Ten years ago, the Food and Drug Administration required that all antidepressants carry a severe black box warning to alert prescribers to the possibility that these medications could cause worsening suicidal thoughts and behavior. A decade later, this issue had faded from the public eye and the media headlines. Nevertheless, research into their use has continued, and antidepressants continue to be prescribed. Have things changed since all the attention in the past? The results may be surprising.

Although there are undoubtedly different views, here is my summary of the five key points with direct implications for pediatricians:

1. The risk of suicide due to antidepressants was overstated. Subsequent analyses from additional clinical trials comparing suicidal thoughts or behavior between youths taking antidepressants versus placebo have increasingly struggled to find that "signal" related to active drug. Perhaps more importantly, several other studies that have examined actual suicides and/or suicide attempts from large databases have not shown links to the taking of antidepressants and, if anything, have suggested that untreated depression poses a greater risk (BMJ 2014;348:g3596). It is worth repeating that there still has never been an actual suicide in any of the antidepressant trials.

2. The efficacy of antidepressants also was overstated. As people began to examine more closely the issue of suicidal behavior and antidepressants, it became evident that there was much more data on this than was obvious from published studies. Many more trials of depression and antidepressants were performed, usually funded by pharmaceutical companies, and many of these trials did not show that antidepressants were superior to placebo (N. Engl. J. Med. 2008;358:252-60). As opposed to the positive trials, however, the negative ones tended not to be published or featured. Overall, it seems that about 60% of depressed children and adolescents respond to antidepressant medication, compared with 50% who respond to placebo.

3. The prescribing of antidepressants is making a comeback. After the 2004 warnings, the number of antidepressant prescriptions dropped. Since around 2008, however, the rate of antidepressant prescribing has increased again, although not at 2004 levels, according to some studies.

4. Antidepressants don’t work by fixing a serotonin "chemical imbalance." Although it is true that antidepressants result in more serotonin being available in brain synapses acutely, depression is not caused by a simple serotonin deficit. Medications likely work by changing the expression of certain genes that relate to how strongly particular brain pathways are connected. This process may explain why antidepressants take time to be effective.

5. Antidepressants actually work better for youths with anxiety rather than depression. More promising results with antidepressants have been found for children with anxiety disorder and obsessive-compulsive disorder (N. Engl. J. Med. 2008;359:2753-66). Although cognitive-behavior therapy remains the recommended first-line intervention for children with anxiety disorders, antidepressants have been shown to be effective both alone and in combination with cognitive-behavior therapy.

There is still much to learn. Children and adolescents who are extremely irritable, unmotivated, and at times suicidal are a diverse group of people whose difficulties can arise from many factors that deserve investigation. When it comes to antidepressants, it appears that both the amount of risk and the amount of benefit associated with this class of medications may be less than what was believed a decade ago.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. Dr. Rettew said he had no financial disclosures relevant to this article.

Ten years ago, the Food and Drug Administration required that all antidepressants carry a severe black box warning to alert prescribers to the possibility that these medications could cause worsening suicidal thoughts and behavior. A decade later, this issue had faded from the public eye and the media headlines. Nevertheless, research into their use has continued, and antidepressants continue to be prescribed. Have things changed since all the attention in the past? The results may be surprising.

Although there are undoubtedly different views, here is my summary of the five key points with direct implications for pediatricians:

1. The risk of suicide due to antidepressants was overstated. Subsequent analyses from additional clinical trials comparing suicidal thoughts or behavior between youths taking antidepressants versus placebo have increasingly struggled to find that "signal" related to active drug. Perhaps more importantly, several other studies that have examined actual suicides and/or suicide attempts from large databases have not shown links to the taking of antidepressants and, if anything, have suggested that untreated depression poses a greater risk (BMJ 2014;348:g3596). It is worth repeating that there still has never been an actual suicide in any of the antidepressant trials.

2. The efficacy of antidepressants also was overstated. As people began to examine more closely the issue of suicidal behavior and antidepressants, it became evident that there was much more data on this than was obvious from published studies. Many more trials of depression and antidepressants were performed, usually funded by pharmaceutical companies, and many of these trials did not show that antidepressants were superior to placebo (N. Engl. J. Med. 2008;358:252-60). As opposed to the positive trials, however, the negative ones tended not to be published or featured. Overall, it seems that about 60% of depressed children and adolescents respond to antidepressant medication, compared with 50% who respond to placebo.

3. The prescribing of antidepressants is making a comeback. After the 2004 warnings, the number of antidepressant prescriptions dropped. Since around 2008, however, the rate of antidepressant prescribing has increased again, although not at 2004 levels, according to some studies.

4. Antidepressants don’t work by fixing a serotonin "chemical imbalance." Although it is true that antidepressants result in more serotonin being available in brain synapses acutely, depression is not caused by a simple serotonin deficit. Medications likely work by changing the expression of certain genes that relate to how strongly particular brain pathways are connected. This process may explain why antidepressants take time to be effective.

5. Antidepressants actually work better for youths with anxiety rather than depression. More promising results with antidepressants have been found for children with anxiety disorder and obsessive-compulsive disorder (N. Engl. J. Med. 2008;359:2753-66). Although cognitive-behavior therapy remains the recommended first-line intervention for children with anxiety disorders, antidepressants have been shown to be effective both alone and in combination with cognitive-behavior therapy.

There is still much to learn. Children and adolescents who are extremely irritable, unmotivated, and at times suicidal are a diverse group of people whose difficulties can arise from many factors that deserve investigation. When it comes to antidepressants, it appears that both the amount of risk and the amount of benefit associated with this class of medications may be less than what was believed a decade ago.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. Dr. Rettew said he had no financial disclosures relevant to this article.

Ten years ago, the Food and Drug Administration required that all antidepressants carry a severe black box warning to alert prescribers to the possibility that these medications could cause worsening suicidal thoughts and behavior. A decade later, this issue had faded from the public eye and the media headlines. Nevertheless, research into their use has continued, and antidepressants continue to be prescribed. Have things changed since all the attention in the past? The results may be surprising.

Although there are undoubtedly different views, here is my summary of the five key points with direct implications for pediatricians:

1. The risk of suicide due to antidepressants was overstated. Subsequent analyses from additional clinical trials comparing suicidal thoughts or behavior between youths taking antidepressants versus placebo have increasingly struggled to find that "signal" related to active drug. Perhaps more importantly, several other studies that have examined actual suicides and/or suicide attempts from large databases have not shown links to the taking of antidepressants and, if anything, have suggested that untreated depression poses a greater risk (BMJ 2014;348:g3596). It is worth repeating that there still has never been an actual suicide in any of the antidepressant trials.

2. The efficacy of antidepressants also was overstated. As people began to examine more closely the issue of suicidal behavior and antidepressants, it became evident that there was much more data on this than was obvious from published studies. Many more trials of depression and antidepressants were performed, usually funded by pharmaceutical companies, and many of these trials did not show that antidepressants were superior to placebo (N. Engl. J. Med. 2008;358:252-60). As opposed to the positive trials, however, the negative ones tended not to be published or featured. Overall, it seems that about 60% of depressed children and adolescents respond to antidepressant medication, compared with 50% who respond to placebo.

3. The prescribing of antidepressants is making a comeback. After the 2004 warnings, the number of antidepressant prescriptions dropped. Since around 2008, however, the rate of antidepressant prescribing has increased again, although not at 2004 levels, according to some studies.

4. Antidepressants don’t work by fixing a serotonin "chemical imbalance." Although it is true that antidepressants result in more serotonin being available in brain synapses acutely, depression is not caused by a simple serotonin deficit. Medications likely work by changing the expression of certain genes that relate to how strongly particular brain pathways are connected. This process may explain why antidepressants take time to be effective.

5. Antidepressants actually work better for youths with anxiety rather than depression. More promising results with antidepressants have been found for children with anxiety disorder and obsessive-compulsive disorder (N. Engl. J. Med. 2008;359:2753-66). Although cognitive-behavior therapy remains the recommended first-line intervention for children with anxiety disorders, antidepressants have been shown to be effective both alone and in combination with cognitive-behavior therapy.

There is still much to learn. Children and adolescents who are extremely irritable, unmotivated, and at times suicidal are a diverse group of people whose difficulties can arise from many factors that deserve investigation. When it comes to antidepressants, it appears that both the amount of risk and the amount of benefit associated with this class of medications may be less than what was believed a decade ago.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. Dr. Rettew said he had no financial disclosures relevant to this article.

Case summary

Dylan is a bright and lively 10-year-old boy who has always been energetic and passionate. His parents have celebrated his exuberance but now have become concerned that there is "something more," after his teacher has needed to remove him from class for several episodes of impulsive and disruptive behavior. Further history reveals that, compared with his classmates, he can be quite distractible and often needs a lot of prompting and redirection to complete his work. Dylan is an intelligent child who has always managed to do well in school despite some longstanding challenges with attention. His performance has slipped somewhat as the academic load increases, although not to the point that he is in jeopardy of being held back.

At home, Dylan enjoys playing outside but also is drawn to video games, an activity that seems to hold his attention well. His parents get frustrated with needing to repeat requests several times and having to remind him to be quieter in the house.

Discussion

Attention-deficit/hyperactivity disorder, like all other psychiatric disorders, is defined in binary terms as being present or not-present. Nonetheless, it has become abundantly clear from research studies that the symptoms exist dimensionally and are normally distributed in a manner such as height. As such, diagnosing ADHD is analogous to diagnosing someone as being tall. Given this reality, how does a clinician figure out when a child really "has" a disorder, versus the behavior being "just" part of normal behavior?

All of the diagnostic criteria for ADHD include behaviors that at age-appropriate levels are considered completely normal. To qualify as a symptom that is present, the behaviors have to occur "often" and be inappropriate to the child’s developmental level. These subjective judgments about moving targets make drawing the line difficult for clinicians. Most children are well within normal limits and others are clearly beyond them, yet that leaves a sizable group somewhere in that middle "gray zone."

Making matters more complicated is the increasing but still insufficient evidence suggesting that this dimensionality exists when it comes to the underlying neurobiology of ADHD as well. In other words, the genes, environmental factors, brain regions, neurotransmitters, etc., that determine why a child has an average attention span or activity level are the same ones involved in ADHD. Such a revelation, however, in no way should be interpreted as ADHD being not "real," any more than other dimensional nonpsychiatric conditions (hypertension, hyperlipidemia).

This continuum of behaviors, however, does present a real diagnostic challenge. The inconvenient reality is that there really may not be any "true" rate of ADHD at 5%, 7%, or more recently, 11%. Many people make much of assessing whether or not there is associated impairment with the behaviors, but the truth of the matter is that impairment itself is dimensional.

Thus, we need to appreciate the complexities and limitations of this challenging diagnosis without throwing up our hands in frustration and giving up. After all, these problems can get significantly better with treatment. Here are a few tips to consider.

1. In making an ADHD diagnosis, use quantitative rating scales that appreciate this dimensional nature. Ideally, these instruments should be standardized by age and sex so that, for example, scores of 8-year-old boys can be compared to those of other 8-year-old boys. Don’t feel compelled to come up with a diagnosis on the spot if this procedure takes a little time in getting input from multiple people (parents, teachers, self-report).

2. Don’t stop investigating just because you arrive at an ADHD diagnosis. There are many factors that can result in a child struggling with these behaviors. Poor sleep, excessive screen time, inadequate nutrition, suboptimal parenting practices, exposures to lead and other substances, and lack of exercise are some factors that can underlie these problems. Correcting them can often make a big difference and in some cases can obviate the need for medication.

3. Approach a dimensional diagnosis with dimensional treatment. Just as many patients with borderline levels of hypertension or borderline glucose levels might be recommended to try nonpharmacological interventions first, the same principle can be applied to ADHD. Parent behavioral management, skills training, and addressing potential causes or exacerbating causes described in No. 2 can all provide important benefits.

The bottom line here, in my view, is to appreciate and respect the inherent blurriness of these boundaries without it leading to clinical paralysis. Children who struggle with inattention and hyperactivity are well known to be at risk for a variety of negative outcomes. Pediatricians have a large number of options to help these children that have been shown to be effective and can be individually tailored to each specific case.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych.

Case summary

Dylan is a bright and lively 10-year-old boy who has always been energetic and passionate. His parents have celebrated his exuberance but now have become concerned that there is "something more," after his teacher has needed to remove him from class for several episodes of impulsive and disruptive behavior. Further history reveals that, compared with his classmates, he can be quite distractible and often needs a lot of prompting and redirection to complete his work. Dylan is an intelligent child who has always managed to do well in school despite some longstanding challenges with attention. His performance has slipped somewhat as the academic load increases, although not to the point that he is in jeopardy of being held back.

At home, Dylan enjoys playing outside but also is drawn to video games, an activity that seems to hold his attention well. His parents get frustrated with needing to repeat requests several times and having to remind him to be quieter in the house.

Discussion

Attention-deficit/hyperactivity disorder, like all other psychiatric disorders, is defined in binary terms as being present or not-present. Nonetheless, it has become abundantly clear from research studies that the symptoms exist dimensionally and are normally distributed in a manner such as height. As such, diagnosing ADHD is analogous to diagnosing someone as being tall. Given this reality, how does a clinician figure out when a child really "has" a disorder, versus the behavior being "just" part of normal behavior?

All of the diagnostic criteria for ADHD include behaviors that at age-appropriate levels are considered completely normal. To qualify as a symptom that is present, the behaviors have to occur "often" and be inappropriate to the child’s developmental level. These subjective judgments about moving targets make drawing the line difficult for clinicians. Most children are well within normal limits and others are clearly beyond them, yet that leaves a sizable group somewhere in that middle "gray zone."

Making matters more complicated is the increasing but still insufficient evidence suggesting that this dimensionality exists when it comes to the underlying neurobiology of ADHD as well. In other words, the genes, environmental factors, brain regions, neurotransmitters, etc., that determine why a child has an average attention span or activity level are the same ones involved in ADHD. Such a revelation, however, in no way should be interpreted as ADHD being not "real," any more than other dimensional nonpsychiatric conditions (hypertension, hyperlipidemia).

This continuum of behaviors, however, does present a real diagnostic challenge. The inconvenient reality is that there really may not be any "true" rate of ADHD at 5%, 7%, or more recently, 11%. Many people make much of assessing whether or not there is associated impairment with the behaviors, but the truth of the matter is that impairment itself is dimensional.

Thus, we need to appreciate the complexities and limitations of this challenging diagnosis without throwing up our hands in frustration and giving up. After all, these problems can get significantly better with treatment. Here are a few tips to consider.

1. In making an ADHD diagnosis, use quantitative rating scales that appreciate this dimensional nature. Ideally, these instruments should be standardized by age and sex so that, for example, scores of 8-year-old boys can be compared to those of other 8-year-old boys. Don’t feel compelled to come up with a diagnosis on the spot if this procedure takes a little time in getting input from multiple people (parents, teachers, self-report).

2. Don’t stop investigating just because you arrive at an ADHD diagnosis. There are many factors that can result in a child struggling with these behaviors. Poor sleep, excessive screen time, inadequate nutrition, suboptimal parenting practices, exposures to lead and other substances, and lack of exercise are some factors that can underlie these problems. Correcting them can often make a big difference and in some cases can obviate the need for medication.

3. Approach a dimensional diagnosis with dimensional treatment. Just as many patients with borderline levels of hypertension or borderline glucose levels might be recommended to try nonpharmacological interventions first, the same principle can be applied to ADHD. Parent behavioral management, skills training, and addressing potential causes or exacerbating causes described in No. 2 can all provide important benefits.

The bottom line here, in my view, is to appreciate and respect the inherent blurriness of these boundaries without it leading to clinical paralysis. Children who struggle with inattention and hyperactivity are well known to be at risk for a variety of negative outcomes. Pediatricians have a large number of options to help these children that have been shown to be effective and can be individually tailored to each specific case.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych.

Case summary

Dylan is a bright and lively 10-year-old boy who has always been energetic and passionate. His parents have celebrated his exuberance but now have become concerned that there is "something more," after his teacher has needed to remove him from class for several episodes of impulsive and disruptive behavior. Further history reveals that, compared with his classmates, he can be quite distractible and often needs a lot of prompting and redirection to complete his work. Dylan is an intelligent child who has always managed to do well in school despite some longstanding challenges with attention. His performance has slipped somewhat as the academic load increases, although not to the point that he is in jeopardy of being held back.

At home, Dylan enjoys playing outside but also is drawn to video games, an activity that seems to hold his attention well. His parents get frustrated with needing to repeat requests several times and having to remind him to be quieter in the house.

Discussion

Attention-deficit/hyperactivity disorder, like all other psychiatric disorders, is defined in binary terms as being present or not-present. Nonetheless, it has become abundantly clear from research studies that the symptoms exist dimensionally and are normally distributed in a manner such as height. As such, diagnosing ADHD is analogous to diagnosing someone as being tall. Given this reality, how does a clinician figure out when a child really "has" a disorder, versus the behavior being "just" part of normal behavior?

All of the diagnostic criteria for ADHD include behaviors that at age-appropriate levels are considered completely normal. To qualify as a symptom that is present, the behaviors have to occur "often" and be inappropriate to the child’s developmental level. These subjective judgments about moving targets make drawing the line difficult for clinicians. Most children are well within normal limits and others are clearly beyond them, yet that leaves a sizable group somewhere in that middle "gray zone."

Making matters more complicated is the increasing but still insufficient evidence suggesting that this dimensionality exists when it comes to the underlying neurobiology of ADHD as well. In other words, the genes, environmental factors, brain regions, neurotransmitters, etc., that determine why a child has an average attention span or activity level are the same ones involved in ADHD. Such a revelation, however, in no way should be interpreted as ADHD being not "real," any more than other dimensional nonpsychiatric conditions (hypertension, hyperlipidemia).

This continuum of behaviors, however, does present a real diagnostic challenge. The inconvenient reality is that there really may not be any "true" rate of ADHD at 5%, 7%, or more recently, 11%. Many people make much of assessing whether or not there is associated impairment with the behaviors, but the truth of the matter is that impairment itself is dimensional.

Thus, we need to appreciate the complexities and limitations of this challenging diagnosis without throwing up our hands in frustration and giving up. After all, these problems can get significantly better with treatment. Here are a few tips to consider.

1. In making an ADHD diagnosis, use quantitative rating scales that appreciate this dimensional nature. Ideally, these instruments should be standardized by age and sex so that, for example, scores of 8-year-old boys can be compared to those of other 8-year-old boys. Don’t feel compelled to come up with a diagnosis on the spot if this procedure takes a little time in getting input from multiple people (parents, teachers, self-report).

2. Don’t stop investigating just because you arrive at an ADHD diagnosis. There are many factors that can result in a child struggling with these behaviors. Poor sleep, excessive screen time, inadequate nutrition, suboptimal parenting practices, exposures to lead and other substances, and lack of exercise are some factors that can underlie these problems. Correcting them can often make a big difference and in some cases can obviate the need for medication.

3. Approach a dimensional diagnosis with dimensional treatment. Just as many patients with borderline levels of hypertension or borderline glucose levels might be recommended to try nonpharmacological interventions first, the same principle can be applied to ADHD. Parent behavioral management, skills training, and addressing potential causes or exacerbating causes described in No. 2 can all provide important benefits.

The bottom line here, in my view, is to appreciate and respect the inherent blurriness of these boundaries without it leading to clinical paralysis. Children who struggle with inattention and hyperactivity are well known to be at risk for a variety of negative outcomes. Pediatricians have a large number of options to help these children that have been shown to be effective and can be individually tailored to each specific case.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych.

Case summary

Owen, an 8-year-old boy, is brought to his pediatrician by his mother. She has noticed that Owen is spending increasing amounts of time doing some repetitive behaviors such as counting to himself and needing to tap particular objects a specified number of times. Certain numbers seem to have special significance, and Owen has expressed some vague concern that something bad could happen if he does not do these behaviors. The rituals are starting to impact his schoolwork, as he often can get "stuck" during assignments. The mother is aware that many kids have some superstitions and wants to know if this is "something more."

Discussion

Obsessive-compulsive disorder (OCD) is a relatively common condition that can respond quite well to treatment. This case example outlines an approach that pediatricians can take to its diagnosis and management in a primary care setting.

Diagnosis

The diagnosis of OCD, according to DSM-5, requires the presence of distressing or impairing obsessions or compulsions. The definition didn’t change much from DSM-IV. Obsessions in children can revolve around things like contamination, disturbing thoughts of harm coming to others, sexual thoughts, or special numbers or words. Compulsions can include rituals with washing, checking, counting, arranging, and hoarding, among other behaviors.

When beginning to evaluate for possible OCD, it is important to talk to both the child and the parent, as it is common for parents to be unaware of the extent of the problem. An instrument called the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) is considered to be the standard in the quantitative assessment of OCD. The rating scale and checklist are easy to administer and appear to be in the public domain.

While the diagnosis is often fairly straightforward, it does take some time, and pediatricians should feel comfortable with the idea of not trying to do everything in one visit. Instead, consider scheduling another visit or two to obtain more time to do a careful assessment. During this evaluation, a couple questions are good to keep in mind.

1. Was a diagnosis of an autistic spectrum disorder missed? OCD behaviors are extremely common among children with autistic spectrum disorders. It might be worthwhile to make sure that the developmental history (pointing, babbling, social smile, odd mannerisms) doesn’t suggest the possibility of autism.

2. Could this be a case of a PANS? There remains discussion about the possibility of an autoimmune origin to some children with OCD. The previous term of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) has been changed to Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) to reflect a broader profile of behaviors and possible infectious triggers. While the idea remains debated in some circles, there may be value in making sure that there is not an infection lurking that should be treated.

Pearl

When querying about particular OCD symptoms, go through a list with a patient (such as provided on the CY-BOCS), and don’t rely on self-disclosure, as some symptoms, such as seeing violent or sexual images, can be quite disturbing to the child, who often won’t bring them up on his or her own.

Treatment

The recommended first-line treatment for OCD is a type of cognitive-behavioral therapy called exposure and response prevention (ERP). It is a structured form of therapy that involves patients unlearning the association that rituals are necessary in order for their fears not to be realized. While effective, the challenge is often finding a therapist with this type of training.

In many cases, it is reasonable to wait on medication treatment until after a course of ERP has been tried. For more severe cases, it is also reasonable to use both psychotherapy and medications at the same time. Some patients will say that the medication helps them do the work required in therapy.

When it comes to medications, there are a number of selective serotonin reuptake inhibitors (SSRIs) that have shown to be effective and have Food and Drug Administration approvals for pediatric OCD (for some reason that escapes me, many pharmaceutical companies have sought FDA approval for OCD and not other child psychiatric disorders). Fluoxetine, sertraline, and fluvoxamine all have FDA approval, in addition to the tricyclic clomipramine for use in refractory cases. As in all children, starting at a low dose is usually prudent (5-10 mg of fluoxetine, 12.5-25 mg of sertraline), but with OCD higher doses are often required for maximal response (more than 100 mg of sertraline or 40 mg of fluoxetine, depending on the patient’s age, size, and tolerance). It is also important to remember that the suicide warning present for the SSRIs also applies to children with anxiety disorders.

An overall treatment plan for an OCD patient, according to a previously discussed model for mental health treatment, might look like the following:

• Education. Discuss diagnosis of OCD with children and family. Let them know about support organizations such as the OC Foundation.

• Individual therapy. Referral to a cognitive-behavioral therapist for exposure and response prevention.

• Parents. Screen parents for their own OCD or other psychopathology and refer if positive. Parental guidance regarding how best to approach the child will occur within cognitive-behavioral therapy.

• School. (This is indicated if the child’s symptoms are affecting school.) Consider a request for evaluation at school to assess the need for a 504 or individualized education plan (IEP).

• Environment. Discuss minimizing OCD triggers at home.

• Medications. Begin fluoxetine 5 mg per day. Informed consent is important, including suicide warnings. (You might delay this step if a therapist is available to begin ERP first.)

• Follow-up should take place in 2 weeks, with a possible increase of fluoxetine to 10 mg and reassessment with CY-BOCS.

When to consult? Many patients with relatively uncomplicated OCD can be effectively managed in the primary care setting. Consultation may be useful for instances of poor treatment response, other occurring psychiatric disorders (such as autism, attention-deficit/hyperactivity disorder), family conflict and resistance, or diagnostic uncertainty with other conditions, such as a psychotic disorder.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He is the author of "Child Temperament: New Thinking About the Boundary between Traits and Illness." Follow him on Twitter @pedipsych.

Case summary

Owen, an 8-year-old boy, is brought to his pediatrician by his mother. She has noticed that Owen is spending increasing amounts of time doing some repetitive behaviors such as counting to himself and needing to tap particular objects a specified number of times. Certain numbers seem to have special significance, and Owen has expressed some vague concern that something bad could happen if he does not do these behaviors. The rituals are starting to impact his schoolwork, as he often can get "stuck" during assignments. The mother is aware that many kids have some superstitions and wants to know if this is "something more."

Discussion

Obsessive-compulsive disorder (OCD) is a relatively common condition that can respond quite well to treatment. This case example outlines an approach that pediatricians can take to its diagnosis and management in a primary care setting.

Diagnosis

The diagnosis of OCD, according to DSM-5, requires the presence of distressing or impairing obsessions or compulsions. The definition didn’t change much from DSM-IV. Obsessions in children can revolve around things like contamination, disturbing thoughts of harm coming to others, sexual thoughts, or special numbers or words. Compulsions can include rituals with washing, checking, counting, arranging, and hoarding, among other behaviors.

When beginning to evaluate for possible OCD, it is important to talk to both the child and the parent, as it is common for parents to be unaware of the extent of the problem. An instrument called the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) is considered to be the standard in the quantitative assessment of OCD. The rating scale and checklist are easy to administer and appear to be in the public domain.

While the diagnosis is often fairly straightforward, it does take some time, and pediatricians should feel comfortable with the idea of not trying to do everything in one visit. Instead, consider scheduling another visit or two to obtain more time to do a careful assessment. During this evaluation, a couple questions are good to keep in mind.

1. Was a diagnosis of an autistic spectrum disorder missed? OCD behaviors are extremely common among children with autistic spectrum disorders. It might be worthwhile to make sure that the developmental history (pointing, babbling, social smile, odd mannerisms) doesn’t suggest the possibility of autism.

2. Could this be a case of a PANS? There remains discussion about the possibility of an autoimmune origin to some children with OCD. The previous term of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) has been changed to Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) to reflect a broader profile of behaviors and possible infectious triggers. While the idea remains debated in some circles, there may be value in making sure that there is not an infection lurking that should be treated.

Pearl

When querying about particular OCD symptoms, go through a list with a patient (such as provided on the CY-BOCS), and don’t rely on self-disclosure, as some symptoms, such as seeing violent or sexual images, can be quite disturbing to the child, who often won’t bring them up on his or her own.

Treatment

The recommended first-line treatment for OCD is a type of cognitive-behavioral therapy called exposure and response prevention (ERP). It is a structured form of therapy that involves patients unlearning the association that rituals are necessary in order for their fears not to be realized. While effective, the challenge is often finding a therapist with this type of training.

In many cases, it is reasonable to wait on medication treatment until after a course of ERP has been tried. For more severe cases, it is also reasonable to use both psychotherapy and medications at the same time. Some patients will say that the medication helps them do the work required in therapy.

When it comes to medications, there are a number of selective serotonin reuptake inhibitors (SSRIs) that have shown to be effective and have Food and Drug Administration approvals for pediatric OCD (for some reason that escapes me, many pharmaceutical companies have sought FDA approval for OCD and not other child psychiatric disorders). Fluoxetine, sertraline, and fluvoxamine all have FDA approval, in addition to the tricyclic clomipramine for use in refractory cases. As in all children, starting at a low dose is usually prudent (5-10 mg of fluoxetine, 12.5-25 mg of sertraline), but with OCD higher doses are often required for maximal response (more than 100 mg of sertraline or 40 mg of fluoxetine, depending on the patient’s age, size, and tolerance). It is also important to remember that the suicide warning present for the SSRIs also applies to children with anxiety disorders.

An overall treatment plan for an OCD patient, according to a previously discussed model for mental health treatment, might look like the following:

• Education. Discuss diagnosis of OCD with children and family. Let them know about support organizations such as the OC Foundation.

• Individual therapy. Referral to a cognitive-behavioral therapist for exposure and response prevention.

• Parents. Screen parents for their own OCD or other psychopathology and refer if positive. Parental guidance regarding how best to approach the child will occur within cognitive-behavioral therapy.

• School. (This is indicated if the child’s symptoms are affecting school.) Consider a request for evaluation at school to assess the need for a 504 or individualized education plan (IEP).

• Environment. Discuss minimizing OCD triggers at home.

• Medications. Begin fluoxetine 5 mg per day. Informed consent is important, including suicide warnings. (You might delay this step if a therapist is available to begin ERP first.)

• Follow-up should take place in 2 weeks, with a possible increase of fluoxetine to 10 mg and reassessment with CY-BOCS.

When to consult? Many patients with relatively uncomplicated OCD can be effectively managed in the primary care setting. Consultation may be useful for instances of poor treatment response, other occurring psychiatric disorders (such as autism, attention-deficit/hyperactivity disorder), family conflict and resistance, or diagnostic uncertainty with other conditions, such as a psychotic disorder.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He is the author of "Child Temperament: New Thinking About the Boundary between Traits and Illness." Follow him on Twitter @pedipsych.

Case summary

Owen, an 8-year-old boy, is brought to his pediatrician by his mother. She has noticed that Owen is spending increasing amounts of time doing some repetitive behaviors such as counting to himself and needing to tap particular objects a specified number of times. Certain numbers seem to have special significance, and Owen has expressed some vague concern that something bad could happen if he does not do these behaviors. The rituals are starting to impact his schoolwork, as he often can get "stuck" during assignments. The mother is aware that many kids have some superstitions and wants to know if this is "something more."

Discussion

Obsessive-compulsive disorder (OCD) is a relatively common condition that can respond quite well to treatment. This case example outlines an approach that pediatricians can take to its diagnosis and management in a primary care setting.

Diagnosis

The diagnosis of OCD, according to DSM-5, requires the presence of distressing or impairing obsessions or compulsions. The definition didn’t change much from DSM-IV. Obsessions in children can revolve around things like contamination, disturbing thoughts of harm coming to others, sexual thoughts, or special numbers or words. Compulsions can include rituals with washing, checking, counting, arranging, and hoarding, among other behaviors.

When beginning to evaluate for possible OCD, it is important to talk to both the child and the parent, as it is common for parents to be unaware of the extent of the problem. An instrument called the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) is considered to be the standard in the quantitative assessment of OCD. The rating scale and checklist are easy to administer and appear to be in the public domain.

While the diagnosis is often fairly straightforward, it does take some time, and pediatricians should feel comfortable with the idea of not trying to do everything in one visit. Instead, consider scheduling another visit or two to obtain more time to do a careful assessment. During this evaluation, a couple questions are good to keep in mind.

1. Was a diagnosis of an autistic spectrum disorder missed? OCD behaviors are extremely common among children with autistic spectrum disorders. It might be worthwhile to make sure that the developmental history (pointing, babbling, social smile, odd mannerisms) doesn’t suggest the possibility of autism.

2. Could this be a case of a PANS? There remains discussion about the possibility of an autoimmune origin to some children with OCD. The previous term of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) has been changed to Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) to reflect a broader profile of behaviors and possible infectious triggers. While the idea remains debated in some circles, there may be value in making sure that there is not an infection lurking that should be treated.

Pearl

When querying about particular OCD symptoms, go through a list with a patient (such as provided on the CY-BOCS), and don’t rely on self-disclosure, as some symptoms, such as seeing violent or sexual images, can be quite disturbing to the child, who often won’t bring them up on his or her own.

Treatment

The recommended first-line treatment for OCD is a type of cognitive-behavioral therapy called exposure and response prevention (ERP). It is a structured form of therapy that involves patients unlearning the association that rituals are necessary in order for their fears not to be realized. While effective, the challenge is often finding a therapist with this type of training.

In many cases, it is reasonable to wait on medication treatment until after a course of ERP has been tried. For more severe cases, it is also reasonable to use both psychotherapy and medications at the same time. Some patients will say that the medication helps them do the work required in therapy.

When it comes to medications, there are a number of selective serotonin reuptake inhibitors (SSRIs) that have shown to be effective and have Food and Drug Administration approvals for pediatric OCD (for some reason that escapes me, many pharmaceutical companies have sought FDA approval for OCD and not other child psychiatric disorders). Fluoxetine, sertraline, and fluvoxamine all have FDA approval, in addition to the tricyclic clomipramine for use in refractory cases. As in all children, starting at a low dose is usually prudent (5-10 mg of fluoxetine, 12.5-25 mg of sertraline), but with OCD higher doses are often required for maximal response (more than 100 mg of sertraline or 40 mg of fluoxetine, depending on the patient’s age, size, and tolerance). It is also important to remember that the suicide warning present for the SSRIs also applies to children with anxiety disorders.

An overall treatment plan for an OCD patient, according to a previously discussed model for mental health treatment, might look like the following:

• Education. Discuss diagnosis of OCD with children and family. Let them know about support organizations such as the OC Foundation.

• Individual therapy. Referral to a cognitive-behavioral therapist for exposure and response prevention.

• Parents. Screen parents for their own OCD or other psychopathology and refer if positive. Parental guidance regarding how best to approach the child will occur within cognitive-behavioral therapy.

• School. (This is indicated if the child’s symptoms are affecting school.) Consider a request for evaluation at school to assess the need for a 504 or individualized education plan (IEP).

• Environment. Discuss minimizing OCD triggers at home.

• Medications. Begin fluoxetine 5 mg per day. Informed consent is important, including suicide warnings. (You might delay this step if a therapist is available to begin ERP first.)

• Follow-up should take place in 2 weeks, with a possible increase of fluoxetine to 10 mg and reassessment with CY-BOCS.

When to consult? Many patients with relatively uncomplicated OCD can be effectively managed in the primary care setting. Consultation may be useful for instances of poor treatment response, other occurring psychiatric disorders (such as autism, attention-deficit/hyperactivity disorder), family conflict and resistance, or diagnostic uncertainty with other conditions, such as a psychotic disorder.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He is the author of "Child Temperament: New Thinking About the Boundary between Traits and Illness." Follow him on Twitter @pedipsych.

Doctor examining a child

Credit: Logan Tuttle

Weekend hospitalization can have its pitfalls, according to a study of pediatric patients newly diagnosed with leukemia.

Patients who were admitted to the hospital over the weekend had a longer length of stay, a slightly longer wait to start chemotherapy, and a higher risk for respiratory failure than patients admitted during the week.

Elizabeth K. Goodman, of the Children’s Hospital of Philadelphia, and her colleagues reported these results in JAMA Pediatrics.

The team examined adverse clinical outcomes associated with a weekend admission for the first hospitalization of pediatric patients newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

The researchers used data from the Pediatric Health Information System database, which included patients admitted to 43 children’s hospitals from 1999 through 2011.

There were 10,720 patients with ALL and 1323 with AML. Roughly 17% of these patients (n=2009) were admitted to the hospital on the weekend.

Patients hospitalized on the weekend were similar to those hospitalized during the week with regard to disease type and sex. However, weekend admissions had significantly higher percentages of patients who were younger than 5 years of age, of nonwhite race/ethnicity, and publicly insured.

Patients admitted on the weekend were also more likely to be severely ill. They were significantly more likely to require ICU-level care within the first 2 days of admission (4.8% vs 3.1%, P<0.001).

An unadjusted analysis showed that inpatient mortality was similar for patients admitted to the hospital during the week and on the weekend (0.8% and 1.0%, respectively).

However, patients admitted on the weekend had a significantly longer mean hospital stay (17.8 vs 15.8 days, P<0.001) and a longer mean wait time for chemotherapy (3.9 vs 3.5 days, P<0.001).

Patients admitted on the weekend also had an increased risk of cardiovascular failure (6.4% vs 5.0%, P=0.01), respiratory failure (8.5% vs 5.7%, P<0.001), and andrenal failure (10.2% vs 8.3%, P=0.01).

However, some of these results changed when the researchers adjusted for demographic variables (disease, sex, age, race/ethnicity, and insurance), the presence of severe illness at admission, and hospital-level factors (presence of a fellowship program, Magnet status, percentage of public payers per admissions per hospital per year, and number of oncology admissions per hospital per year).

In the adjusted analysis, weekend admission remained associated with an increase in the length of hospital stay (1.4 days) and an increase in the time to chemotherapy (0.4 days).

Weekend admission also remained associated with an increased risk of respiratory failure (odds ratio, 1.5), but it was no longer associated with an increased risk of cardiovascular or renal failure.

The researchers said these findings highlight a potential area for improvement in patient care and cost reduction. Increasing weekend resources could help reduce patients’ length of stay and ensure they receive comprehensive care.

On the other hand, it might also raise hospital expenditures without decreasing negative outcomes. So additional research is needed to determine the most clinically and cost-effective combination of hospital resources to reduce the length of stay and improve outcomes for pediatric leukemia patients.

An editorial related to this study is available in JAMA Pediatrics.

Doctor examining a child

Credit: Logan Tuttle

Weekend hospitalization can have its pitfalls, according to a study of pediatric patients newly diagnosed with leukemia.

Patients who were admitted to the hospital over the weekend had a longer length of stay, a slightly longer wait to start chemotherapy, and a higher risk for respiratory failure than patients admitted during the week.

Elizabeth K. Goodman, of the Children’s Hospital of Philadelphia, and her colleagues reported these results in JAMA Pediatrics.

The team examined adverse clinical outcomes associated with a weekend admission for the first hospitalization of pediatric patients newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

The researchers used data from the Pediatric Health Information System database, which included patients admitted to 43 children’s hospitals from 1999 through 2011.

There were 10,720 patients with ALL and 1323 with AML. Roughly 17% of these patients (n=2009) were admitted to the hospital on the weekend.

Patients hospitalized on the weekend were similar to those hospitalized during the week with regard to disease type and sex. However, weekend admissions had significantly higher percentages of patients who were younger than 5 years of age, of nonwhite race/ethnicity, and publicly insured.

Patients admitted on the weekend were also more likely to be severely ill. They were significantly more likely to require ICU-level care within the first 2 days of admission (4.8% vs 3.1%, P<0.001).

An unadjusted analysis showed that inpatient mortality was similar for patients admitted to the hospital during the week and on the weekend (0.8% and 1.0%, respectively).

However, patients admitted on the weekend had a significantly longer mean hospital stay (17.8 vs 15.8 days, P<0.001) and a longer mean wait time for chemotherapy (3.9 vs 3.5 days, P<0.001).

Patients admitted on the weekend also had an increased risk of cardiovascular failure (6.4% vs 5.0%, P=0.01), respiratory failure (8.5% vs 5.7%, P<0.001), and andrenal failure (10.2% vs 8.3%, P=0.01).

However, some of these results changed when the researchers adjusted for demographic variables (disease, sex, age, race/ethnicity, and insurance), the presence of severe illness at admission, and hospital-level factors (presence of a fellowship program, Magnet status, percentage of public payers per admissions per hospital per year, and number of oncology admissions per hospital per year).

In the adjusted analysis, weekend admission remained associated with an increase in the length of hospital stay (1.4 days) and an increase in the time to chemotherapy (0.4 days).

Weekend admission also remained associated with an increased risk of respiratory failure (odds ratio, 1.5), but it was no longer associated with an increased risk of cardiovascular or renal failure.

The researchers said these findings highlight a potential area for improvement in patient care and cost reduction. Increasing weekend resources could help reduce patients’ length of stay and ensure they receive comprehensive care.

On the other hand, it might also raise hospital expenditures without decreasing negative outcomes. So additional research is needed to determine the most clinically and cost-effective combination of hospital resources to reduce the length of stay and improve outcomes for pediatric leukemia patients.

An editorial related to this study is available in JAMA Pediatrics.

Doctor examining a child

Credit: Logan Tuttle

Weekend hospitalization can have its pitfalls, according to a study of pediatric patients newly diagnosed with leukemia.

Patients who were admitted to the hospital over the weekend had a longer length of stay, a slightly longer wait to start chemotherapy, and a higher risk for respiratory failure than patients admitted during the week.

Elizabeth K. Goodman, of the Children’s Hospital of Philadelphia, and her colleagues reported these results in JAMA Pediatrics.

The team examined adverse clinical outcomes associated with a weekend admission for the first hospitalization of pediatric patients newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

The researchers used data from the Pediatric Health Information System database, which included patients admitted to 43 children’s hospitals from 1999 through 2011.

There were 10,720 patients with ALL and 1323 with AML. Roughly 17% of these patients (n=2009) were admitted to the hospital on the weekend.

Patients hospitalized on the weekend were similar to those hospitalized during the week with regard to disease type and sex. However, weekend admissions had significantly higher percentages of patients who were younger than 5 years of age, of nonwhite race/ethnicity, and publicly insured.

Patients admitted on the weekend were also more likely to be severely ill. They were significantly more likely to require ICU-level care within the first 2 days of admission (4.8% vs 3.1%, P<0.001).

An unadjusted analysis showed that inpatient mortality was similar for patients admitted to the hospital during the week and on the weekend (0.8% and 1.0%, respectively).

However, patients admitted on the weekend had a significantly longer mean hospital stay (17.8 vs 15.8 days, P<0.001) and a longer mean wait time for chemotherapy (3.9 vs 3.5 days, P<0.001).

Patients admitted on the weekend also had an increased risk of cardiovascular failure (6.4% vs 5.0%, P=0.01), respiratory failure (8.5% vs 5.7%, P<0.001), and andrenal failure (10.2% vs 8.3%, P=0.01).

However, some of these results changed when the researchers adjusted for demographic variables (disease, sex, age, race/ethnicity, and insurance), the presence of severe illness at admission, and hospital-level factors (presence of a fellowship program, Magnet status, percentage of public payers per admissions per hospital per year, and number of oncology admissions per hospital per year).

In the adjusted analysis, weekend admission remained associated with an increase in the length of hospital stay (1.4 days) and an increase in the time to chemotherapy (0.4 days).

Weekend admission also remained associated with an increased risk of respiratory failure (odds ratio, 1.5), but it was no longer associated with an increased risk of cardiovascular or renal failure.

The researchers said these findings highlight a potential area for improvement in patient care and cost reduction. Increasing weekend resources could help reduce patients’ length of stay and ensure they receive comprehensive care.

On the other hand, it might also raise hospital expenditures without decreasing negative outcomes. So additional research is needed to determine the most clinically and cost-effective combination of hospital resources to reduce the length of stay and improve outcomes for pediatric leukemia patients.

An editorial related to this study is available in JAMA Pediatrics.

The US Food and Drug Administration (FDA) has approved eltrombopag (Promacta) for use in patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

Eltrombopag is an oral thrombopoietin receptor agonist that helps to induce the proliferation and differentiation of hematopoietic stem cells to increase blood cell production.

Eltrombopag is already FDA approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The drug is also approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.

The latest FDA approval is based on results from an investigator-sponsored phase 2 study (09-H-0154) conducted by the National Heart, Lung and Blood Institute. Results of this trial were previously published in The New England Journal of Medicine.

Eltrombopag in SAA: Latest trial results

In this study, researchers evaluated eltrombopag in 43 SAA patients who had an insufficient response to at least 1 prior IST and a platelet count of 30 x 10⁹/L or less.

At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, the absolute neutrophil count was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L.

Patients had a median age of 45 years (range, 17 to 77 years), and 56% were male. The majority of patients (84%) received at least 2 prior ISTs.

Patients received eltrombopag at an initial dose of 50 mg once daily for 2 weeks. The dose increased over 2-week periods to a maximum of 150 mg once daily.

The study’s primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment. Treatment was discontinued after 16 weeks in patients who did not exhibit a hematologic response.

Forty percent of patients (N=17) experienced a hematologic response in at least one lineage—platelets, red blood cells (RBCs), or white blood cells—after week 12.

In the extension phase of the study, 8 patients achieved a multilineage response. Four of these patients subsequently tapered off treatment and maintained the response. The median follow up was 8.1 months (range, 7.2 to 10.6 months).

Ninety-one percent of patients were platelet-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require platelet transfusions for a median of 200 days (range, 8 to 1096 days).

Eighty-six percent of patients were RBC-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require RBC transfusions for a median of 208 days (range, 15 to 1082 days).

The most common adverse events (≥20%) associated with eltrombopag were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).

Patients also had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality after treatment, including 5 patients who had complex changes in chromosome 7.

Patients who develop new cytogenetic abnormalities while on eltrombopag may need to be taken off treatment.

Eltrombopag is marketed by GlaxoSmithKline under the brand name Promacta in the US and Revolade in most other countries. For more information on eltrombopag, see the prescribing information.

The US Food and Drug Administration (FDA) has approved eltrombopag (Promacta) for use in patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

Eltrombopag is an oral thrombopoietin receptor agonist that helps to induce the proliferation and differentiation of hematopoietic stem cells to increase blood cell production.

Eltrombopag is already FDA approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The drug is also approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.

The latest FDA approval is based on results from an investigator-sponsored phase 2 study (09-H-0154) conducted by the National Heart, Lung and Blood Institute. Results of this trial were previously published in The New England Journal of Medicine.

Eltrombopag in SAA: Latest trial results

In this study, researchers evaluated eltrombopag in 43 SAA patients who had an insufficient response to at least 1 prior IST and a platelet count of 30 x 10⁹/L or less.

At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, the absolute neutrophil count was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L.

Patients had a median age of 45 years (range, 17 to 77 years), and 56% were male. The majority of patients (84%) received at least 2 prior ISTs.

Patients received eltrombopag at an initial dose of 50 mg once daily for 2 weeks. The dose increased over 2-week periods to a maximum of 150 mg once daily.

The study’s primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment. Treatment was discontinued after 16 weeks in patients who did not exhibit a hematologic response.

Forty percent of patients (N=17) experienced a hematologic response in at least one lineage—platelets, red blood cells (RBCs), or white blood cells—after week 12.

In the extension phase of the study, 8 patients achieved a multilineage response. Four of these patients subsequently tapered off treatment and maintained the response. The median follow up was 8.1 months (range, 7.2 to 10.6 months).

Ninety-one percent of patients were platelet-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require platelet transfusions for a median of 200 days (range, 8 to 1096 days).

Eighty-six percent of patients were RBC-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require RBC transfusions for a median of 208 days (range, 15 to 1082 days).

The most common adverse events (≥20%) associated with eltrombopag were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).

Patients also had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality after treatment, including 5 patients who had complex changes in chromosome 7.

Patients who develop new cytogenetic abnormalities while on eltrombopag may need to be taken off treatment.

Eltrombopag is marketed by GlaxoSmithKline under the brand name Promacta in the US and Revolade in most other countries. For more information on eltrombopag, see the prescribing information.

The US Food and Drug Administration (FDA) has approved eltrombopag (Promacta) for use in patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

Eltrombopag is an oral thrombopoietin receptor agonist that helps to induce the proliferation and differentiation of hematopoietic stem cells to increase blood cell production.

Eltrombopag is already FDA approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The drug is also approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.

The latest FDA approval is based on results from an investigator-sponsored phase 2 study (09-H-0154) conducted by the National Heart, Lung and Blood Institute. Results of this trial were previously published in The New England Journal of Medicine.

Eltrombopag in SAA: Latest trial results

In this study, researchers evaluated eltrombopag in 43 SAA patients who had an insufficient response to at least 1 prior IST and a platelet count of 30 x 10⁹/L or less.

At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, the absolute neutrophil count was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L.

Patients had a median age of 45 years (range, 17 to 77 years), and 56% were male. The majority of patients (84%) received at least 2 prior ISTs.

Patients received eltrombopag at an initial dose of 50 mg once daily for 2 weeks. The dose increased over 2-week periods to a maximum of 150 mg once daily.

The study’s primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment. Treatment was discontinued after 16 weeks in patients who did not exhibit a hematologic response.

Forty percent of patients (N=17) experienced a hematologic response in at least one lineage—platelets, red blood cells (RBCs), or white blood cells—after week 12.

In the extension phase of the study, 8 patients achieved a multilineage response. Four of these patients subsequently tapered off treatment and maintained the response. The median follow up was 8.1 months (range, 7.2 to 10.6 months).

Ninety-one percent of patients were platelet-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require platelet transfusions for a median of 200 days (range, 8 to 1096 days).

Eighty-six percent of patients were RBC-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require RBC transfusions for a median of 208 days (range, 15 to 1082 days).

The most common adverse events (≥20%) associated with eltrombopag were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).

Patients also had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality after treatment, including 5 patients who had complex changes in chromosome 7.

Patients who develop new cytogenetic abnormalities while on eltrombopag may need to be taken off treatment.

Eltrombopag is marketed by GlaxoSmithKline under the brand name Promacta in the US and Revolade in most other countries. For more information on eltrombopag, see the prescribing information.

Sleeping infant

Credit: Bertrand Devouard

Erythropoietin (EPO) can reduce the risk of brain injury in preterm infants, a new study suggests.

Infants who received 3 doses of EPO within 42 hours of birth were less likely than their untreated peers to have abnormal scores for white matter injury, white matter signal intensity, periventricular white matter loss, and gray matter injury.

Russia Ha-Vinh Leuchter, MD, of the University Hospital of Geneva in Switzerland, and her colleagues recounted these findings in JAMA.

The researchers evaluated 495 infants who were born in Switzerland between 2005 and 2012—at 26 weeks of gestation to 31 weeks and 6 days of gestation.

The children were randomized to receive EPO (n=256) or placebo (n=239) intravenously at 3 time points: before they reached 3 hours of age, at 12 to 18 hours after birth, and at 36 to 42 hours after birth.

Due to the limited availability of MRI, the researchers were only able to assess brain injury in a nonrandomized subset of 165 infants. Seventy-seven of these children received EPO, and 88 received placebo.

The patients underwent MRI at a median gestation age of 40 weeks and 5 days (range, 35 weeks and 5 days to 44 weeks and 6 days).

“We found that the brains of the children who had received the treatment had much less damage than those in the control group,” Dr Ha-Vinh Leuchter said. “This is the first time that the beneficial effect of the EPO hormone on the brains of premature babies has been shown.”

Specifically, the results showed that, at term-equivalent age, infants treated with EPO were less likely than controls to have abnormal scores for white matter injury (22% vs 36%), white matter signal intensity (3% vs 11%), periventricular white matter loss (18% vs 33%), and gray matter injury (7% vs 19%).

These results are only the first part of this study, according to the researchers. The second—and main—part of the work will focus on the neurocognitive development of these children, who will take part in various developmental tests at 2 and 5 years of age.

“[The tests] should confirm the effect that EPO treatment has on the neurodevelopmental disabilities that very premature babies often show during their infancy,” said Petra Hüppi, MD, also of the University Hospital of Geneva.

“If this does turn out to be the case, we will have taken an important step in preventing brain damage and its long-term consequences in premature babies.”

Sleeping infant

Credit: Bertrand Devouard

Erythropoietin (EPO) can reduce the risk of brain injury in preterm infants, a new study suggests.

Infants who received 3 doses of EPO within 42 hours of birth were less likely than their untreated peers to have abnormal scores for white matter injury, white matter signal intensity, periventricular white matter loss, and gray matter injury.

Russia Ha-Vinh Leuchter, MD, of the University Hospital of Geneva in Switzerland, and her colleagues recounted these findings in JAMA.

The researchers evaluated 495 infants who were born in Switzerland between 2005 and 2012—at 26 weeks of gestation to 31 weeks and 6 days of gestation.

The children were randomized to receive EPO (n=256) or placebo (n=239) intravenously at 3 time points: before they reached 3 hours of age, at 12 to 18 hours after birth, and at 36 to 42 hours after birth.

Due to the limited availability of MRI, the researchers were only able to assess brain injury in a nonrandomized subset of 165 infants. Seventy-seven of these children received EPO, and 88 received placebo.

The patients underwent MRI at a median gestation age of 40 weeks and 5 days (range, 35 weeks and 5 days to 44 weeks and 6 days).

“We found that the brains of the children who had received the treatment had much less damage than those in the control group,” Dr Ha-Vinh Leuchter said. “This is the first time that the beneficial effect of the EPO hormone on the brains of premature babies has been shown.”

Specifically, the results showed that, at term-equivalent age, infants treated with EPO were less likely than controls to have abnormal scores for white matter injury (22% vs 36%), white matter signal intensity (3% vs 11%), periventricular white matter loss (18% vs 33%), and gray matter injury (7% vs 19%).

These results are only the first part of this study, according to the researchers. The second—and main—part of the work will focus on the neurocognitive development of these children, who will take part in various developmental tests at 2 and 5 years of age.

“[The tests] should confirm the effect that EPO treatment has on the neurodevelopmental disabilities that very premature babies often show during their infancy,” said Petra Hüppi, MD, also of the University Hospital of Geneva.

“If this does turn out to be the case, we will have taken an important step in preventing brain damage and its long-term consequences in premature babies.”

Sleeping infant

Credit: Bertrand Devouard

Erythropoietin (EPO) can reduce the risk of brain injury in preterm infants, a new study suggests.

Infants who received 3 doses of EPO within 42 hours of birth were less likely than their untreated peers to have abnormal scores for white matter injury, white matter signal intensity, periventricular white matter loss, and gray matter injury.

Russia Ha-Vinh Leuchter, MD, of the University Hospital of Geneva in Switzerland, and her colleagues recounted these findings in JAMA.

The researchers evaluated 495 infants who were born in Switzerland between 2005 and 2012—at 26 weeks of gestation to 31 weeks and 6 days of gestation.

The children were randomized to receive EPO (n=256) or placebo (n=239) intravenously at 3 time points: before they reached 3 hours of age, at 12 to 18 hours after birth, and at 36 to 42 hours after birth.

Due to the limited availability of MRI, the researchers were only able to assess brain injury in a nonrandomized subset of 165 infants. Seventy-seven of these children received EPO, and 88 received placebo.

The patients underwent MRI at a median gestation age of 40 weeks and 5 days (range, 35 weeks and 5 days to 44 weeks and 6 days).

“We found that the brains of the children who had received the treatment had much less damage than those in the control group,” Dr Ha-Vinh Leuchter said. “This is the first time that the beneficial effect of the EPO hormone on the brains of premature babies has been shown.”

Specifically, the results showed that, at term-equivalent age, infants treated with EPO were less likely than controls to have abnormal scores for white matter injury (22% vs 36%), white matter signal intensity (3% vs 11%), periventricular white matter loss (18% vs 33%), and gray matter injury (7% vs 19%).

These results are only the first part of this study, according to the researchers. The second—and main—part of the work will focus on the neurocognitive development of these children, who will take part in various developmental tests at 2 and 5 years of age.

“[The tests] should confirm the effect that EPO treatment has on the neurodevelopmental disabilities that very premature babies often show during their infancy,” said Petra Hüppi, MD, also of the University Hospital of Geneva.

“If this does turn out to be the case, we will have taken an important step in preventing brain damage and its long-term consequences in premature babies.”

Thrombus

Credit: Andre E.X. Brown

Regado Biosciences, Inc., has permanently terminated enrollment in the phase 3 REGULATE-PCI trial due to serious allergic reactions in patients treated with the Revolixys Kit (also known as REG-1).

The kit is a 2-component system consisting of pegnivacogin, an anticoagulant aptamer specifically targeting coagulation factor IXa, and its complementary oligonucleotide active control agent, anivamersen.

The REGULATE-PCI trial is a comparison of the Revolixys Kit and bivilarudin in patients undergoing percutaneous coronary intervention.

A data and safety monitoring board analyzed data from the roughly 3250 patients initially enrolled in the trial and discovered serious allergic reactions in patients treated with Revolixys.

“The [board] indicated that the level of serious allergic adverse events associated with Revolixys was of a frequency and severity such that they recommended that we do not enroll any further patients in the REGULATE-PCI trial,” said David J. Mazzo, PhD, CEO of Regado.

“We will now undertake a complete review of the unblinded database from REGULATE-PCI, which we expect will take several months to complete.”

Dr Mazzo did not provide details as to the type of allergic reactions patients experienced or the incidence of these events. He did say the exact cause of the reactions is unknown, but the data review and investigation should reveal that information.

The review should also provide information that will help Regado decide how to move forward with its development of Revolixys (REG-1) and a related system known as REG-2.

For more information on REG-1 and REG-2, visit Regado’s website.  For more information on REGULATE-PCI, visit clinicaltrials.gov.

Thrombus

Credit: Andre E.X. Brown

Regado Biosciences, Inc., has permanently terminated enrollment in the phase 3 REGULATE-PCI trial due to serious allergic reactions in patients treated with the Revolixys Kit (also known as REG-1).

The kit is a 2-component system consisting of pegnivacogin, an anticoagulant aptamer specifically targeting coagulation factor IXa, and its complementary oligonucleotide active control agent, anivamersen.

The REGULATE-PCI trial is a comparison of the Revolixys Kit and bivilarudin in patients undergoing percutaneous coronary intervention.

A data and safety monitoring board analyzed data from the roughly 3250 patients initially enrolled in the trial and discovered serious allergic reactions in patients treated with Revolixys.

“The [board] indicated that the level of serious allergic adverse events associated with Revolixys was of a frequency and severity such that they recommended that we do not enroll any further patients in the REGULATE-PCI trial,” said David J. Mazzo, PhD, CEO of Regado.

“We will now undertake a complete review of the unblinded database from REGULATE-PCI, which we expect will take several months to complete.”

Dr Mazzo did not provide details as to the type of allergic reactions patients experienced or the incidence of these events. He did say the exact cause of the reactions is unknown, but the data review and investigation should reveal that information.

The review should also provide information that will help Regado decide how to move forward with its development of Revolixys (REG-1) and a related system known as REG-2.

For more information on REG-1 and REG-2, visit Regado’s website.  For more information on REGULATE-PCI, visit clinicaltrials.gov.

Thrombus

Credit: Andre E.X. Brown

Regado Biosciences, Inc., has permanently terminated enrollment in the phase 3 REGULATE-PCI trial due to serious allergic reactions in patients treated with the Revolixys Kit (also known as REG-1).

The kit is a 2-component system consisting of pegnivacogin, an anticoagulant aptamer specifically targeting coagulation factor IXa, and its complementary oligonucleotide active control agent, anivamersen.

The REGULATE-PCI trial is a comparison of the Revolixys Kit and bivilarudin in patients undergoing percutaneous coronary intervention.

A data and safety monitoring board analyzed data from the roughly 3250 patients initially enrolled in the trial and discovered serious allergic reactions in patients treated with Revolixys.

“The [board] indicated that the level of serious allergic adverse events associated with Revolixys was of a frequency and severity such that they recommended that we do not enroll any further patients in the REGULATE-PCI trial,” said David J. Mazzo, PhD, CEO of Regado.

“We will now undertake a complete review of the unblinded database from REGULATE-PCI, which we expect will take several months to complete.”

Dr Mazzo did not provide details as to the type of allergic reactions patients experienced or the incidence of these events. He did say the exact cause of the reactions is unknown, but the data review and investigation should reveal that information.

The review should also provide information that will help Regado decide how to move forward with its development of Revolixys (REG-1) and a related system known as REG-2.

For more information on REG-1 and REG-2, visit Regado’s website.  For more information on REGULATE-PCI, visit clinicaltrials.gov.

SAN FRANCISCO – The indication for liver transplant, the selection of immunosuppression therapy, and smoking status influence the long-term risk of new solid organ malignancies after liver transplantation, Dr. Sebastian Rademacher reported at the 2014 World Transplant Congress.

Multivariate analysis showed that recipients’ risk of a new solid organ cancer was elevated for those who had a history of smoking (1.89). Risk was reduced for recipients who received tacrolimus, compared with cyclosporine A (0.56), and for patients who had primary biliary cirrhosis/primary sclerosing cholangitis (0.47) or hepatitis C infection (0.21) as the indication for transplantation.

"I think we have to reoptimize and reevaluate the currently used immunosuppressive regimens," Dr. Rademacher said. "We have to adapt cancer surveillance programs for high-risk patients. Further studies into surveillance protocols and surrogate markers and long-term outcomes are recommended."

Researchers led by Dr. Rademacher, a surgeon at the Campus Virchow Clinic, Charité, Berlin, retrospectively studied 1,179 consecutive adults who underwent liver transplantation between 1988 and 2002 and had follow-up evaluations until 2013. Patients were 47 years old, on average, at the time of transplantation, and the median follow-up was 13.3 years.

Their 20-year cumulative incidence of solid organ cancers was 14%, he reported at the congress, which was sponsored by the American Society of Transplant Surgeons. The mean age at cancer diagnosis was 56 years.

The researchers used age- and sex-matched individuals from the German general population for comparison. The standardized incidence ratio in transplant recipients was 1.2 for breast cancer, 9.4 for cancer of the oropharynx and larynx, 1.7 for cancers of the colon and rectum, 3.0 for lung cancer, 3.9 for esophageal and stomach cancers, 4.5 for kidney and bladder cancers, and 4.6 for cancers of the female genitourinary system.

"We tried to evaluate the different immunosuppressive regimens and, over time, we had, I think, 27 different primary regimens," Dr. Rademacher said. Steroid-free regimens and low-dose steroid were part of that consideration, "but we segregated them out. For the five most frequent regimens, there was no significance. We assessed immunosuppressive regimens given over at least 2 years, but there was no difference between the regimens. Also, the trough levels of tacrolimus did not have any significant influence," he said.

The investigators did not have data on cumulative immunosuppression or mTOR [mammalian target of rapamycin] inhibitors, which were introduced late in the study period, according to Dr. Rademacher, who disclosed no relevant conflicts of interest. A surrogate marker of immunosuppression, rejection frequency, did not significantly predict the development of solid organ malignancies.

SAN FRANCISCO – The indication for liver transplant, the selection of immunosuppression therapy, and smoking status influence the long-term risk of new solid organ malignancies after liver transplantation, Dr. Sebastian Rademacher reported at the 2014 World Transplant Congress.

Multivariate analysis showed that recipients’ risk of a new solid organ cancer was elevated for those who had a history of smoking (1.89). Risk was reduced for recipients who received tacrolimus, compared with cyclosporine A (0.56), and for patients who had primary biliary cirrhosis/primary sclerosing cholangitis (0.47) or hepatitis C infection (0.21) as the indication for transplantation.

"I think we have to reoptimize and reevaluate the currently used immunosuppressive regimens," Dr. Rademacher said. "We have to adapt cancer surveillance programs for high-risk patients. Further studies into surveillance protocols and surrogate markers and long-term outcomes are recommended."

Researchers led by Dr. Rademacher, a surgeon at the Campus Virchow Clinic, Charité, Berlin, retrospectively studied 1,179 consecutive adults who underwent liver transplantation between 1988 and 2002 and had follow-up evaluations until 2013. Patients were 47 years old, on average, at the time of transplantation, and the median follow-up was 13.3 years.

Their 20-year cumulative incidence of solid organ cancers was 14%, he reported at the congress, which was sponsored by the American Society of Transplant Surgeons. The mean age at cancer diagnosis was 56 years.

The researchers used age- and sex-matched individuals from the German general population for comparison. The standardized incidence ratio in transplant recipients was 1.2 for breast cancer, 9.4 for cancer of the oropharynx and larynx, 1.7 for cancers of the colon and rectum, 3.0 for lung cancer, 3.9 for esophageal and stomach cancers, 4.5 for kidney and bladder cancers, and 4.6 for cancers of the female genitourinary system.

"We tried to evaluate the different immunosuppressive regimens and, over time, we had, I think, 27 different primary regimens," Dr. Rademacher said. Steroid-free regimens and low-dose steroid were part of that consideration, "but we segregated them out. For the five most frequent regimens, there was no significance. We assessed immunosuppressive regimens given over at least 2 years, but there was no difference between the regimens. Also, the trough levels of tacrolimus did not have any significant influence," he said.

The investigators did not have data on cumulative immunosuppression or mTOR [mammalian target of rapamycin] inhibitors, which were introduced late in the study period, according to Dr. Rademacher, who disclosed no relevant conflicts of interest. A surrogate marker of immunosuppression, rejection frequency, did not significantly predict the development of solid organ malignancies.

SAN FRANCISCO – The indication for liver transplant, the selection of immunosuppression therapy, and smoking status influence the long-term risk of new solid organ malignancies after liver transplantation, Dr. Sebastian Rademacher reported at the 2014 World Transplant Congress.

Multivariate analysis showed that recipients’ risk of a new solid organ cancer was elevated for those who had a history of smoking (1.89). Risk was reduced for recipients who received tacrolimus, compared with cyclosporine A (0.56), and for patients who had primary biliary cirrhosis/primary sclerosing cholangitis (0.47) or hepatitis C infection (0.21) as the indication for transplantation.

"I think we have to reoptimize and reevaluate the currently used immunosuppressive regimens," Dr. Rademacher said. "We have to adapt cancer surveillance programs for high-risk patients. Further studies into surveillance protocols and surrogate markers and long-term outcomes are recommended."

Researchers led by Dr. Rademacher, a surgeon at the Campus Virchow Clinic, Charité, Berlin, retrospectively studied 1,179 consecutive adults who underwent liver transplantation between 1988 and 2002 and had follow-up evaluations until 2013. Patients were 47 years old, on average, at the time of transplantation, and the median follow-up was 13.3 years.

Their 20-year cumulative incidence of solid organ cancers was 14%, he reported at the congress, which was sponsored by the American Society of Transplant Surgeons. The mean age at cancer diagnosis was 56 years.

The researchers used age- and sex-matched individuals from the German general population for comparison. The standardized incidence ratio in transplant recipients was 1.2 for breast cancer, 9.4 for cancer of the oropharynx and larynx, 1.7 for cancers of the colon and rectum, 3.0 for lung cancer, 3.9 for esophageal and stomach cancers, 4.5 for kidney and bladder cancers, and 4.6 for cancers of the female genitourinary system.

"We tried to evaluate the different immunosuppressive regimens and, over time, we had, I think, 27 different primary regimens," Dr. Rademacher said. Steroid-free regimens and low-dose steroid were part of that consideration, "but we segregated them out. For the five most frequent regimens, there was no significance. We assessed immunosuppressive regimens given over at least 2 years, but there was no difference between the regimens. Also, the trough levels of tacrolimus did not have any significant influence," he said.

The investigators did not have data on cumulative immunosuppression or mTOR [mammalian target of rapamycin] inhibitors, which were introduced late in the study period, according to Dr. Rademacher, who disclosed no relevant conflicts of interest. A surrogate marker of immunosuppression, rejection frequency, did not significantly predict the development of solid organ malignancies.

SAN FRANCISCO – Use of an everolimus-containing regimen with early stopping of cyclosporine after de novo heart transplantation improves renal function and reduces cardiac allograft vasculopathy, without compromising graft outcomes, new data suggest.

These was among key findings of the randomized, open-label SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study with Early Calcineurin Inhibitor Avoidance) reported at the 2014 World Transplant Congress.

"Renal dysfunction and cardiac allograft vasculopathy are markers for increased morbidity and mortality after heart transplantation," lead author Dr. Vilborg Sigurdardottir commented when introducing the study.

Patients in the trial were randomized evenly to a three-drug regimen containing the calcineurin inhibitor cyclosporine (Sandimmune) or to a four-drug regimen also containing the mTOR inhibitor everolimus (Zortress) with discontinuation of cyclosporine at week 7-11. Everolimus is currently approved by the Food and Drug Administration to prevent graft rejection in kidney and liver transplant recipients and, under another brand name, to treat some cancers.

Measured glomerular filtration rate (GFR) at 12 months, the trial’s primary outcome, was 30% better in the everolimus group than in the cyclosporine group (79.8 vs. 61.5 mL/min per 1.73 m²; P less than .001), according to results presented at the congress and recently published (Am. J. Transplant. 2014;14:1828-38).

The urinary albumin-creatinine ratio was higher in the everolimus group, but none of the patients had nephrotic levels of proteinuria.

Rates of adverse events were similar, with the exception that the everolimus group had a lower rate of cytomegalovirus infection (5% vs. 30%) and a higher rate of pneumonia (12% vs. 3%), Dr. Sigurdardottir reported at the congress, which was sponsored by the American Society of Transplant Surgeons.

The incidence of biopsy-proven acute rejection of at least grade 2R was greater with everolimus (40% vs. 18%, P = .01). However, at 12 months, the groups did not differ with respect to left ventricular function as assessed by echocardiography and biomarkers, and, in a cardiac reserve substudy, with respect to cardiac output and pulmonary capillary wedge pressure.

The incidence of cardiac allograft vasculopathy, defined as a mean media-intima thickness of at least 0.5 mm on intravascular ultrasound (IVUS), was lower in the everolimus group (51% vs. 65%, P less than .01), and progression assessed as the change in percent atheroma volume was slower in that group.

"Everolimus initiation and early cyclosporine elimination in de novo heart transplant recipients showed a highly significant improvement of renal function in terms of measured GFR, a reduced incidence of cytomegalovirus [a confirmatory result of previous large-scale studies], similar numbers of adverse and serious adverse events, and an increased incidence of treated acute rejection, however, without hemodynamic compromise and with preserved cardiac function and preserved cardiac reserve," concluded Dr. Sigurdardottir, who is medical director of heart transplantation at the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden. "We saw also favorable coronary remodeling and less graft vasculopathy, as previously shown."

Among patients whose donor hearts had such disease, the increase in media-intima thickness and percent atheroma volume was less with everolimus than with cyclosporine, Dr. Sigurdardottir said. "Interestingly, we saw here that the total atheroma volume decreased between baseline and 12 months in the everolimus group in the patients who had preexisting donor disease."

An attendee from Norway said, "I am a nephrologist, and if I were to get a new heart, I’d rather have a GFR of 61 and no rejection than a GFR of 73 with rejection. Have you looked at the development of donor-specific antibodies in the ones who had rejection, because I’d like to live for more than a year – I’d like to live 3 years or 5 years or 10 years."

"You are absolutely right. At the time of transplantation, we would be looking at the acute problems, and we often see the kidney dysfunction, so we want to do something about that. But of course these studies need to tell us how patients fare longer term," Dr. Sigurdardottir agreed. None of the patients were found to have donor-specific antibodies, but the trial protocol did not mandate routine measurement, she said.

An attendee from Los Angeles commented, "We tried to do CNI [calcineurin inhibitor] weaning in 2006 and had hemodynamically compromised rejection. Now, I congratulate you on being innovative and having quadruple therapy from the get-go and then taking off the CNI. But the issue of increased rejection is important because ISHLT [International Society for Heart and Lung Transplantation] data show that that does lead to poorer outcome. It is countered by your improvement in renal function, but also your IVUS result, I think, is very important as well."

"Rejection is an important issue, but it is a common issue after transplantation. It was usually manageable. Since we didn’t see any hemodynamic compromise, it was up to each investigator to evaluate what to do. There were nine patients who converted to combination therapy," Dr. Sigurdardottir reported. "The future needs to tell us what the relevance of this rejection is, and we will do a follow-up at 3 and 5 years."

Dr. Sigurdardottir disclosed no relevant conflicts of interest. The trial was sponsored by Novartis, manufacturer of everolimus.

SAN FRANCISCO – Use of an everolimus-containing regimen with early stopping of cyclosporine after de novo heart transplantation improves renal function and reduces cardiac allograft vasculopathy, without compromising graft outcomes, new data suggest.

These was among key findings of the randomized, open-label SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study with Early Calcineurin Inhibitor Avoidance) reported at the 2014 World Transplant Congress.

"Renal dysfunction and cardiac allograft vasculopathy are markers for increased morbidity and mortality after heart transplantation," lead author Dr. Vilborg Sigurdardottir commented when introducing the study.

Patients in the trial were randomized evenly to a three-drug regimen containing the calcineurin inhibitor cyclosporine (Sandimmune) or to a four-drug regimen also containing the mTOR inhibitor everolimus (Zortress) with discontinuation of cyclosporine at week 7-11. Everolimus is currently approved by the Food and Drug Administration to prevent graft rejection in kidney and liver transplant recipients and, under another brand name, to treat some cancers.

Measured glomerular filtration rate (GFR) at 12 months, the trial’s primary outcome, was 30% better in the everolimus group than in the cyclosporine group (79.8 vs. 61.5 mL/min per 1.73 m²; P less than .001), according to results presented at the congress and recently published (Am. J. Transplant. 2014;14:1828-38).

The urinary albumin-creatinine ratio was higher in the everolimus group, but none of the patients had nephrotic levels of proteinuria.

Rates of adverse events were similar, with the exception that the everolimus group had a lower rate of cytomegalovirus infection (5% vs. 30%) and a higher rate of pneumonia (12% vs. 3%), Dr. Sigurdardottir reported at the congress, which was sponsored by the American Society of Transplant Surgeons.

The incidence of biopsy-proven acute rejection of at least grade 2R was greater with everolimus (40% vs. 18%, P = .01). However, at 12 months, the groups did not differ with respect to left ventricular function as assessed by echocardiography and biomarkers, and, in a cardiac reserve substudy, with respect to cardiac output and pulmonary capillary wedge pressure.

The incidence of cardiac allograft vasculopathy, defined as a mean media-intima thickness of at least 0.5 mm on intravascular ultrasound (IVUS), was lower in the everolimus group (51% vs. 65%, P less than .01), and progression assessed as the change in percent atheroma volume was slower in that group.

"Everolimus initiation and early cyclosporine elimination in de novo heart transplant recipients showed a highly significant improvement of renal function in terms of measured GFR, a reduced incidence of cytomegalovirus [a confirmatory result of previous large-scale studies], similar numbers of adverse and serious adverse events, and an increased incidence of treated acute rejection, however, without hemodynamic compromise and with preserved cardiac function and preserved cardiac reserve," concluded Dr. Sigurdardottir, who is medical director of heart transplantation at the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden. "We saw also favorable coronary remodeling and less graft vasculopathy, as previously shown."

Among patients whose donor hearts had such disease, the increase in media-intima thickness and percent atheroma volume was less with everolimus than with cyclosporine, Dr. Sigurdardottir said. "Interestingly, we saw here that the total atheroma volume decreased between baseline and 12 months in the everolimus group in the patients who had preexisting donor disease."

An attendee from Norway said, "I am a nephrologist, and if I were to get a new heart, I’d rather have a GFR of 61 and no rejection than a GFR of 73 with rejection. Have you looked at the development of donor-specific antibodies in the ones who had rejection, because I’d like to live for more than a year – I’d like to live 3 years or 5 years or 10 years."

"You are absolutely right. At the time of transplantation, we would be looking at the acute problems, and we often see the kidney dysfunction, so we want to do something about that. But of course these studies need to tell us how patients fare longer term," Dr. Sigurdardottir agreed. None of the patients were found to have donor-specific antibodies, but the trial protocol did not mandate routine measurement, she said.

An attendee from Los Angeles commented, "We tried to do CNI [calcineurin inhibitor] weaning in 2006 and had hemodynamically compromised rejection. Now, I congratulate you on being innovative and having quadruple therapy from the get-go and then taking off the CNI. But the issue of increased rejection is important because ISHLT [International Society for Heart and Lung Transplantation] data show that that does lead to poorer outcome. It is countered by your improvement in renal function, but also your IVUS result, I think, is very important as well."

"Rejection is an important issue, but it is a common issue after transplantation. It was usually manageable. Since we didn’t see any hemodynamic compromise, it was up to each investigator to evaluate what to do. There were nine patients who converted to combination therapy," Dr. Sigurdardottir reported. "The future needs to tell us what the relevance of this rejection is, and we will do a follow-up at 3 and 5 years."

Dr. Sigurdardottir disclosed no relevant conflicts of interest. The trial was sponsored by Novartis, manufacturer of everolimus.

SAN FRANCISCO – Use of an everolimus-containing regimen with early stopping of cyclosporine after de novo heart transplantation improves renal function and reduces cardiac allograft vasculopathy, without compromising graft outcomes, new data suggest.

These was among key findings of the randomized, open-label SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study with Early Calcineurin Inhibitor Avoidance) reported at the 2014 World Transplant Congress.

"Renal dysfunction and cardiac allograft vasculopathy are markers for increased morbidity and mortality after heart transplantation," lead author Dr. Vilborg Sigurdardottir commented when introducing the study.

Patients in the trial were randomized evenly to a three-drug regimen containing the calcineurin inhibitor cyclosporine (Sandimmune) or to a four-drug regimen also containing the mTOR inhibitor everolimus (Zortress) with discontinuation of cyclosporine at week 7-11. Everolimus is currently approved by the Food and Drug Administration to prevent graft rejection in kidney and liver transplant recipients and, under another brand name, to treat some cancers.

Measured glomerular filtration rate (GFR) at 12 months, the trial’s primary outcome, was 30% better in the everolimus group than in the cyclosporine group (79.8 vs. 61.5 mL/min per 1.73 m²; P less than .001), according to results presented at the congress and recently published (Am. J. Transplant. 2014;14:1828-38).

The urinary albumin-creatinine ratio was higher in the everolimus group, but none of the patients had nephrotic levels of proteinuria.

Rates of adverse events were similar, with the exception that the everolimus group had a lower rate of cytomegalovirus infection (5% vs. 30%) and a higher rate of pneumonia (12% vs. 3%), Dr. Sigurdardottir reported at the congress, which was sponsored by the American Society of Transplant Surgeons.

The incidence of biopsy-proven acute rejection of at least grade 2R was greater with everolimus (40% vs. 18%, P = .01). However, at 12 months, the groups did not differ with respect to left ventricular function as assessed by echocardiography and biomarkers, and, in a cardiac reserve substudy, with respect to cardiac output and pulmonary capillary wedge pressure.

The incidence of cardiac allograft vasculopathy, defined as a mean media-intima thickness of at least 0.5 mm on intravascular ultrasound (IVUS), was lower in the everolimus group (51% vs. 65%, P less than .01), and progression assessed as the change in percent atheroma volume was slower in that group.

"Everolimus initiation and early cyclosporine elimination in de novo heart transplant recipients showed a highly significant improvement of renal function in terms of measured GFR, a reduced incidence of cytomegalovirus [a confirmatory result of previous large-scale studies], similar numbers of adverse and serious adverse events, and an increased incidence of treated acute rejection, however, without hemodynamic compromise and with preserved cardiac function and preserved cardiac reserve," concluded Dr. Sigurdardottir, who is medical director of heart transplantation at the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden. "We saw also favorable coronary remodeling and less graft vasculopathy, as previously shown."

Among patients whose donor hearts had such disease, the increase in media-intima thickness and percent atheroma volume was less with everolimus than with cyclosporine, Dr. Sigurdardottir said. "Interestingly, we saw here that the total atheroma volume decreased between baseline and 12 months in the everolimus group in the patients who had preexisting donor disease."

An attendee from Norway said, "I am a nephrologist, and if I were to get a new heart, I’d rather have a GFR of 61 and no rejection than a GFR of 73 with rejection. Have you looked at the development of donor-specific antibodies in the ones who had rejection, because I’d like to live for more than a year – I’d like to live 3 years or 5 years or 10 years."

"You are absolutely right. At the time of transplantation, we would be looking at the acute problems, and we often see the kidney dysfunction, so we want to do something about that. But of course these studies need to tell us how patients fare longer term," Dr. Sigurdardottir agreed. None of the patients were found to have donor-specific antibodies, but the trial protocol did not mandate routine measurement, she said.

An attendee from Los Angeles commented, "We tried to do CNI [calcineurin inhibitor] weaning in 2006 and had hemodynamically compromised rejection. Now, I congratulate you on being innovative and having quadruple therapy from the get-go and then taking off the CNI. But the issue of increased rejection is important because ISHLT [International Society for Heart and Lung Transplantation] data show that that does lead to poorer outcome. It is countered by your improvement in renal function, but also your IVUS result, I think, is very important as well."

"Rejection is an important issue, but it is a common issue after transplantation. It was usually manageable. Since we didn’t see any hemodynamic compromise, it was up to each investigator to evaluate what to do. There were nine patients who converted to combination therapy," Dr. Sigurdardottir reported. "The future needs to tell us what the relevance of this rejection is, and we will do a follow-up at 3 and 5 years."

Dr. Sigurdardottir disclosed no relevant conflicts of interest. The trial was sponsored by Novartis, manufacturer of everolimus.