioral problems. Alanine aminotransferase elevations were more common with efavirenz, as was nausea.

The adverse neuropsychiatric effects of efavirenz are well-known. After 4 weeks of treatment, 26% of children taking efavirenz had trouble sleeping or had nightmares, compared with no children in the other study group. However, this difference disappeared by 8 weeks. Two children developed seizure disorders presumed to be related to efavirenz. Both were found to have genetic mutations known to be associated with delayed drug clearance or abnormally high blood levels of efavirenz, and the seizures resolved after the drug was discontinued.

Off-label prescribing of drugs is common and very likely to cause adverse events, particularly when no strong scientific evidence supports the off-label use, according to a report published online Nov. 2 in JAMA Internal Medicine.

No systematic investigation of the off-label use of prescription drugs has been done to date, in part because physicians aren’t required to document intended indications. But recent innovations in electronic health records provided an opportunity to track off-label prescribing and its influence on adverse drug events in the Canadian province of Quebec, which provides health insurance for all 8.5 million residents. There, physicians must provide the indication(s) for every new prescription, the reason(s) for any dose changes or drug discontinuation, and the nature of any adverse events, said Dr. Tewodros Eguale of the department of epidemiology, biostatistics, and occupational health at McGill University, Montreal, and his associates.

istockphoto.com

In what they described as the first large study of its kind, the investigators analyzed the prescribing information in electronic medical records of 46,021 adults (mean age 58 years) given 151,305 new prescriptions during a 5-year period. Physicians reported off-label use in 17,847 (11.8%) of these prescriptions, and that off-label use lacked strong scientific evidence in the great majority of cases (80.9%). The median follow-up time for use of prescribed medications was 386 days (range, 1 day to 6 years).

Prescribed drugs were discontinued because of adverse events in 3,484 cases. The incidence of adverse events was 44% higher for off-label use (19.7 per 10,000 person-months) than for on-label use (12.5 per 10,000 person-months). Moreover, the incidence of adverse events was 54% higher for off-label use unsupported by strong scientific evidence (21.7 per 10,000 person-months) than for off-label use supported by strong scientific evidence (13.2 per 10,000 person-months), the investigators said (JAMA Intern Med. 2015 Nov 2. doi:10.1001/jamainternmed.2015.6058).

The class of drugs with the highest rate of adverse effects was anti-infective agents (66.2 per 10,000 person-months), followed by central nervous system drugs such as antidepressants, anxiolytics, and antimigraine medicine (18.1 per 10,000); cardiovascular drugs (15.9 per 10,000); hormonal agents (12.7); autonomic drugs including albuterol and terbutaline (8.4); gastrointestinal drugs (6.1); ear, nose, and throat medications (2.8); and “other” agents such as antihistamines, blood thinners, and antineoplastics (1.3).

“Selected examples of adverse events associated with the most frequently used off-label drugs include akathisia resulting from the use of gabapentin for neurogenic pain; agitation associated with the use of amitriptyline hydrochloride for migraine; hallucinations with the use of trazodone hydrochloride for insomnia; QT interval prolongation with the use of quetiapine fumarate for depression; and weight gain with the use of olanzapine for depression,” the authors added.

“Off-label use may be clinically appropriate given the complexity of the patient’s condition, the lack of alternative effective drugs, or after exhausting approved drugs.” However, previous research has shown that physicians’ lack of knowledge of approved treatment indications was one important factor contributing to off-label prescribing. And one study showed that physicians are finding it difficult to keep up with rapidly changing medication information, and this lack of knowledge is affecting treatment, Dr. Eguale and his associates said.

That knowledge gap could be filled by supplying clinicians with information regarding drug approval status and the quality of supporting scientific evidence at the point of care, when they write prescriptions into patients’ electronic health records, the investigators noted. This would have the added advantage of facilitating communication among physicians, pharmacists, and patients, and could reduce medication errors such as those caused by giving drugs to the wrong patients or by giving patients sound-alike or look-alike drugs.

No sponsors were identified for this study. Dr. Tewodros Eguale and his associates reported having no relevant financial disclosures.

Off-label prescribing of drugs is common and very likely to cause adverse events, particularly when no strong scientific evidence supports the off-label use, according to a report published online Nov. 2 in JAMA Internal Medicine.

No systematic investigation of the off-label use of prescription drugs has been done to date, in part because physicians aren’t required to document intended indications. But recent innovations in electronic health records provided an opportunity to track off-label prescribing and its influence on adverse drug events in the Canadian province of Quebec, which provides health insurance for all 8.5 million residents. There, physicians must provide the indication(s) for every new prescription, the reason(s) for any dose changes or drug discontinuation, and the nature of any adverse events, said Dr. Tewodros Eguale of the department of epidemiology, biostatistics, and occupational health at McGill University, Montreal, and his associates.

istockphoto.com

In what they described as the first large study of its kind, the investigators analyzed the prescribing information in electronic medical records of 46,021 adults (mean age 58 years) given 151,305 new prescriptions during a 5-year period. Physicians reported off-label use in 17,847 (11.8%) of these prescriptions, and that off-label use lacked strong scientific evidence in the great majority of cases (80.9%). The median follow-up time for use of prescribed medications was 386 days (range, 1 day to 6 years).

Prescribed drugs were discontinued because of adverse events in 3,484 cases. The incidence of adverse events was 44% higher for off-label use (19.7 per 10,000 person-months) than for on-label use (12.5 per 10,000 person-months). Moreover, the incidence of adverse events was 54% higher for off-label use unsupported by strong scientific evidence (21.7 per 10,000 person-months) than for off-label use supported by strong scientific evidence (13.2 per 10,000 person-months), the investigators said (JAMA Intern Med. 2015 Nov 2. doi:10.1001/jamainternmed.2015.6058).

The class of drugs with the highest rate of adverse effects was anti-infective agents (66.2 per 10,000 person-months), followed by central nervous system drugs such as antidepressants, anxiolytics, and antimigraine medicine (18.1 per 10,000); cardiovascular drugs (15.9 per 10,000); hormonal agents (12.7); autonomic drugs including albuterol and terbutaline (8.4); gastrointestinal drugs (6.1); ear, nose, and throat medications (2.8); and “other” agents such as antihistamines, blood thinners, and antineoplastics (1.3).

“Selected examples of adverse events associated with the most frequently used off-label drugs include akathisia resulting from the use of gabapentin for neurogenic pain; agitation associated with the use of amitriptyline hydrochloride for migraine; hallucinations with the use of trazodone hydrochloride for insomnia; QT interval prolongation with the use of quetiapine fumarate for depression; and weight gain with the use of olanzapine for depression,” the authors added.

“Off-label use may be clinically appropriate given the complexity of the patient’s condition, the lack of alternative effective drugs, or after exhausting approved drugs.” However, previous research has shown that physicians’ lack of knowledge of approved treatment indications was one important factor contributing to off-label prescribing. And one study showed that physicians are finding it difficult to keep up with rapidly changing medication information, and this lack of knowledge is affecting treatment, Dr. Eguale and his associates said.

That knowledge gap could be filled by supplying clinicians with information regarding drug approval status and the quality of supporting scientific evidence at the point of care, when they write prescriptions into patients’ electronic health records, the investigators noted. This would have the added advantage of facilitating communication among physicians, pharmacists, and patients, and could reduce medication errors such as those caused by giving drugs to the wrong patients or by giving patients sound-alike or look-alike drugs.

No sponsors were identified for this study. Dr. Tewodros Eguale and his associates reported having no relevant financial disclosures.

Off-label prescribing of drugs is common and very likely to cause adverse events, particularly when no strong scientific evidence supports the off-label use, according to a report published online Nov. 2 in JAMA Internal Medicine.

No systematic investigation of the off-label use of prescription drugs has been done to date, in part because physicians aren’t required to document intended indications. But recent innovations in electronic health records provided an opportunity to track off-label prescribing and its influence on adverse drug events in the Canadian province of Quebec, which provides health insurance for all 8.5 million residents. There, physicians must provide the indication(s) for every new prescription, the reason(s) for any dose changes or drug discontinuation, and the nature of any adverse events, said Dr. Tewodros Eguale of the department of epidemiology, biostatistics, and occupational health at McGill University, Montreal, and his associates.

istockphoto.com

In what they described as the first large study of its kind, the investigators analyzed the prescribing information in electronic medical records of 46,021 adults (mean age 58 years) given 151,305 new prescriptions during a 5-year period. Physicians reported off-label use in 17,847 (11.8%) of these prescriptions, and that off-label use lacked strong scientific evidence in the great majority of cases (80.9%). The median follow-up time for use of prescribed medications was 386 days (range, 1 day to 6 years).

Prescribed drugs were discontinued because of adverse events in 3,484 cases. The incidence of adverse events was 44% higher for off-label use (19.7 per 10,000 person-months) than for on-label use (12.5 per 10,000 person-months). Moreover, the incidence of adverse events was 54% higher for off-label use unsupported by strong scientific evidence (21.7 per 10,000 person-months) than for off-label use supported by strong scientific evidence (13.2 per 10,000 person-months), the investigators said (JAMA Intern Med. 2015 Nov 2. doi:10.1001/jamainternmed.2015.6058).

The class of drugs with the highest rate of adverse effects was anti-infective agents (66.2 per 10,000 person-months), followed by central nervous system drugs such as antidepressants, anxiolytics, and antimigraine medicine (18.1 per 10,000); cardiovascular drugs (15.9 per 10,000); hormonal agents (12.7); autonomic drugs including albuterol and terbutaline (8.4); gastrointestinal drugs (6.1); ear, nose, and throat medications (2.8); and “other” agents such as antihistamines, blood thinners, and antineoplastics (1.3).

“Selected examples of adverse events associated with the most frequently used off-label drugs include akathisia resulting from the use of gabapentin for neurogenic pain; agitation associated with the use of amitriptyline hydrochloride for migraine; hallucinations with the use of trazodone hydrochloride for insomnia; QT interval prolongation with the use of quetiapine fumarate for depression; and weight gain with the use of olanzapine for depression,” the authors added.

“Off-label use may be clinically appropriate given the complexity of the patient’s condition, the lack of alternative effective drugs, or after exhausting approved drugs.” However, previous research has shown that physicians’ lack of knowledge of approved treatment indications was one important factor contributing to off-label prescribing. And one study showed that physicians are finding it difficult to keep up with rapidly changing medication information, and this lack of knowledge is affecting treatment, Dr. Eguale and his associates said.

That knowledge gap could be filled by supplying clinicians with information regarding drug approval status and the quality of supporting scientific evidence at the point of care, when they write prescriptions into patients’ electronic health records, the investigators noted. This would have the added advantage of facilitating communication among physicians, pharmacists, and patients, and could reduce medication errors such as those caused by giving drugs to the wrong patients or by giving patients sound-alike or look-alike drugs.

No sponsors were identified for this study. Dr. Tewodros Eguale and his associates reported having no relevant financial disclosures.

Daily oral olaparib induced a 33% response rate in refractory, progressing prostate cancer in an international phase II clinical trial. The study was published online Oct. 29 in the New England Journal of Medicine.

Researchers hypothesized that olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor recently approved for treatment of ovarian cancers with BRCA1/2 mutations, would also show antitumor activity in sporadic cases of metastatic, castration-resistant prostate cancer in which the tumors expressed DNA-repair defects. During a 2-year period, the researchers identified 49 patients at seven medical centers to participate in the study.

©2015 AACR/Todd Buchanan

Fresh biopsy samples, obtained before treatment began, were used for germline whole-exome sequencing and transcriptome studies, said Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, both in London, and his associates.

Participants took 400-mg tablets of olaparib twice daily until they showed radiologic progression, unequivocal clinical progression, or unacceptable side effects, or until they died. After a median follow-up of 14.4 months (range, 1.4-21.9 months), median overall survival was 10.1 months. Twelve patients survived more than 6 months on olaparib, and four survived more than 12 months on the drug.

The primary end point – treatment response rate – was 33%, with 16 of the 49 patients demonstrating a radiologic response on CT scanning, regression of bone metastases on serial MRI scanning, a reduction of 50% or more in PSA level, and/or “impressive” reductions in the number of circulating tumor cells to less than 5 per 7.5 mL (N Engl J Med. 2015 Oct 29. doi:10.1056/NEJMoa1506859).

Genetic testing of the tumor samples showed that 16 patients had tumor aberrations in DNA-repair genes, including BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2. Fourteen of these 16 patients responded to olaparib. In contrast, 2 of the 33 patients whose tumors did not have aberrations in DNA-repair genes responded to olaparib. In addition, radiologic progression-free survival was significantly longer in the group with mutations in the DNA-repair genes (median, 9.8 months) than in the other group (2.7 months). Overall survival also was significantly longer (median 13.8 months vs. 7.5 months).

Three patients permanently discontinued olaparib because of adverse events, chiefly anemia. Another 13 patients required dose reductions. Drug-related toxicity included anemia (affecting 20% of patients), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%).

Prostate cancers characterized by defects in DNA repair are thought to comprise 25%-30% of all sporadic, castration-resistant prostate cancers. These study findings suggest that this commonly occurring subset of tumors can be molecularly stratified for treatment. Their results demonstrate that identifying predictive biomarkers from fresh tumor-biopsy samples is feasible, and that “next-generation sequencing analyses of tumor-biopsy samples can increase our understanding of treatment responses,” Dr. Mateo and his associates said.

They added that the DNA-repair defects found in these tumors may prove sensitive to platinum-based chemotherapies. This type of treatment usually is not used for metastatic, castration-resistant prostate cancer because phase III studies haven’t shown a survival benefit in unselected patients. However, anecdotal responses to platinum analogues have been reported, and emerging data show that PAPR-inhibitors show antitumor activity against similar (ovarian) cancers.

Cancer Research U.K., Royal Marsden NHS Foundation Trust, Stand Up To Cancer–Prostate Cancer Foundation, Prostate Cancer U.K., National Institute for Health Research, Medical Research Council–Prostate Cancer U.K., Swiss Cancer League, Marie Curie International Incoming Fellowship, and the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Institute for Health Research Cancer Research Network funded the study. AstraZeneca provided the olaparib used in the trial. Dr. Mateo reported having no disclosures; his associates reported ties to numerous industry sources.

Daily oral olaparib induced a 33% response rate in refractory, progressing prostate cancer in an international phase II clinical trial. The study was published online Oct. 29 in the New England Journal of Medicine.

Researchers hypothesized that olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor recently approved for treatment of ovarian cancers with BRCA1/2 mutations, would also show antitumor activity in sporadic cases of metastatic, castration-resistant prostate cancer in which the tumors expressed DNA-repair defects. During a 2-year period, the researchers identified 49 patients at seven medical centers to participate in the study.

©2015 AACR/Todd Buchanan

Fresh biopsy samples, obtained before treatment began, were used for germline whole-exome sequencing and transcriptome studies, said Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, both in London, and his associates.

Participants took 400-mg tablets of olaparib twice daily until they showed radiologic progression, unequivocal clinical progression, or unacceptable side effects, or until they died. After a median follow-up of 14.4 months (range, 1.4-21.9 months), median overall survival was 10.1 months. Twelve patients survived more than 6 months on olaparib, and four survived more than 12 months on the drug.

The primary end point – treatment response rate – was 33%, with 16 of the 49 patients demonstrating a radiologic response on CT scanning, regression of bone metastases on serial MRI scanning, a reduction of 50% or more in PSA level, and/or “impressive” reductions in the number of circulating tumor cells to less than 5 per 7.5 mL (N Engl J Med. 2015 Oct 29. doi:10.1056/NEJMoa1506859).

Genetic testing of the tumor samples showed that 16 patients had tumor aberrations in DNA-repair genes, including BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2. Fourteen of these 16 patients responded to olaparib. In contrast, 2 of the 33 patients whose tumors did not have aberrations in DNA-repair genes responded to olaparib. In addition, radiologic progression-free survival was significantly longer in the group with mutations in the DNA-repair genes (median, 9.8 months) than in the other group (2.7 months). Overall survival also was significantly longer (median 13.8 months vs. 7.5 months).

Three patients permanently discontinued olaparib because of adverse events, chiefly anemia. Another 13 patients required dose reductions. Drug-related toxicity included anemia (affecting 20% of patients), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%).

Prostate cancers characterized by defects in DNA repair are thought to comprise 25%-30% of all sporadic, castration-resistant prostate cancers. These study findings suggest that this commonly occurring subset of tumors can be molecularly stratified for treatment. Their results demonstrate that identifying predictive biomarkers from fresh tumor-biopsy samples is feasible, and that “next-generation sequencing analyses of tumor-biopsy samples can increase our understanding of treatment responses,” Dr. Mateo and his associates said.

They added that the DNA-repair defects found in these tumors may prove sensitive to platinum-based chemotherapies. This type of treatment usually is not used for metastatic, castration-resistant prostate cancer because phase III studies haven’t shown a survival benefit in unselected patients. However, anecdotal responses to platinum analogues have been reported, and emerging data show that PAPR-inhibitors show antitumor activity against similar (ovarian) cancers.

Cancer Research U.K., Royal Marsden NHS Foundation Trust, Stand Up To Cancer–Prostate Cancer Foundation, Prostate Cancer U.K., National Institute for Health Research, Medical Research Council–Prostate Cancer U.K., Swiss Cancer League, Marie Curie International Incoming Fellowship, and the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Institute for Health Research Cancer Research Network funded the study. AstraZeneca provided the olaparib used in the trial. Dr. Mateo reported having no disclosures; his associates reported ties to numerous industry sources.

Daily oral olaparib induced a 33% response rate in refractory, progressing prostate cancer in an international phase II clinical trial. The study was published online Oct. 29 in the New England Journal of Medicine.

Researchers hypothesized that olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor recently approved for treatment of ovarian cancers with BRCA1/2 mutations, would also show antitumor activity in sporadic cases of metastatic, castration-resistant prostate cancer in which the tumors expressed DNA-repair defects. During a 2-year period, the researchers identified 49 patients at seven medical centers to participate in the study.

©2015 AACR/Todd Buchanan

Fresh biopsy samples, obtained before treatment began, were used for germline whole-exome sequencing and transcriptome studies, said Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, both in London, and his associates.

Participants took 400-mg tablets of olaparib twice daily until they showed radiologic progression, unequivocal clinical progression, or unacceptable side effects, or until they died. After a median follow-up of 14.4 months (range, 1.4-21.9 months), median overall survival was 10.1 months. Twelve patients survived more than 6 months on olaparib, and four survived more than 12 months on the drug.

The primary end point – treatment response rate – was 33%, with 16 of the 49 patients demonstrating a radiologic response on CT scanning, regression of bone metastases on serial MRI scanning, a reduction of 50% or more in PSA level, and/or “impressive” reductions in the number of circulating tumor cells to less than 5 per 7.5 mL (N Engl J Med. 2015 Oct 29. doi:10.1056/NEJMoa1506859).

Genetic testing of the tumor samples showed that 16 patients had tumor aberrations in DNA-repair genes, including BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2. Fourteen of these 16 patients responded to olaparib. In contrast, 2 of the 33 patients whose tumors did not have aberrations in DNA-repair genes responded to olaparib. In addition, radiologic progression-free survival was significantly longer in the group with mutations in the DNA-repair genes (median, 9.8 months) than in the other group (2.7 months). Overall survival also was significantly longer (median 13.8 months vs. 7.5 months).

Three patients permanently discontinued olaparib because of adverse events, chiefly anemia. Another 13 patients required dose reductions. Drug-related toxicity included anemia (affecting 20% of patients), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%).

Prostate cancers characterized by defects in DNA repair are thought to comprise 25%-30% of all sporadic, castration-resistant prostate cancers. These study findings suggest that this commonly occurring subset of tumors can be molecularly stratified for treatment. Their results demonstrate that identifying predictive biomarkers from fresh tumor-biopsy samples is feasible, and that “next-generation sequencing analyses of tumor-biopsy samples can increase our understanding of treatment responses,” Dr. Mateo and his associates said.

They added that the DNA-repair defects found in these tumors may prove sensitive to platinum-based chemotherapies. This type of treatment usually is not used for metastatic, castration-resistant prostate cancer because phase III studies haven’t shown a survival benefit in unselected patients. However, anecdotal responses to platinum analogues have been reported, and emerging data show that PAPR-inhibitors show antitumor activity against similar (ovarian) cancers.

Cancer Research U.K., Royal Marsden NHS Foundation Trust, Stand Up To Cancer–Prostate Cancer Foundation, Prostate Cancer U.K., National Institute for Health Research, Medical Research Council–Prostate Cancer U.K., Swiss Cancer League, Marie Curie International Incoming Fellowship, and the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Institute for Health Research Cancer Research Network funded the study. AstraZeneca provided the olaparib used in the trial. Dr. Mateo reported having no disclosures; his associates reported ties to numerous industry sources.