A continuously updating database of clinical and genomic details on patients with non–small cell lung cancer accurately represented correlations between genomics and outcomes, based on an analysis of more than 4,000 patients.

“Most efforts to identify clinicogenomic associations currently rely on clinical trials, single-institution series, or national registries,” wrote Gaurav Singal, MD, of Foundation Medicine in Cambridge, Mass., and colleagues in JAMA.

To explore the feasibility of a clinicogenomic database, the researchers combined clinical data from electronic health records with comprehensive genetic profiling data from 28,889 patients; 4,064 adults with non–small cell lung cancer were included in the analysis of associations among tumor genomics, patient characteristics, and clinical outcomes. The data were collected between Jan. 1, 2011, and Jan. 1, 2018, from 275 U.S. oncology practices.

The researchers examined implications of clinical and genomic features for 3,522 patients with advanced disease. Among these, the median overall survival was 10.3 months and the 5-year survival rate was 3.8%. Factors influencing a longer overall survival included never smoking and having nonsquamous pathology; the presence of mutations in genes TP53 and RB1 were associated with shorter survival.

For each patient, researchers calculated the tumor mutational burden (TMB), defined as “a measure of the number of somatic mutations identified per megabase of DNA sequenced.” TMB was significantly higher among smokers, compared with nonsmokers, and “alterations in EGFR, ALK, ROS1, and RET were associated with significantly lower TMB than wild-type cases,” the researchers wrote.

Overall, the results “replicated previously described associations between clinical and genomic characteristics, driver mutations and response to targeted therapy, and TMB and response to immunotherapy,” the researchers wrote.

The findings were limited by several factors, notably the quality and completeness of mortality data, as well as potential biases from the inclusion of comprehensive genetic profiling results and analysis of therapeutic exposures in an unrandomized trial, as well as a study population limited to patients with advanced stage disease, the researchers noted.

However, the results support data from similar studies and further show that clinicogenomic databases can be used in research to augment drug development and improve the design of clinical trials, they wrote.

The study was supported by Flatiron Health and Foundation Medicine, which are both owned by the Roche Group. Dr. Singal and several coauthors are employees of Foundation Medicine.

SOURCE: Singal G et al. JAMA. 2019;321:1391-9.

A continuously updating database of clinical and genomic details on patients with non–small cell lung cancer accurately represented correlations between genomics and outcomes, based on an analysis of more than 4,000 patients.

“Most efforts to identify clinicogenomic associations currently rely on clinical trials, single-institution series, or national registries,” wrote Gaurav Singal, MD, of Foundation Medicine in Cambridge, Mass., and colleagues in JAMA.

To explore the feasibility of a clinicogenomic database, the researchers combined clinical data from electronic health records with comprehensive genetic profiling data from 28,889 patients; 4,064 adults with non–small cell lung cancer were included in the analysis of associations among tumor genomics, patient characteristics, and clinical outcomes. The data were collected between Jan. 1, 2011, and Jan. 1, 2018, from 275 U.S. oncology practices.

The researchers examined implications of clinical and genomic features for 3,522 patients with advanced disease. Among these, the median overall survival was 10.3 months and the 5-year survival rate was 3.8%. Factors influencing a longer overall survival included never smoking and having nonsquamous pathology; the presence of mutations in genes TP53 and RB1 were associated with shorter survival.

For each patient, researchers calculated the tumor mutational burden (TMB), defined as “a measure of the number of somatic mutations identified per megabase of DNA sequenced.” TMB was significantly higher among smokers, compared with nonsmokers, and “alterations in EGFR, ALK, ROS1, and RET were associated with significantly lower TMB than wild-type cases,” the researchers wrote.

Overall, the results “replicated previously described associations between clinical and genomic characteristics, driver mutations and response to targeted therapy, and TMB and response to immunotherapy,” the researchers wrote.

The findings were limited by several factors, notably the quality and completeness of mortality data, as well as potential biases from the inclusion of comprehensive genetic profiling results and analysis of therapeutic exposures in an unrandomized trial, as well as a study population limited to patients with advanced stage disease, the researchers noted.

However, the results support data from similar studies and further show that clinicogenomic databases can be used in research to augment drug development and improve the design of clinical trials, they wrote.

The study was supported by Flatiron Health and Foundation Medicine, which are both owned by the Roche Group. Dr. Singal and several coauthors are employees of Foundation Medicine.

SOURCE: Singal G et al. JAMA. 2019;321:1391-9.

A continuously updating database of clinical and genomic details on patients with non–small cell lung cancer accurately represented correlations between genomics and outcomes, based on an analysis of more than 4,000 patients.

“Most efforts to identify clinicogenomic associations currently rely on clinical trials, single-institution series, or national registries,” wrote Gaurav Singal, MD, of Foundation Medicine in Cambridge, Mass., and colleagues in JAMA.

To explore the feasibility of a clinicogenomic database, the researchers combined clinical data from electronic health records with comprehensive genetic profiling data from 28,889 patients; 4,064 adults with non–small cell lung cancer were included in the analysis of associations among tumor genomics, patient characteristics, and clinical outcomes. The data were collected between Jan. 1, 2011, and Jan. 1, 2018, from 275 U.S. oncology practices.

The researchers examined implications of clinical and genomic features for 3,522 patients with advanced disease. Among these, the median overall survival was 10.3 months and the 5-year survival rate was 3.8%. Factors influencing a longer overall survival included never smoking and having nonsquamous pathology; the presence of mutations in genes TP53 and RB1 were associated with shorter survival.

For each patient, researchers calculated the tumor mutational burden (TMB), defined as “a measure of the number of somatic mutations identified per megabase of DNA sequenced.” TMB was significantly higher among smokers, compared with nonsmokers, and “alterations in EGFR, ALK, ROS1, and RET were associated with significantly lower TMB than wild-type cases,” the researchers wrote.

Overall, the results “replicated previously described associations between clinical and genomic characteristics, driver mutations and response to targeted therapy, and TMB and response to immunotherapy,” the researchers wrote.

The findings were limited by several factors, notably the quality and completeness of mortality data, as well as potential biases from the inclusion of comprehensive genetic profiling results and analysis of therapeutic exposures in an unrandomized trial, as well as a study population limited to patients with advanced stage disease, the researchers noted.

However, the results support data from similar studies and further show that clinicogenomic databases can be used in research to augment drug development and improve the design of clinical trials, they wrote.

The study was supported by Flatiron Health and Foundation Medicine, which are both owned by the Roche Group. Dr. Singal and several coauthors are employees of Foundation Medicine.

SOURCE: Singal G et al. JAMA. 2019;321:1391-9.

An international group of scientists have announced they have an image of a black hole. This feat of scientific achievement and teamwork is another giant step in humankind’s understanding of the universe. It isn’t easy to find something that isn’t there. Black holes exist and this one is about 6.5 billion times more massive than Earth’s sun. That is a lot of “there.”

In medical research, most articles are about discovering something new. Lately, it is also common to publish studies that claim that something doesn’t exist. No difference is found between treatment A and treatment B. Two decades ago those negative studies rarely were published, but there was merit in the idea that more of them should be published. However, that merit presupposed that the negative studies worthy of publication would be well designed, robust, and, most importantly, contain a power calculation showing that the methodology would have detected the phenomenon if the phenomenon were large enough to be clinically important. Alas, the literature has been flooded with negative studies finding no effect because the studies were hopelessly underpowered and never had a realistic chance of detecting anything. This fake news pollutes our medical knowledge.

To clarify, let me provide a simple example. With my myopia, at 100 yards and without my glasses, I can’t detect the difference between Lebron James and Megan Rapinoe, although I know Megan is better at corner kicks.

Now let me give a second, more complex example that obfuscates the same detection issue. Are there moons circling Jupiter? I go out each night, find Jupiter, take a picture with my trusty cell phone, and examine the picture for any evidence of an object(s) circling the planet. I do this many times. How many? Well, if I only do it three times, people will doubt my science, but doing it 1,000 times would take too long. In my experience, most negative studies seem to involve about 30-50 patients. So one picture a week for a year will produce 52 observations. That is a lot of cold nights under the stars. I will use my scientific knowledge and ability to read sky charts to locate Jupiter. (There is an app for that.) I will use my experience to distinguish Jupiter from Venus and Mars. There will be cloudy days, so maybe only 30 clear pictures will be obtained. I will have a second observer examine the photos. We will calculate a kappa statistic for inter-rater agreement. There will be pictures and tables of numbers. When I’m done, I will publish an article saying that Jupiter doesn’t have moons because I didn’t find any. Trust me, I’m a doctor.

Science doesn’t work that way. Science doesn’t care how smart I am, how dedicated I am, how expensive my cell phone is, or how much work I put into the project, science wants empiric proof. My failure to find moons does not refute their existence. A claim that something does NOT exist cannot be correctly made by simply showing that the P value is greater than .05. A statistically insignificant P value also might also mean that my experiment, despite all my time, effort, commitment, and data collection, is simply inadequate to detect the phenomenon. My cell phone has enough pixels to see Jupiter but not its moons. The phone isn’t powerful enough. My claim is a type II error.

Proving zero difference with statistics is impossible. One needs to specify the threshold size of a clinically important effect and then show that your methods and results were powerful enough to have detected something that small. Only then may you correctly publish a conclusion that there is nothing there, a donut hole in the black void of space.

I invite you to do your own survey. As you read journal articles, identify the next 10 times you read a conclusion that claims no effect was found. Scour that article carefully for any indication of the size of effect that those methods and results would have been able to detect. Look for a power calculation. Grade the article with a simple pass/fail on that point. Did the authors provide that information in a way you can understand, or do you just have to trust them? Take President Reagan’s advice, “Trust, but verify.” Most of the 10 articles will lack the calculation and many negative claims are type II errors.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

An international group of scientists have announced they have an image of a black hole. This feat of scientific achievement and teamwork is another giant step in humankind’s understanding of the universe. It isn’t easy to find something that isn’t there. Black holes exist and this one is about 6.5 billion times more massive than Earth’s sun. That is a lot of “there.”

In medical research, most articles are about discovering something new. Lately, it is also common to publish studies that claim that something doesn’t exist. No difference is found between treatment A and treatment B. Two decades ago those negative studies rarely were published, but there was merit in the idea that more of them should be published. However, that merit presupposed that the negative studies worthy of publication would be well designed, robust, and, most importantly, contain a power calculation showing that the methodology would have detected the phenomenon if the phenomenon were large enough to be clinically important. Alas, the literature has been flooded with negative studies finding no effect because the studies were hopelessly underpowered and never had a realistic chance of detecting anything. This fake news pollutes our medical knowledge.

To clarify, let me provide a simple example. With my myopia, at 100 yards and without my glasses, I can’t detect the difference between Lebron James and Megan Rapinoe, although I know Megan is better at corner kicks.

Now let me give a second, more complex example that obfuscates the same detection issue. Are there moons circling Jupiter? I go out each night, find Jupiter, take a picture with my trusty cell phone, and examine the picture for any evidence of an object(s) circling the planet. I do this many times. How many? Well, if I only do it three times, people will doubt my science, but doing it 1,000 times would take too long. In my experience, most negative studies seem to involve about 30-50 patients. So one picture a week for a year will produce 52 observations. That is a lot of cold nights under the stars. I will use my scientific knowledge and ability to read sky charts to locate Jupiter. (There is an app for that.) I will use my experience to distinguish Jupiter from Venus and Mars. There will be cloudy days, so maybe only 30 clear pictures will be obtained. I will have a second observer examine the photos. We will calculate a kappa statistic for inter-rater agreement. There will be pictures and tables of numbers. When I’m done, I will publish an article saying that Jupiter doesn’t have moons because I didn’t find any. Trust me, I’m a doctor.

Science doesn’t work that way. Science doesn’t care how smart I am, how dedicated I am, how expensive my cell phone is, or how much work I put into the project, science wants empiric proof. My failure to find moons does not refute their existence. A claim that something does NOT exist cannot be correctly made by simply showing that the P value is greater than .05. A statistically insignificant P value also might also mean that my experiment, despite all my time, effort, commitment, and data collection, is simply inadequate to detect the phenomenon. My cell phone has enough pixels to see Jupiter but not its moons. The phone isn’t powerful enough. My claim is a type II error.

Proving zero difference with statistics is impossible. One needs to specify the threshold size of a clinically important effect and then show that your methods and results were powerful enough to have detected something that small. Only then may you correctly publish a conclusion that there is nothing there, a donut hole in the black void of space.

I invite you to do your own survey. As you read journal articles, identify the next 10 times you read a conclusion that claims no effect was found. Scour that article carefully for any indication of the size of effect that those methods and results would have been able to detect. Look for a power calculation. Grade the article with a simple pass/fail on that point. Did the authors provide that information in a way you can understand, or do you just have to trust them? Take President Reagan’s advice, “Trust, but verify.” Most of the 10 articles will lack the calculation and many negative claims are type II errors.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

An international group of scientists have announced they have an image of a black hole. This feat of scientific achievement and teamwork is another giant step in humankind’s understanding of the universe. It isn’t easy to find something that isn’t there. Black holes exist and this one is about 6.5 billion times more massive than Earth’s sun. That is a lot of “there.”

In medical research, most articles are about discovering something new. Lately, it is also common to publish studies that claim that something doesn’t exist. No difference is found between treatment A and treatment B. Two decades ago those negative studies rarely were published, but there was merit in the idea that more of them should be published. However, that merit presupposed that the negative studies worthy of publication would be well designed, robust, and, most importantly, contain a power calculation showing that the methodology would have detected the phenomenon if the phenomenon were large enough to be clinically important. Alas, the literature has been flooded with negative studies finding no effect because the studies were hopelessly underpowered and never had a realistic chance of detecting anything. This fake news pollutes our medical knowledge.

To clarify, let me provide a simple example. With my myopia, at 100 yards and without my glasses, I can’t detect the difference between Lebron James and Megan Rapinoe, although I know Megan is better at corner kicks.

Now let me give a second, more complex example that obfuscates the same detection issue. Are there moons circling Jupiter? I go out each night, find Jupiter, take a picture with my trusty cell phone, and examine the picture for any evidence of an object(s) circling the planet. I do this many times. How many? Well, if I only do it three times, people will doubt my science, but doing it 1,000 times would take too long. In my experience, most negative studies seem to involve about 30-50 patients. So one picture a week for a year will produce 52 observations. That is a lot of cold nights under the stars. I will use my scientific knowledge and ability to read sky charts to locate Jupiter. (There is an app for that.) I will use my experience to distinguish Jupiter from Venus and Mars. There will be cloudy days, so maybe only 30 clear pictures will be obtained. I will have a second observer examine the photos. We will calculate a kappa statistic for inter-rater agreement. There will be pictures and tables of numbers. When I’m done, I will publish an article saying that Jupiter doesn’t have moons because I didn’t find any. Trust me, I’m a doctor.

Science doesn’t work that way. Science doesn’t care how smart I am, how dedicated I am, how expensive my cell phone is, or how much work I put into the project, science wants empiric proof. My failure to find moons does not refute their existence. A claim that something does NOT exist cannot be correctly made by simply showing that the P value is greater than .05. A statistically insignificant P value also might also mean that my experiment, despite all my time, effort, commitment, and data collection, is simply inadequate to detect the phenomenon. My cell phone has enough pixels to see Jupiter but not its moons. The phone isn’t powerful enough. My claim is a type II error.

Proving zero difference with statistics is impossible. One needs to specify the threshold size of a clinically important effect and then show that your methods and results were powerful enough to have detected something that small. Only then may you correctly publish a conclusion that there is nothing there, a donut hole in the black void of space.

I invite you to do your own survey. As you read journal articles, identify the next 10 times you read a conclusion that claims no effect was found. Scour that article carefully for any indication of the size of effect that those methods and results would have been able to detect. Look for a power calculation. Grade the article with a simple pass/fail on that point. Did the authors provide that information in a way you can understand, or do you just have to trust them? Take President Reagan’s advice, “Trust, but verify.” Most of the 10 articles will lack the calculation and many negative claims are type II errors.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

ORLANDO – The landscape for drug development in schizophrenia includes several new promising targets as the field tries to regain its footing after a series of disappointments in recent years, a group of experts said in a session preceding the annual congress of the Schizophrenia International Research Society.

However, the experts also expressed a sense of urgency that trial design and better patient selection have to be improved. Some recent trial failures are likely because of faulty design rather than choosing the wrong target, they said in a satellite session that was funded and organized by Sunovion Pharmaceuticals.

“The question is really critical, because we’ve seen too many major pharma [companies] completely withdraw from this field because of their costly failures,” said Herbert Y. Meltzer, MD, director of the translational neuropharmacology program at Northwestern University, Chicago. “We’ve got to get it right.”

Some of the more prominent, recent trials that were embarked on with hope only to end with unfavorable results include pomaglumetad, a metabotropic glutamate receptor agonist that tried but failed to reduce residual positive and negative schizophrenia symptoms; bitopertin, a glycine transporter 1 inhibitor, for similar symptoms; several phosphodiesterase-10 inhibitors targeting acutely exacerbated schizophrenia symptoms; encenicline, a nicotinic receptor agonist for cognition; and Lu AF35700, a dopamine-and serotonin-receptor agonist, which the manufacturer recently announced failed to reduce positive and negative symptom scores.

Chrisoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., said it’s possible that the phosphodiesterase-10 inhibitors could be looked at again.

“Maybe there is an approach to treat negative symptoms,” he said, adding that some trials might not have chosen patients effectively. “They may have had the wrong patients. They might have had also the wrong prior treatment and not having washed out patients enough.”

Dr. Meltzer said it’s clear to him that the encenicline trial, in particular, involved a problem of design. “There’s no way increasing cholinergic activity through the nicotinic receptor agonist is not going to improve cognition.”

He said embracing genetics is the best way forward, saying that the “shotgun approach” of the past has siphoned money and time away from more important work. “The future of the field is in the genetics – we’re going to have to get the right people into the right trials for the right drug and design them accordingly. If we don’t get into the genetic era very quickly, we’re not going to have a lot of new successful drugs.”

Oliver Howes, MD, PhD, professor of psychiatry at King’s College London, described new areas of interest in the disease pathway, ahead of the dopamine receptor, which has long been a dominant focus of research and treatment efforts.

“How might we target these upstream factors that might regulate dopamine synthesis and release capacity?” is a key research question at the moment, he said.

A drug – called SEP-363856 – that targets the trace amine-associated receptor 1, which has a role in neurotransmission, significantly improved Positive and Negative Syndrome Scale scores in phase 2 trials. Researchers are also making progress in employing parvalbumin interneurons to dampen dopamine synthesis, Dr. Howes said.

Drugmakers halted development of a drug that targeted dopamine firing regulated by the muscarinic receptors M4 and M1 because of gastrointestinal side effects. But there is renewed hope of a more refined approach that targets only M4, rather than M1, which was thought to be responsible for the effects. Some preclinical efforts have been encouraging in this regard, Dr. Howes said.

“This more selective M4 agonist,” he said, “could manipulate the dopamine system in the way that we want.”

Dr. Meltzer, Dr. Correll, and Dr. Howes reported financial relationships with Sunovion, Alkermes, Bristol-Myers Squibb, Lundbeck, Takeda, and other companies.

ORLANDO – The landscape for drug development in schizophrenia includes several new promising targets as the field tries to regain its footing after a series of disappointments in recent years, a group of experts said in a session preceding the annual congress of the Schizophrenia International Research Society.

However, the experts also expressed a sense of urgency that trial design and better patient selection have to be improved. Some recent trial failures are likely because of faulty design rather than choosing the wrong target, they said in a satellite session that was funded and organized by Sunovion Pharmaceuticals.

“The question is really critical, because we’ve seen too many major pharma [companies] completely withdraw from this field because of their costly failures,” said Herbert Y. Meltzer, MD, director of the translational neuropharmacology program at Northwestern University, Chicago. “We’ve got to get it right.”

Some of the more prominent, recent trials that were embarked on with hope only to end with unfavorable results include pomaglumetad, a metabotropic glutamate receptor agonist that tried but failed to reduce residual positive and negative schizophrenia symptoms; bitopertin, a glycine transporter 1 inhibitor, for similar symptoms; several phosphodiesterase-10 inhibitors targeting acutely exacerbated schizophrenia symptoms; encenicline, a nicotinic receptor agonist for cognition; and Lu AF35700, a dopamine-and serotonin-receptor agonist, which the manufacturer recently announced failed to reduce positive and negative symptom scores.

Chrisoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., said it’s possible that the phosphodiesterase-10 inhibitors could be looked at again.

“Maybe there is an approach to treat negative symptoms,” he said, adding that some trials might not have chosen patients effectively. “They may have had the wrong patients. They might have had also the wrong prior treatment and not having washed out patients enough.”

Dr. Meltzer said it’s clear to him that the encenicline trial, in particular, involved a problem of design. “There’s no way increasing cholinergic activity through the nicotinic receptor agonist is not going to improve cognition.”

He said embracing genetics is the best way forward, saying that the “shotgun approach” of the past has siphoned money and time away from more important work. “The future of the field is in the genetics – we’re going to have to get the right people into the right trials for the right drug and design them accordingly. If we don’t get into the genetic era very quickly, we’re not going to have a lot of new successful drugs.”

Oliver Howes, MD, PhD, professor of psychiatry at King’s College London, described new areas of interest in the disease pathway, ahead of the dopamine receptor, which has long been a dominant focus of research and treatment efforts.

“How might we target these upstream factors that might regulate dopamine synthesis and release capacity?” is a key research question at the moment, he said.

A drug – called SEP-363856 – that targets the trace amine-associated receptor 1, which has a role in neurotransmission, significantly improved Positive and Negative Syndrome Scale scores in phase 2 trials. Researchers are also making progress in employing parvalbumin interneurons to dampen dopamine synthesis, Dr. Howes said.

Drugmakers halted development of a drug that targeted dopamine firing regulated by the muscarinic receptors M4 and M1 because of gastrointestinal side effects. But there is renewed hope of a more refined approach that targets only M4, rather than M1, which was thought to be responsible for the effects. Some preclinical efforts have been encouraging in this regard, Dr. Howes said.

“This more selective M4 agonist,” he said, “could manipulate the dopamine system in the way that we want.”

Dr. Meltzer, Dr. Correll, and Dr. Howes reported financial relationships with Sunovion, Alkermes, Bristol-Myers Squibb, Lundbeck, Takeda, and other companies.

ORLANDO – The landscape for drug development in schizophrenia includes several new promising targets as the field tries to regain its footing after a series of disappointments in recent years, a group of experts said in a session preceding the annual congress of the Schizophrenia International Research Society.

However, the experts also expressed a sense of urgency that trial design and better patient selection have to be improved. Some recent trial failures are likely because of faulty design rather than choosing the wrong target, they said in a satellite session that was funded and organized by Sunovion Pharmaceuticals.

“The question is really critical, because we’ve seen too many major pharma [companies] completely withdraw from this field because of their costly failures,” said Herbert Y. Meltzer, MD, director of the translational neuropharmacology program at Northwestern University, Chicago. “We’ve got to get it right.”

Some of the more prominent, recent trials that were embarked on with hope only to end with unfavorable results include pomaglumetad, a metabotropic glutamate receptor agonist that tried but failed to reduce residual positive and negative schizophrenia symptoms; bitopertin, a glycine transporter 1 inhibitor, for similar symptoms; several phosphodiesterase-10 inhibitors targeting acutely exacerbated schizophrenia symptoms; encenicline, a nicotinic receptor agonist for cognition; and Lu AF35700, a dopamine-and serotonin-receptor agonist, which the manufacturer recently announced failed to reduce positive and negative symptom scores.

Chrisoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., said it’s possible that the phosphodiesterase-10 inhibitors could be looked at again.

“Maybe there is an approach to treat negative symptoms,” he said, adding that some trials might not have chosen patients effectively. “They may have had the wrong patients. They might have had also the wrong prior treatment and not having washed out patients enough.”

Dr. Meltzer said it’s clear to him that the encenicline trial, in particular, involved a problem of design. “There’s no way increasing cholinergic activity through the nicotinic receptor agonist is not going to improve cognition.”

He said embracing genetics is the best way forward, saying that the “shotgun approach” of the past has siphoned money and time away from more important work. “The future of the field is in the genetics – we’re going to have to get the right people into the right trials for the right drug and design them accordingly. If we don’t get into the genetic era very quickly, we’re not going to have a lot of new successful drugs.”

Oliver Howes, MD, PhD, professor of psychiatry at King’s College London, described new areas of interest in the disease pathway, ahead of the dopamine receptor, which has long been a dominant focus of research and treatment efforts.

“How might we target these upstream factors that might regulate dopamine synthesis and release capacity?” is a key research question at the moment, he said.

A drug – called SEP-363856 – that targets the trace amine-associated receptor 1, which has a role in neurotransmission, significantly improved Positive and Negative Syndrome Scale scores in phase 2 trials. Researchers are also making progress in employing parvalbumin interneurons to dampen dopamine synthesis, Dr. Howes said.

Drugmakers halted development of a drug that targeted dopamine firing regulated by the muscarinic receptors M4 and M1 because of gastrointestinal side effects. But there is renewed hope of a more refined approach that targets only M4, rather than M1, which was thought to be responsible for the effects. Some preclinical efforts have been encouraging in this regard, Dr. Howes said.

“This more selective M4 agonist,” he said, “could manipulate the dopamine system in the way that we want.”

Dr. Meltzer, Dr. Correll, and Dr. Howes reported financial relationships with Sunovion, Alkermes, Bristol-Myers Squibb, Lundbeck, Takeda, and other companies.

Click to Read.

This CME supplement to OBG Management provides readers with an understanding of the following topics: 

• The relationship between chronic pelvic pain and endometriosis
• The limitations of laparocopy in the diagnosis of endometriosis
• The emerging role of imaging in the diagnosis of endometriosis

Click Here to read the full supplement and access a posttest and evaluation for CME credit.

Click to Read.

This CME supplement to OBG Management provides readers with an understanding of the following topics: 

• The relationship between chronic pelvic pain and endometriosis
• The limitations of laparocopy in the diagnosis of endometriosis
• The emerging role of imaging in the diagnosis of endometriosis

Click Here to read the full supplement and access a posttest and evaluation for CME credit.

Click to Read.

This CME supplement to OBG Management provides readers with an understanding of the following topics: 

• The relationship between chronic pelvic pain and endometriosis
• The limitations of laparocopy in the diagnosis of endometriosis
• The emerging role of imaging in the diagnosis of endometriosis

Click Here to read the full supplement and access a posttest and evaluation for CME credit.

BALTIMORE – Patients who take benzodiazepines for anxiety and have laparoscopic Nissen fundoplication for gastroesophageal reflux disease achieve similar outcomes as other patients, but also have much lower rates of postop satisfaction, according to a study from the Ohio State University presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons.

DAJ/Thinkstock

Carla Holcomb, MD, a minimally invasive surgery/bariatric fellow at the Ohio State’s Wexner Medical Center, Columbus, reported the upshot of the study findings. “Preoperative counseling is especially important regarding postoperative expectations in patients with anxiety,” she said.

The retrospective study evaluated 271 patients who had laparoscopic Nissen fundoplication (LNF) during 2011-2016 at the medical center, comparing outcomes in patients who were on serotonin-modulating medication for depression (n = 103), benzodiazepines for anxiety (n = 44), or neither (n = 124). The researchers evaluated a number of metrics – DeMeester score of esophageal acid exposure, pre- and postoperative health-related quality of life, and postoperative antacid use and need for endoscopic dilation – across all cohorts. While some scores among the anxiety cohort trended higher (DeMeester score of 43 vs. 38 for the no-anxiety patients) they were not statistically significant, Dr. Holcomb noted. Patients taking antidepressants reported similar subjective outcomes and satisfaction rates to those not taking antidepressants.

However, when patients were queried about their overall satisfaction after laparoscopic Nissen fundoplication 77%-87% in the no-depression, depression, and no-anxiety groups reported they were satisfied, while only 37% of those in the anxiety group did so. That is based on a response rate of 53% to a telephone inquiry 15 months after LNF.

“The patients who had anxiety looked vastly different from the rest of the population,” said Dr. Holcomb. “Patients taking antidepressants reported similar objective outcomes and high satisfaction rates, [compared with] patients not taking antidepressants after LNF, and although LNF does improve gastroesophageal reflux disease symptoms in patients taking anxiolytics, they rarely achieve satisfaction in long-term follow-up.”

Among the study limitations Dr. Holcomb acknowledged were the 53% long-term response rate and not knowing if an anatomical reason may explain the higher health-related quality of life scores in the anxiety group – 7 vs. 4 in the no-anxiety group – at long-term follow-up, although the overall score was low at 5.

Dr. Holcomb had no relevant financial disclosures.

SOURCE: Holcomb CN et al. SAGES 2019, Session SS04.

BALTIMORE – Patients who take benzodiazepines for anxiety and have laparoscopic Nissen fundoplication for gastroesophageal reflux disease achieve similar outcomes as other patients, but also have much lower rates of postop satisfaction, according to a study from the Ohio State University presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons.

DAJ/Thinkstock

Carla Holcomb, MD, a minimally invasive surgery/bariatric fellow at the Ohio State’s Wexner Medical Center, Columbus, reported the upshot of the study findings. “Preoperative counseling is especially important regarding postoperative expectations in patients with anxiety,” she said.

The retrospective study evaluated 271 patients who had laparoscopic Nissen fundoplication (LNF) during 2011-2016 at the medical center, comparing outcomes in patients who were on serotonin-modulating medication for depression (n = 103), benzodiazepines for anxiety (n = 44), or neither (n = 124). The researchers evaluated a number of metrics – DeMeester score of esophageal acid exposure, pre- and postoperative health-related quality of life, and postoperative antacid use and need for endoscopic dilation – across all cohorts. While some scores among the anxiety cohort trended higher (DeMeester score of 43 vs. 38 for the no-anxiety patients) they were not statistically significant, Dr. Holcomb noted. Patients taking antidepressants reported similar subjective outcomes and satisfaction rates to those not taking antidepressants.

However, when patients were queried about their overall satisfaction after laparoscopic Nissen fundoplication 77%-87% in the no-depression, depression, and no-anxiety groups reported they were satisfied, while only 37% of those in the anxiety group did so. That is based on a response rate of 53% to a telephone inquiry 15 months after LNF.

“The patients who had anxiety looked vastly different from the rest of the population,” said Dr. Holcomb. “Patients taking antidepressants reported similar objective outcomes and high satisfaction rates, [compared with] patients not taking antidepressants after LNF, and although LNF does improve gastroesophageal reflux disease symptoms in patients taking anxiolytics, they rarely achieve satisfaction in long-term follow-up.”

Among the study limitations Dr. Holcomb acknowledged were the 53% long-term response rate and not knowing if an anatomical reason may explain the higher health-related quality of life scores in the anxiety group – 7 vs. 4 in the no-anxiety group – at long-term follow-up, although the overall score was low at 5.

Dr. Holcomb had no relevant financial disclosures.

SOURCE: Holcomb CN et al. SAGES 2019, Session SS04.

BALTIMORE – Patients who take benzodiazepines for anxiety and have laparoscopic Nissen fundoplication for gastroesophageal reflux disease achieve similar outcomes as other patients, but also have much lower rates of postop satisfaction, according to a study from the Ohio State University presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons.

DAJ/Thinkstock

Carla Holcomb, MD, a minimally invasive surgery/bariatric fellow at the Ohio State’s Wexner Medical Center, Columbus, reported the upshot of the study findings. “Preoperative counseling is especially important regarding postoperative expectations in patients with anxiety,” she said.

The retrospective study evaluated 271 patients who had laparoscopic Nissen fundoplication (LNF) during 2011-2016 at the medical center, comparing outcomes in patients who were on serotonin-modulating medication for depression (n = 103), benzodiazepines for anxiety (n = 44), or neither (n = 124). The researchers evaluated a number of metrics – DeMeester score of esophageal acid exposure, pre- and postoperative health-related quality of life, and postoperative antacid use and need for endoscopic dilation – across all cohorts. While some scores among the anxiety cohort trended higher (DeMeester score of 43 vs. 38 for the no-anxiety patients) they were not statistically significant, Dr. Holcomb noted. Patients taking antidepressants reported similar subjective outcomes and satisfaction rates to those not taking antidepressants.

However, when patients were queried about their overall satisfaction after laparoscopic Nissen fundoplication 77%-87% in the no-depression, depression, and no-anxiety groups reported they were satisfied, while only 37% of those in the anxiety group did so. That is based on a response rate of 53% to a telephone inquiry 15 months after LNF.

“The patients who had anxiety looked vastly different from the rest of the population,” said Dr. Holcomb. “Patients taking antidepressants reported similar objective outcomes and high satisfaction rates, [compared with] patients not taking antidepressants after LNF, and although LNF does improve gastroesophageal reflux disease symptoms in patients taking anxiolytics, they rarely achieve satisfaction in long-term follow-up.”

Among the study limitations Dr. Holcomb acknowledged were the 53% long-term response rate and not knowing if an anatomical reason may explain the higher health-related quality of life scores in the anxiety group – 7 vs. 4 in the no-anxiety group – at long-term follow-up, although the overall score was low at 5.

Dr. Holcomb had no relevant financial disclosures.

SOURCE: Holcomb CN et al. SAGES 2019, Session SS04.

Colchicine inhibits the formation of the Nod-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome, a key component in the obesity-associated inflammatory cascade. In a retrospective study, long-term colchicine treatment had glycemic benefit in patients with gout. Other research has suggested that suppressing NLRP3 could improve peripheral insulin resistance as well as β-cell insulin production. However, no randomized controlled trial had yet investigated colchicine’s long-term effects on glucose metabolism in adults with obesity and metabolic syndrome (MetS).

The NIH researchers enrolled 40 adults to receive either colchicine or placebo; 37 completed the 3-month study. Adherence was high in both groups.

Colchicine significantly reduced multiple markers of obesity-associated inflammation, including high sensitivity C-reactive protein and erythrocyte sedimentation rate. The colchicine group also had moderate but statistically significant reductions in white blood cell count, monocytes, neutrophils, and platelets, without significant effects on lymphocyte count.

Although colchicine’s effects on the primary outcome of insulin sensitivity were not significant, some of the secondary outcomes related to glucose homeostasis—eg, insulin resistance and fasting insulin—suggest colchicine treatment may improve hepatic insulin sensitivity. Moreover, the researchers say, a trend toward improvement in disposition index suggests that the drug might potentially delay the onset of diabetes in people at risk. 

While some small, short-term studies had suggested that colchicine might worsen metabolic variables by inhibiting insulin secretion, other recent retrospective studies found long-term colchicine use did not negatively affect insulin secretion or glycemic control. In this study, similarly, the researchers say, chronic colchicine use did not impair first-phase insulin response or insulin sensitivity, and other markers of metabolic health, such as hemoglobin A_1c and cholesterol, were not significantly changed. However, the researchers acknowledge that their study may have been too small to confirm those differences, and say larger studies are warranted.

Colchicine inhibits the formation of the Nod-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome, a key component in the obesity-associated inflammatory cascade. In a retrospective study, long-term colchicine treatment had glycemic benefit in patients with gout. Other research has suggested that suppressing NLRP3 could improve peripheral insulin resistance as well as β-cell insulin production. However, no randomized controlled trial had yet investigated colchicine’s long-term effects on glucose metabolism in adults with obesity and metabolic syndrome (MetS).

The NIH researchers enrolled 40 adults to receive either colchicine or placebo; 37 completed the 3-month study. Adherence was high in both groups.

Colchicine significantly reduced multiple markers of obesity-associated inflammation, including high sensitivity C-reactive protein and erythrocyte sedimentation rate. The colchicine group also had moderate but statistically significant reductions in white blood cell count, monocytes, neutrophils, and platelets, without significant effects on lymphocyte count.

Although colchicine’s effects on the primary outcome of insulin sensitivity were not significant, some of the secondary outcomes related to glucose homeostasis—eg, insulin resistance and fasting insulin—suggest colchicine treatment may improve hepatic insulin sensitivity. Moreover, the researchers say, a trend toward improvement in disposition index suggests that the drug might potentially delay the onset of diabetes in people at risk. 

While some small, short-term studies had suggested that colchicine might worsen metabolic variables by inhibiting insulin secretion, other recent retrospective studies found long-term colchicine use did not negatively affect insulin secretion or glycemic control. In this study, similarly, the researchers say, chronic colchicine use did not impair first-phase insulin response or insulin sensitivity, and other markers of metabolic health, such as hemoglobin A_1c and cholesterol, were not significantly changed. However, the researchers acknowledge that their study may have been too small to confirm those differences, and say larger studies are warranted.

Colchicine inhibits the formation of the Nod-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome, a key component in the obesity-associated inflammatory cascade. In a retrospective study, long-term colchicine treatment had glycemic benefit in patients with gout. Other research has suggested that suppressing NLRP3 could improve peripheral insulin resistance as well as β-cell insulin production. However, no randomized controlled trial had yet investigated colchicine’s long-term effects on glucose metabolism in adults with obesity and metabolic syndrome (MetS).

The NIH researchers enrolled 40 adults to receive either colchicine or placebo; 37 completed the 3-month study. Adherence was high in both groups.

Colchicine significantly reduced multiple markers of obesity-associated inflammation, including high sensitivity C-reactive protein and erythrocyte sedimentation rate. The colchicine group also had moderate but statistically significant reductions in white blood cell count, monocytes, neutrophils, and platelets, without significant effects on lymphocyte count.

Although colchicine’s effects on the primary outcome of insulin sensitivity were not significant, some of the secondary outcomes related to glucose homeostasis—eg, insulin resistance and fasting insulin—suggest colchicine treatment may improve hepatic insulin sensitivity. Moreover, the researchers say, a trend toward improvement in disposition index suggests that the drug might potentially delay the onset of diabetes in people at risk. 

While some small, short-term studies had suggested that colchicine might worsen metabolic variables by inhibiting insulin secretion, other recent retrospective studies found long-term colchicine use did not negatively affect insulin secretion or glycemic control. In this study, similarly, the researchers say, chronic colchicine use did not impair first-phase insulin response or insulin sensitivity, and other markers of metabolic health, such as hemoglobin A_1c and cholesterol, were not significantly changed. However, the researchers acknowledge that their study may have been too small to confirm those differences, and say larger studies are warranted.

Advances in genomics and technology perpetually change and improve therapies in oncology. Enhanced comprehension of cellular signaling, division, and replication has created a platform to selectively restrict neoplastic growth while preserving the integrity of benign cells.

This article reviews therapies that were newly approved in 2018, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.

Click on the PDF above to download the full article and charts in an easy-to-print format. 

Apalutamide (Erleada)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 240 mg orally, once daily.

Adverse Events (AEs): Hyperkalemia and increased risks of seizures, falls, and fractures.

Phase 3 SPARTAN trial (NCT01946204): 40.5-month metastasis-free survival rate, compared with 16.2 months in the placebo group.

ADMIRAL trial (NCT02421939): 21% of the patients who received gilteritinib exhibited complete remission or complete remission with partial hematologic recovery.

NETTER-1 trial (NCT01578239): 65% of adults who received lutetium Lu 177 showed improved progression-free survival at 20 months, compared with just 10.8% in the control group.

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mentzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and a professor of medicine at the University of Pennsylvania.

Advances in genomics and technology perpetually change and improve therapies in oncology. Enhanced comprehension of cellular signaling, division, and replication has created a platform to selectively restrict neoplastic growth while preserving the integrity of benign cells.

This article reviews therapies that were newly approved in 2018, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.

Click on the PDF above to download the full article and charts in an easy-to-print format. 

Apalutamide (Erleada)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 240 mg orally, once daily.

Adverse Events (AEs): Hyperkalemia and increased risks of seizures, falls, and fractures.

Phase 3 SPARTAN trial (NCT01946204): 40.5-month metastasis-free survival rate, compared with 16.2 months in the placebo group.

ADMIRAL trial (NCT02421939): 21% of the patients who received gilteritinib exhibited complete remission or complete remission with partial hematologic recovery.

NETTER-1 trial (NCT01578239): 65% of adults who received lutetium Lu 177 showed improved progression-free survival at 20 months, compared with just 10.8% in the control group.

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mentzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and a professor of medicine at the University of Pennsylvania.

Advances in genomics and technology perpetually change and improve therapies in oncology. Enhanced comprehension of cellular signaling, division, and replication has created a platform to selectively restrict neoplastic growth while preserving the integrity of benign cells.

This article reviews therapies that were newly approved in 2018, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.

Click on the PDF above to download the full article and charts in an easy-to-print format. 

Apalutamide (Erleada)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 240 mg orally, once daily.

Adverse Events (AEs): Hyperkalemia and increased risks of seizures, falls, and fractures.

Phase 3 SPARTAN trial (NCT01946204): 40.5-month metastasis-free survival rate, compared with 16.2 months in the placebo group.

ADMIRAL trial (NCT02421939): 21% of the patients who received gilteritinib exhibited complete remission or complete remission with partial hematologic recovery.

NETTER-1 trial (NCT01578239): 65% of adults who received lutetium Lu 177 showed improved progression-free survival at 20 months, compared with just 10.8% in the control group.

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mentzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and a professor of medicine at the University of Pennsylvania.

The pace of reporting of new measles cases has increased over the last month, bringing the total number for the year to 555 in the United States, according to the Centers for Disease Control and Prevention.

The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.

New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.

Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.

The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.

[email protected]

The pace of reporting of new measles cases has increased over the last month, bringing the total number for the year to 555 in the United States, according to the Centers for Disease Control and Prevention.

The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.

New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.

Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.

The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.

[email protected]

The pace of reporting of new measles cases has increased over the last month, bringing the total number for the year to 555 in the United States, according to the Centers for Disease Control and Prevention.

The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.

New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.

Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.

The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.

[email protected]

Of the 1.5 million nulliparous women who deliver annually in the United States, more than 50% are low-risk pregnancies. Among clinicians, there is a hesitancy to offer elective induction of labor to low-risk nulliparous women, mainly due to early observational studies that noted an association between elective induction of labor and higher rates of cesarean delivery (CD) and other adverse maternal and perinatal outcomes. ^1-3 This reluctance over time has permeated throughout the ObGyn specialty and is culturally embedded in contemporary practice. The early observational studies lacked proper comparison groups because outcomes of women undergoing induction (elective and medically indicated) were compared to those in spontaneous labor. Since women who are being induced do not have the option to be in spontaneous labor, the appropriate comparator group for women undergoing elective induction is women who are being managed expectantly.

ARRIVE addresses appropriate comparator groups

Challenging this pervaded practice, in August 2018, Grobman and colleagues published the findings of the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management).⁴ This trial, conducted by Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network, recruited participants from 41 geographically dispersed centers in the United States. Nulliparous women with low-risk pregnancies between 34 0/7 and 38 6/7 weeks were randomly assigned to either induction of labor at 39 0/7 to 39 4/7 weeks or to expectant management, which was defined as delaying induction until 40 5/7 to 42 2/7 weeks. The objective of the ARRIVE trial was to determine if, among low-risk nulliparous women, elective induction of labor at 39 weeks, compared with expectant management, would reduce the rate of adverse outcomes.

The primary outcome was a composite: perinatal death or severe neonatal complications (need for respiratory support within 72 hours of birth, Apgar score of ≤ 3 at 5 minutes, hypoxic-ischemic encephalopathy, seizures, infection [confirmed sepsis or pneumonia], meconium aspiration syndrome, birth trauma [bone fracture, neurologic injury, or retinal damage], intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support). The secondary outcomes included CD, hypertensive disorders of pregnancy, number of hours in the labor and delivery (L&D) unit, length of postpartum hospital stay, and assessment of satisfaction with labor process.

Mothers induced at 39 weeks fared better, while neonatal outcomes were similar. Of 22,533 eligible women, 6,106 (27%) were randomized: 3,062 were assigned to the induction group, and, 3,044 to the expectant management group. The primary composite outcome—perinatal death or severe neonatal complications—was similar in both groups (4.3% in the induction group vs 5.4% in the expectant management group).

However, women who were induced had significantly lower rates of:

• CD (18.6% with induction vs 22.2% for expectant management; relative risk [RR], 0.84; 95% confidence interval [CI], 0.76–0.93)
• hypertensive disorders of pregnancy (9.1% vs 14.1%; RR, 0.64; 95% CI, 0.56–0.74)
• neonatal respiratory support (3.0% vs. 4.2%; RR, 0.71; 95% CI, 0.55–0.93).

In addition, although women in the induction group had a longer stay in the L&D unit (an expected outcome), the overall postpartum length of stay was shorter. Finally, women in the induction group had higher patient satisfaction scores, with less pain and more control reported during labor.
 

Continue to: What about uncommon adverse outcomes compared at 39 vs 41 weeks?

What about uncommon adverse outcomes compared at 39 vs 41 weeks?

Due to the study’s sample size, ARRIVE investigators could not ascertain if uncommon adverse outcomes (maternal admission to intensive care unit or neonatal seizure) are significantly more common at 40 and 41 weeks, than at 39 weeks.

To address the issue of uncommon adverse outcomes, Chen and colleagues analyzed the US Vital Statistics datasets to compare composite maternal and neonatal morbidity among low-risk nulliparous women with nonanomalous singleton gestations who labored at 39 to 41 weeks.⁵ The primary outcome was composite neonatal morbidity that included Apgar score < 5 at 5 minutes, assisted ventilation longer than 6 hours, seizure, or neonatal mortality. The secondary outcome was composite maternal morbidity that included intensive care unit admission, blood transfusion, uterine rupture, or unplanned hysterectomy.

The investigators found that from 2011–2015, among 19.8 million live births in the United States, there were 3.3 million live births among low-risk nulliparous women. Among these women, 43% delivered at 39 weeks’ gestation, 41% at 40 weeks, and 15% at 41 weeks. The overall rate of composite neonatal morbidity was 8.8 per 1,000 live births; compared with those who delivered at 39 weeks, composite neonatal morbidity was significantly higher for those delivered at 40 (adjusted RR [aRR], 1.22; 95% CI, 1.19–1.25) and 41 weeks (aRR, 1.53; 95% CI, 1.49–1.58).

The secondary outcome, the overall rate of composite maternal morbidity, was 2.8 per 1,000 live births. As with composite neonatal morbidity, the risk of composite maternal morbidity was also significantly higher for those delivered at 40 (aRR, 1.19; 95% CI, 1.14–1.25) and 41 weeks’ gestation (aRR, 1.56; 95% CI, 1.47–1.65) than at 39 weeks.

Thus, among low-risk nulliparous pregnancies, there is an incremental increase in the rates of composite neonatal and maternal morbidity from 39 to 41 weeks.
 

Is induction of labor at 39 weeks feasible?

As the evidence demonstrating multiple benefits of 39-week inductions increases, concerns regarding the feasibility and cost of implementation in the current US health care system mount. A planned secondary analysis of the ARRIVE trial evaluated medical resource utilization among low-risk nulliparous women randomly assigned to elective induction at 39 weeks or expectant management.⁶ Resource utilization was compared between the 2 groups during the antepartum period, delivery admission, and from discharge to 8 weeks postpartum.

For the antepartum period, women in the induction group were significantly less likely than women undergoing expectant management to have at least 1: office visit for routine prenatal care (32.4% vs 68.4%), unanticipated office visit (0.5% vs 2.6%), urgent care/emergency department/triage visit (16.2% vs 44.3%), or hospital admission (0.8% vs 2.2%). When admitted for delivery, as expected, women in the induction group spent significantly more time on the L&D unit (14 hours vs 20 hours) and were more likely to receive interventions for induction (cervical ripening, oxytocin, intrauterine pressure catheter placement). However, they required magnesium sulfate and antibiotics significantly less frequently. For the postpartum group comparison, women in the induction group and their neonates had a significantly shorter duration of hospital stay.

In summary, the investigators found that, compared to women undergoing expectant management, women undergoing elective induction spent longer duration in L&D units and utilized more resources, but they required significantly fewer antepartum clinic and hospital visits, treatments for hypertensive disorders or chorioamnionitis, and had shorter duration of postpartum length of stay.
 

Continue to: Is induction of labor at 39 weeks cost-effective?

Is induction of labor at 39 weeks cost-effective?

Hersh and colleagues performed a cost-effectiveness analysis for induction of labor at 39 weeks versus expectant management for low-risk nulliparous women.⁷ Based on 2016 National Vital Statistics Data, there were 3.5 million term births in the United States. Following the exclusion of high-risk pregnancies and term parous low-risk pregnancies, a theoretical cohort of 1.6 million low-risk nulliparous women was included in the analysis. A decision-tree analytic model was created, in which the initial node stratified low-risk nulliparous women into 2 categories: elective induction at 39 weeks and expectant management. Probabilities of maternal and neonatal outcomes were derived from the literature.

Maternal outcomes included hypertensive disorders of pregnancy and delivery mode. Neonatal outcomes included macrosomia, shoulder dystocia, brachial plexus injury, stillbirth, and neonatal death. Costs of clinic and triage visits, induction of labor, modes of delivery, and maternal and neonatal outcomes were derived from previous studies and adjusted for inflation to 2018 dollars. Finally, quality-adjusted life years (QALYs) were calculated for mothers and neonates and were then used to estimate the incremental cost-effectiveness ratio (ICER) of elective induction of labor at 39 weeks. Following accepted standards, the threshold for cost-effectiveness was set at $100,000/QALYs or less.

Induction at 39 weeks comes in lower cost-wise than the standard threshold for QALY. In their analysis, the investigators found that if all 1.6 million women in their theoretical cohort underwent an elective induction of labor at 39 weeks (rather than expectant management), there would be 54,498 fewer CDs, 79,152 fewer cases of hypertensive disorders, 795 fewer cases of stillbirth, and 11 fewer neonatal deaths. Due to the decreased CD rates, the investigators did project an estimated 86 additional cases of neonatal brachial plexus injury. Using these estimates, costs, and utilities, the authors demonstrated that, compared with expectant management, elective induction of labor at 39 weeks was marginally cost-effective with an ICER of $87,692 per QALY, which was lower than the cost-effectiveness threshold of $100,000 per QALY.

Based on additional sensitivity analyses, the authors concluded that cost-effectiveness of elective induction of labor varied based on variations in model inputs. Specifically, the authors demonstrated that cost-effectiveness of induction of labor varied based on labor induction techniques, modes of delivery, and fluctuations in the rates of CD in induction versus expectant management groups.

Despite these theoretically imputed findings, the authors acknowledged the limitations of their study. Their cost-effectiveness model did not account for costs associated with long-term health impact of CD and hypertensive disease of pregnancy. Additionally, their model did not account for an increase in cost and resource utilization associated with increased time on L&D units to accommodate women undergoing induction. Furthermore, the analysis did not take into account the bundled payments for vaginal versus CDs, which are increasing in prevalence. Lastly, the analysis did not consider the incremental increase in severe neonatal and maternal morbidity from 39 to 41 weeks that Chen et al found in their study.⁵

Will ARRIVE finally arrive?

Cognizant of the medical and economic benefits of 39-week inductions, the Society for Maternal-Fetal Medicine and the American College of Obstetrics and Gynecology published a joint practice advisory recommending “shared decision-making” when counseling low-risk women about induction.⁸ While more research is needed to validate the aforementioned findings, particularly in regard to resource utilization, the ARRIVE trial and its associated analyses suggest that a reconsideration to deliver term low-risk nulliparous women at 39 weeks is warranted.

In summary, the overwhelming evidence suggests that, among low-risk nulliparous women there are maternal and neonatal benefits with delivery at 39 weeks, as compared with expectant management. Logistical concerns should not interfere with women’s desideratum for optimal outcomes.

Of the 1.5 million nulliparous women who deliver annually in the United States, more than 50% are low-risk pregnancies. Among clinicians, there is a hesitancy to offer elective induction of labor to low-risk nulliparous women, mainly due to early observational studies that noted an association between elective induction of labor and higher rates of cesarean delivery (CD) and other adverse maternal and perinatal outcomes. ^1-3 This reluctance over time has permeated throughout the ObGyn specialty and is culturally embedded in contemporary practice. The early observational studies lacked proper comparison groups because outcomes of women undergoing induction (elective and medically indicated) were compared to those in spontaneous labor. Since women who are being induced do not have the option to be in spontaneous labor, the appropriate comparator group for women undergoing elective induction is women who are being managed expectantly.

ARRIVE addresses appropriate comparator groups

Challenging this pervaded practice, in August 2018, Grobman and colleagues published the findings of the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management).⁴ This trial, conducted by Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network, recruited participants from 41 geographically dispersed centers in the United States. Nulliparous women with low-risk pregnancies between 34 0/7 and 38 6/7 weeks were randomly assigned to either induction of labor at 39 0/7 to 39 4/7 weeks or to expectant management, which was defined as delaying induction until 40 5/7 to 42 2/7 weeks. The objective of the ARRIVE trial was to determine if, among low-risk nulliparous women, elective induction of labor at 39 weeks, compared with expectant management, would reduce the rate of adverse outcomes.

The primary outcome was a composite: perinatal death or severe neonatal complications (need for respiratory support within 72 hours of birth, Apgar score of ≤ 3 at 5 minutes, hypoxic-ischemic encephalopathy, seizures, infection [confirmed sepsis or pneumonia], meconium aspiration syndrome, birth trauma [bone fracture, neurologic injury, or retinal damage], intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support). The secondary outcomes included CD, hypertensive disorders of pregnancy, number of hours in the labor and delivery (L&D) unit, length of postpartum hospital stay, and assessment of satisfaction with labor process.

Mothers induced at 39 weeks fared better, while neonatal outcomes were similar. Of 22,533 eligible women, 6,106 (27%) were randomized: 3,062 were assigned to the induction group, and, 3,044 to the expectant management group. The primary composite outcome—perinatal death or severe neonatal complications—was similar in both groups (4.3% in the induction group vs 5.4% in the expectant management group).

However, women who were induced had significantly lower rates of:

• CD (18.6% with induction vs 22.2% for expectant management; relative risk [RR], 0.84; 95% confidence interval [CI], 0.76–0.93)
• hypertensive disorders of pregnancy (9.1% vs 14.1%; RR, 0.64; 95% CI, 0.56–0.74)
• neonatal respiratory support (3.0% vs. 4.2%; RR, 0.71; 95% CI, 0.55–0.93).

In addition, although women in the induction group had a longer stay in the L&D unit (an expected outcome), the overall postpartum length of stay was shorter. Finally, women in the induction group had higher patient satisfaction scores, with less pain and more control reported during labor.
 

Continue to: What about uncommon adverse outcomes compared at 39 vs 41 weeks?

What about uncommon adverse outcomes compared at 39 vs 41 weeks?

Due to the study’s sample size, ARRIVE investigators could not ascertain if uncommon adverse outcomes (maternal admission to intensive care unit or neonatal seizure) are significantly more common at 40 and 41 weeks, than at 39 weeks.

To address the issue of uncommon adverse outcomes, Chen and colleagues analyzed the US Vital Statistics datasets to compare composite maternal and neonatal morbidity among low-risk nulliparous women with nonanomalous singleton gestations who labored at 39 to 41 weeks.⁵ The primary outcome was composite neonatal morbidity that included Apgar score < 5 at 5 minutes, assisted ventilation longer than 6 hours, seizure, or neonatal mortality. The secondary outcome was composite maternal morbidity that included intensive care unit admission, blood transfusion, uterine rupture, or unplanned hysterectomy.

The investigators found that from 2011–2015, among 19.8 million live births in the United States, there were 3.3 million live births among low-risk nulliparous women. Among these women, 43% delivered at 39 weeks’ gestation, 41% at 40 weeks, and 15% at 41 weeks. The overall rate of composite neonatal morbidity was 8.8 per 1,000 live births; compared with those who delivered at 39 weeks, composite neonatal morbidity was significantly higher for those delivered at 40 (adjusted RR [aRR], 1.22; 95% CI, 1.19–1.25) and 41 weeks (aRR, 1.53; 95% CI, 1.49–1.58).

The secondary outcome, the overall rate of composite maternal morbidity, was 2.8 per 1,000 live births. As with composite neonatal morbidity, the risk of composite maternal morbidity was also significantly higher for those delivered at 40 (aRR, 1.19; 95% CI, 1.14–1.25) and 41 weeks’ gestation (aRR, 1.56; 95% CI, 1.47–1.65) than at 39 weeks.

Thus, among low-risk nulliparous pregnancies, there is an incremental increase in the rates of composite neonatal and maternal morbidity from 39 to 41 weeks.
 

Is induction of labor at 39 weeks feasible?

As the evidence demonstrating multiple benefits of 39-week inductions increases, concerns regarding the feasibility and cost of implementation in the current US health care system mount. A planned secondary analysis of the ARRIVE trial evaluated medical resource utilization among low-risk nulliparous women randomly assigned to elective induction at 39 weeks or expectant management.⁶ Resource utilization was compared between the 2 groups during the antepartum period, delivery admission, and from discharge to 8 weeks postpartum.

For the antepartum period, women in the induction group were significantly less likely than women undergoing expectant management to have at least 1: office visit for routine prenatal care (32.4% vs 68.4%), unanticipated office visit (0.5% vs 2.6%), urgent care/emergency department/triage visit (16.2% vs 44.3%), or hospital admission (0.8% vs 2.2%). When admitted for delivery, as expected, women in the induction group spent significantly more time on the L&D unit (14 hours vs 20 hours) and were more likely to receive interventions for induction (cervical ripening, oxytocin, intrauterine pressure catheter placement). However, they required magnesium sulfate and antibiotics significantly less frequently. For the postpartum group comparison, women in the induction group and their neonates had a significantly shorter duration of hospital stay.

In summary, the investigators found that, compared to women undergoing expectant management, women undergoing elective induction spent longer duration in L&D units and utilized more resources, but they required significantly fewer antepartum clinic and hospital visits, treatments for hypertensive disorders or chorioamnionitis, and had shorter duration of postpartum length of stay.
 

Continue to: Is induction of labor at 39 weeks cost-effective?

Is induction of labor at 39 weeks cost-effective?

Hersh and colleagues performed a cost-effectiveness analysis for induction of labor at 39 weeks versus expectant management for low-risk nulliparous women.⁷ Based on 2016 National Vital Statistics Data, there were 3.5 million term births in the United States. Following the exclusion of high-risk pregnancies and term parous low-risk pregnancies, a theoretical cohort of 1.6 million low-risk nulliparous women was included in the analysis. A decision-tree analytic model was created, in which the initial node stratified low-risk nulliparous women into 2 categories: elective induction at 39 weeks and expectant management. Probabilities of maternal and neonatal outcomes were derived from the literature.

Maternal outcomes included hypertensive disorders of pregnancy and delivery mode. Neonatal outcomes included macrosomia, shoulder dystocia, brachial plexus injury, stillbirth, and neonatal death. Costs of clinic and triage visits, induction of labor, modes of delivery, and maternal and neonatal outcomes were derived from previous studies and adjusted for inflation to 2018 dollars. Finally, quality-adjusted life years (QALYs) were calculated for mothers and neonates and were then used to estimate the incremental cost-effectiveness ratio (ICER) of elective induction of labor at 39 weeks. Following accepted standards, the threshold for cost-effectiveness was set at $100,000/QALYs or less.

Induction at 39 weeks comes in lower cost-wise than the standard threshold for QALY. In their analysis, the investigators found that if all 1.6 million women in their theoretical cohort underwent an elective induction of labor at 39 weeks (rather than expectant management), there would be 54,498 fewer CDs, 79,152 fewer cases of hypertensive disorders, 795 fewer cases of stillbirth, and 11 fewer neonatal deaths. Due to the decreased CD rates, the investigators did project an estimated 86 additional cases of neonatal brachial plexus injury. Using these estimates, costs, and utilities, the authors demonstrated that, compared with expectant management, elective induction of labor at 39 weeks was marginally cost-effective with an ICER of $87,692 per QALY, which was lower than the cost-effectiveness threshold of $100,000 per QALY.

Based on additional sensitivity analyses, the authors concluded that cost-effectiveness of elective induction of labor varied based on variations in model inputs. Specifically, the authors demonstrated that cost-effectiveness of induction of labor varied based on labor induction techniques, modes of delivery, and fluctuations in the rates of CD in induction versus expectant management groups.

Despite these theoretically imputed findings, the authors acknowledged the limitations of their study. Their cost-effectiveness model did not account for costs associated with long-term health impact of CD and hypertensive disease of pregnancy. Additionally, their model did not account for an increase in cost and resource utilization associated with increased time on L&D units to accommodate women undergoing induction. Furthermore, the analysis did not take into account the bundled payments for vaginal versus CDs, which are increasing in prevalence. Lastly, the analysis did not consider the incremental increase in severe neonatal and maternal morbidity from 39 to 41 weeks that Chen et al found in their study.⁵

Will ARRIVE finally arrive?

Cognizant of the medical and economic benefits of 39-week inductions, the Society for Maternal-Fetal Medicine and the American College of Obstetrics and Gynecology published a joint practice advisory recommending “shared decision-making” when counseling low-risk women about induction.⁸ While more research is needed to validate the aforementioned findings, particularly in regard to resource utilization, the ARRIVE trial and its associated analyses suggest that a reconsideration to deliver term low-risk nulliparous women at 39 weeks is warranted.

In summary, the overwhelming evidence suggests that, among low-risk nulliparous women there are maternal and neonatal benefits with delivery at 39 weeks, as compared with expectant management. Logistical concerns should not interfere with women’s desideratum for optimal outcomes.

Of the 1.5 million nulliparous women who deliver annually in the United States, more than 50% are low-risk pregnancies. Among clinicians, there is a hesitancy to offer elective induction of labor to low-risk nulliparous women, mainly due to early observational studies that noted an association between elective induction of labor and higher rates of cesarean delivery (CD) and other adverse maternal and perinatal outcomes. ^1-3 This reluctance over time has permeated throughout the ObGyn specialty and is culturally embedded in contemporary practice. The early observational studies lacked proper comparison groups because outcomes of women undergoing induction (elective and medically indicated) were compared to those in spontaneous labor. Since women who are being induced do not have the option to be in spontaneous labor, the appropriate comparator group for women undergoing elective induction is women who are being managed expectantly.

ARRIVE addresses appropriate comparator groups

Challenging this pervaded practice, in August 2018, Grobman and colleagues published the findings of the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management).⁴ This trial, conducted by Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network, recruited participants from 41 geographically dispersed centers in the United States. Nulliparous women with low-risk pregnancies between 34 0/7 and 38 6/7 weeks were randomly assigned to either induction of labor at 39 0/7 to 39 4/7 weeks or to expectant management, which was defined as delaying induction until 40 5/7 to 42 2/7 weeks. The objective of the ARRIVE trial was to determine if, among low-risk nulliparous women, elective induction of labor at 39 weeks, compared with expectant management, would reduce the rate of adverse outcomes.

The primary outcome was a composite: perinatal death or severe neonatal complications (need for respiratory support within 72 hours of birth, Apgar score of ≤ 3 at 5 minutes, hypoxic-ischemic encephalopathy, seizures, infection [confirmed sepsis or pneumonia], meconium aspiration syndrome, birth trauma [bone fracture, neurologic injury, or retinal damage], intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support). The secondary outcomes included CD, hypertensive disorders of pregnancy, number of hours in the labor and delivery (L&D) unit, length of postpartum hospital stay, and assessment of satisfaction with labor process.

Mothers induced at 39 weeks fared better, while neonatal outcomes were similar. Of 22,533 eligible women, 6,106 (27%) were randomized: 3,062 were assigned to the induction group, and, 3,044 to the expectant management group. The primary composite outcome—perinatal death or severe neonatal complications—was similar in both groups (4.3% in the induction group vs 5.4% in the expectant management group).

However, women who were induced had significantly lower rates of:

• CD (18.6% with induction vs 22.2% for expectant management; relative risk [RR], 0.84; 95% confidence interval [CI], 0.76–0.93)
• hypertensive disorders of pregnancy (9.1% vs 14.1%; RR, 0.64; 95% CI, 0.56–0.74)
• neonatal respiratory support (3.0% vs. 4.2%; RR, 0.71; 95% CI, 0.55–0.93).

In addition, although women in the induction group had a longer stay in the L&D unit (an expected outcome), the overall postpartum length of stay was shorter. Finally, women in the induction group had higher patient satisfaction scores, with less pain and more control reported during labor.
 

Continue to: What about uncommon adverse outcomes compared at 39 vs 41 weeks?

What about uncommon adverse outcomes compared at 39 vs 41 weeks?

Due to the study’s sample size, ARRIVE investigators could not ascertain if uncommon adverse outcomes (maternal admission to intensive care unit or neonatal seizure) are significantly more common at 40 and 41 weeks, than at 39 weeks.

To address the issue of uncommon adverse outcomes, Chen and colleagues analyzed the US Vital Statistics datasets to compare composite maternal and neonatal morbidity among low-risk nulliparous women with nonanomalous singleton gestations who labored at 39 to 41 weeks.⁵ The primary outcome was composite neonatal morbidity that included Apgar score < 5 at 5 minutes, assisted ventilation longer than 6 hours, seizure, or neonatal mortality. The secondary outcome was composite maternal morbidity that included intensive care unit admission, blood transfusion, uterine rupture, or unplanned hysterectomy.

The investigators found that from 2011–2015, among 19.8 million live births in the United States, there were 3.3 million live births among low-risk nulliparous women. Among these women, 43% delivered at 39 weeks’ gestation, 41% at 40 weeks, and 15% at 41 weeks. The overall rate of composite neonatal morbidity was 8.8 per 1,000 live births; compared with those who delivered at 39 weeks, composite neonatal morbidity was significantly higher for those delivered at 40 (adjusted RR [aRR], 1.22; 95% CI, 1.19–1.25) and 41 weeks (aRR, 1.53; 95% CI, 1.49–1.58).

The secondary outcome, the overall rate of composite maternal morbidity, was 2.8 per 1,000 live births. As with composite neonatal morbidity, the risk of composite maternal morbidity was also significantly higher for those delivered at 40 (aRR, 1.19; 95% CI, 1.14–1.25) and 41 weeks’ gestation (aRR, 1.56; 95% CI, 1.47–1.65) than at 39 weeks.

Thus, among low-risk nulliparous pregnancies, there is an incremental increase in the rates of composite neonatal and maternal morbidity from 39 to 41 weeks.
 

Is induction of labor at 39 weeks feasible?

As the evidence demonstrating multiple benefits of 39-week inductions increases, concerns regarding the feasibility and cost of implementation in the current US health care system mount. A planned secondary analysis of the ARRIVE trial evaluated medical resource utilization among low-risk nulliparous women randomly assigned to elective induction at 39 weeks or expectant management.⁶ Resource utilization was compared between the 2 groups during the antepartum period, delivery admission, and from discharge to 8 weeks postpartum.

For the antepartum period, women in the induction group were significantly less likely than women undergoing expectant management to have at least 1: office visit for routine prenatal care (32.4% vs 68.4%), unanticipated office visit (0.5% vs 2.6%), urgent care/emergency department/triage visit (16.2% vs 44.3%), or hospital admission (0.8% vs 2.2%). When admitted for delivery, as expected, women in the induction group spent significantly more time on the L&D unit (14 hours vs 20 hours) and were more likely to receive interventions for induction (cervical ripening, oxytocin, intrauterine pressure catheter placement). However, they required magnesium sulfate and antibiotics significantly less frequently. For the postpartum group comparison, women in the induction group and their neonates had a significantly shorter duration of hospital stay.

In summary, the investigators found that, compared to women undergoing expectant management, women undergoing elective induction spent longer duration in L&D units and utilized more resources, but they required significantly fewer antepartum clinic and hospital visits, treatments for hypertensive disorders or chorioamnionitis, and had shorter duration of postpartum length of stay.
 

Continue to: Is induction of labor at 39 weeks cost-effective?

Is induction of labor at 39 weeks cost-effective?

Hersh and colleagues performed a cost-effectiveness analysis for induction of labor at 39 weeks versus expectant management for low-risk nulliparous women.⁷ Based on 2016 National Vital Statistics Data, there were 3.5 million term births in the United States. Following the exclusion of high-risk pregnancies and term parous low-risk pregnancies, a theoretical cohort of 1.6 million low-risk nulliparous women was included in the analysis. A decision-tree analytic model was created, in which the initial node stratified low-risk nulliparous women into 2 categories: elective induction at 39 weeks and expectant management. Probabilities of maternal and neonatal outcomes were derived from the literature.

Maternal outcomes included hypertensive disorders of pregnancy and delivery mode. Neonatal outcomes included macrosomia, shoulder dystocia, brachial plexus injury, stillbirth, and neonatal death. Costs of clinic and triage visits, induction of labor, modes of delivery, and maternal and neonatal outcomes were derived from previous studies and adjusted for inflation to 2018 dollars. Finally, quality-adjusted life years (QALYs) were calculated for mothers and neonates and were then used to estimate the incremental cost-effectiveness ratio (ICER) of elective induction of labor at 39 weeks. Following accepted standards, the threshold for cost-effectiveness was set at $100,000/QALYs or less.

Induction at 39 weeks comes in lower cost-wise than the standard threshold for QALY. In their analysis, the investigators found that if all 1.6 million women in their theoretical cohort underwent an elective induction of labor at 39 weeks (rather than expectant management), there would be 54,498 fewer CDs, 79,152 fewer cases of hypertensive disorders, 795 fewer cases of stillbirth, and 11 fewer neonatal deaths. Due to the decreased CD rates, the investigators did project an estimated 86 additional cases of neonatal brachial plexus injury. Using these estimates, costs, and utilities, the authors demonstrated that, compared with expectant management, elective induction of labor at 39 weeks was marginally cost-effective with an ICER of $87,692 per QALY, which was lower than the cost-effectiveness threshold of $100,000 per QALY.

Based on additional sensitivity analyses, the authors concluded that cost-effectiveness of elective induction of labor varied based on variations in model inputs. Specifically, the authors demonstrated that cost-effectiveness of induction of labor varied based on labor induction techniques, modes of delivery, and fluctuations in the rates of CD in induction versus expectant management groups.

Despite these theoretically imputed findings, the authors acknowledged the limitations of their study. Their cost-effectiveness model did not account for costs associated with long-term health impact of CD and hypertensive disease of pregnancy. Additionally, their model did not account for an increase in cost and resource utilization associated with increased time on L&D units to accommodate women undergoing induction. Furthermore, the analysis did not take into account the bundled payments for vaginal versus CDs, which are increasing in prevalence. Lastly, the analysis did not consider the incremental increase in severe neonatal and maternal morbidity from 39 to 41 weeks that Chen et al found in their study.⁵

Will ARRIVE finally arrive?

Cognizant of the medical and economic benefits of 39-week inductions, the Society for Maternal-Fetal Medicine and the American College of Obstetrics and Gynecology published a joint practice advisory recommending “shared decision-making” when counseling low-risk women about induction.⁸ While more research is needed to validate the aforementioned findings, particularly in regard to resource utilization, the ARRIVE trial and its associated analyses suggest that a reconsideration to deliver term low-risk nulliparous women at 39 weeks is warranted.

In summary, the overwhelming evidence suggests that, among low-risk nulliparous women there are maternal and neonatal benefits with delivery at 39 weeks, as compared with expectant management. Logistical concerns should not interfere with women’s desideratum for optimal outcomes.