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Healthy youth sports participation excludes early specialization
CHICAGO – When a boy receives five college football scholarship offers and a girl commits to playing soccer for a university before either of them starts ninth grade, it’s time to take several steps back in youth sports.
, including the risk of potentially discouraging a lifetime of healthy athletic participation, according to Joel S. Brenner, MD, MPH, a sports medicine expert at the Children’s Hospital of The King’s Daughters and Eastern Virginia Medical School, both in Norfolk.
“This paradigm should be discouraged by society,” Dr. Brenner told attendees at the American Academy of Pediatrics annual meeting. “Sports specialization refers to focusing on one sport to the exclusion of all others, often playing that single sport year-round. Dr. Brenner authored the AAP’s 2016 clinical report on sports specialization and intensive training in young athletes.
Dr. Brenner emphasized the benefits of delaying sports specialization until after puberty, the risks of specializing sooner, and the importance of rest to prevent burnout and injuries.
This is not a new problem, he noted, showing the attendees two Time Magazine covers, from 1999 and 2017, that featured the concern of “Sports Crazed Kids.” But it is so far-reaching that it will requires more than just physicians to change.
“This is not just an athlete problem, a parent problem, a coach problem, or even a physician problem,” Dr. Brenner said. “It’s a societal problem, a youth sports culture problem, and one that all of us as stakeholders need to attack and try to change the culture.”
Youth sports offer a broad range of benefits, such as developing physical activity, and leadership skills, and promoting self-esteem, socialization, and teamwork, Dr. Brenner said.
“But one benefit that often gets forgotten by people, including the coaches, the parents, and the athletes, is that sports is supposed to be about having fun,” he said.
The old model of kids’ sports was loosely organized fun, with kids playing multiple sports throughout the year and less direct involvement from adults, such as street hockey games and pick-up basketball. But those bygone days, Dr. Brenner noted wistfully, have been replaced with a different paradigm today: Children specialize in a single sport very early, and parents and coaches are the driving forces behind their involvement.
Today’s culture of very early sports specialization and college recruitment increases pressure on parents and young athletes to play year-round on multiple teams to stay on the radar of scouts and colleges. And this specialization has expanded to younger and younger ages, with 7-year-olds participating in travel leagues and national rankings of children in their sport as early as sixth grade.
“We should not be ranking kids in middle school or even in early high school,” Dr. Brenner said to wide applause. “We should allow kids to develop in a low-pressure, healthy system before we do that.”
The effects of high pressure have potentially lifelong ramifications. By the time children are 13 years old, 70% have dropped out of organized sports, Dr. Brenner said, and injuries from overuse account for more than half of all sports-related injuries in youth.
Yet the alternative – early diversification and late specialization – can really benefit kids, he said. The early specialization paradigm of playing just one sport focuses on deliberate practice and performance from the start. By contrast, early diversification with multiple sports focuses on deliberate play, during which children develop foundational athletic skills. Children who play a variety of sports are more likely to participate for more years – and it meets youth’s more realistic, long-term needs for lifelong physical activity through “fun, variety, and play,” he said.
Dr. Brenner said that just 1% of high school athletes receive any athletic scholarships, and only 3%-11% of high school athletes compete at the college level. The numbers for high school athletes that go on to play at the professional level is, of course, even smaller: 0.03% to 0.5%, depending on the sport.
And the irony is that the goal of early specialization – producing such elite level athletes – is actually better accomplished through playing multiple sports, Dr. Brenner said. Most Division 1 National Collegiate Athletic Association (NCAA) athletes and 90% of National Football League (NFL) first-round picks played multiple sports in high school. So the benefits of waiting until late adolescence to specialize are twofold: a greater likelihood of athletic success, even at elite levels, and minimizing the risks of injury.
Overuse injuries pose serious risks
More than half of sports injuries are from overuse, and a number of factors contribute to those injuries, such as muscle imbalance, playing surfaces, and training errors, Dr. Brenner said. But the biggest contributors are early specialization, playing year-round sports, and playing on multiple teams.
“This is a problem we see daily,” Dr. Brenner said. “We can see the young dancer, who’s dancing 6-7 days a week, who develops back pain and continues to dance, and develops a stress fracture in her lumbar spine known spondylosis.
“Or we see the young soccer player who plays on multiple teams and develops heel pain, who starts limping with activities of daily living, continues to play soccer despite limping, and develops calcaneal apophysitis, known as Sever’s disease. Or the young baseball pitcher, who pitches for two teams, who develops arm pain and weakness, who has a stress fracture through the proximal humeral epiphysis, known as Little League shoulder.” 
Two broad pieces of guidance can help reduce the risk of injuries, particularly from overuse. First, young athletes should take off at least 1 month from a specific sport at least three times a year to give them adequate time for physical and psychological recovery. Second, ensuring young athletes take at least 1 or 2 days off of practice each week further reduces the likelihood of injury.
In addition to the physical problems these young athletes may develop, they also risk anxiety, depression, burnout, early retirement, and social isolation from peers who don’t play their sport, Dr. Brenner said. Family members also may experience greater stress, he added. And then there’s the risk of missing out on learning other sports they may excel in that offer a lifetime of enjoyment, such as tennis or swimming.
It is not clear where the threshold of involvement is for reducing overuse injury, burnout, and attrition, but Dr. Brenner provided some guidelines as a starting place. High school athletes should not train more 16 hours a week, and organized sports should not exceed free play time by a greater ratio than 2:1. Another guideline is not to exceed more hours per week in organized sports than a child’s age in years.
The primary focus of sports should be learning lifelong physical activity skills and having fun, Dr. Brenner said. Pediatricians should encourage patients to play in a wide variety of sports at least until puberty, thereby decreasing the chance of injuries, stress, and burnout, he said. That can include sports that are not necessarily an official part of school or club competition. Waiting until later to specialize may lead to a higher likelihood of athletic success.
Dr. Brenner said he had no relevant financial disclosures.
CHICAGO – When a boy receives five college football scholarship offers and a girl commits to playing soccer for a university before either of them starts ninth grade, it’s time to take several steps back in youth sports.
, including the risk of potentially discouraging a lifetime of healthy athletic participation, according to Joel S. Brenner, MD, MPH, a sports medicine expert at the Children’s Hospital of The King’s Daughters and Eastern Virginia Medical School, both in Norfolk.
“This paradigm should be discouraged by society,” Dr. Brenner told attendees at the American Academy of Pediatrics annual meeting. “Sports specialization refers to focusing on one sport to the exclusion of all others, often playing that single sport year-round. Dr. Brenner authored the AAP’s 2016 clinical report on sports specialization and intensive training in young athletes.
Dr. Brenner emphasized the benefits of delaying sports specialization until after puberty, the risks of specializing sooner, and the importance of rest to prevent burnout and injuries.
This is not a new problem, he noted, showing the attendees two Time Magazine covers, from 1999 and 2017, that featured the concern of “Sports Crazed Kids.” But it is so far-reaching that it will requires more than just physicians to change.
“This is not just an athlete problem, a parent problem, a coach problem, or even a physician problem,” Dr. Brenner said. “It’s a societal problem, a youth sports culture problem, and one that all of us as stakeholders need to attack and try to change the culture.”
Youth sports offer a broad range of benefits, such as developing physical activity, and leadership skills, and promoting self-esteem, socialization, and teamwork, Dr. Brenner said.
“But one benefit that often gets forgotten by people, including the coaches, the parents, and the athletes, is that sports is supposed to be about having fun,” he said.
The old model of kids’ sports was loosely organized fun, with kids playing multiple sports throughout the year and less direct involvement from adults, such as street hockey games and pick-up basketball. But those bygone days, Dr. Brenner noted wistfully, have been replaced with a different paradigm today: Children specialize in a single sport very early, and parents and coaches are the driving forces behind their involvement.
Today’s culture of very early sports specialization and college recruitment increases pressure on parents and young athletes to play year-round on multiple teams to stay on the radar of scouts and colleges. And this specialization has expanded to younger and younger ages, with 7-year-olds participating in travel leagues and national rankings of children in their sport as early as sixth grade.
“We should not be ranking kids in middle school or even in early high school,” Dr. Brenner said to wide applause. “We should allow kids to develop in a low-pressure, healthy system before we do that.”
The effects of high pressure have potentially lifelong ramifications. By the time children are 13 years old, 70% have dropped out of organized sports, Dr. Brenner said, and injuries from overuse account for more than half of all sports-related injuries in youth.
Yet the alternative – early diversification and late specialization – can really benefit kids, he said. The early specialization paradigm of playing just one sport focuses on deliberate practice and performance from the start. By contrast, early diversification with multiple sports focuses on deliberate play, during which children develop foundational athletic skills. Children who play a variety of sports are more likely to participate for more years – and it meets youth’s more realistic, long-term needs for lifelong physical activity through “fun, variety, and play,” he said.
Dr. Brenner said that just 1% of high school athletes receive any athletic scholarships, and only 3%-11% of high school athletes compete at the college level. The numbers for high school athletes that go on to play at the professional level is, of course, even smaller: 0.03% to 0.5%, depending on the sport.
And the irony is that the goal of early specialization – producing such elite level athletes – is actually better accomplished through playing multiple sports, Dr. Brenner said. Most Division 1 National Collegiate Athletic Association (NCAA) athletes and 90% of National Football League (NFL) first-round picks played multiple sports in high school. So the benefits of waiting until late adolescence to specialize are twofold: a greater likelihood of athletic success, even at elite levels, and minimizing the risks of injury.
Overuse injuries pose serious risks
More than half of sports injuries are from overuse, and a number of factors contribute to those injuries, such as muscle imbalance, playing surfaces, and training errors, Dr. Brenner said. But the biggest contributors are early specialization, playing year-round sports, and playing on multiple teams.
“This is a problem we see daily,” Dr. Brenner said. “We can see the young dancer, who’s dancing 6-7 days a week, who develops back pain and continues to dance, and develops a stress fracture in her lumbar spine known spondylosis.
“Or we see the young soccer player who plays on multiple teams and develops heel pain, who starts limping with activities of daily living, continues to play soccer despite limping, and develops calcaneal apophysitis, known as Sever’s disease. Or the young baseball pitcher, who pitches for two teams, who develops arm pain and weakness, who has a stress fracture through the proximal humeral epiphysis, known as Little League shoulder.”
Two broad pieces of guidance can help reduce the risk of injuries, particularly from overuse. First, young athletes should take off at least 1 month from a specific sport at least three times a year to give them adequate time for physical and psychological recovery. Second, ensuring young athletes take at least 1 or 2 days off of practice each week further reduces the likelihood of injury.
In addition to the physical problems these young athletes may develop, they also risk anxiety, depression, burnout, early retirement, and social isolation from peers who don’t play their sport, Dr. Brenner said. Family members also may experience greater stress, he added. And then there’s the risk of missing out on learning other sports they may excel in that offer a lifetime of enjoyment, such as tennis or swimming.
It is not clear where the threshold of involvement is for reducing overuse injury, burnout, and attrition, but Dr. Brenner provided some guidelines as a starting place. High school athletes should not train more 16 hours a week, and organized sports should not exceed free play time by a greater ratio than 2:1. Another guideline is not to exceed more hours per week in organized sports than a child’s age in years.
The primary focus of sports should be learning lifelong physical activity skills and having fun, Dr. Brenner said. Pediatricians should encourage patients to play in a wide variety of sports at least until puberty, thereby decreasing the chance of injuries, stress, and burnout, he said. That can include sports that are not necessarily an official part of school or club competition. Waiting until later to specialize may lead to a higher likelihood of athletic success.
Dr. Brenner said he had no relevant financial disclosures.
CHICAGO – When a boy receives five college football scholarship offers and a girl commits to playing soccer for a university before either of them starts ninth grade, it’s time to take several steps back in youth sports.
, including the risk of potentially discouraging a lifetime of healthy athletic participation, according to Joel S. Brenner, MD, MPH, a sports medicine expert at the Children’s Hospital of The King’s Daughters and Eastern Virginia Medical School, both in Norfolk.
“This paradigm should be discouraged by society,” Dr. Brenner told attendees at the American Academy of Pediatrics annual meeting. “Sports specialization refers to focusing on one sport to the exclusion of all others, often playing that single sport year-round. Dr. Brenner authored the AAP’s 2016 clinical report on sports specialization and intensive training in young athletes.
Dr. Brenner emphasized the benefits of delaying sports specialization until after puberty, the risks of specializing sooner, and the importance of rest to prevent burnout and injuries.
This is not a new problem, he noted, showing the attendees two Time Magazine covers, from 1999 and 2017, that featured the concern of “Sports Crazed Kids.” But it is so far-reaching that it will requires more than just physicians to change.
“This is not just an athlete problem, a parent problem, a coach problem, or even a physician problem,” Dr. Brenner said. “It’s a societal problem, a youth sports culture problem, and one that all of us as stakeholders need to attack and try to change the culture.”
Youth sports offer a broad range of benefits, such as developing physical activity, and leadership skills, and promoting self-esteem, socialization, and teamwork, Dr. Brenner said.
“But one benefit that often gets forgotten by people, including the coaches, the parents, and the athletes, is that sports is supposed to be about having fun,” he said.
The old model of kids’ sports was loosely organized fun, with kids playing multiple sports throughout the year and less direct involvement from adults, such as street hockey games and pick-up basketball. But those bygone days, Dr. Brenner noted wistfully, have been replaced with a different paradigm today: Children specialize in a single sport very early, and parents and coaches are the driving forces behind their involvement.
Today’s culture of very early sports specialization and college recruitment increases pressure on parents and young athletes to play year-round on multiple teams to stay on the radar of scouts and colleges. And this specialization has expanded to younger and younger ages, with 7-year-olds participating in travel leagues and national rankings of children in their sport as early as sixth grade.
“We should not be ranking kids in middle school or even in early high school,” Dr. Brenner said to wide applause. “We should allow kids to develop in a low-pressure, healthy system before we do that.”
The effects of high pressure have potentially lifelong ramifications. By the time children are 13 years old, 70% have dropped out of organized sports, Dr. Brenner said, and injuries from overuse account for more than half of all sports-related injuries in youth.
Yet the alternative – early diversification and late specialization – can really benefit kids, he said. The early specialization paradigm of playing just one sport focuses on deliberate practice and performance from the start. By contrast, early diversification with multiple sports focuses on deliberate play, during which children develop foundational athletic skills. Children who play a variety of sports are more likely to participate for more years – and it meets youth’s more realistic, long-term needs for lifelong physical activity through “fun, variety, and play,” he said.
Dr. Brenner said that just 1% of high school athletes receive any athletic scholarships, and only 3%-11% of high school athletes compete at the college level. The numbers for high school athletes that go on to play at the professional level is, of course, even smaller: 0.03% to 0.5%, depending on the sport.
And the irony is that the goal of early specialization – producing such elite level athletes – is actually better accomplished through playing multiple sports, Dr. Brenner said. Most Division 1 National Collegiate Athletic Association (NCAA) athletes and 90% of National Football League (NFL) first-round picks played multiple sports in high school. So the benefits of waiting until late adolescence to specialize are twofold: a greater likelihood of athletic success, even at elite levels, and minimizing the risks of injury.
Overuse injuries pose serious risks
More than half of sports injuries are from overuse, and a number of factors contribute to those injuries, such as muscle imbalance, playing surfaces, and training errors, Dr. Brenner said. But the biggest contributors are early specialization, playing year-round sports, and playing on multiple teams.
“This is a problem we see daily,” Dr. Brenner said. “We can see the young dancer, who’s dancing 6-7 days a week, who develops back pain and continues to dance, and develops a stress fracture in her lumbar spine known spondylosis.
“Or we see the young soccer player who plays on multiple teams and develops heel pain, who starts limping with activities of daily living, continues to play soccer despite limping, and develops calcaneal apophysitis, known as Sever’s disease. Or the young baseball pitcher, who pitches for two teams, who develops arm pain and weakness, who has a stress fracture through the proximal humeral epiphysis, known as Little League shoulder.”
Two broad pieces of guidance can help reduce the risk of injuries, particularly from overuse. First, young athletes should take off at least 1 month from a specific sport at least three times a year to give them adequate time for physical and psychological recovery. Second, ensuring young athletes take at least 1 or 2 days off of practice each week further reduces the likelihood of injury.
In addition to the physical problems these young athletes may develop, they also risk anxiety, depression, burnout, early retirement, and social isolation from peers who don’t play their sport, Dr. Brenner said. Family members also may experience greater stress, he added. And then there’s the risk of missing out on learning other sports they may excel in that offer a lifetime of enjoyment, such as tennis or swimming.
It is not clear where the threshold of involvement is for reducing overuse injury, burnout, and attrition, but Dr. Brenner provided some guidelines as a starting place. High school athletes should not train more 16 hours a week, and organized sports should not exceed free play time by a greater ratio than 2:1. Another guideline is not to exceed more hours per week in organized sports than a child’s age in years.
The primary focus of sports should be learning lifelong physical activity skills and having fun, Dr. Brenner said. Pediatricians should encourage patients to play in a wide variety of sports at least until puberty, thereby decreasing the chance of injuries, stress, and burnout, he said. That can include sports that are not necessarily an official part of school or club competition. Waiting until later to specialize may lead to a higher likelihood of athletic success.
Dr. Brenner said he had no relevant financial disclosures.
EXPERT ANALYSIS FROM AAP 2017
Teratogenicity may not be a yes or no question
Since thalidomide, the medical community has sought to ensure that we do not miss any safety signal that a drug could cause malformations or developmental delays after in utero exposure.
At the time of a drug’s debut, there are relatively small numbers of exposures in pregnancy, and it’s difficult to decipher teratogenicity. As the number of exposures increases, we are generally able to answer “yes” or “no” to the question of teratogenicity. But in the last decade or so, data on drug exposure in pregnancy has become robust enough – thanks in part to large registries – to provide potentially more useful answers on safety. Specifically, .
Animal studies show us that there is a dose dependent effect in pregnancy, and not every dose causes harm to the fetus. However, that information is not easily translated into clinical practice because of the vast differences between animal and human pharmacokinetics and sensitivity to toxicity.
The first drug that came into focus as having dose dependent teratogenicity in pregnancy is the epilepsy drug valproic acid. In the late 1980s, studies showed that the drug was associated with an increased risk for spina bifida. Later, more congenital malformations were linked to valproic acid, including oral cleft, cardiac and limb defects, developmental delays, lower IQ, and even autism. But in the last few years, an increasing number of studies point to a lower dose that may represent an acceptable risk for some pregnant women.
Looking at data from EURAP, an international registry of antiepileptic drugs and pregnancy, researchers showed that the dose of valproic acid with the greatest risk for harm was 1,500 mg per day or greater, with a 24% frequency of major congenital malformations. But at less than 700 mg per day, the frequency of major malformations dropped to 5.9% (Neurology. 2015 Sep 8;85[10]:866-72).
Another analysis of the EURAP data showed the same dose-dependent relationship with other drugs. The researchers calculated rates of major congenital malformations in 1,402 pregnancies exposed to carbamazepine, 1,280 on lamotrigine, 1,010 on valproic acid, and 217 on phenobarbital, and all showed that the frequency of birth defects increased along with the dose of the drug.
The study identified the dose for each drug with the lowest rates of malformation. For lamotrigine, it was a dose of less than 300 mg per day, with a 2% frequency of malformations. Similarly, the dose was less than 400 mg per day for carbamazepine (3.4% rate of malformations). Overall, risks of malformation were significantly higher in valproic acid and phenobarbital at all tested doses and carbamazepine at doses greater than 400 mg per day, compared with lamotrigine monotherapy at less than 300 mg per day (Lancet Neurol. 2011 Jul;10[7]:609-17).
The study is important because it gives us a benchmark for these drugs, allowing us to see the risks at lower doses.
But not all the data are in agreement. In 2016, a Cochrane review of different antiepileptic drugs in pregnancy found that only with valproic acid could the risk of a malformation be clearly linked to the size of the dose (Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224).
Most recently, a large U.S. database of Medicaid patients, which included more than 1.3 million pregnancies, showed the dose-dependent risk of malformations associated with lithium, still widely used in treating bipolar disorder. The researchers examined the risk of cardiac malformations after first-trimester lithium exposure.
With the publication of each of these studies, we are moving toward an era where the question of teratogenicity is no longer just “yes” or “no,” but dose dependent. Soon, I hope we will be able to expand our knowledge by evaluating doses in milligrams per kilogram, rather than just a per day dose, thus addressing body size in evaluating the risk.
As more than half of pregnancies are unplanned, there are often times when women have been exposed to teratogens during early pregnancy and knowing the size of the risk is an invaluable decision-making tool. We don’t have the full risk picture yet, but it is growing clearer.
Dr. Koren is professor of pediatrics at Western University in Ontario and Tel Aviv University in Israel, and is the founder of the Motherisk Program. He reported having no relevant financial disclosures.
Since thalidomide, the medical community has sought to ensure that we do not miss any safety signal that a drug could cause malformations or developmental delays after in utero exposure.
At the time of a drug’s debut, there are relatively small numbers of exposures in pregnancy, and it’s difficult to decipher teratogenicity. As the number of exposures increases, we are generally able to answer “yes” or “no” to the question of teratogenicity. But in the last decade or so, data on drug exposure in pregnancy has become robust enough – thanks in part to large registries – to provide potentially more useful answers on safety. Specifically, .
Animal studies show us that there is a dose dependent effect in pregnancy, and not every dose causes harm to the fetus. However, that information is not easily translated into clinical practice because of the vast differences between animal and human pharmacokinetics and sensitivity to toxicity.
The first drug that came into focus as having dose dependent teratogenicity in pregnancy is the epilepsy drug valproic acid. In the late 1980s, studies showed that the drug was associated with an increased risk for spina bifida. Later, more congenital malformations were linked to valproic acid, including oral cleft, cardiac and limb defects, developmental delays, lower IQ, and even autism. But in the last few years, an increasing number of studies point to a lower dose that may represent an acceptable risk for some pregnant women.
Looking at data from EURAP, an international registry of antiepileptic drugs and pregnancy, researchers showed that the dose of valproic acid with the greatest risk for harm was 1,500 mg per day or greater, with a 24% frequency of major congenital malformations. But at less than 700 mg per day, the frequency of major malformations dropped to 5.9% (Neurology. 2015 Sep 8;85[10]:866-72).
Another analysis of the EURAP data showed the same dose-dependent relationship with other drugs. The researchers calculated rates of major congenital malformations in 1,402 pregnancies exposed to carbamazepine, 1,280 on lamotrigine, 1,010 on valproic acid, and 217 on phenobarbital, and all showed that the frequency of birth defects increased along with the dose of the drug.
The study identified the dose for each drug with the lowest rates of malformation. For lamotrigine, it was a dose of less than 300 mg per day, with a 2% frequency of malformations. Similarly, the dose was less than 400 mg per day for carbamazepine (3.4% rate of malformations). Overall, risks of malformation were significantly higher in valproic acid and phenobarbital at all tested doses and carbamazepine at doses greater than 400 mg per day, compared with lamotrigine monotherapy at less than 300 mg per day (Lancet Neurol. 2011 Jul;10[7]:609-17).
The study is important because it gives us a benchmark for these drugs, allowing us to see the risks at lower doses.
But not all the data are in agreement. In 2016, a Cochrane review of different antiepileptic drugs in pregnancy found that only with valproic acid could the risk of a malformation be clearly linked to the size of the dose (Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224).
Most recently, a large U.S. database of Medicaid patients, which included more than 1.3 million pregnancies, showed the dose-dependent risk of malformations associated with lithium, still widely used in treating bipolar disorder. The researchers examined the risk of cardiac malformations after first-trimester lithium exposure.
With the publication of each of these studies, we are moving toward an era where the question of teratogenicity is no longer just “yes” or “no,” but dose dependent. Soon, I hope we will be able to expand our knowledge by evaluating doses in milligrams per kilogram, rather than just a per day dose, thus addressing body size in evaluating the risk.
As more than half of pregnancies are unplanned, there are often times when women have been exposed to teratogens during early pregnancy and knowing the size of the risk is an invaluable decision-making tool. We don’t have the full risk picture yet, but it is growing clearer.
Dr. Koren is professor of pediatrics at Western University in Ontario and Tel Aviv University in Israel, and is the founder of the Motherisk Program. He reported having no relevant financial disclosures.
Since thalidomide, the medical community has sought to ensure that we do not miss any safety signal that a drug could cause malformations or developmental delays after in utero exposure.
At the time of a drug’s debut, there are relatively small numbers of exposures in pregnancy, and it’s difficult to decipher teratogenicity. As the number of exposures increases, we are generally able to answer “yes” or “no” to the question of teratogenicity. But in the last decade or so, data on drug exposure in pregnancy has become robust enough – thanks in part to large registries – to provide potentially more useful answers on safety. Specifically, .
Animal studies show us that there is a dose dependent effect in pregnancy, and not every dose causes harm to the fetus. However, that information is not easily translated into clinical practice because of the vast differences between animal and human pharmacokinetics and sensitivity to toxicity.
The first drug that came into focus as having dose dependent teratogenicity in pregnancy is the epilepsy drug valproic acid. In the late 1980s, studies showed that the drug was associated with an increased risk for spina bifida. Later, more congenital malformations were linked to valproic acid, including oral cleft, cardiac and limb defects, developmental delays, lower IQ, and even autism. But in the last few years, an increasing number of studies point to a lower dose that may represent an acceptable risk for some pregnant women.
Looking at data from EURAP, an international registry of antiepileptic drugs and pregnancy, researchers showed that the dose of valproic acid with the greatest risk for harm was 1,500 mg per day or greater, with a 24% frequency of major congenital malformations. But at less than 700 mg per day, the frequency of major malformations dropped to 5.9% (Neurology. 2015 Sep 8;85[10]:866-72).
Another analysis of the EURAP data showed the same dose-dependent relationship with other drugs. The researchers calculated rates of major congenital malformations in 1,402 pregnancies exposed to carbamazepine, 1,280 on lamotrigine, 1,010 on valproic acid, and 217 on phenobarbital, and all showed that the frequency of birth defects increased along with the dose of the drug.
The study identified the dose for each drug with the lowest rates of malformation. For lamotrigine, it was a dose of less than 300 mg per day, with a 2% frequency of malformations. Similarly, the dose was less than 400 mg per day for carbamazepine (3.4% rate of malformations). Overall, risks of malformation were significantly higher in valproic acid and phenobarbital at all tested doses and carbamazepine at doses greater than 400 mg per day, compared with lamotrigine monotherapy at less than 300 mg per day (Lancet Neurol. 2011 Jul;10[7]:609-17).
The study is important because it gives us a benchmark for these drugs, allowing us to see the risks at lower doses.
But not all the data are in agreement. In 2016, a Cochrane review of different antiepileptic drugs in pregnancy found that only with valproic acid could the risk of a malformation be clearly linked to the size of the dose (Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224).
Most recently, a large U.S. database of Medicaid patients, which included more than 1.3 million pregnancies, showed the dose-dependent risk of malformations associated with lithium, still widely used in treating bipolar disorder. The researchers examined the risk of cardiac malformations after first-trimester lithium exposure.
With the publication of each of these studies, we are moving toward an era where the question of teratogenicity is no longer just “yes” or “no,” but dose dependent. Soon, I hope we will be able to expand our knowledge by evaluating doses in milligrams per kilogram, rather than just a per day dose, thus addressing body size in evaluating the risk.
As more than half of pregnancies are unplanned, there are often times when women have been exposed to teratogens during early pregnancy and knowing the size of the risk is an invaluable decision-making tool. We don’t have the full risk picture yet, but it is growing clearer.
Dr. Koren is professor of pediatrics at Western University in Ontario and Tel Aviv University in Israel, and is the founder of the Motherisk Program. He reported having no relevant financial disclosures.
Too few RA patients get timely adjustment of DMARDs
Adjustment of disease-modifying antirheumatic drug (DMARD) therapy is not happening quickly enough for a substantial minority of rheumatoid arthritis patients with moderate to high disease activity, according to the findings of a registry study that is the first to evaluate this association.
Investigators led by Yomei Shaw, PhD, a research fellow with the National Data Bank for Rheumatic Diseases, retrospectively analyzed data from 538 patients in the university’s Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry who had moderate to high disease activity. Dr. Shaw conducted the study as a doctoral student in the department of health policy and management at the University of Pittsburgh.
In 40% of patients who had persistent disease activity of this severity, clinicians waited more than the 90 days recommended by treat-to-target (T2T) guidelines to adjust DMARDs, according to published results (Arthritis Care Res. 2017 Sep 21. doi: 10.1002/acr.23418). Such delay was more common for certain groups, including those on biologics and those who had rheumatoid arthritis (RA) for longer.
Compared with peers whose therapy was adjusted sooner, patients with such delayed adjustment were about one-quarter less likely to achieve low disease activity or remission during follow-up.
“The results of our survival analyses suggest that delays in DMARD adjustment of more than 3 months are common among RA patients with [moderate to high disease activity], highlighting an important potential gap in quality of care for these patients,” Dr. Shaw and her colleagues wrote.
They acknowledge that some of the delays in adjustment may have been unavoidable. For example, patients on biologic DMARDs may have needed insurance approval to start a new biologic, and patients with long-standing disease may have had fewer options remaining or symptoms that clinicians attributed to irreversible joint damage.
The study’s findings provide additional evidence of the importance of timely, guideline-adherent DMARD adjustment in reducing the amount of time patients spend in moderate to high disease activity, the investigators further contend.
“Promoting T2T in clinical practice requires coordinated change at the system, rheumatology practice, and individual levels,” such as consistently documenting the treatment target, assessing disease activity at every visit, and mandating a minimum visit frequency, they conclude.
Dr. Shaw and her colleagues studied patients having moderate to high disease activity, defined according to the 28-joint Disease Activity Score with C-reactive protein criteria (score of greater than 3.2).
The investigators reported a median time to adjustment of DMARD therapy of 154 days during 943.5 patient-years of follow-up. These adjustments could be adding, switching, or increasing the dose of a DMARD medication (excluding corticosteroids).
In multivariate analysis, patients had a longer time to DMARD adjustment if they were aged 75 years or older (subdistribution hazard ratio, 0.61; P = .02), had lower baseline disease activity (0.72; P less than .01), had longer duration of rheumatoid arthritis (0.98; P less than .01), or were receiving a biologic DMARD at baseline (0.71; P less than .01).
The median time to achieving low disease activity or remission was 301 days for the entire cohort. Patients had a longer time to achieve this goal if their DMARD therapy was not adjusted within 90 days (hazard ratio, 0.76; P = .01) or if they were African American (0.63; P = .01) or had higher baseline disease activity (0.75; P less than .01). They had a shorter time if they had better mental health (1.01; P = .03) or physical health (1.01; P = .02) as assessed with the 12-item Short Form Health Survey.
One of the study authors received research funding from Genentech and is currently employed by AbbVie. The registry used was funded by the National Institutes of Health and Genentech.
Randomized controlled trials demonstrate that statin lipid–lowering drugs reduce repeat cardiovascular events. Based on this evidence, clinicians agree that the vast majority of patients should receive statin lipid-lowering drugs after a CV event, and that providers not prescribing statins to these patients are providing suboptimal care.
By analogy, the data provided in this new analysis by Shaw and her colleagues suggests that many rheumatologists are providing suboptimal care. Many randomized, controlled trials testing a treat-to-target (T2T) paradigm demonstrate the clinical benefits of changing treatments for patients with rheumatoid arthritis who are in moderate or high disease activity. Yet, this analysis found many patients do not change treatments despite poor disease control. While the current study does not examine the reasons for suboptimal care, some correlates include:
• Patient preference to not change treatment;
• Provider desire to give treatments more time to work; and
• Health system issues such as drug payment complexities.
Continuing medical education may be necessary, but it is not a sufficient lever to push providers to implement T2T. Audit and feedback – providing individual providers with their performance metrics – alerts rheumatic disease providers when improvement is necessary. Yet, most providers need specific strategies within their practice to implement T2T. Collaborative learning between providers with a common purpose and coaches that understand the complexities of implementing T2T have been shown in the recently published TRACTION trial to produce improvements (Arthritis Rheumatol. 2017;69[7]:1374-80). The article by Shaw and her colleagues should sound the alarm to rheumatic disease providers: Care for RA needs improving if we want to produce optimal outcomes.
Daniel H. Solomon, MD, is a professor of medicine at Harvard University, and chief of the section of clinical sciences in the division of rheumatology at Brigham and Women’s Hospital, both in Boston. He has no relevant disclosures.
Randomized controlled trials demonstrate that statin lipid–lowering drugs reduce repeat cardiovascular events. Based on this evidence, clinicians agree that the vast majority of patients should receive statin lipid-lowering drugs after a CV event, and that providers not prescribing statins to these patients are providing suboptimal care.
By analogy, the data provided in this new analysis by Shaw and her colleagues suggests that many rheumatologists are providing suboptimal care. Many randomized, controlled trials testing a treat-to-target (T2T) paradigm demonstrate the clinical benefits of changing treatments for patients with rheumatoid arthritis who are in moderate or high disease activity. Yet, this analysis found many patients do not change treatments despite poor disease control. While the current study does not examine the reasons for suboptimal care, some correlates include:
• Patient preference to not change treatment;
• Provider desire to give treatments more time to work; and
• Health system issues such as drug payment complexities.
Continuing medical education may be necessary, but it is not a sufficient lever to push providers to implement T2T. Audit and feedback – providing individual providers with their performance metrics – alerts rheumatic disease providers when improvement is necessary. Yet, most providers need specific strategies within their practice to implement T2T. Collaborative learning between providers with a common purpose and coaches that understand the complexities of implementing T2T have been shown in the recently published TRACTION trial to produce improvements (Arthritis Rheumatol. 2017;69[7]:1374-80). The article by Shaw and her colleagues should sound the alarm to rheumatic disease providers: Care for RA needs improving if we want to produce optimal outcomes.
Daniel H. Solomon, MD, is a professor of medicine at Harvard University, and chief of the section of clinical sciences in the division of rheumatology at Brigham and Women’s Hospital, both in Boston. He has no relevant disclosures.
Randomized controlled trials demonstrate that statin lipid–lowering drugs reduce repeat cardiovascular events. Based on this evidence, clinicians agree that the vast majority of patients should receive statin lipid-lowering drugs after a CV event, and that providers not prescribing statins to these patients are providing suboptimal care.
By analogy, the data provided in this new analysis by Shaw and her colleagues suggests that many rheumatologists are providing suboptimal care. Many randomized, controlled trials testing a treat-to-target (T2T) paradigm demonstrate the clinical benefits of changing treatments for patients with rheumatoid arthritis who are in moderate or high disease activity. Yet, this analysis found many patients do not change treatments despite poor disease control. While the current study does not examine the reasons for suboptimal care, some correlates include:
• Patient preference to not change treatment;
• Provider desire to give treatments more time to work; and
• Health system issues such as drug payment complexities.
Continuing medical education may be necessary, but it is not a sufficient lever to push providers to implement T2T. Audit and feedback – providing individual providers with their performance metrics – alerts rheumatic disease providers when improvement is necessary. Yet, most providers need specific strategies within their practice to implement T2T. Collaborative learning between providers with a common purpose and coaches that understand the complexities of implementing T2T have been shown in the recently published TRACTION trial to produce improvements (Arthritis Rheumatol. 2017;69[7]:1374-80). The article by Shaw and her colleagues should sound the alarm to rheumatic disease providers: Care for RA needs improving if we want to produce optimal outcomes.
Daniel H. Solomon, MD, is a professor of medicine at Harvard University, and chief of the section of clinical sciences in the division of rheumatology at Brigham and Women’s Hospital, both in Boston. He has no relevant disclosures.
Adjustment of disease-modifying antirheumatic drug (DMARD) therapy is not happening quickly enough for a substantial minority of rheumatoid arthritis patients with moderate to high disease activity, according to the findings of a registry study that is the first to evaluate this association.
Investigators led by Yomei Shaw, PhD, a research fellow with the National Data Bank for Rheumatic Diseases, retrospectively analyzed data from 538 patients in the university’s Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry who had moderate to high disease activity. Dr. Shaw conducted the study as a doctoral student in the department of health policy and management at the University of Pittsburgh.
In 40% of patients who had persistent disease activity of this severity, clinicians waited more than the 90 days recommended by treat-to-target (T2T) guidelines to adjust DMARDs, according to published results (Arthritis Care Res. 2017 Sep 21. doi: 10.1002/acr.23418). Such delay was more common for certain groups, including those on biologics and those who had rheumatoid arthritis (RA) for longer.
Compared with peers whose therapy was adjusted sooner, patients with such delayed adjustment were about one-quarter less likely to achieve low disease activity or remission during follow-up.
“The results of our survival analyses suggest that delays in DMARD adjustment of more than 3 months are common among RA patients with [moderate to high disease activity], highlighting an important potential gap in quality of care for these patients,” Dr. Shaw and her colleagues wrote.
They acknowledge that some of the delays in adjustment may have been unavoidable. For example, patients on biologic DMARDs may have needed insurance approval to start a new biologic, and patients with long-standing disease may have had fewer options remaining or symptoms that clinicians attributed to irreversible joint damage.
The study’s findings provide additional evidence of the importance of timely, guideline-adherent DMARD adjustment in reducing the amount of time patients spend in moderate to high disease activity, the investigators further contend.
“Promoting T2T in clinical practice requires coordinated change at the system, rheumatology practice, and individual levels,” such as consistently documenting the treatment target, assessing disease activity at every visit, and mandating a minimum visit frequency, they conclude.
Dr. Shaw and her colleagues studied patients having moderate to high disease activity, defined according to the 28-joint Disease Activity Score with C-reactive protein criteria (score of greater than 3.2).
The investigators reported a median time to adjustment of DMARD therapy of 154 days during 943.5 patient-years of follow-up. These adjustments could be adding, switching, or increasing the dose of a DMARD medication (excluding corticosteroids).
In multivariate analysis, patients had a longer time to DMARD adjustment if they were aged 75 years or older (subdistribution hazard ratio, 0.61; P = .02), had lower baseline disease activity (0.72; P less than .01), had longer duration of rheumatoid arthritis (0.98; P less than .01), or were receiving a biologic DMARD at baseline (0.71; P less than .01).
The median time to achieving low disease activity or remission was 301 days for the entire cohort. Patients had a longer time to achieve this goal if their DMARD therapy was not adjusted within 90 days (hazard ratio, 0.76; P = .01) or if they were African American (0.63; P = .01) or had higher baseline disease activity (0.75; P less than .01). They had a shorter time if they had better mental health (1.01; P = .03) or physical health (1.01; P = .02) as assessed with the 12-item Short Form Health Survey.
One of the study authors received research funding from Genentech and is currently employed by AbbVie. The registry used was funded by the National Institutes of Health and Genentech.
Adjustment of disease-modifying antirheumatic drug (DMARD) therapy is not happening quickly enough for a substantial minority of rheumatoid arthritis patients with moderate to high disease activity, according to the findings of a registry study that is the first to evaluate this association.
Investigators led by Yomei Shaw, PhD, a research fellow with the National Data Bank for Rheumatic Diseases, retrospectively analyzed data from 538 patients in the university’s Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry who had moderate to high disease activity. Dr. Shaw conducted the study as a doctoral student in the department of health policy and management at the University of Pittsburgh.
In 40% of patients who had persistent disease activity of this severity, clinicians waited more than the 90 days recommended by treat-to-target (T2T) guidelines to adjust DMARDs, according to published results (Arthritis Care Res. 2017 Sep 21. doi: 10.1002/acr.23418). Such delay was more common for certain groups, including those on biologics and those who had rheumatoid arthritis (RA) for longer.
Compared with peers whose therapy was adjusted sooner, patients with such delayed adjustment were about one-quarter less likely to achieve low disease activity or remission during follow-up.
“The results of our survival analyses suggest that delays in DMARD adjustment of more than 3 months are common among RA patients with [moderate to high disease activity], highlighting an important potential gap in quality of care for these patients,” Dr. Shaw and her colleagues wrote.
They acknowledge that some of the delays in adjustment may have been unavoidable. For example, patients on biologic DMARDs may have needed insurance approval to start a new biologic, and patients with long-standing disease may have had fewer options remaining or symptoms that clinicians attributed to irreversible joint damage.
The study’s findings provide additional evidence of the importance of timely, guideline-adherent DMARD adjustment in reducing the amount of time patients spend in moderate to high disease activity, the investigators further contend.
“Promoting T2T in clinical practice requires coordinated change at the system, rheumatology practice, and individual levels,” such as consistently documenting the treatment target, assessing disease activity at every visit, and mandating a minimum visit frequency, they conclude.
Dr. Shaw and her colleagues studied patients having moderate to high disease activity, defined according to the 28-joint Disease Activity Score with C-reactive protein criteria (score of greater than 3.2).
The investigators reported a median time to adjustment of DMARD therapy of 154 days during 943.5 patient-years of follow-up. These adjustments could be adding, switching, or increasing the dose of a DMARD medication (excluding corticosteroids).
In multivariate analysis, patients had a longer time to DMARD adjustment if they were aged 75 years or older (subdistribution hazard ratio, 0.61; P = .02), had lower baseline disease activity (0.72; P less than .01), had longer duration of rheumatoid arthritis (0.98; P less than .01), or were receiving a biologic DMARD at baseline (0.71; P less than .01).
The median time to achieving low disease activity or remission was 301 days for the entire cohort. Patients had a longer time to achieve this goal if their DMARD therapy was not adjusted within 90 days (hazard ratio, 0.76; P = .01) or if they were African American (0.63; P = .01) or had higher baseline disease activity (0.75; P less than .01). They had a shorter time if they had better mental health (1.01; P = .03) or physical health (1.01; P = .02) as assessed with the 12-item Short Form Health Survey.
One of the study authors received research funding from Genentech and is currently employed by AbbVie. The registry used was funded by the National Institutes of Health and Genentech.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point:
Major finding: In 40% of patients who had persistent disease activity of this severity, clinicians waited more than the 90 days recommended by treat-to-target guidelines to adjust DMARDs.
Data source: A retrospective cohort study of 538 patients with RA having moderate to high disease activity.
Disclosures: One of the study authors received research funding from Genentech and is currently employed by AbbVie. The study registry used was funded by the National Institutes of Health and Genentech.
Bearing the Standard
An esteemed ethics colleague forwarded me a Washington Post column that raises an important, neglected aspect of the Choice program and other VA forms of purchased care: potentially unequal and uneven standards of care.1 Congress authorized Choice to increase veterans’ ability to access needed clinical care in a timely and effective manner. The emphasis on access though may have inadvertently led to an equally serious gap in quality, especially for ethical standards of practice.
The Washington Post columnist Joe Davidson compares the often less demanding standard of opioid prescribing in the community with those of the VA and DoD. This difference in the monitoring of prescriptions the reporter suggests may be contributing to the epidemic of completed suicides—many by medication ingestion—and nonfatal but serious opioid overdoses. As Davidson writes, “The gap in coordination, adding to different clinical standards among VA and non-VA community providers, can be deadly. Health professionals outside the VA are not required to follow departmental guidelines.”1
The VA and DOD are required to follow rigorous, evidence-based practices, documented in the VA/DoD Practice Guideline for Opioid Therapy for Chronic Pain revised and reissued in February 2017. In addition, VA has a comprehensive, systematic, and standardized program of education and monitoring its Opioid Safety Initiative (OSI). The OSI was launched to improve and rationalize opioid prescribing especially when opioids are combined with benzodiazepines, which increases the risk of lethal outcomes from overdoses.
It is not just journalists who have expressed concerns about this disparity in prescribing rigor: The VA Office of Inspector General and several veterans service organizations also have called attention to what is in effect a double standard in care.2 All these entities have underscored another aspect of the Choice program that widens the quality and, hence, safety chasm—the fragmentation of clinical communication between community and VA providers. It is true that as of this writing, every state has passed prescription monitoring program (PMP) legislation. Prior to the change in federal regulation, VA was not permitted to release its controlled substance prescriptions to these pharmacy databases. But in the interest of patient safety, the privacy rules were modified to permit VA pharmacies to share records with the states. This has been a huge step forward in identifying patients who are receiving opioids, benzodiazepines, and stimulants, among other drugs, from a VAMC and 1 or more community prescribers.
Of course, it would be hubristic provincialism to think that there are not excellent clinicians and outstanding institutions in the community that equal or surpass the DoD/VA practice criteria. We are fortunate that because of Choice, veterans and service members now have available to them this level of expertise, which often is not present in smaller federal health care facilities. What is concerning, however, is those prescribers whose practice patterns are routinely and significantly below the bar and thereby place veterans in harms way.However, the efficacy of the PMPs to notify practitioners of prescribing patterns is dependent on the conscientiousness, given the death toll, even the conscience, of those who have prescribing privileges. I should emphasize that prescribing medications is a privilege and that states bestow this power only to those professionals who have met the stipulated education, training, credentialing, and licensing requirements. This professional preparation is crucial when there is not a shared medical record. Without the medical record, the practitioner, especiallyone who does not check the PMP or who does not have sufficient education and training in addiction and pain, is dependent on the history of the patient. The very substances being prescribed or sought may impair the ability of the patient to provide an accurate history due to ignorance, addiction, pain, or fear of losing pain relief.
There is a shortage of addiction and pain specialists in and outside the federal system.3,4 Therefore, we need Choice in order to meet the needs of service members and veterans. Congress has authorized bureaucratic mechanisms and payment sources to enable veterans to receive treatment from community providers. But a regulatory means to ensure that those providers adhere to the same high standards of care as that of VA and DoD practitioners must be established.
Critics of the VA have in many cases rightly made accountability the watchword of their campaigns. To its credit, the VA has embraced the cause in the I CARE value of integrity. “Act with high moral principle. Adhere to the highest professional standards. Maintain the trust and confidence of all with whom I engage.”
But that sense of responsibility must extend to all those who provide care to veterans—especially those who prescribe medications that have the immense double-edged potential to relieve pain and disability but at the same time also cause suffering and death.
While this inability to enforce VA/DoD responsible prescribing requirements in the community is likely more urgent and life threatening, there still are many other federal clinical and organizational policies and regulations to which the community is not required to adhere. I will discuss some of these and their potentially negative implications in future columns. For the promise of Choice to be realized, we all must work together to bear the highest possible standard of care for those who serve and have served.
1. Davidson J. Veterans’ health-care gap creates ‘greater risk’ for opioid use [news release]. Washington Post. August 7, 2017. https://www.washingtonpost.com/news/powerpost/wp/2017/08/07/veterans-health-care-gap-creates-greater-risk-for -opioid-abuse/?utm_term=.e4ec9596db6b. Accessed September 18, 2017.
2. Department of Veterans Affairs Office of Inspector General. Office of Healthcare Inspections. Report No. 17-01846-316. Opioid prescribing to high-risk veterans receiving VA purchased care. https://www.va.gov/oig/pubs/VAOIG-17-01846-316.pdf. Published July 31, 2017. Accessed September 18, 2017.
3. Vestal C. How severe is the shortage of substance abuse specialists? http://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2015/4/01/how-severe-is-the-shortage-of-substance-abuse -specialists. Published April 1, 2015. Accessed September 28, 2017.
4. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.
5. U.S. Department of Veterans Affairs. I care quick reference core values. https://www.va.gov/icare/docs/core_values_quick_reference.pdf. Accessed September 18, 2017.
An esteemed ethics colleague forwarded me a Washington Post column that raises an important, neglected aspect of the Choice program and other VA forms of purchased care: potentially unequal and uneven standards of care.1 Congress authorized Choice to increase veterans’ ability to access needed clinical care in a timely and effective manner. The emphasis on access though may have inadvertently led to an equally serious gap in quality, especially for ethical standards of practice.
The Washington Post columnist Joe Davidson compares the often less demanding standard of opioid prescribing in the community with those of the VA and DoD. This difference in the monitoring of prescriptions the reporter suggests may be contributing to the epidemic of completed suicides—many by medication ingestion—and nonfatal but serious opioid overdoses. As Davidson writes, “The gap in coordination, adding to different clinical standards among VA and non-VA community providers, can be deadly. Health professionals outside the VA are not required to follow departmental guidelines.”1
The VA and DOD are required to follow rigorous, evidence-based practices, documented in the VA/DoD Practice Guideline for Opioid Therapy for Chronic Pain revised and reissued in February 2017. In addition, VA has a comprehensive, systematic, and standardized program of education and monitoring its Opioid Safety Initiative (OSI). The OSI was launched to improve and rationalize opioid prescribing especially when opioids are combined with benzodiazepines, which increases the risk of lethal outcomes from overdoses.
It is not just journalists who have expressed concerns about this disparity in prescribing rigor: The VA Office of Inspector General and several veterans service organizations also have called attention to what is in effect a double standard in care.2 All these entities have underscored another aspect of the Choice program that widens the quality and, hence, safety chasm—the fragmentation of clinical communication between community and VA providers. It is true that as of this writing, every state has passed prescription monitoring program (PMP) legislation. Prior to the change in federal regulation, VA was not permitted to release its controlled substance prescriptions to these pharmacy databases. But in the interest of patient safety, the privacy rules were modified to permit VA pharmacies to share records with the states. This has been a huge step forward in identifying patients who are receiving opioids, benzodiazepines, and stimulants, among other drugs, from a VAMC and 1 or more community prescribers.
Of course, it would be hubristic provincialism to think that there are not excellent clinicians and outstanding institutions in the community that equal or surpass the DoD/VA practice criteria. We are fortunate that because of Choice, veterans and service members now have available to them this level of expertise, which often is not present in smaller federal health care facilities. What is concerning, however, is those prescribers whose practice patterns are routinely and significantly below the bar and thereby place veterans in harms way.However, the efficacy of the PMPs to notify practitioners of prescribing patterns is dependent on the conscientiousness, given the death toll, even the conscience, of those who have prescribing privileges. I should emphasize that prescribing medications is a privilege and that states bestow this power only to those professionals who have met the stipulated education, training, credentialing, and licensing requirements. This professional preparation is crucial when there is not a shared medical record. Without the medical record, the practitioner, especiallyone who does not check the PMP or who does not have sufficient education and training in addiction and pain, is dependent on the history of the patient. The very substances being prescribed or sought may impair the ability of the patient to provide an accurate history due to ignorance, addiction, pain, or fear of losing pain relief.
There is a shortage of addiction and pain specialists in and outside the federal system.3,4 Therefore, we need Choice in order to meet the needs of service members and veterans. Congress has authorized bureaucratic mechanisms and payment sources to enable veterans to receive treatment from community providers. But a regulatory means to ensure that those providers adhere to the same high standards of care as that of VA and DoD practitioners must be established.
Critics of the VA have in many cases rightly made accountability the watchword of their campaigns. To its credit, the VA has embraced the cause in the I CARE value of integrity. “Act with high moral principle. Adhere to the highest professional standards. Maintain the trust and confidence of all with whom I engage.”
But that sense of responsibility must extend to all those who provide care to veterans—especially those who prescribe medications that have the immense double-edged potential to relieve pain and disability but at the same time also cause suffering and death.
While this inability to enforce VA/DoD responsible prescribing requirements in the community is likely more urgent and life threatening, there still are many other federal clinical and organizational policies and regulations to which the community is not required to adhere. I will discuss some of these and their potentially negative implications in future columns. For the promise of Choice to be realized, we all must work together to bear the highest possible standard of care for those who serve and have served.
An esteemed ethics colleague forwarded me a Washington Post column that raises an important, neglected aspect of the Choice program and other VA forms of purchased care: potentially unequal and uneven standards of care.1 Congress authorized Choice to increase veterans’ ability to access needed clinical care in a timely and effective manner. The emphasis on access though may have inadvertently led to an equally serious gap in quality, especially for ethical standards of practice.
The Washington Post columnist Joe Davidson compares the often less demanding standard of opioid prescribing in the community with those of the VA and DoD. This difference in the monitoring of prescriptions the reporter suggests may be contributing to the epidemic of completed suicides—many by medication ingestion—and nonfatal but serious opioid overdoses. As Davidson writes, “The gap in coordination, adding to different clinical standards among VA and non-VA community providers, can be deadly. Health professionals outside the VA are not required to follow departmental guidelines.”1
The VA and DOD are required to follow rigorous, evidence-based practices, documented in the VA/DoD Practice Guideline for Opioid Therapy for Chronic Pain revised and reissued in February 2017. In addition, VA has a comprehensive, systematic, and standardized program of education and monitoring its Opioid Safety Initiative (OSI). The OSI was launched to improve and rationalize opioid prescribing especially when opioids are combined with benzodiazepines, which increases the risk of lethal outcomes from overdoses.
It is not just journalists who have expressed concerns about this disparity in prescribing rigor: The VA Office of Inspector General and several veterans service organizations also have called attention to what is in effect a double standard in care.2 All these entities have underscored another aspect of the Choice program that widens the quality and, hence, safety chasm—the fragmentation of clinical communication between community and VA providers. It is true that as of this writing, every state has passed prescription monitoring program (PMP) legislation. Prior to the change in federal regulation, VA was not permitted to release its controlled substance prescriptions to these pharmacy databases. But in the interest of patient safety, the privacy rules were modified to permit VA pharmacies to share records with the states. This has been a huge step forward in identifying patients who are receiving opioids, benzodiazepines, and stimulants, among other drugs, from a VAMC and 1 or more community prescribers.
Of course, it would be hubristic provincialism to think that there are not excellent clinicians and outstanding institutions in the community that equal or surpass the DoD/VA practice criteria. We are fortunate that because of Choice, veterans and service members now have available to them this level of expertise, which often is not present in smaller federal health care facilities. What is concerning, however, is those prescribers whose practice patterns are routinely and significantly below the bar and thereby place veterans in harms way.However, the efficacy of the PMPs to notify practitioners of prescribing patterns is dependent on the conscientiousness, given the death toll, even the conscience, of those who have prescribing privileges. I should emphasize that prescribing medications is a privilege and that states bestow this power only to those professionals who have met the stipulated education, training, credentialing, and licensing requirements. This professional preparation is crucial when there is not a shared medical record. Without the medical record, the practitioner, especiallyone who does not check the PMP or who does not have sufficient education and training in addiction and pain, is dependent on the history of the patient. The very substances being prescribed or sought may impair the ability of the patient to provide an accurate history due to ignorance, addiction, pain, or fear of losing pain relief.
There is a shortage of addiction and pain specialists in and outside the federal system.3,4 Therefore, we need Choice in order to meet the needs of service members and veterans. Congress has authorized bureaucratic mechanisms and payment sources to enable veterans to receive treatment from community providers. But a regulatory means to ensure that those providers adhere to the same high standards of care as that of VA and DoD practitioners must be established.
Critics of the VA have in many cases rightly made accountability the watchword of their campaigns. To its credit, the VA has embraced the cause in the I CARE value of integrity. “Act with high moral principle. Adhere to the highest professional standards. Maintain the trust and confidence of all with whom I engage.”
But that sense of responsibility must extend to all those who provide care to veterans—especially those who prescribe medications that have the immense double-edged potential to relieve pain and disability but at the same time also cause suffering and death.
While this inability to enforce VA/DoD responsible prescribing requirements in the community is likely more urgent and life threatening, there still are many other federal clinical and organizational policies and regulations to which the community is not required to adhere. I will discuss some of these and their potentially negative implications in future columns. For the promise of Choice to be realized, we all must work together to bear the highest possible standard of care for those who serve and have served.
1. Davidson J. Veterans’ health-care gap creates ‘greater risk’ for opioid use [news release]. Washington Post. August 7, 2017. https://www.washingtonpost.com/news/powerpost/wp/2017/08/07/veterans-health-care-gap-creates-greater-risk-for -opioid-abuse/?utm_term=.e4ec9596db6b. Accessed September 18, 2017.
2. Department of Veterans Affairs Office of Inspector General. Office of Healthcare Inspections. Report No. 17-01846-316. Opioid prescribing to high-risk veterans receiving VA purchased care. https://www.va.gov/oig/pubs/VAOIG-17-01846-316.pdf. Published July 31, 2017. Accessed September 18, 2017.
3. Vestal C. How severe is the shortage of substance abuse specialists? http://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2015/4/01/how-severe-is-the-shortage-of-substance-abuse -specialists. Published April 1, 2015. Accessed September 28, 2017.
4. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.
5. U.S. Department of Veterans Affairs. I care quick reference core values. https://www.va.gov/icare/docs/core_values_quick_reference.pdf. Accessed September 18, 2017.
1. Davidson J. Veterans’ health-care gap creates ‘greater risk’ for opioid use [news release]. Washington Post. August 7, 2017. https://www.washingtonpost.com/news/powerpost/wp/2017/08/07/veterans-health-care-gap-creates-greater-risk-for -opioid-abuse/?utm_term=.e4ec9596db6b. Accessed September 18, 2017.
2. Department of Veterans Affairs Office of Inspector General. Office of Healthcare Inspections. Report No. 17-01846-316. Opioid prescribing to high-risk veterans receiving VA purchased care. https://www.va.gov/oig/pubs/VAOIG-17-01846-316.pdf. Published July 31, 2017. Accessed September 18, 2017.
3. Vestal C. How severe is the shortage of substance abuse specialists? http://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2015/4/01/how-severe-is-the-shortage-of-substance-abuse -specialists. Published April 1, 2015. Accessed September 28, 2017.
4. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.
5. U.S. Department of Veterans Affairs. I care quick reference core values. https://www.va.gov/icare/docs/core_values_quick_reference.pdf. Accessed September 18, 2017.
Caplacizumab may enhance treatment of aTTP
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab. 
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Drug receives breakthrough designation for HL
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (BV, Adcetris) for use in combination with chemotherapy as frontline treatment of advanced classical Hodgkin lymphoma (HL).
Seattle Genetics and Takeda plan to submit a supplemental biologics license application seeking approval for BV in this indication before the end of this year.
The breakthrough designation is based on positive topline results from the phase 3 ECHELON-1 trial.
Full results from this trial are expected to be presented at the 2017 ASH Annual Meeting in December.
BV is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
BV is currently FDA-approved to treat:
- Classical HL after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
- Classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation.
BV also has accelerated approval from the FDA for the treatment of systemic anaplastic large-cell lymphoma after failure of at least 1 prior multi-agent chemotherapy regimen. This approval is based on overall response rate. Continued approval of BV for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
ECHELON-1 trial
In this phase 3 trial, researchers compared BV in combination with doxorubicin, vinblastine, and dacarbazine to a recognized standard of care chemotherapy regimen in patients with previously untreated, advanced classical HL.
The study enrolled 1334 patients who had a histologically confirmed diagnosis of stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy.
The study’s primary endpoint is modified progression-free survival (PFS) per an independent review facility. Modified PFS is defined as the time to progression, death, or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy.
There was a significant improvement in modified PFS in the BV arm compared to the control arm (hazard ratio=0.770; P=0.035). The 2-year modified PFS rate was 82.1% in the BV arm and 77.2% in the control arm.
An interim analysis of overall survival revealed a trend in favor of the BV arm.
The safety profile of BV plus chemotherapy was consistent with the profile known for the single-agent components of the regimen.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (BV, Adcetris) for use in combination with chemotherapy as frontline treatment of advanced classical Hodgkin lymphoma (HL).
Seattle Genetics and Takeda plan to submit a supplemental biologics license application seeking approval for BV in this indication before the end of this year.
The breakthrough designation is based on positive topline results from the phase 3 ECHELON-1 trial.
Full results from this trial are expected to be presented at the 2017 ASH Annual Meeting in December.
BV is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
BV is currently FDA-approved to treat:
- Classical HL after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
- Classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation.
BV also has accelerated approval from the FDA for the treatment of systemic anaplastic large-cell lymphoma after failure of at least 1 prior multi-agent chemotherapy regimen. This approval is based on overall response rate. Continued approval of BV for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
ECHELON-1 trial
In this phase 3 trial, researchers compared BV in combination with doxorubicin, vinblastine, and dacarbazine to a recognized standard of care chemotherapy regimen in patients with previously untreated, advanced classical HL.
The study enrolled 1334 patients who had a histologically confirmed diagnosis of stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy.
The study’s primary endpoint is modified progression-free survival (PFS) per an independent review facility. Modified PFS is defined as the time to progression, death, or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy.
There was a significant improvement in modified PFS in the BV arm compared to the control arm (hazard ratio=0.770; P=0.035). The 2-year modified PFS rate was 82.1% in the BV arm and 77.2% in the control arm.
An interim analysis of overall survival revealed a trend in favor of the BV arm.
The safety profile of BV plus chemotherapy was consistent with the profile known for the single-agent components of the regimen.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (BV, Adcetris) for use in combination with chemotherapy as frontline treatment of advanced classical Hodgkin lymphoma (HL).
Seattle Genetics and Takeda plan to submit a supplemental biologics license application seeking approval for BV in this indication before the end of this year.
The breakthrough designation is based on positive topline results from the phase 3 ECHELON-1 trial.
Full results from this trial are expected to be presented at the 2017 ASH Annual Meeting in December.
BV is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
BV is currently FDA-approved to treat:
- Classical HL after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
- Classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation.
BV also has accelerated approval from the FDA for the treatment of systemic anaplastic large-cell lymphoma after failure of at least 1 prior multi-agent chemotherapy regimen. This approval is based on overall response rate. Continued approval of BV for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
ECHELON-1 trial
In this phase 3 trial, researchers compared BV in combination with doxorubicin, vinblastine, and dacarbazine to a recognized standard of care chemotherapy regimen in patients with previously untreated, advanced classical HL.
The study enrolled 1334 patients who had a histologically confirmed diagnosis of stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy.
The study’s primary endpoint is modified progression-free survival (PFS) per an independent review facility. Modified PFS is defined as the time to progression, death, or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy.
There was a significant improvement in modified PFS in the BV arm compared to the control arm (hazard ratio=0.770; P=0.035). The 2-year modified PFS rate was 82.1% in the BV arm and 77.2% in the control arm.
An interim analysis of overall survival revealed a trend in favor of the BV arm.
The safety profile of BV plus chemotherapy was consistent with the profile known for the single-agent components of the regimen.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA grants EUA to Zika testing system
The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for Chembio Diagnostics, Inc.’s DPP® Zika System.
The system includes the DPP Zika IgM Assay, which enables in vitro qualitative detection of human IgM antibodies to Zika virus, and the DPP Micro Reader, which is a portable, hand-held device intended to reduce the risk of human error during test interpretation.
The DPP Zika System provides results in 15 to 20 minutes from 10 µL of blood.
The system is designed to detect Zika virus IgM antibodies in finger-stick whole blood, EDTA venous whole blood, EDTA plasma (each collected alongside a patient-matched serum specimen), or serum (plain or separation gel) specimens.
The EUA for the DPP Zika System does not mean it is FDA cleared or approved.
An EUA allows for the use of unapproved medical products (or unapproved uses of approved medical products) in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the DPP Zika System means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the DPP Zika System is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The DPP Zika System can be used to test individuals who meet the Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (eg, a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, a history of residence in or travel to a geographic region with active Zika transmission at the time of travel or other epidemiological criteria for which Zika virus testing may be indicated).
The DPP Zika System can be used starting 8 days after symptom onset or risk of exposure and for up to 12 weeks after that point.
Where there are reactive results from the DPP Zika IgM Assay, confirmation of the presence of anti-Zika IgM antibodies requires additional testing and/or consideration alongside test results for other patient-matched specimens using the latest CDC testing algorithms for the diagnosis of Zika virus infection.
Development of the DPP Zika System has been funded, in part, with federal funds from the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the US Department of Health and Human Services.
Chembio Diagnostics, Inc. has been awarded a contract for $5.9 million to develop the product and obtain EUA and 510(k) clearance from the FDA, with the potential of $13.2 million in total funding from BARDA if all options are exercised, to advance clinical development of the DPP Zika System and DPP® Zika/Dengue/Chikungunya System.
More information on the DPP Zika System and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for Chembio Diagnostics, Inc.’s DPP® Zika System.
The system includes the DPP Zika IgM Assay, which enables in vitro qualitative detection of human IgM antibodies to Zika virus, and the DPP Micro Reader, which is a portable, hand-held device intended to reduce the risk of human error during test interpretation.
The DPP Zika System provides results in 15 to 20 minutes from 10 µL of blood.
The system is designed to detect Zika virus IgM antibodies in finger-stick whole blood, EDTA venous whole blood, EDTA plasma (each collected alongside a patient-matched serum specimen), or serum (plain or separation gel) specimens.
The EUA for the DPP Zika System does not mean it is FDA cleared or approved.
An EUA allows for the use of unapproved medical products (or unapproved uses of approved medical products) in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the DPP Zika System means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the DPP Zika System is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The DPP Zika System can be used to test individuals who meet the Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (eg, a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, a history of residence in or travel to a geographic region with active Zika transmission at the time of travel or other epidemiological criteria for which Zika virus testing may be indicated).
The DPP Zika System can be used starting 8 days after symptom onset or risk of exposure and for up to 12 weeks after that point.
Where there are reactive results from the DPP Zika IgM Assay, confirmation of the presence of anti-Zika IgM antibodies requires additional testing and/or consideration alongside test results for other patient-matched specimens using the latest CDC testing algorithms for the diagnosis of Zika virus infection.
Development of the DPP Zika System has been funded, in part, with federal funds from the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the US Department of Health and Human Services.
Chembio Diagnostics, Inc. has been awarded a contract for $5.9 million to develop the product and obtain EUA and 510(k) clearance from the FDA, with the potential of $13.2 million in total funding from BARDA if all options are exercised, to advance clinical development of the DPP Zika System and DPP® Zika/Dengue/Chikungunya System.
More information on the DPP Zika System and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for Chembio Diagnostics, Inc.’s DPP® Zika System.
The system includes the DPP Zika IgM Assay, which enables in vitro qualitative detection of human IgM antibodies to Zika virus, and the DPP Micro Reader, which is a portable, hand-held device intended to reduce the risk of human error during test interpretation.
The DPP Zika System provides results in 15 to 20 minutes from 10 µL of blood.
The system is designed to detect Zika virus IgM antibodies in finger-stick whole blood, EDTA venous whole blood, EDTA plasma (each collected alongside a patient-matched serum specimen), or serum (plain or separation gel) specimens.
The EUA for the DPP Zika System does not mean it is FDA cleared or approved.
An EUA allows for the use of unapproved medical products (or unapproved uses of approved medical products) in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the DPP Zika System means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the DPP Zika System is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The DPP Zika System can be used to test individuals who meet the Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (eg, a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, a history of residence in or travel to a geographic region with active Zika transmission at the time of travel or other epidemiological criteria for which Zika virus testing may be indicated).
The DPP Zika System can be used starting 8 days after symptom onset or risk of exposure and for up to 12 weeks after that point.
Where there are reactive results from the DPP Zika IgM Assay, confirmation of the presence of anti-Zika IgM antibodies requires additional testing and/or consideration alongside test results for other patient-matched specimens using the latest CDC testing algorithms for the diagnosis of Zika virus infection.
Development of the DPP Zika System has been funded, in part, with federal funds from the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the US Department of Health and Human Services.
Chembio Diagnostics, Inc. has been awarded a contract for $5.9 million to develop the product and obtain EUA and 510(k) clearance from the FDA, with the potential of $13.2 million in total funding from BARDA if all options are exercised, to advance clinical development of the DPP Zika System and DPP® Zika/Dengue/Chikungunya System.
More information on the DPP Zika System and other Zika tests granted EUAs can be found on the FDA’s EUA page.
Do PPIs Pose a Danger to Kidneys?
Q) Is it true that PPI use can cause kidney disease?
Proton pump inhibitors (PPIs) have been available in the United States since 1990, with OTC options available since 2009. While these medications play a vital role in the treatment of gastrointestinal (GI) conditions, observational studies have linked PPI use to serious adverse events, including dementia, community-acquired pneumonia, hip fracture, and Clostridium difficile infection.1-4
Studies have also found an association between PPI use and kidney problems such as acute kidney injury (AKI), acute interstitial nephritis, and incident chronic kidney disease (CKD).5-7 One observational study used the Department of Veterans Affairs (VA) national databases to track the renal outcomes of 173,321 new PPI users and 20,270 new histamine H2 receptor antagonist (H2RA) users over the course of five years. Those who used PPIs demonstrated a significant risk for decreased renal function, lower estimated glomerular filtration rate (eGFR), doubled serum creatinine levels, and progression to end-stage renal disease (ESRD).8
Another study of 10,482 patients (322 PPI; 956 H2RA; 9,204 nonusers) and a replicate study of 248,751 patients (16,900 PPI; 6,640 H2RA; 225,211 nonusers) with an initial eGFR ≥ 60 mL/min/1.73m2 also found an association between PPI use and incident CKD, which persisted when compared to the other groups. Additionally, twice-daily PPI use was associated with a higher CKD risk than once-daily use.9
The pathophysiology of PPI use and kidney deterioration is poorly understood at this point. It is known that AKI can increase the risk for CKD, and AKI has been an assumed precursor to PPI-associated CKD. However, a study by Xie and colleagues reported an association between PPI use and increased risk for CKD, progression of CKD, and ESRD in the absence of preceding AKI. Using the VA databases, the researchers identified 144,032 new users of acid-suppressing medications (125,596 PPI; 18,436 H2RA) who had no history of kidney disease and followed them for five years. PPI users were found to be at increased risk for CKD, and a graded association was discovered between length of PPI use and risk for CKD.10
While these studies are observational and therefore do not prove causation, they do suggest a need for attentive monitoring of kidney function in patients using PPIs. Evaluating the need for PPIs and inquiring about OTC use of these medications is highly recommended, as research has found 25% to 70% of PPI prescriptions are not prescribed for an appropriate indication.11 Considerations regarding PPI use should include dosage, length of use, and whether alternate use of an H2RA is appropriate. —CAS
Cynthia A. Smith, DNP, CNN-NP, FNP-BC, APRN
Renal Consultants, PLLC, South Charleston, West Virginia
1. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410-416.
2. Lambert AA, Lam JO, Paik JJ, et al. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PloS One. 2015;10(6):e0128004.
3. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296(24):2947-2953.
4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-38.
5. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study. BMC Nephrol. 2013;14:150.
6. Blank ML, Parkin L, Paul C, et al. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86:837-844.
7. Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015;3(2):E166-171.
8. Xie Y, Bowe B, Li T, et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153-3163.
9. Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246.
10. Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 2017;91(6):1482-1494.
11. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336(7634):2-3.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National KidneyFoundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Cynthia A. Smith, DNP, CNN-NP, FNP-BC, APRN, who practices at Renal Consultants, PLLC, in South Charleston, West Virginia, and Marlene Shaw-Gallagher, MS, PA-C, who is an Assistant Professor at University of Detroit Mercy in Michigan and practices in the Division of Nephrology at the University of Michigan in Ann Arbor.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National KidneyFoundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Cynthia A. Smith, DNP, CNN-NP, FNP-BC, APRN, who practices at Renal Consultants, PLLC, in South Charleston, West Virginia, and Marlene Shaw-Gallagher, MS, PA-C, who is an Assistant Professor at University of Detroit Mercy in Michigan and practices in the Division of Nephrology at the University of Michigan in Ann Arbor.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National KidneyFoundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Cynthia A. Smith, DNP, CNN-NP, FNP-BC, APRN, who practices at Renal Consultants, PLLC, in South Charleston, West Virginia, and Marlene Shaw-Gallagher, MS, PA-C, who is an Assistant Professor at University of Detroit Mercy in Michigan and practices in the Division of Nephrology at the University of Michigan in Ann Arbor.
Q) Is it true that PPI use can cause kidney disease?
Proton pump inhibitors (PPIs) have been available in the United States since 1990, with OTC options available since 2009. While these medications play a vital role in the treatment of gastrointestinal (GI) conditions, observational studies have linked PPI use to serious adverse events, including dementia, community-acquired pneumonia, hip fracture, and Clostridium difficile infection.1-4
Studies have also found an association between PPI use and kidney problems such as acute kidney injury (AKI), acute interstitial nephritis, and incident chronic kidney disease (CKD).5-7 One observational study used the Department of Veterans Affairs (VA) national databases to track the renal outcomes of 173,321 new PPI users and 20,270 new histamine H2 receptor antagonist (H2RA) users over the course of five years. Those who used PPIs demonstrated a significant risk for decreased renal function, lower estimated glomerular filtration rate (eGFR), doubled serum creatinine levels, and progression to end-stage renal disease (ESRD).8
Another study of 10,482 patients (322 PPI; 956 H2RA; 9,204 nonusers) and a replicate study of 248,751 patients (16,900 PPI; 6,640 H2RA; 225,211 nonusers) with an initial eGFR ≥ 60 mL/min/1.73m2 also found an association between PPI use and incident CKD, which persisted when compared to the other groups. Additionally, twice-daily PPI use was associated with a higher CKD risk than once-daily use.9
The pathophysiology of PPI use and kidney deterioration is poorly understood at this point. It is known that AKI can increase the risk for CKD, and AKI has been an assumed precursor to PPI-associated CKD. However, a study by Xie and colleagues reported an association between PPI use and increased risk for CKD, progression of CKD, and ESRD in the absence of preceding AKI. Using the VA databases, the researchers identified 144,032 new users of acid-suppressing medications (125,596 PPI; 18,436 H2RA) who had no history of kidney disease and followed them for five years. PPI users were found to be at increased risk for CKD, and a graded association was discovered between length of PPI use and risk for CKD.10
While these studies are observational and therefore do not prove causation, they do suggest a need for attentive monitoring of kidney function in patients using PPIs. Evaluating the need for PPIs and inquiring about OTC use of these medications is highly recommended, as research has found 25% to 70% of PPI prescriptions are not prescribed for an appropriate indication.11 Considerations regarding PPI use should include dosage, length of use, and whether alternate use of an H2RA is appropriate. —CAS
Cynthia A. Smith, DNP, CNN-NP, FNP-BC, APRN
Renal Consultants, PLLC, South Charleston, West Virginia
Q) Is it true that PPI use can cause kidney disease?
Proton pump inhibitors (PPIs) have been available in the United States since 1990, with OTC options available since 2009. While these medications play a vital role in the treatment of gastrointestinal (GI) conditions, observational studies have linked PPI use to serious adverse events, including dementia, community-acquired pneumonia, hip fracture, and Clostridium difficile infection.1-4
Studies have also found an association between PPI use and kidney problems such as acute kidney injury (AKI), acute interstitial nephritis, and incident chronic kidney disease (CKD).5-7 One observational study used the Department of Veterans Affairs (VA) national databases to track the renal outcomes of 173,321 new PPI users and 20,270 new histamine H2 receptor antagonist (H2RA) users over the course of five years. Those who used PPIs demonstrated a significant risk for decreased renal function, lower estimated glomerular filtration rate (eGFR), doubled serum creatinine levels, and progression to end-stage renal disease (ESRD).8
Another study of 10,482 patients (322 PPI; 956 H2RA; 9,204 nonusers) and a replicate study of 248,751 patients (16,900 PPI; 6,640 H2RA; 225,211 nonusers) with an initial eGFR ≥ 60 mL/min/1.73m2 also found an association between PPI use and incident CKD, which persisted when compared to the other groups. Additionally, twice-daily PPI use was associated with a higher CKD risk than once-daily use.9
The pathophysiology of PPI use and kidney deterioration is poorly understood at this point. It is known that AKI can increase the risk for CKD, and AKI has been an assumed precursor to PPI-associated CKD. However, a study by Xie and colleagues reported an association between PPI use and increased risk for CKD, progression of CKD, and ESRD in the absence of preceding AKI. Using the VA databases, the researchers identified 144,032 new users of acid-suppressing medications (125,596 PPI; 18,436 H2RA) who had no history of kidney disease and followed them for five years. PPI users were found to be at increased risk for CKD, and a graded association was discovered between length of PPI use and risk for CKD.10
While these studies are observational and therefore do not prove causation, they do suggest a need for attentive monitoring of kidney function in patients using PPIs. Evaluating the need for PPIs and inquiring about OTC use of these medications is highly recommended, as research has found 25% to 70% of PPI prescriptions are not prescribed for an appropriate indication.11 Considerations regarding PPI use should include dosage, length of use, and whether alternate use of an H2RA is appropriate. —CAS
Cynthia A. Smith, DNP, CNN-NP, FNP-BC, APRN
Renal Consultants, PLLC, South Charleston, West Virginia
1. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410-416.
2. Lambert AA, Lam JO, Paik JJ, et al. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PloS One. 2015;10(6):e0128004.
3. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296(24):2947-2953.
4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-38.
5. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study. BMC Nephrol. 2013;14:150.
6. Blank ML, Parkin L, Paul C, et al. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86:837-844.
7. Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015;3(2):E166-171.
8. Xie Y, Bowe B, Li T, et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153-3163.
9. Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246.
10. Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 2017;91(6):1482-1494.
11. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336(7634):2-3.
1. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410-416.
2. Lambert AA, Lam JO, Paik JJ, et al. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PloS One. 2015;10(6):e0128004.
3. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296(24):2947-2953.
4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-38.
5. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study. BMC Nephrol. 2013;14:150.
6. Blank ML, Parkin L, Paul C, et al. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86:837-844.
7. Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015;3(2):E166-171.
8. Xie Y, Bowe B, Li T, et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153-3163.
9. Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246.
10. Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 2017;91(6):1482-1494.
11. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336(7634):2-3.
Sepsis time to treatment
Clinical question: Does early identification and treatment of sepsis using protocols improve outcomes?
Background: International clinical guidelines recommend early detection and treatment of sepsis with broad spectrum antibiotics and intravenous fluids which are supported by preclinical and observation studies that show a reduction in avoidable deaths. However, controversy remains in the timing of these treatments on how it relates to patient outcomes such as risk-adjusted mortality.
Study design: Retrospective cohort study using data reported to the New York State Department of Health from April 1, 2014, to June 30, 2016.
Setting: New York hospitals.
Synopsis: For patients with sepsis and septic shock, a sepsis protocol was initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care (that is, blood cultures, broad-spectrum antibiotic, and lactate measurement) completed within 12 hours. Among 49,331 patients at 149 hospitals, higher risk-adjusted in-hospital mortality was associated with longer time to the completion of the bundle (P less than .001), administration of antibiotics (P less than .001), but not completion of a bolus of intravenous fluids (P = .21).
Study limitations include being nonrandomized, hospitals all from one state possibly introducing epidemiologic distinct features of sepsis inherent to the region, and accuracy of the data collection (that is, start time).
No association was found between time to completion of the initial bolus of fluids and improved outcomes in risk-adjusted mortality; however, the analysis of time of the initial fluid bolus was most vulnerable to confounding; a causal relationship will need further study.
Bottom line: A lower risk-adjusted in-hospital mortality was associated with rapid administration of antibiotics and a faster completion of a 3-hour bundle of sepsis care, but there was no discernable association with the rapid administration of initial bolus of intravenous fluids.
Citation: Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017; 376:2235-44.
Dr. Choe is a hospitalist at Ochsner Health System, New Orleans.
Clinical question: Does early identification and treatment of sepsis using protocols improve outcomes?
Background: International clinical guidelines recommend early detection and treatment of sepsis with broad spectrum antibiotics and intravenous fluids which are supported by preclinical and observation studies that show a reduction in avoidable deaths. However, controversy remains in the timing of these treatments on how it relates to patient outcomes such as risk-adjusted mortality.
Study design: Retrospective cohort study using data reported to the New York State Department of Health from April 1, 2014, to June 30, 2016.
Setting: New York hospitals.
Synopsis: For patients with sepsis and septic shock, a sepsis protocol was initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care (that is, blood cultures, broad-spectrum antibiotic, and lactate measurement) completed within 12 hours. Among 49,331 patients at 149 hospitals, higher risk-adjusted in-hospital mortality was associated with longer time to the completion of the bundle (P less than .001), administration of antibiotics (P less than .001), but not completion of a bolus of intravenous fluids (P = .21).
Study limitations include being nonrandomized, hospitals all from one state possibly introducing epidemiologic distinct features of sepsis inherent to the region, and accuracy of the data collection (that is, start time).
No association was found between time to completion of the initial bolus of fluids and improved outcomes in risk-adjusted mortality; however, the analysis of time of the initial fluid bolus was most vulnerable to confounding; a causal relationship will need further study.
Bottom line: A lower risk-adjusted in-hospital mortality was associated with rapid administration of antibiotics and a faster completion of a 3-hour bundle of sepsis care, but there was no discernable association with the rapid administration of initial bolus of intravenous fluids.
Citation: Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017; 376:2235-44.
Dr. Choe is a hospitalist at Ochsner Health System, New Orleans.
Clinical question: Does early identification and treatment of sepsis using protocols improve outcomes?
Background: International clinical guidelines recommend early detection and treatment of sepsis with broad spectrum antibiotics and intravenous fluids which are supported by preclinical and observation studies that show a reduction in avoidable deaths. However, controversy remains in the timing of these treatments on how it relates to patient outcomes such as risk-adjusted mortality.
Study design: Retrospective cohort study using data reported to the New York State Department of Health from April 1, 2014, to June 30, 2016.
Setting: New York hospitals.
Synopsis: For patients with sepsis and septic shock, a sepsis protocol was initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care (that is, blood cultures, broad-spectrum antibiotic, and lactate measurement) completed within 12 hours. Among 49,331 patients at 149 hospitals, higher risk-adjusted in-hospital mortality was associated with longer time to the completion of the bundle (P less than .001), administration of antibiotics (P less than .001), but not completion of a bolus of intravenous fluids (P = .21).
Study limitations include being nonrandomized, hospitals all from one state possibly introducing epidemiologic distinct features of sepsis inherent to the region, and accuracy of the data collection (that is, start time).
No association was found between time to completion of the initial bolus of fluids and improved outcomes in risk-adjusted mortality; however, the analysis of time of the initial fluid bolus was most vulnerable to confounding; a causal relationship will need further study.
Bottom line: A lower risk-adjusted in-hospital mortality was associated with rapid administration of antibiotics and a faster completion of a 3-hour bundle of sepsis care, but there was no discernable association with the rapid administration of initial bolus of intravenous fluids.
Citation: Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017; 376:2235-44.
Dr. Choe is a hospitalist at Ochsner Health System, New Orleans.
How Does Gender Influence Perceived Health in Older People With MS?
Older men adapt more poorly to aging with multiple sclerosis (MS), compared with older women, according to research published in the July–August issue of International Journal of MS Care. Health and lifestyle behaviors may put older men with MS at greater risk of health decline, said the authors. Older women, however, appear to have more confidence in their ability to cope with challenges and control the course of their disease.
Healthy Aging With MS
Improved longevity in patients with MS has increased interest in understanding factors associated with healthy aging. Previous studies suggested that factors such as depression, disability, decreased levels of social support, and unemployment predict health-related quality of life in MS.
Two studies examining sex differences in health-related quality of life in young to middle-aged patients with MS found that the association between disability and health-related quality of life was stronger in men than in women. No studies, however, have examined sex differences in health perception among older people with MS, according to the authors.
Analysis of a Canadian Postal Survey
To determine whether older women and men with MS have different health and lifestyle behaviors and whether there are sex differences in contributors to perceived health, Dr. Ploughman and colleagues analyzed data from the Canadian Survey of Health, Lifestyle, and Aging With MS. This cross-sectional study included Canadians older than 55 who had had MS for at least 20 years. Of 921 people contacted, 743 (577 women) returned the mailed questionnaire.
The questionnaire asked about biologic factors (eg, comorbid conditions, years since MS diagnosis), symptoms (eg, depression, anxiety, fatigue, and stress), function (eg, disability and participation), and individual and environmental factors (eg, socioeconomic status, education, and social or health support). Researchers used multiple regression analysis to build explanatory models of health perception.
Older Men With MS Were Less Resilient
Investigators found no differences in disability between men and women, nor differences in age, years of education, or years since MS diagnosis. Older men had lower perceived health and lower resilience, and participated less in life roles than did older women.
In addition, men had more depressive symptoms, and women reported more anxiety. Women also reported higher adherence to a healthy diet (ie, one high in fruits and vegetables and low in meat). Men consumed more alcohol weekly.
Depression was the strongest predictor of health perception in women and men. Other contributors included household participation, fatigue, resilience, and disability in women and physical activity, financial flexibility, and alcohol use in men.
More research is necessary to examine healthy aging in the oldest people with MS, such as octogenarians, said the authors.
—Erica Tricarico
Suggested Reading
Ploughman M, Collins K, Wallack EM, et al. Women’s and men’s differing experiences of health, lifestyle, and aging with multiple sclerosis. Int J MS Care. 2017;19(4):165-171.
Older men adapt more poorly to aging with multiple sclerosis (MS), compared with older women, according to research published in the July–August issue of International Journal of MS Care. Health and lifestyle behaviors may put older men with MS at greater risk of health decline, said the authors. Older women, however, appear to have more confidence in their ability to cope with challenges and control the course of their disease.
Healthy Aging With MS
Improved longevity in patients with MS has increased interest in understanding factors associated with healthy aging. Previous studies suggested that factors such as depression, disability, decreased levels of social support, and unemployment predict health-related quality of life in MS.
Two studies examining sex differences in health-related quality of life in young to middle-aged patients with MS found that the association between disability and health-related quality of life was stronger in men than in women. No studies, however, have examined sex differences in health perception among older people with MS, according to the authors.
Analysis of a Canadian Postal Survey
To determine whether older women and men with MS have different health and lifestyle behaviors and whether there are sex differences in contributors to perceived health, Dr. Ploughman and colleagues analyzed data from the Canadian Survey of Health, Lifestyle, and Aging With MS. This cross-sectional study included Canadians older than 55 who had had MS for at least 20 years. Of 921 people contacted, 743 (577 women) returned the mailed questionnaire.
The questionnaire asked about biologic factors (eg, comorbid conditions, years since MS diagnosis), symptoms (eg, depression, anxiety, fatigue, and stress), function (eg, disability and participation), and individual and environmental factors (eg, socioeconomic status, education, and social or health support). Researchers used multiple regression analysis to build explanatory models of health perception.
Older Men With MS Were Less Resilient
Investigators found no differences in disability between men and women, nor differences in age, years of education, or years since MS diagnosis. Older men had lower perceived health and lower resilience, and participated less in life roles than did older women.
In addition, men had more depressive symptoms, and women reported more anxiety. Women also reported higher adherence to a healthy diet (ie, one high in fruits and vegetables and low in meat). Men consumed more alcohol weekly.
Depression was the strongest predictor of health perception in women and men. Other contributors included household participation, fatigue, resilience, and disability in women and physical activity, financial flexibility, and alcohol use in men.
More research is necessary to examine healthy aging in the oldest people with MS, such as octogenarians, said the authors.
—Erica Tricarico
Suggested Reading
Ploughman M, Collins K, Wallack EM, et al. Women’s and men’s differing experiences of health, lifestyle, and aging with multiple sclerosis. Int J MS Care. 2017;19(4):165-171.
Older men adapt more poorly to aging with multiple sclerosis (MS), compared with older women, according to research published in the July–August issue of International Journal of MS Care. Health and lifestyle behaviors may put older men with MS at greater risk of health decline, said the authors. Older women, however, appear to have more confidence in their ability to cope with challenges and control the course of their disease.
Healthy Aging With MS
Improved longevity in patients with MS has increased interest in understanding factors associated with healthy aging. Previous studies suggested that factors such as depression, disability, decreased levels of social support, and unemployment predict health-related quality of life in MS.
Two studies examining sex differences in health-related quality of life in young to middle-aged patients with MS found that the association between disability and health-related quality of life was stronger in men than in women. No studies, however, have examined sex differences in health perception among older people with MS, according to the authors.
Analysis of a Canadian Postal Survey
To determine whether older women and men with MS have different health and lifestyle behaviors and whether there are sex differences in contributors to perceived health, Dr. Ploughman and colleagues analyzed data from the Canadian Survey of Health, Lifestyle, and Aging With MS. This cross-sectional study included Canadians older than 55 who had had MS for at least 20 years. Of 921 people contacted, 743 (577 women) returned the mailed questionnaire.
The questionnaire asked about biologic factors (eg, comorbid conditions, years since MS diagnosis), symptoms (eg, depression, anxiety, fatigue, and stress), function (eg, disability and participation), and individual and environmental factors (eg, socioeconomic status, education, and social or health support). Researchers used multiple regression analysis to build explanatory models of health perception.
Older Men With MS Were Less Resilient
Investigators found no differences in disability between men and women, nor differences in age, years of education, or years since MS diagnosis. Older men had lower perceived health and lower resilience, and participated less in life roles than did older women.
In addition, men had more depressive symptoms, and women reported more anxiety. Women also reported higher adherence to a healthy diet (ie, one high in fruits and vegetables and low in meat). Men consumed more alcohol weekly.
Depression was the strongest predictor of health perception in women and men. Other contributors included household participation, fatigue, resilience, and disability in women and physical activity, financial flexibility, and alcohol use in men.
More research is necessary to examine healthy aging in the oldest people with MS, such as octogenarians, said the authors.
—Erica Tricarico
Suggested Reading
Ploughman M, Collins K, Wallack EM, et al. Women’s and men’s differing experiences of health, lifestyle, and aging with multiple sclerosis. Int J MS Care. 2017;19(4):165-171.