BROOKLYN, N.Y. – There are studies demonstrating depression is more likely to resolve if depressed parents are also treated dating back more than 10 years, but new evidence suggests this effect may extend to children as young as 3 years of age, according to an update on current strategies for early intervention presented at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Of multiple triggers that can be caught and treated early to prevent children from progressing to chronic depression, addressing parental depression is an important target, according to Karen Dineen Wagner, MD, Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch in Galveston.

In an overview of strategies for intervening early in children who have or are at risk for depression, Dr. Wagner looked at several targets. The purpose of recognizing and addressing such targets as parental depression is to get children well faster and avoid disease chronicity.

“If we want to intervene and potentially prevent the occurrence of depression, we need to look at disorders or triggers that may precede the depression and that, had they been treated, might have eliminated the stressors that tip the child into depression,” Dr. Wagner said.

Parental depression was just one of these factors, but along with others, such as child abuse of any kind and bullying, each poses a threat for chronic mood disorders, according to Dr. Wagner.

In the case of parental depression, Dr. Wagner cited numerous studies demonstrating a close correlation between remission in the parent and remission in the child. These trajectories interact, so children are less likely to get well if an affected parent does not get well.

“Make sure you consider depression in the parent when you are doing an evaluation, and it is not just depression in the parent who is there. Ask about the other partner who is not there,” Dr. Wagner advised. Parents reluctant to address their own depression should be informed that the mental health of their child is at risk.

The most recent evidence to show benefit from treating both child and parent was drawn from a controlled study that enrolled young children (Luby JL et al. Am J Psychiatry. 2018 Jun 20. doi: 10.1176/appi.ajp.2018.18030321).

In this study, 229 parent-child dyads were randomized to receive parent-child psychotherapy for early childhood depression or to a wait-list. The age range for the children was 3-6.2 years. The therapy was specifically designed to improve the parents’ ability to help young children cope with their feelings.

The parent-child interaction therapy “focused on emotional development which was designed to train parents to work with the child on developing emotional competence in which the child understands their emotions, understands how events affect how they are feeling, and controls emotional reactivity,” Dr. Wagner explained.

For the primary outcome of depression at the end of 18 weeks, the rates were significantly lower in those who participated in the interaction therapy than they were in those on the wait-list. Measures of parent depression and stress were also lower in the therapy group.

Currently, the U. S. Preventive Task Force recommends screening all children at age 12 for depression with the adolescent version of the Patient Health Questionnaire (PHQ-A), according to Dr. Wagner. Given the rising prevalence of depression in adolescents, which climbed 46% from 2005 (8.7%) to 2015 (12.7%) according to a published national survey, this screening is prudent, Dr. Wagner indicated. However, she further suggested that it is reasonable to screen children with risk factors, such as learning disorders or anxiety disorders, even earlier.

The reason is that there are effective therapies. Early treatment may prevent chronic and more severe forms of depression, according to Dr. Wagner. She suggested that there is a growing emphasis on not just treating depression at its early stages but also in recognizing the child at risk, identifying subsyndromal symptoms leading toward depression, and preventing children from ever reaching diagnostic criteria.

Indeed, an initiative for better and earlier detection and treatment of depression in children was begun by the AACAP when Dr. Wagner served recently as its president. Several parts of that program have now been launched. Dr. Wagner encouraged those with an interest to visit the AACAP website, where more information about this initiative can be accessed.

Dr. Wagner reported no potential conflicts of interest.

BROOKLYN, N.Y. – There are studies demonstrating depression is more likely to resolve if depressed parents are also treated dating back more than 10 years, but new evidence suggests this effect may extend to children as young as 3 years of age, according to an update on current strategies for early intervention presented at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Of multiple triggers that can be caught and treated early to prevent children from progressing to chronic depression, addressing parental depression is an important target, according to Karen Dineen Wagner, MD, Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch in Galveston.

In an overview of strategies for intervening early in children who have or are at risk for depression, Dr. Wagner looked at several targets. The purpose of recognizing and addressing such targets as parental depression is to get children well faster and avoid disease chronicity.

“If we want to intervene and potentially prevent the occurrence of depression, we need to look at disorders or triggers that may precede the depression and that, had they been treated, might have eliminated the stressors that tip the child into depression,” Dr. Wagner said.

Parental depression was just one of these factors, but along with others, such as child abuse of any kind and bullying, each poses a threat for chronic mood disorders, according to Dr. Wagner.

In the case of parental depression, Dr. Wagner cited numerous studies demonstrating a close correlation between remission in the parent and remission in the child. These trajectories interact, so children are less likely to get well if an affected parent does not get well.

“Make sure you consider depression in the parent when you are doing an evaluation, and it is not just depression in the parent who is there. Ask about the other partner who is not there,” Dr. Wagner advised. Parents reluctant to address their own depression should be informed that the mental health of their child is at risk.

The most recent evidence to show benefit from treating both child and parent was drawn from a controlled study that enrolled young children (Luby JL et al. Am J Psychiatry. 2018 Jun 20. doi: 10.1176/appi.ajp.2018.18030321).

In this study, 229 parent-child dyads were randomized to receive parent-child psychotherapy for early childhood depression or to a wait-list. The age range for the children was 3-6.2 years. The therapy was specifically designed to improve the parents’ ability to help young children cope with their feelings.

The parent-child interaction therapy “focused on emotional development which was designed to train parents to work with the child on developing emotional competence in which the child understands their emotions, understands how events affect how they are feeling, and controls emotional reactivity,” Dr. Wagner explained.

For the primary outcome of depression at the end of 18 weeks, the rates were significantly lower in those who participated in the interaction therapy than they were in those on the wait-list. Measures of parent depression and stress were also lower in the therapy group.

Currently, the U. S. Preventive Task Force recommends screening all children at age 12 for depression with the adolescent version of the Patient Health Questionnaire (PHQ-A), according to Dr. Wagner. Given the rising prevalence of depression in adolescents, which climbed 46% from 2005 (8.7%) to 2015 (12.7%) according to a published national survey, this screening is prudent, Dr. Wagner indicated. However, she further suggested that it is reasonable to screen children with risk factors, such as learning disorders or anxiety disorders, even earlier.

The reason is that there are effective therapies. Early treatment may prevent chronic and more severe forms of depression, according to Dr. Wagner. She suggested that there is a growing emphasis on not just treating depression at its early stages but also in recognizing the child at risk, identifying subsyndromal symptoms leading toward depression, and preventing children from ever reaching diagnostic criteria.

Indeed, an initiative for better and earlier detection and treatment of depression in children was begun by the AACAP when Dr. Wagner served recently as its president. Several parts of that program have now been launched. Dr. Wagner encouraged those with an interest to visit the AACAP website, where more information about this initiative can be accessed.

Dr. Wagner reported no potential conflicts of interest.

BROOKLYN, N.Y. – There are studies demonstrating depression is more likely to resolve if depressed parents are also treated dating back more than 10 years, but new evidence suggests this effect may extend to children as young as 3 years of age, according to an update on current strategies for early intervention presented at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Of multiple triggers that can be caught and treated early to prevent children from progressing to chronic depression, addressing parental depression is an important target, according to Karen Dineen Wagner, MD, Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch in Galveston.

In an overview of strategies for intervening early in children who have or are at risk for depression, Dr. Wagner looked at several targets. The purpose of recognizing and addressing such targets as parental depression is to get children well faster and avoid disease chronicity.

“If we want to intervene and potentially prevent the occurrence of depression, we need to look at disorders or triggers that may precede the depression and that, had they been treated, might have eliminated the stressors that tip the child into depression,” Dr. Wagner said.

Parental depression was just one of these factors, but along with others, such as child abuse of any kind and bullying, each poses a threat for chronic mood disorders, according to Dr. Wagner.

In the case of parental depression, Dr. Wagner cited numerous studies demonstrating a close correlation between remission in the parent and remission in the child. These trajectories interact, so children are less likely to get well if an affected parent does not get well.

“Make sure you consider depression in the parent when you are doing an evaluation, and it is not just depression in the parent who is there. Ask about the other partner who is not there,” Dr. Wagner advised. Parents reluctant to address their own depression should be informed that the mental health of their child is at risk.

The most recent evidence to show benefit from treating both child and parent was drawn from a controlled study that enrolled young children (Luby JL et al. Am J Psychiatry. 2018 Jun 20. doi: 10.1176/appi.ajp.2018.18030321).

In this study, 229 parent-child dyads were randomized to receive parent-child psychotherapy for early childhood depression or to a wait-list. The age range for the children was 3-6.2 years. The therapy was specifically designed to improve the parents’ ability to help young children cope with their feelings.

The parent-child interaction therapy “focused on emotional development which was designed to train parents to work with the child on developing emotional competence in which the child understands their emotions, understands how events affect how they are feeling, and controls emotional reactivity,” Dr. Wagner explained.

For the primary outcome of depression at the end of 18 weeks, the rates were significantly lower in those who participated in the interaction therapy than they were in those on the wait-list. Measures of parent depression and stress were also lower in the therapy group.

Currently, the U. S. Preventive Task Force recommends screening all children at age 12 for depression with the adolescent version of the Patient Health Questionnaire (PHQ-A), according to Dr. Wagner. Given the rising prevalence of depression in adolescents, which climbed 46% from 2005 (8.7%) to 2015 (12.7%) according to a published national survey, this screening is prudent, Dr. Wagner indicated. However, she further suggested that it is reasonable to screen children with risk factors, such as learning disorders or anxiety disorders, even earlier.

The reason is that there are effective therapies. Early treatment may prevent chronic and more severe forms of depression, according to Dr. Wagner. She suggested that there is a growing emphasis on not just treating depression at its early stages but also in recognizing the child at risk, identifying subsyndromal symptoms leading toward depression, and preventing children from ever reaching diagnostic criteria.

Indeed, an initiative for better and earlier detection and treatment of depression in children was begun by the AACAP when Dr. Wagner served recently as its president. Several parts of that program have now been launched. Dr. Wagner encouraged those with an interest to visit the AACAP website, where more information about this initiative can be accessed.

Dr. Wagner reported no potential conflicts of interest.

BOSTON – Sixty-three patients with atrial fibrillation (AF) and a history of intracranial hemorrhage have safely received a Watchman device for left atrial appendage (LAA) closure followed by 6 months of treatment with an individualized drug regimen to prevent thrombus formation at three U.S. centers. The 6-month outcomes of these patients were as good as the outcomes of 95 similar patients who did not have a history of intracranial hemorrhage, Moussa C. Mansour, MD, said at the annual International AF Symposium.

Mitchel L. Zoler/MDedge News

“Individualized, postprocedural antithrombotic management ranging from dual antiplatelet therapy to oral anticoagulation plus aspirin can be used short term,” said Dr. Mansour, director of the atrial AF program at Massachusetts General Hospital. He and his associates devised this approach “out of necessity,” he said. The findings “show that you can get these patients through the initial postprocedural period” by individualizing their antiplatelet or anticoagulant treatment.

Not many U.S. operators are currently placing LAA closure devices in patients with a history of intracranial hemorrhage (ICH). “No one knows what to do with them. There is no standard approach; it’s an evolving field,” he said in an interview.

Dr. Mansour reviewed his group’s experience at Massachusetts General with LAA closure using the Watchman device combined with the experience of teams at the Texas Cardiac Arrhythmia Institute in Austin and the HCA Midwest Health in Overland Park, Kan. This included 63 AF patients with an ICH history and 95 similar AF patients with no hemorrhagic history. Nearly half of the patients with a prior ICH also had a history of at least one ischemic stroke or transient ischemic attack, compared with just over a third of the patients without a prior ICH. The two groups had nearly identical CHA2DS2-VASc scores, 4.9 and 4.7, and also very similar HAS-BLED scores.

The patients with a prior ICH included 57% with a prior intracerebral hemorrhage, 29% with a prior subdural hemorrhage, 10% with a subarachnoid hemorrhage, and the remainder unspecified.

Thirty-two of the 63 patients with an ICH history received postprocedural anticoagulation with a direct-acting oral anticoagulant, 18 received warfarin, and 13 received dual antiplatelet therapy but no anticoagulant. Among the 45 patients treated with an oral anticoagulant, 27 also received aspirin. Among the 95 patients reviewed without an ICH history, 93 received an oral anticoagulant, and 2 received dual antiplatelet therapy.

During 180 days of follow-up, the combined incidence of death, stroke, or a major bleed was about 5% among the patients with an ICH history and about 10% among those without this history, a difference that was not statistically significant, Dr. Mansour said.

At Massachusetts General, the decision on how to treat AF patients with an ICH history after they undergo LAA closure is made by a multidisciplinary team of clinicians from the arrhythmia, neurology, radiology, anesthesia, and cardiovascular surgery services. A key factor when determining the drug regimen these patients will receive is the location and size of the ICH when imaged with CT or MRI, Dr. Mansour said. The team also assessed the current likelihood that the patient will bleed. “One size does not fit all” patients, he explained.

A randomized trial, ASAP-TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is now in progress and was designed to compare the safety and efficacy of LAA closure using Watchman with medical management in 888 patients deemed ineligible for anticoagulation, but enrollment into the trial has been slow. As of early 2019, the study’s organizers posted an estimated completion date of late 2023. Until that study finishes, the field will have no definitive data on how to manage these patients, Dr. Mansour said. He noted that a handful of other reports have presented evidence for the safety of LAA closure in these patients, including a review from the Cleveland Clinic on 38 AF patients who received the Watchman device after an ICH (Heart Rhythm. 2018 Dec 2. doi: 10.1016/j.hrthm.2018.11.022); a review of the Amplatzer Cardiac Plug registry, which included 198 patients with an ICH history (Int J Cardiol. 2017 June 1;236[1]:232-6); and a single-center review of 46 French patients who underwent LAA closure after intracerebral hemorrhage (J Stroke Cerebrovasc Dis. 2017 March;26[3]:545-51).

[email protected]

BOSTON – Sixty-three patients with atrial fibrillation (AF) and a history of intracranial hemorrhage have safely received a Watchman device for left atrial appendage (LAA) closure followed by 6 months of treatment with an individualized drug regimen to prevent thrombus formation at three U.S. centers. The 6-month outcomes of these patients were as good as the outcomes of 95 similar patients who did not have a history of intracranial hemorrhage, Moussa C. Mansour, MD, said at the annual International AF Symposium.

Mitchel L. Zoler/MDedge News

“Individualized, postprocedural antithrombotic management ranging from dual antiplatelet therapy to oral anticoagulation plus aspirin can be used short term,” said Dr. Mansour, director of the atrial AF program at Massachusetts General Hospital. He and his associates devised this approach “out of necessity,” he said. The findings “show that you can get these patients through the initial postprocedural period” by individualizing their antiplatelet or anticoagulant treatment.

Not many U.S. operators are currently placing LAA closure devices in patients with a history of intracranial hemorrhage (ICH). “No one knows what to do with them. There is no standard approach; it’s an evolving field,” he said in an interview.

Dr. Mansour reviewed his group’s experience at Massachusetts General with LAA closure using the Watchman device combined with the experience of teams at the Texas Cardiac Arrhythmia Institute in Austin and the HCA Midwest Health in Overland Park, Kan. This included 63 AF patients with an ICH history and 95 similar AF patients with no hemorrhagic history. Nearly half of the patients with a prior ICH also had a history of at least one ischemic stroke or transient ischemic attack, compared with just over a third of the patients without a prior ICH. The two groups had nearly identical CHA2DS2-VASc scores, 4.9 and 4.7, and also very similar HAS-BLED scores.

The patients with a prior ICH included 57% with a prior intracerebral hemorrhage, 29% with a prior subdural hemorrhage, 10% with a subarachnoid hemorrhage, and the remainder unspecified.

Thirty-two of the 63 patients with an ICH history received postprocedural anticoagulation with a direct-acting oral anticoagulant, 18 received warfarin, and 13 received dual antiplatelet therapy but no anticoagulant. Among the 45 patients treated with an oral anticoagulant, 27 also received aspirin. Among the 95 patients reviewed without an ICH history, 93 received an oral anticoagulant, and 2 received dual antiplatelet therapy.

During 180 days of follow-up, the combined incidence of death, stroke, or a major bleed was about 5% among the patients with an ICH history and about 10% among those without this history, a difference that was not statistically significant, Dr. Mansour said.

At Massachusetts General, the decision on how to treat AF patients with an ICH history after they undergo LAA closure is made by a multidisciplinary team of clinicians from the arrhythmia, neurology, radiology, anesthesia, and cardiovascular surgery services. A key factor when determining the drug regimen these patients will receive is the location and size of the ICH when imaged with CT or MRI, Dr. Mansour said. The team also assessed the current likelihood that the patient will bleed. “One size does not fit all” patients, he explained.

A randomized trial, ASAP-TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is now in progress and was designed to compare the safety and efficacy of LAA closure using Watchman with medical management in 888 patients deemed ineligible for anticoagulation, but enrollment into the trial has been slow. As of early 2019, the study’s organizers posted an estimated completion date of late 2023. Until that study finishes, the field will have no definitive data on how to manage these patients, Dr. Mansour said. He noted that a handful of other reports have presented evidence for the safety of LAA closure in these patients, including a review from the Cleveland Clinic on 38 AF patients who received the Watchman device after an ICH (Heart Rhythm. 2018 Dec 2. doi: 10.1016/j.hrthm.2018.11.022); a review of the Amplatzer Cardiac Plug registry, which included 198 patients with an ICH history (Int J Cardiol. 2017 June 1;236[1]:232-6); and a single-center review of 46 French patients who underwent LAA closure after intracerebral hemorrhage (J Stroke Cerebrovasc Dis. 2017 March;26[3]:545-51).

[email protected]

BOSTON – Sixty-three patients with atrial fibrillation (AF) and a history of intracranial hemorrhage have safely received a Watchman device for left atrial appendage (LAA) closure followed by 6 months of treatment with an individualized drug regimen to prevent thrombus formation at three U.S. centers. The 6-month outcomes of these patients were as good as the outcomes of 95 similar patients who did not have a history of intracranial hemorrhage, Moussa C. Mansour, MD, said at the annual International AF Symposium.

Mitchel L. Zoler/MDedge News

“Individualized, postprocedural antithrombotic management ranging from dual antiplatelet therapy to oral anticoagulation plus aspirin can be used short term,” said Dr. Mansour, director of the atrial AF program at Massachusetts General Hospital. He and his associates devised this approach “out of necessity,” he said. The findings “show that you can get these patients through the initial postprocedural period” by individualizing their antiplatelet or anticoagulant treatment.

Not many U.S. operators are currently placing LAA closure devices in patients with a history of intracranial hemorrhage (ICH). “No one knows what to do with them. There is no standard approach; it’s an evolving field,” he said in an interview.

Dr. Mansour reviewed his group’s experience at Massachusetts General with LAA closure using the Watchman device combined with the experience of teams at the Texas Cardiac Arrhythmia Institute in Austin and the HCA Midwest Health in Overland Park, Kan. This included 63 AF patients with an ICH history and 95 similar AF patients with no hemorrhagic history. Nearly half of the patients with a prior ICH also had a history of at least one ischemic stroke or transient ischemic attack, compared with just over a third of the patients without a prior ICH. The two groups had nearly identical CHA2DS2-VASc scores, 4.9 and 4.7, and also very similar HAS-BLED scores.

The patients with a prior ICH included 57% with a prior intracerebral hemorrhage, 29% with a prior subdural hemorrhage, 10% with a subarachnoid hemorrhage, and the remainder unspecified.

Thirty-two of the 63 patients with an ICH history received postprocedural anticoagulation with a direct-acting oral anticoagulant, 18 received warfarin, and 13 received dual antiplatelet therapy but no anticoagulant. Among the 45 patients treated with an oral anticoagulant, 27 also received aspirin. Among the 95 patients reviewed without an ICH history, 93 received an oral anticoagulant, and 2 received dual antiplatelet therapy.

During 180 days of follow-up, the combined incidence of death, stroke, or a major bleed was about 5% among the patients with an ICH history and about 10% among those without this history, a difference that was not statistically significant, Dr. Mansour said.

At Massachusetts General, the decision on how to treat AF patients with an ICH history after they undergo LAA closure is made by a multidisciplinary team of clinicians from the arrhythmia, neurology, radiology, anesthesia, and cardiovascular surgery services. A key factor when determining the drug regimen these patients will receive is the location and size of the ICH when imaged with CT or MRI, Dr. Mansour said. The team also assessed the current likelihood that the patient will bleed. “One size does not fit all” patients, he explained.

A randomized trial, ASAP-TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is now in progress and was designed to compare the safety and efficacy of LAA closure using Watchman with medical management in 888 patients deemed ineligible for anticoagulation, but enrollment into the trial has been slow. As of early 2019, the study’s organizers posted an estimated completion date of late 2023. Until that study finishes, the field will have no definitive data on how to manage these patients, Dr. Mansour said. He noted that a handful of other reports have presented evidence for the safety of LAA closure in these patients, including a review from the Cleveland Clinic on 38 AF patients who received the Watchman device after an ICH (Heart Rhythm. 2018 Dec 2. doi: 10.1016/j.hrthm.2018.11.022); a review of the Amplatzer Cardiac Plug registry, which included 198 patients with an ICH history (Int J Cardiol. 2017 June 1;236[1]:232-6); and a single-center review of 46 French patients who underwent LAA closure after intracerebral hemorrhage (J Stroke Cerebrovasc Dis. 2017 March;26[3]:545-51).

[email protected]

Although first detected in summer 2018, angiotensin II receptor blockers (ARBs) contaminated with nitrosamines have been on the market in the United States for 4 years, according to the Food and Drug Administration.

“FDA scientists estimate that, if 8,000 people took the highest daily valsartan dose (320 mg) that contained NDMA [N-Nitrosodimethylamine] for 4 years (the time we think the affected products had been on the U.S. market), there may be one additional case of cancer beyond the average cancer rate among those 8,000 Americans,” the agency said in a Jan. 25 update from Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research.

“The vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario. Since not all ARBs are affected, it’s very likely that a patient taking an ARB for 4 years would not have always received one of the affected products. We’re still seeking to similarly quantify the risk from NDEA [N-Nitrosodiethylamine] and plan to communicate our findings as soon as possible,” they said.

“While the total exposure to these impurities for most patients was small, we are deeply concerned that patients were exposed to this impurity in the first place and that the presence of nitrosamines went undetected for a period of time,” Dr. Gottlieb and Dr. Woodcock said in the statement. Through ongoing and “exhaustive” efforts, they pledged the agency will resolve the problem and ensure it never happens again.

Meanwhile, the ongoing recalls have led to a shortage of valsartan, and other ARBs may soon follow suit. The agency hoped the one case of cancer per 8,000 patients analysis would help providers “balance the risk of patients ingesting low levels of the impurities ... for a short period of time” during shortages until a suitable replacement or alternative is found.

The problem surfaced last year when FDA was alerted to nitrosamine contamination in valsartan manufactured in China and marketed in the U.S. by generic pharmaceutical companies. Contamination has since been detected in generic irbesartan and losartan.

The impurities are generated “when specific chemicals and reaction conditions are present in the manufacturing process ... and may also result from the reuse of materials, such as solvents,” something “neither regulators nor industry fully understood” before. The agency has developed and shared new tests to detect nitrosamines. “Manufacturers using processes at risk for these impurities are expected to test for them to ensure that active ingredients and finished products are free of detectable levels,” it said.

Meanwhile, the recalls keep coming, the latest for losartan and hydrochlorothiazide combination tablets from Torrent Pharmaceuticals. The recalls are listed on FDA’s website.

[email protected]

Although first detected in summer 2018, angiotensin II receptor blockers (ARBs) contaminated with nitrosamines have been on the market in the United States for 4 years, according to the Food and Drug Administration.

“FDA scientists estimate that, if 8,000 people took the highest daily valsartan dose (320 mg) that contained NDMA [N-Nitrosodimethylamine] for 4 years (the time we think the affected products had been on the U.S. market), there may be one additional case of cancer beyond the average cancer rate among those 8,000 Americans,” the agency said in a Jan. 25 update from Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research.

“The vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario. Since not all ARBs are affected, it’s very likely that a patient taking an ARB for 4 years would not have always received one of the affected products. We’re still seeking to similarly quantify the risk from NDEA [N-Nitrosodiethylamine] and plan to communicate our findings as soon as possible,” they said.

“While the total exposure to these impurities for most patients was small, we are deeply concerned that patients were exposed to this impurity in the first place and that the presence of nitrosamines went undetected for a period of time,” Dr. Gottlieb and Dr. Woodcock said in the statement. Through ongoing and “exhaustive” efforts, they pledged the agency will resolve the problem and ensure it never happens again.

Meanwhile, the ongoing recalls have led to a shortage of valsartan, and other ARBs may soon follow suit. The agency hoped the one case of cancer per 8,000 patients analysis would help providers “balance the risk of patients ingesting low levels of the impurities ... for a short period of time” during shortages until a suitable replacement or alternative is found.

The problem surfaced last year when FDA was alerted to nitrosamine contamination in valsartan manufactured in China and marketed in the U.S. by generic pharmaceutical companies. Contamination has since been detected in generic irbesartan and losartan.

The impurities are generated “when specific chemicals and reaction conditions are present in the manufacturing process ... and may also result from the reuse of materials, such as solvents,” something “neither regulators nor industry fully understood” before. The agency has developed and shared new tests to detect nitrosamines. “Manufacturers using processes at risk for these impurities are expected to test for them to ensure that active ingredients and finished products are free of detectable levels,” it said.

Meanwhile, the recalls keep coming, the latest for losartan and hydrochlorothiazide combination tablets from Torrent Pharmaceuticals. The recalls are listed on FDA’s website.

[email protected]

Although first detected in summer 2018, angiotensin II receptor blockers (ARBs) contaminated with nitrosamines have been on the market in the United States for 4 years, according to the Food and Drug Administration.

“FDA scientists estimate that, if 8,000 people took the highest daily valsartan dose (320 mg) that contained NDMA [N-Nitrosodimethylamine] for 4 years (the time we think the affected products had been on the U.S. market), there may be one additional case of cancer beyond the average cancer rate among those 8,000 Americans,” the agency said in a Jan. 25 update from Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research.

“The vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario. Since not all ARBs are affected, it’s very likely that a patient taking an ARB for 4 years would not have always received one of the affected products. We’re still seeking to similarly quantify the risk from NDEA [N-Nitrosodiethylamine] and plan to communicate our findings as soon as possible,” they said.

“While the total exposure to these impurities for most patients was small, we are deeply concerned that patients were exposed to this impurity in the first place and that the presence of nitrosamines went undetected for a period of time,” Dr. Gottlieb and Dr. Woodcock said in the statement. Through ongoing and “exhaustive” efforts, they pledged the agency will resolve the problem and ensure it never happens again.

Meanwhile, the ongoing recalls have led to a shortage of valsartan, and other ARBs may soon follow suit. The agency hoped the one case of cancer per 8,000 patients analysis would help providers “balance the risk of patients ingesting low levels of the impurities ... for a short period of time” during shortages until a suitable replacement or alternative is found.

The problem surfaced last year when FDA was alerted to nitrosamine contamination in valsartan manufactured in China and marketed in the U.S. by generic pharmaceutical companies. Contamination has since been detected in generic irbesartan and losartan.

The impurities are generated “when specific chemicals and reaction conditions are present in the manufacturing process ... and may also result from the reuse of materials, such as solvents,” something “neither regulators nor industry fully understood” before. The agency has developed and shared new tests to detect nitrosamines. “Manufacturers using processes at risk for these impurities are expected to test for them to ensure that active ingredients and finished products are free of detectable levels,” it said.

Meanwhile, the recalls keep coming, the latest for losartan and hydrochlorothiazide combination tablets from Torrent Pharmaceuticals. The recalls are listed on FDA’s website.

[email protected]

Sanofi hasn’t given up on its SGLT1/2 inhibitor sotagliflozin (Zynquista) for type 1 diabetes mellitus despite a recent 8-to-8 split decision on recommendation for approval from the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee.

In the company’s three trials, involving about 3,000 insulin-dependent adults treated for up to a year, the drug lowered hemoglobin A_1c a respectable 0.5% without increasing hypoglycemia risk; reduced glucose variability; and increased time in range, with some modest benefits in both weight loss and lower blood pressure. There was no sign of the increased amputation risk that has bedeviled the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana), already on the market for type 2 diabetes mellitus.

The fly in the ointment was diabetic ketoacidosis (DKA); the drug increased the risk eightfold versus placebo, and, although there were no DKA deaths and over 60% of patients resumed sotagliflozin after recovering, the cases were serious and sometimes occurred in patients with glucose levels as low as 150 mg/dL. Younger people and women seemed to be at higher risk, according to the data.

DKA risk was 4 cases per 100 patients/year, a 4% risk, and that was in the ideal setting of a trial, not everyday practice. The annual background risk of DKA is 1% or less in type 1 diabetes mellitus (T1DM).

“It’s got to be safer than this,” said committee chair Peter Wilson, MD, professor of cardiology and public health at Emory University, Atlanta.

Dr. Wilson voted to recommend approval but with the major caveat that Sanofi have a strong risk mitigation program in place, perhaps based on ketone monitoring to catch emerging DKA before people end up in the ED. That was a universal request among others who voted for recommendation; among those who voted against, the concern in large part was that, even with such a program, the risk of DKA was still too high.

“If they had already developed a mitigation program that had been piloted, and they showed us some data, there would have been more enthusiasm, but we didn’t have that,” he said in an interview after the hearing.

Sanofi did suggest possible risk mitigation strategies during the meeting. In a statement afterwards, spokesman Nicolas Kressmann said, “While we acknowledge the increase in incidence of DKA observed with the addition of sotagliflozin to insulin, we believe that the risks may be mitigated and managed with proper patient selection and education regarding appropriate ketone monitoring. We will continue to work with the FDA to ensure the agency has the data it needs to evaluate the safety and efficacy of sotagliflozin when used as an oral treatment together with insulin by adults with T1DM. We are confident in the data of our T1DM clinical program.”

Meanwhile, the company’s development for T2DMs is ongoing, with results from a number of trials expected later in 2019. Sotagliflozin would join canagliflozin and two other SGLT2 inhibitors already on the market for T2DM, none of which have been approved for T1DM disease. The approved drugs work by increasing renal glucose excretion.

A significant proportion of DKA cases in sotagliflozin’s T1DM trials were preceded by infections and other well-known triggers, “but there were a proportion of patients where they couldn’t identify the cause; it just kind of came out of the blue. Something about the medication lowers the threshold,” said panelist and endocrinologist Cecilia Low Wang, MD, director of the glucose management team at the University of Colorado Anschutz Medical Campus, Aurora, who voted against recommending approval.

“There’s definitely an increased risk” with other SGLT2 inhibitors, as well, when used off label for T1DM. “No one really knows why,” she said.

Dr. Wilson was also concerned that insulin wasn’t more tightly titrated in the placebo groups, which might have led to the 0.5% improvement seen with sotagliflozin, but “they wanted to have trials that were likely to be beneficial, so it’s reasonable to do what they did,” he said.

Overall, “we don’t really have many options for type 1, and many of us were sympathetic to the idea of increasing options.” In T1DM, “you can lose your concentration” on insulin dosing for a couple hours, “and the next thing you know you are going too high or too low and going off the road. These pills help smooth out your ups and downs. I would like to think [sotagliflozin] might be approved for a restricted group, for which we’ve really sorted out the ketone data,” he said.

Dr. Wilson and Dr. Low Wang did not have any disclosures.

[email protected]

Sanofi hasn’t given up on its SGLT1/2 inhibitor sotagliflozin (Zynquista) for type 1 diabetes mellitus despite a recent 8-to-8 split decision on recommendation for approval from the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee.

In the company’s three trials, involving about 3,000 insulin-dependent adults treated for up to a year, the drug lowered hemoglobin A_1c a respectable 0.5% without increasing hypoglycemia risk; reduced glucose variability; and increased time in range, with some modest benefits in both weight loss and lower blood pressure. There was no sign of the increased amputation risk that has bedeviled the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana), already on the market for type 2 diabetes mellitus.

The fly in the ointment was diabetic ketoacidosis (DKA); the drug increased the risk eightfold versus placebo, and, although there were no DKA deaths and over 60% of patients resumed sotagliflozin after recovering, the cases were serious and sometimes occurred in patients with glucose levels as low as 150 mg/dL. Younger people and women seemed to be at higher risk, according to the data.

DKA risk was 4 cases per 100 patients/year, a 4% risk, and that was in the ideal setting of a trial, not everyday practice. The annual background risk of DKA is 1% or less in type 1 diabetes mellitus (T1DM).

“It’s got to be safer than this,” said committee chair Peter Wilson, MD, professor of cardiology and public health at Emory University, Atlanta.

Dr. Wilson voted to recommend approval but with the major caveat that Sanofi have a strong risk mitigation program in place, perhaps based on ketone monitoring to catch emerging DKA before people end up in the ED. That was a universal request among others who voted for recommendation; among those who voted against, the concern in large part was that, even with such a program, the risk of DKA was still too high.

“If they had already developed a mitigation program that had been piloted, and they showed us some data, there would have been more enthusiasm, but we didn’t have that,” he said in an interview after the hearing.

Sanofi did suggest possible risk mitigation strategies during the meeting. In a statement afterwards, spokesman Nicolas Kressmann said, “While we acknowledge the increase in incidence of DKA observed with the addition of sotagliflozin to insulin, we believe that the risks may be mitigated and managed with proper patient selection and education regarding appropriate ketone monitoring. We will continue to work with the FDA to ensure the agency has the data it needs to evaluate the safety and efficacy of sotagliflozin when used as an oral treatment together with insulin by adults with T1DM. We are confident in the data of our T1DM clinical program.”

Meanwhile, the company’s development for T2DMs is ongoing, with results from a number of trials expected later in 2019. Sotagliflozin would join canagliflozin and two other SGLT2 inhibitors already on the market for T2DM, none of which have been approved for T1DM disease. The approved drugs work by increasing renal glucose excretion.

A significant proportion of DKA cases in sotagliflozin’s T1DM trials were preceded by infections and other well-known triggers, “but there were a proportion of patients where they couldn’t identify the cause; it just kind of came out of the blue. Something about the medication lowers the threshold,” said panelist and endocrinologist Cecilia Low Wang, MD, director of the glucose management team at the University of Colorado Anschutz Medical Campus, Aurora, who voted against recommending approval.

“There’s definitely an increased risk” with other SGLT2 inhibitors, as well, when used off label for T1DM. “No one really knows why,” she said.

Dr. Wilson was also concerned that insulin wasn’t more tightly titrated in the placebo groups, which might have led to the 0.5% improvement seen with sotagliflozin, but “they wanted to have trials that were likely to be beneficial, so it’s reasonable to do what they did,” he said.

Overall, “we don’t really have many options for type 1, and many of us were sympathetic to the idea of increasing options.” In T1DM, “you can lose your concentration” on insulin dosing for a couple hours, “and the next thing you know you are going too high or too low and going off the road. These pills help smooth out your ups and downs. I would like to think [sotagliflozin] might be approved for a restricted group, for which we’ve really sorted out the ketone data,” he said.

Dr. Wilson and Dr. Low Wang did not have any disclosures.

[email protected]

Sanofi hasn’t given up on its SGLT1/2 inhibitor sotagliflozin (Zynquista) for type 1 diabetes mellitus despite a recent 8-to-8 split decision on recommendation for approval from the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee.

In the company’s three trials, involving about 3,000 insulin-dependent adults treated for up to a year, the drug lowered hemoglobin A_1c a respectable 0.5% without increasing hypoglycemia risk; reduced glucose variability; and increased time in range, with some modest benefits in both weight loss and lower blood pressure. There was no sign of the increased amputation risk that has bedeviled the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana), already on the market for type 2 diabetes mellitus.

The fly in the ointment was diabetic ketoacidosis (DKA); the drug increased the risk eightfold versus placebo, and, although there were no DKA deaths and over 60% of patients resumed sotagliflozin after recovering, the cases were serious and sometimes occurred in patients with glucose levels as low as 150 mg/dL. Younger people and women seemed to be at higher risk, according to the data.

DKA risk was 4 cases per 100 patients/year, a 4% risk, and that was in the ideal setting of a trial, not everyday practice. The annual background risk of DKA is 1% or less in type 1 diabetes mellitus (T1DM).

“It’s got to be safer than this,” said committee chair Peter Wilson, MD, professor of cardiology and public health at Emory University, Atlanta.

Dr. Wilson voted to recommend approval but with the major caveat that Sanofi have a strong risk mitigation program in place, perhaps based on ketone monitoring to catch emerging DKA before people end up in the ED. That was a universal request among others who voted for recommendation; among those who voted against, the concern in large part was that, even with such a program, the risk of DKA was still too high.

“If they had already developed a mitigation program that had been piloted, and they showed us some data, there would have been more enthusiasm, but we didn’t have that,” he said in an interview after the hearing.

Sanofi did suggest possible risk mitigation strategies during the meeting. In a statement afterwards, spokesman Nicolas Kressmann said, “While we acknowledge the increase in incidence of DKA observed with the addition of sotagliflozin to insulin, we believe that the risks may be mitigated and managed with proper patient selection and education regarding appropriate ketone monitoring. We will continue to work with the FDA to ensure the agency has the data it needs to evaluate the safety and efficacy of sotagliflozin when used as an oral treatment together with insulin by adults with T1DM. We are confident in the data of our T1DM clinical program.”

Meanwhile, the company’s development for T2DMs is ongoing, with results from a number of trials expected later in 2019. Sotagliflozin would join canagliflozin and two other SGLT2 inhibitors already on the market for T2DM, none of which have been approved for T1DM disease. The approved drugs work by increasing renal glucose excretion.

A significant proportion of DKA cases in sotagliflozin’s T1DM trials were preceded by infections and other well-known triggers, “but there were a proportion of patients where they couldn’t identify the cause; it just kind of came out of the blue. Something about the medication lowers the threshold,” said panelist and endocrinologist Cecilia Low Wang, MD, director of the glucose management team at the University of Colorado Anschutz Medical Campus, Aurora, who voted against recommending approval.

“There’s definitely an increased risk” with other SGLT2 inhibitors, as well, when used off label for T1DM. “No one really knows why,” she said.

Dr. Wilson was also concerned that insulin wasn’t more tightly titrated in the placebo groups, which might have led to the 0.5% improvement seen with sotagliflozin, but “they wanted to have trials that were likely to be beneficial, so it’s reasonable to do what they did,” he said.

Overall, “we don’t really have many options for type 1, and many of us were sympathetic to the idea of increasing options.” In T1DM, “you can lose your concentration” on insulin dosing for a couple hours, “and the next thing you know you are going too high or too low and going off the road. These pills help smooth out your ups and downs. I would like to think [sotagliflozin] might be approved for a restricted group, for which we’ve really sorted out the ketone data,” he said.

Dr. Wilson and Dr. Low Wang did not have any disclosures.

[email protected]

A proposal by the Trump Administration to pay for Medicare drugs administered in the physician office is not going over well with doctors.

monkeybusinessimages/thinkstockphotos.com

The Centers for Medicare & Medicaid Services in October 2018 issued an ”advance notice of proposed rulemaking with comment” outlining a test that would pay for Part B drugs with price points more closely aligned with international rates through the use of private sector vendors that would negotiate drug prices, procure the products, distribute them to physicians and hospitals, and take on the responsibility of billing Medicare.

Although the so-called International Pricing Index (IPI) model is not fully fleshed out in the regulatory filing, one of the key details that has been announced is that the demonstration project would have mandatory participation. This did not sit well with medical societies offering feedback to CMS.

The American Gastroenterological Association stated in comments filed with the agency that “AGA opposes mandatory physician participation and we urge CMS to implement the model on a voluntary basis.” AGA further noted that, while they support the Administration’s goal of reducing drug costs, “we are concerned that the model, as described, will make acquisition of Part B drugs more complex and will shift costs to physicians and practices, increasing administrative burden. Moreover, we are concerned that the IPI model may restrict access to clinically appropriate therapies for people with digestive diseases.”

And while the Community Oncology Alliance also spoke against making participation in the IPI model demonstration project mandatory, it went further with its criticism of the proposal.

“COA does not support the IPI Model as proposed in the pre-proposed rule published by [CMS] because we have serious concerns about its impact on cancer patient care and even its legality,” the group said on Dec. 31, 2018, comments filed with the agency, adding that “mandatory demonstration projects are clearly not in the charter of CMMI [Center for Medicare & Medicaid Innovation] as written into law by Congress. ... That would either be illegal or unconstitutional, with the latter case invalidating the section of the law that created and funded CMMI.”

The AGA, like other groups, also took exception to CMS’s “insinuation” in its regulatory preproposal that physicians select treatments based on reimbursement ahead of patient need. “CMS has repeatedly suggested that physicians prescribe therapies to patients not based on clinical evidence and judgment, but rather based on how much Medicare revenue it will generate for them. AGA objects to this premise. There is no objective evidence to support this idea.”

While none of the groups offered support for the IPI demonstration project, all offered suggestions on what could be done to improve on the details outlined in the advanced noticed of proposed rulemaking. AGA made recommendations, including making IPI Model participation voluntary; allowing individual physicians and physician groups to become model vendors, even if they intend to serve only their own practice or their own geographic region; prohibiting model vendors from implementing utilization management; and making model vendors responsible for collecting beneficiary cost-sharing. The American Medical Association in Dec. 20, 2018, comments to the agency took issue with the focus on single-source drugs and biologics indexed with international pricing, which could create access issues and have immediate adverse patient impacts.
 

[email protected]

A proposal by the Trump Administration to pay for Medicare drugs administered in the physician office is not going over well with doctors.

monkeybusinessimages/thinkstockphotos.com

The Centers for Medicare & Medicaid Services in October 2018 issued an ”advance notice of proposed rulemaking with comment” outlining a test that would pay for Part B drugs with price points more closely aligned with international rates through the use of private sector vendors that would negotiate drug prices, procure the products, distribute them to physicians and hospitals, and take on the responsibility of billing Medicare.

Although the so-called International Pricing Index (IPI) model is not fully fleshed out in the regulatory filing, one of the key details that has been announced is that the demonstration project would have mandatory participation. This did not sit well with medical societies offering feedback to CMS.

The American Gastroenterological Association stated in comments filed with the agency that “AGA opposes mandatory physician participation and we urge CMS to implement the model on a voluntary basis.” AGA further noted that, while they support the Administration’s goal of reducing drug costs, “we are concerned that the model, as described, will make acquisition of Part B drugs more complex and will shift costs to physicians and practices, increasing administrative burden. Moreover, we are concerned that the IPI model may restrict access to clinically appropriate therapies for people with digestive diseases.”

And while the Community Oncology Alliance also spoke against making participation in the IPI model demonstration project mandatory, it went further with its criticism of the proposal.

“COA does not support the IPI Model as proposed in the pre-proposed rule published by [CMS] because we have serious concerns about its impact on cancer patient care and even its legality,” the group said on Dec. 31, 2018, comments filed with the agency, adding that “mandatory demonstration projects are clearly not in the charter of CMMI [Center for Medicare & Medicaid Innovation] as written into law by Congress. ... That would either be illegal or unconstitutional, with the latter case invalidating the section of the law that created and funded CMMI.”

The AGA, like other groups, also took exception to CMS’s “insinuation” in its regulatory preproposal that physicians select treatments based on reimbursement ahead of patient need. “CMS has repeatedly suggested that physicians prescribe therapies to patients not based on clinical evidence and judgment, but rather based on how much Medicare revenue it will generate for them. AGA objects to this premise. There is no objective evidence to support this idea.”

While none of the groups offered support for the IPI demonstration project, all offered suggestions on what could be done to improve on the details outlined in the advanced noticed of proposed rulemaking. AGA made recommendations, including making IPI Model participation voluntary; allowing individual physicians and physician groups to become model vendors, even if they intend to serve only their own practice or their own geographic region; prohibiting model vendors from implementing utilization management; and making model vendors responsible for collecting beneficiary cost-sharing. The American Medical Association in Dec. 20, 2018, comments to the agency took issue with the focus on single-source drugs and biologics indexed with international pricing, which could create access issues and have immediate adverse patient impacts.
 

[email protected]

A proposal by the Trump Administration to pay for Medicare drugs administered in the physician office is not going over well with doctors.

monkeybusinessimages/thinkstockphotos.com

The Centers for Medicare & Medicaid Services in October 2018 issued an ”advance notice of proposed rulemaking with comment” outlining a test that would pay for Part B drugs with price points more closely aligned with international rates through the use of private sector vendors that would negotiate drug prices, procure the products, distribute them to physicians and hospitals, and take on the responsibility of billing Medicare.

Although the so-called International Pricing Index (IPI) model is not fully fleshed out in the regulatory filing, one of the key details that has been announced is that the demonstration project would have mandatory participation. This did not sit well with medical societies offering feedback to CMS.

The American Gastroenterological Association stated in comments filed with the agency that “AGA opposes mandatory physician participation and we urge CMS to implement the model on a voluntary basis.” AGA further noted that, while they support the Administration’s goal of reducing drug costs, “we are concerned that the model, as described, will make acquisition of Part B drugs more complex and will shift costs to physicians and practices, increasing administrative burden. Moreover, we are concerned that the IPI model may restrict access to clinically appropriate therapies for people with digestive diseases.”

And while the Community Oncology Alliance also spoke against making participation in the IPI model demonstration project mandatory, it went further with its criticism of the proposal.

“COA does not support the IPI Model as proposed in the pre-proposed rule published by [CMS] because we have serious concerns about its impact on cancer patient care and even its legality,” the group said on Dec. 31, 2018, comments filed with the agency, adding that “mandatory demonstration projects are clearly not in the charter of CMMI [Center for Medicare & Medicaid Innovation] as written into law by Congress. ... That would either be illegal or unconstitutional, with the latter case invalidating the section of the law that created and funded CMMI.”

The AGA, like other groups, also took exception to CMS’s “insinuation” in its regulatory preproposal that physicians select treatments based on reimbursement ahead of patient need. “CMS has repeatedly suggested that physicians prescribe therapies to patients not based on clinical evidence and judgment, but rather based on how much Medicare revenue it will generate for them. AGA objects to this premise. There is no objective evidence to support this idea.”

While none of the groups offered support for the IPI demonstration project, all offered suggestions on what could be done to improve on the details outlined in the advanced noticed of proposed rulemaking. AGA made recommendations, including making IPI Model participation voluntary; allowing individual physicians and physician groups to become model vendors, even if they intend to serve only their own practice or their own geographic region; prohibiting model vendors from implementing utilization management; and making model vendors responsible for collecting beneficiary cost-sharing. The American Medical Association in Dec. 20, 2018, comments to the agency took issue with the focus on single-source drugs and biologics indexed with international pricing, which could create access issues and have immediate adverse patient impacts.
 

[email protected]

The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).

The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.

Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.

The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).

The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.

The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.

The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.

Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.

[email protected]

The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).

The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.

Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.

The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).

The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.

The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.

The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.

Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.

[email protected]

The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).

The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.

Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.

The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).

The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.

The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.

The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.

Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.

[email protected]

ORLANDO – The first time a man walks in for an aesthetic consultation, he probably doesn’t know what to expect, according to Terrence Keaney, MD, a dermatologist in private practice in Arlington, Va. And he may not even be sure what he’s looking for.

However, he probably knows what he doesn’t like about his appearance. When men are questioned, the three areas they are most concerned about is their hairline, their eyes, and their jawline, said Dr. Keaney, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.

It’s important to evaluate men differently, not just for anatomic differences from women, but also for behavioral and psychological factors unique to men as aesthetic patients, he noted.

Anatomic differences are significant and fundamentally shape treatment decisions, Dr. Keaney said. Broadly speaking, “the male face is traditionally more square, with a prominent supraorbital ridge.” Rather than emphasizing breadth across the cheeks, as in rejuvenation for women, a strong, youthful male face will have a square jaw, appropriate width across the cheeks, and a strong brow line with an arch that is flatter than what women seek.

Male cosmetic goals can be complicated by the fact that men “age poorly” and tend to look older than their stated age, he continued, referring to a study that found that men appear about one-third year older than their age, and women about a half year younger. A higher rate of smoking and excess ultraviolet light exposure among men may contribute to this discrepancy, he said.

Overall, men see steady atrophy of facial soft tissue throughout adulthood, in contrast to women who see a more rapid decline that starts at menopause. This makes sense in the context of the slow drop in circulating testosterone that men see beginning at about age 30, at which time men can expect a decrease of about 1% per year, he noted.

A common opener from men, said Dr. Keaney, is “’I look tired.’ When I hear that, I’m thinking about the eyes.” Men are more likely to develop tear troughs and a sunken appearance because of their larger orbital cavities and smaller orbital fat pads, so periocular fillers are often a treatment tool to consider.

Around mens’ eyes, “it’s not just the presence, but the pattern of wrinkles that guides treatment,” he noted. At the lateral canthi, both at rest and with maximum smile, the predominant wrinkle pattern in crows’ feet is the lower fan. The cheek elevator musculature, including the zygomaticus major, are more involved in animation around the eyes with smiling, which is important because reaching for botulinum toxin alone is probably not going to give the patient his desired effect, he added.

Other differences in the male wrinkle pattern can be found on the brow. The “U” contraction pattern between the brows is more common in men than women, at least partly because men have greater involvement of the procerus muscle, Dr. Keaney said.

Taking all of this into account, caution is the watchword when using botulinum toxin for the glabellar and brow region. “Beware of eyebrow ptosis: avoid the frontalis in patients with eyebrow ptosis,” he said. Treating the corrugators can also be an unwise move, since toxin can diffuse to the inferior fibers of the frontalis muscle, he added.

For men with jawline concerns, consider a combination approach, Dr. Keaney said. The lower face and neck can be rejuvenated by a redraping solution, such as skin tightening with high frequency ultrasound or radiofrequency ablation.

Sometimes, a clean, tight sweep of jawline can be restored with dermal fillers to the lower face, along with a noninvasive fat reduction approach, said Dr. Keaney.

Knowing men’s unique anatomy and aging patterns is only half the battle, though. “How you communicate with men and evaluate them has to take into account that you might be seeing a sweaty, nervous, treatment-naive patient,” at the initial consultation, said Dr. Keaney. “Do men care? Yes, but men display a different set of motivations.”

Plan for all of this to take time. “The initial consultation tends to be longer” for male patients, who are “less savvy” about cosmetic procedures than women, he pointed out.

A clear discussion of side effects is critical when discussing treatment options with men. “If they get a side effect, you’ll never see them again – and you won’t ever hear about it,” he added.

Though overall, women have been shown to be more sensitive to pain, in cosmetic procedures, “men are less tolerant of pain.” Plan for this, set reasonable expectations but be proactive about pain control, and still expect a need for some hand-holding, said Dr. Keaney.

“Men do not like surprises,” he added. Clearly define what expected side effects may be, what they’ll look like, and what downtime the patient should expect.

For Dr. Keaney’s part, he’s found that the best way to retain men in his cosmetic practice is to “start with a home run treatment to earn trust.” Men often appreciate a slow and steady approach to addressing concerns. “Make sure to connect the treatment plan to the primary cosmetic concern.”

Dr. Keaney reported that he has relationships with multiple pharmaceutical and cosmetic companies.

[email protected]

ORLANDO – The first time a man walks in for an aesthetic consultation, he probably doesn’t know what to expect, according to Terrence Keaney, MD, a dermatologist in private practice in Arlington, Va. And he may not even be sure what he’s looking for.

However, he probably knows what he doesn’t like about his appearance. When men are questioned, the three areas they are most concerned about is their hairline, their eyes, and their jawline, said Dr. Keaney, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.

It’s important to evaluate men differently, not just for anatomic differences from women, but also for behavioral and psychological factors unique to men as aesthetic patients, he noted.

Anatomic differences are significant and fundamentally shape treatment decisions, Dr. Keaney said. Broadly speaking, “the male face is traditionally more square, with a prominent supraorbital ridge.” Rather than emphasizing breadth across the cheeks, as in rejuvenation for women, a strong, youthful male face will have a square jaw, appropriate width across the cheeks, and a strong brow line with an arch that is flatter than what women seek.

Male cosmetic goals can be complicated by the fact that men “age poorly” and tend to look older than their stated age, he continued, referring to a study that found that men appear about one-third year older than their age, and women about a half year younger. A higher rate of smoking and excess ultraviolet light exposure among men may contribute to this discrepancy, he said.

Overall, men see steady atrophy of facial soft tissue throughout adulthood, in contrast to women who see a more rapid decline that starts at menopause. This makes sense in the context of the slow drop in circulating testosterone that men see beginning at about age 30, at which time men can expect a decrease of about 1% per year, he noted.

A common opener from men, said Dr. Keaney, is “’I look tired.’ When I hear that, I’m thinking about the eyes.” Men are more likely to develop tear troughs and a sunken appearance because of their larger orbital cavities and smaller orbital fat pads, so periocular fillers are often a treatment tool to consider.

Around mens’ eyes, “it’s not just the presence, but the pattern of wrinkles that guides treatment,” he noted. At the lateral canthi, both at rest and with maximum smile, the predominant wrinkle pattern in crows’ feet is the lower fan. The cheek elevator musculature, including the zygomaticus major, are more involved in animation around the eyes with smiling, which is important because reaching for botulinum toxin alone is probably not going to give the patient his desired effect, he added.

Other differences in the male wrinkle pattern can be found on the brow. The “U” contraction pattern between the brows is more common in men than women, at least partly because men have greater involvement of the procerus muscle, Dr. Keaney said.

Taking all of this into account, caution is the watchword when using botulinum toxin for the glabellar and brow region. “Beware of eyebrow ptosis: avoid the frontalis in patients with eyebrow ptosis,” he said. Treating the corrugators can also be an unwise move, since toxin can diffuse to the inferior fibers of the frontalis muscle, he added.

For men with jawline concerns, consider a combination approach, Dr. Keaney said. The lower face and neck can be rejuvenated by a redraping solution, such as skin tightening with high frequency ultrasound or radiofrequency ablation.

Sometimes, a clean, tight sweep of jawline can be restored with dermal fillers to the lower face, along with a noninvasive fat reduction approach, said Dr. Keaney.

Knowing men’s unique anatomy and aging patterns is only half the battle, though. “How you communicate with men and evaluate them has to take into account that you might be seeing a sweaty, nervous, treatment-naive patient,” at the initial consultation, said Dr. Keaney. “Do men care? Yes, but men display a different set of motivations.”

Plan for all of this to take time. “The initial consultation tends to be longer” for male patients, who are “less savvy” about cosmetic procedures than women, he pointed out.

A clear discussion of side effects is critical when discussing treatment options with men. “If they get a side effect, you’ll never see them again – and you won’t ever hear about it,” he added.

Though overall, women have been shown to be more sensitive to pain, in cosmetic procedures, “men are less tolerant of pain.” Plan for this, set reasonable expectations but be proactive about pain control, and still expect a need for some hand-holding, said Dr. Keaney.

“Men do not like surprises,” he added. Clearly define what expected side effects may be, what they’ll look like, and what downtime the patient should expect.

For Dr. Keaney’s part, he’s found that the best way to retain men in his cosmetic practice is to “start with a home run treatment to earn trust.” Men often appreciate a slow and steady approach to addressing concerns. “Make sure to connect the treatment plan to the primary cosmetic concern.”

Dr. Keaney reported that he has relationships with multiple pharmaceutical and cosmetic companies.

[email protected]

ORLANDO – The first time a man walks in for an aesthetic consultation, he probably doesn’t know what to expect, according to Terrence Keaney, MD, a dermatologist in private practice in Arlington, Va. And he may not even be sure what he’s looking for.

However, he probably knows what he doesn’t like about his appearance. When men are questioned, the three areas they are most concerned about is their hairline, their eyes, and their jawline, said Dr. Keaney, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.

It’s important to evaluate men differently, not just for anatomic differences from women, but also for behavioral and psychological factors unique to men as aesthetic patients, he noted.

Anatomic differences are significant and fundamentally shape treatment decisions, Dr. Keaney said. Broadly speaking, “the male face is traditionally more square, with a prominent supraorbital ridge.” Rather than emphasizing breadth across the cheeks, as in rejuvenation for women, a strong, youthful male face will have a square jaw, appropriate width across the cheeks, and a strong brow line with an arch that is flatter than what women seek.

Male cosmetic goals can be complicated by the fact that men “age poorly” and tend to look older than their stated age, he continued, referring to a study that found that men appear about one-third year older than their age, and women about a half year younger. A higher rate of smoking and excess ultraviolet light exposure among men may contribute to this discrepancy, he said.

Overall, men see steady atrophy of facial soft tissue throughout adulthood, in contrast to women who see a more rapid decline that starts at menopause. This makes sense in the context of the slow drop in circulating testosterone that men see beginning at about age 30, at which time men can expect a decrease of about 1% per year, he noted.

A common opener from men, said Dr. Keaney, is “’I look tired.’ When I hear that, I’m thinking about the eyes.” Men are more likely to develop tear troughs and a sunken appearance because of their larger orbital cavities and smaller orbital fat pads, so periocular fillers are often a treatment tool to consider.

Around mens’ eyes, “it’s not just the presence, but the pattern of wrinkles that guides treatment,” he noted. At the lateral canthi, both at rest and with maximum smile, the predominant wrinkle pattern in crows’ feet is the lower fan. The cheek elevator musculature, including the zygomaticus major, are more involved in animation around the eyes with smiling, which is important because reaching for botulinum toxin alone is probably not going to give the patient his desired effect, he added.

Other differences in the male wrinkle pattern can be found on the brow. The “U” contraction pattern between the brows is more common in men than women, at least partly because men have greater involvement of the procerus muscle, Dr. Keaney said.

Taking all of this into account, caution is the watchword when using botulinum toxin for the glabellar and brow region. “Beware of eyebrow ptosis: avoid the frontalis in patients with eyebrow ptosis,” he said. Treating the corrugators can also be an unwise move, since toxin can diffuse to the inferior fibers of the frontalis muscle, he added.

For men with jawline concerns, consider a combination approach, Dr. Keaney said. The lower face and neck can be rejuvenated by a redraping solution, such as skin tightening with high frequency ultrasound or radiofrequency ablation.

Sometimes, a clean, tight sweep of jawline can be restored with dermal fillers to the lower face, along with a noninvasive fat reduction approach, said Dr. Keaney.

Knowing men’s unique anatomy and aging patterns is only half the battle, though. “How you communicate with men and evaluate them has to take into account that you might be seeing a sweaty, nervous, treatment-naive patient,” at the initial consultation, said Dr. Keaney. “Do men care? Yes, but men display a different set of motivations.”

Plan for all of this to take time. “The initial consultation tends to be longer” for male patients, who are “less savvy” about cosmetic procedures than women, he pointed out.

A clear discussion of side effects is critical when discussing treatment options with men. “If they get a side effect, you’ll never see them again – and you won’t ever hear about it,” he added.

Though overall, women have been shown to be more sensitive to pain, in cosmetic procedures, “men are less tolerant of pain.” Plan for this, set reasonable expectations but be proactive about pain control, and still expect a need for some hand-holding, said Dr. Keaney.

“Men do not like surprises,” he added. Clearly define what expected side effects may be, what they’ll look like, and what downtime the patient should expect.

For Dr. Keaney’s part, he’s found that the best way to retain men in his cosmetic practice is to “start with a home run treatment to earn trust.” Men often appreciate a slow and steady approach to addressing concerns. “Make sure to connect the treatment plan to the primary cosmetic concern.”

Dr. Keaney reported that he has relationships with multiple pharmaceutical and cosmetic companies.

[email protected]

BOSTON – Ablation of atrial fibrillation led to significantly better quality of life improvements, compared with antiarrhythmic drug therapy, in a prespecified, secondary analysis of data from the CABANA multicenter, randomized trial with 2,204 patients.

Mitchel L. Zoler/MDedge News

The improvements in quality of life measures in atrial fibrillation (AF) patients following ablation were “clinically meaningful” relative to drug therapy and were sustained for 5 years of follow-up, said Douglas L. Packer, MD, at the annual International AF Symposium.

The apparent incremental benefit in quality of life after ablation, compared with patients treated with drug therapy, added to the benefits previously reported from CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) using ablation that included a highly significant reduction in recurrent AF and a significant reduction in the combined endpoint of mortality or cardiovascular hospitalization. However, the trial’s results were neutral for the study’s prespecified primary endpoint, a combination of the rate of total mortality, disabling stroke, serious bleeding, or cardiac arrest in an intention-to-treat analysis, a result first reported by Dr. Packer at the annual scientific sessions of the Heart Rhythm Society in May 2018.

When Dr. Packer spoke at the AF Symposium in late January 2019, the CABANA results had still not been published. He said that he expected an article with the main findings to appear online sometime in February 2019.

The quality of life analysis, focused on two measures, the Mayo AF-Specific Symptoms Inventory (MAFSI) (Circulation. 2008 Oct 28;118[suppl 18]:S589) and the Atrial Fibrillation Affect on Quality of Life (AFEQT) (Circ Arrhythm Electrophysiol. 2011 Feb;4[1]:15-25). The patients enrolled in the two treatment arms of CABANA had essentially identical baseline MAFSI frequency scores, but starting 3 months after entry patients randomized to the ablation arm had an average, statistically significant 1.6-point improvement in their adjusted MAFSI frequency score, compared with patients in the drug-therapy arm; this reduction persisted at about the same statistically significant level through 5 years, said Dr. Packer, an electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn., and lead investigator of CABANA. Patients who remained in follow-up throughout the study’s entire 60 months underwent a total of seven MAFSI assessments after their initial treatment; the average, adjusted difference in MAFSI frequency scores throughout CABANA was a statistically significant 1.4 points lower among ablated patients, compared with those randomized to drug therapy, said Dr. Packer, who presented data first reported by the CABANA researchers in 2018.

The pattern of change in the AFEQT scores was very similar. The average, adjusted AFEQT summary scores were virtually identical at baseline for the two treatment arms, but at 3 months after the study began patients in the ablation arm had an average, adjusted, statistically significant 3-point improvement in their AFEQT summary scores, compared with drug-treated patients; this incremental increase in AFEQT scores remained consistent and statistically significant through 5 years of follow-up. Throughout the study, the average, adjusted, incremental improvement in AFEQT after ablation was a statistically significant 3.4 points, said Dr. Packer.

Mitchel L. Zoler/MDedge News

But these quality of life measures in patients who received unblinded assignment to an ablation procedure or drug treatment in CABANA are likely unreliable, commented Peter R. Kowey, MD, an electrophysiologist at the Lankenau Heart Institute in Wynnewood, Penn., and professor of medicine at Jefferson Medical College, Philadelphia.

“Assessing quality of life in an unblinded trial seems to me to be pretty shallow,” said Dr. Kowey, a member of the CABANA steering committee and a participant in a panel at the Symposium that discussed the results. Patients who have just gone through a 6-hour procedure will often say they now feel a whole lot better, he suggested. “They’re concerned what will get done to them if they don’t say they feel better.” The same confounding also applies to other “soft” secondary endpoints used in CABANA, such as hospitalization rates.

The reliability of these more subjective outcome measures is reduced in an unblinded trial, Dr. Kowey maintained. The CABANA results “don’t change the fundamental principal of using hard endpoints,” such as those that made up the primary endpoint of the study, he said in an interview. “We put secondary endpoints into the study because they are legitimate things to look at, but they have questionable reliability,” as measures of ablation’s efficacy.

Dr. Kowey also cautioned against focusing on the per-protocol and treatment-received analyses of the CABANA results, prespecified analyses that Dr. Packer highlighted because of the high number of crossovers in the trial: 9% of patients assigned to ablation never received it and 28% of patients assigned to drug therapy actually received ablation.

The CABANA steering committee anticipated a high crossover rate, but still set the intention-to-treat analysis as primary because “per protocol introduces many biases and can’t be relied on for a study of this magnitude,” Dr. Kowey said. He also cited the statistical pitfalls of looking at multiple secondary endpoints in the CABANA results and the danger of reading too much into subgroup analyses, all from a trial with a neutral primary endpoint.

Another concern he raised centered on the generalizability of CABANA’s safety findings, which showed roughly similar adverse event rates between the two treatment arms – about 9% with ablation, 4% with drugs – although the distribution of complications types differed between the two arms. The “ ‘remarkably safe’ performance of ablation in CABANA can be attributed to ‘cherry-picked’ investigators” who performed the ablation procedures at high-volume centers, said Dr. Kowey. “The safety of ablation was predictable” in CABANA because of the selection of participating centers. “Seventy percent of U.S. ablations are being done at centers that do fewer than 25 ablations annually,” Dr. Kowey said. “We don’t know what goes on” at lower-volume centers; “ablation can’t be considered as safe as we presume” when done at centers outside the 118 sites that participated in CABANA, he maintained.

CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in AF mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

[email protected]

BOSTON – Ablation of atrial fibrillation led to significantly better quality of life improvements, compared with antiarrhythmic drug therapy, in a prespecified, secondary analysis of data from the CABANA multicenter, randomized trial with 2,204 patients.

Mitchel L. Zoler/MDedge News

The improvements in quality of life measures in atrial fibrillation (AF) patients following ablation were “clinically meaningful” relative to drug therapy and were sustained for 5 years of follow-up, said Douglas L. Packer, MD, at the annual International AF Symposium.

The apparent incremental benefit in quality of life after ablation, compared with patients treated with drug therapy, added to the benefits previously reported from CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) using ablation that included a highly significant reduction in recurrent AF and a significant reduction in the combined endpoint of mortality or cardiovascular hospitalization. However, the trial’s results were neutral for the study’s prespecified primary endpoint, a combination of the rate of total mortality, disabling stroke, serious bleeding, or cardiac arrest in an intention-to-treat analysis, a result first reported by Dr. Packer at the annual scientific sessions of the Heart Rhythm Society in May 2018.

When Dr. Packer spoke at the AF Symposium in late January 2019, the CABANA results had still not been published. He said that he expected an article with the main findings to appear online sometime in February 2019.

The quality of life analysis, focused on two measures, the Mayo AF-Specific Symptoms Inventory (MAFSI) (Circulation. 2008 Oct 28;118[suppl 18]:S589) and the Atrial Fibrillation Affect on Quality of Life (AFEQT) (Circ Arrhythm Electrophysiol. 2011 Feb;4[1]:15-25). The patients enrolled in the two treatment arms of CABANA had essentially identical baseline MAFSI frequency scores, but starting 3 months after entry patients randomized to the ablation arm had an average, statistically significant 1.6-point improvement in their adjusted MAFSI frequency score, compared with patients in the drug-therapy arm; this reduction persisted at about the same statistically significant level through 5 years, said Dr. Packer, an electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn., and lead investigator of CABANA. Patients who remained in follow-up throughout the study’s entire 60 months underwent a total of seven MAFSI assessments after their initial treatment; the average, adjusted difference in MAFSI frequency scores throughout CABANA was a statistically significant 1.4 points lower among ablated patients, compared with those randomized to drug therapy, said Dr. Packer, who presented data first reported by the CABANA researchers in 2018.

The pattern of change in the AFEQT scores was very similar. The average, adjusted AFEQT summary scores were virtually identical at baseline for the two treatment arms, but at 3 months after the study began patients in the ablation arm had an average, adjusted, statistically significant 3-point improvement in their AFEQT summary scores, compared with drug-treated patients; this incremental increase in AFEQT scores remained consistent and statistically significant through 5 years of follow-up. Throughout the study, the average, adjusted, incremental improvement in AFEQT after ablation was a statistically significant 3.4 points, said Dr. Packer.

Mitchel L. Zoler/MDedge News

But these quality of life measures in patients who received unblinded assignment to an ablation procedure or drug treatment in CABANA are likely unreliable, commented Peter R. Kowey, MD, an electrophysiologist at the Lankenau Heart Institute in Wynnewood, Penn., and professor of medicine at Jefferson Medical College, Philadelphia.

“Assessing quality of life in an unblinded trial seems to me to be pretty shallow,” said Dr. Kowey, a member of the CABANA steering committee and a participant in a panel at the Symposium that discussed the results. Patients who have just gone through a 6-hour procedure will often say they now feel a whole lot better, he suggested. “They’re concerned what will get done to them if they don’t say they feel better.” The same confounding also applies to other “soft” secondary endpoints used in CABANA, such as hospitalization rates.

The reliability of these more subjective outcome measures is reduced in an unblinded trial, Dr. Kowey maintained. The CABANA results “don’t change the fundamental principal of using hard endpoints,” such as those that made up the primary endpoint of the study, he said in an interview. “We put secondary endpoints into the study because they are legitimate things to look at, but they have questionable reliability,” as measures of ablation’s efficacy.

Dr. Kowey also cautioned against focusing on the per-protocol and treatment-received analyses of the CABANA results, prespecified analyses that Dr. Packer highlighted because of the high number of crossovers in the trial: 9% of patients assigned to ablation never received it and 28% of patients assigned to drug therapy actually received ablation.

The CABANA steering committee anticipated a high crossover rate, but still set the intention-to-treat analysis as primary because “per protocol introduces many biases and can’t be relied on for a study of this magnitude,” Dr. Kowey said. He also cited the statistical pitfalls of looking at multiple secondary endpoints in the CABANA results and the danger of reading too much into subgroup analyses, all from a trial with a neutral primary endpoint.

Another concern he raised centered on the generalizability of CABANA’s safety findings, which showed roughly similar adverse event rates between the two treatment arms – about 9% with ablation, 4% with drugs – although the distribution of complications types differed between the two arms. The “ ‘remarkably safe’ performance of ablation in CABANA can be attributed to ‘cherry-picked’ investigators” who performed the ablation procedures at high-volume centers, said Dr. Kowey. “The safety of ablation was predictable” in CABANA because of the selection of participating centers. “Seventy percent of U.S. ablations are being done at centers that do fewer than 25 ablations annually,” Dr. Kowey said. “We don’t know what goes on” at lower-volume centers; “ablation can’t be considered as safe as we presume” when done at centers outside the 118 sites that participated in CABANA, he maintained.

CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in AF mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

[email protected]

BOSTON – Ablation of atrial fibrillation led to significantly better quality of life improvements, compared with antiarrhythmic drug therapy, in a prespecified, secondary analysis of data from the CABANA multicenter, randomized trial with 2,204 patients.

Mitchel L. Zoler/MDedge News

The improvements in quality of life measures in atrial fibrillation (AF) patients following ablation were “clinically meaningful” relative to drug therapy and were sustained for 5 years of follow-up, said Douglas L. Packer, MD, at the annual International AF Symposium.

The apparent incremental benefit in quality of life after ablation, compared with patients treated with drug therapy, added to the benefits previously reported from CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) using ablation that included a highly significant reduction in recurrent AF and a significant reduction in the combined endpoint of mortality or cardiovascular hospitalization. However, the trial’s results were neutral for the study’s prespecified primary endpoint, a combination of the rate of total mortality, disabling stroke, serious bleeding, or cardiac arrest in an intention-to-treat analysis, a result first reported by Dr. Packer at the annual scientific sessions of the Heart Rhythm Society in May 2018.

When Dr. Packer spoke at the AF Symposium in late January 2019, the CABANA results had still not been published. He said that he expected an article with the main findings to appear online sometime in February 2019.

The quality of life analysis, focused on two measures, the Mayo AF-Specific Symptoms Inventory (MAFSI) (Circulation. 2008 Oct 28;118[suppl 18]:S589) and the Atrial Fibrillation Affect on Quality of Life (AFEQT) (Circ Arrhythm Electrophysiol. 2011 Feb;4[1]:15-25). The patients enrolled in the two treatment arms of CABANA had essentially identical baseline MAFSI frequency scores, but starting 3 months after entry patients randomized to the ablation arm had an average, statistically significant 1.6-point improvement in their adjusted MAFSI frequency score, compared with patients in the drug-therapy arm; this reduction persisted at about the same statistically significant level through 5 years, said Dr. Packer, an electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn., and lead investigator of CABANA. Patients who remained in follow-up throughout the study’s entire 60 months underwent a total of seven MAFSI assessments after their initial treatment; the average, adjusted difference in MAFSI frequency scores throughout CABANA was a statistically significant 1.4 points lower among ablated patients, compared with those randomized to drug therapy, said Dr. Packer, who presented data first reported by the CABANA researchers in 2018.

The pattern of change in the AFEQT scores was very similar. The average, adjusted AFEQT summary scores were virtually identical at baseline for the two treatment arms, but at 3 months after the study began patients in the ablation arm had an average, adjusted, statistically significant 3-point improvement in their AFEQT summary scores, compared with drug-treated patients; this incremental increase in AFEQT scores remained consistent and statistically significant through 5 years of follow-up. Throughout the study, the average, adjusted, incremental improvement in AFEQT after ablation was a statistically significant 3.4 points, said Dr. Packer.

Mitchel L. Zoler/MDedge News

But these quality of life measures in patients who received unblinded assignment to an ablation procedure or drug treatment in CABANA are likely unreliable, commented Peter R. Kowey, MD, an electrophysiologist at the Lankenau Heart Institute in Wynnewood, Penn., and professor of medicine at Jefferson Medical College, Philadelphia.

“Assessing quality of life in an unblinded trial seems to me to be pretty shallow,” said Dr. Kowey, a member of the CABANA steering committee and a participant in a panel at the Symposium that discussed the results. Patients who have just gone through a 6-hour procedure will often say they now feel a whole lot better, he suggested. “They’re concerned what will get done to them if they don’t say they feel better.” The same confounding also applies to other “soft” secondary endpoints used in CABANA, such as hospitalization rates.

The reliability of these more subjective outcome measures is reduced in an unblinded trial, Dr. Kowey maintained. The CABANA results “don’t change the fundamental principal of using hard endpoints,” such as those that made up the primary endpoint of the study, he said in an interview. “We put secondary endpoints into the study because they are legitimate things to look at, but they have questionable reliability,” as measures of ablation’s efficacy.

Dr. Kowey also cautioned against focusing on the per-protocol and treatment-received analyses of the CABANA results, prespecified analyses that Dr. Packer highlighted because of the high number of crossovers in the trial: 9% of patients assigned to ablation never received it and 28% of patients assigned to drug therapy actually received ablation.

The CABANA steering committee anticipated a high crossover rate, but still set the intention-to-treat analysis as primary because “per protocol introduces many biases and can’t be relied on for a study of this magnitude,” Dr. Kowey said. He also cited the statistical pitfalls of looking at multiple secondary endpoints in the CABANA results and the danger of reading too much into subgroup analyses, all from a trial with a neutral primary endpoint.

Another concern he raised centered on the generalizability of CABANA’s safety findings, which showed roughly similar adverse event rates between the two treatment arms – about 9% with ablation, 4% with drugs – although the distribution of complications types differed between the two arms. The “ ‘remarkably safe’ performance of ablation in CABANA can be attributed to ‘cherry-picked’ investigators” who performed the ablation procedures at high-volume centers, said Dr. Kowey. “The safety of ablation was predictable” in CABANA because of the selection of participating centers. “Seventy percent of U.S. ablations are being done at centers that do fewer than 25 ablations annually,” Dr. Kowey said. “We don’t know what goes on” at lower-volume centers; “ablation can’t be considered as safe as we presume” when done at centers outside the 118 sites that participated in CABANA, he maintained.

CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in AF mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

[email protected]

CORONADO, CALIF. – Raw data from the Fitbit and sleep applications for smartphones should not be recommended as screening tools for obstructive sleep apnea, results from a single-center study suggest.

Doug Brunk/MDedge News

“Currently, the gold standard for diagnosis is a polysomnography (PSG), which is basically a sleep study test,” one of the study authors, Daniel Chung, MD, said in an interview in advance of the Triological Society’s Combined Sections Meeting. “While it is very thorough, it is expensive, intrusive, and gives data on only 1 night of sleep and cannot give information on a patient’s sleep pattern over several days. Using wrist-worn devices such as Fitbit products or smartphone applications such as Sleep Cycle would be much cheaper alternatives with little distraction that can provide continuous data over several days if accurate.”

According to Dr. Chung, an otolaryngology head and neck surgery resident in the department of surgery at the George Washington University, Washington, previous studies about this topic are inconclusive.

“Most have been studied only in the pediatric population, and in general, show that Fitbit overestimates PSG measurements,” he said. “Also, prior studies have looked into 20-60 patients, depending on the study.”

In an effort to address these limitations, he and his colleagues prospectively evaluated 180 adult patients who were already scheduled to undergo a PSG with or without CPAP testing from the sleep lab. The overnight test was performed with a Fitbit Alta HR on their wrist of choice and a smartphone at their bedside. Each smartphone was randomly assigned and had a popular sleep application installed, with Sleep as Android on the Android phone and Sleep Cycle on the Apple iPhone. For the main outcomes of interest, the researchers collected the total sleep time, sleep efficiency, and apnea-hypopnea index (AHI) from the PSG and compared them with their equivalents from Fitbit and smartphone applications. For statistical analysis, they performed Bland-Altman plots, paired t-tests, and regression lines to assess R2, slope, and Y-intercept.

Dr. Chung and his colleagues found that both Fitbit Alta HR (P = .0014) and smartphone applications (P less than .0001) significantly overestimated the total sleep time, compared with PSG, while moderate correlation for sleep efficiency was observed between PSG and Fitbit (r = 0.38). Other findings of note were that the number of times awake recorded by Fitbit significantly underestimated the PSG AHI (P less than .0001), the snoring noise measurements from Sleep as Android had strong associations with PSG AHI (R2 = 0.43), and those from Sleep Cycle had modest associations with PSG AHI (R2 = 0.12). However, Bland-Altman plots showed wide limits of agreement for total sleep time and sleep efficiency, though as sleep efficiency approached 100%, the discrepancy between the PSG and Fitbit decreased.

“While there are various tools out right now that claim to measure sleep in a more comforting setting, we cannot recommend any product to act as a screening device or replacement for the PSG at this time,” Dr. Chung said.

He acknowledged certain limitations of the study, including the fact that Fitbit is unable to fully record sleep data if the wearer is asleep for fewer than 3 hours, which can happen in patients with severe OSA. In addition, the smartphone applications require the user to begin and conclude the recording. “This was performed only by the sleep technicians and not the patients, and can be a significant source of error, particularly with the Sleep as Android application, as it had a less intuitive interface,” he noted. “This lead to multiple unusable data points. There were also incidences where the Fitbit Alta HR failed to record sleep data even though it was fully charged and correctly placed, which led to only a smaller number of patients having both measurements at the same time.”

Dr. Chung reported having no financial disclosures. The meeting was jointly sponsored by the Triological Society and the American College of Surgeons.
 

[email protected]

SOURCE: Chung D et al. Triological CSM, Abstracts.

CORONADO, CALIF. – Raw data from the Fitbit and sleep applications for smartphones should not be recommended as screening tools for obstructive sleep apnea, results from a single-center study suggest.

Doug Brunk/MDedge News

“Currently, the gold standard for diagnosis is a polysomnography (PSG), which is basically a sleep study test,” one of the study authors, Daniel Chung, MD, said in an interview in advance of the Triological Society’s Combined Sections Meeting. “While it is very thorough, it is expensive, intrusive, and gives data on only 1 night of sleep and cannot give information on a patient’s sleep pattern over several days. Using wrist-worn devices such as Fitbit products or smartphone applications such as Sleep Cycle would be much cheaper alternatives with little distraction that can provide continuous data over several days if accurate.”

According to Dr. Chung, an otolaryngology head and neck surgery resident in the department of surgery at the George Washington University, Washington, previous studies about this topic are inconclusive.

“Most have been studied only in the pediatric population, and in general, show that Fitbit overestimates PSG measurements,” he said. “Also, prior studies have looked into 20-60 patients, depending on the study.”

In an effort to address these limitations, he and his colleagues prospectively evaluated 180 adult patients who were already scheduled to undergo a PSG with or without CPAP testing from the sleep lab. The overnight test was performed with a Fitbit Alta HR on their wrist of choice and a smartphone at their bedside. Each smartphone was randomly assigned and had a popular sleep application installed, with Sleep as Android on the Android phone and Sleep Cycle on the Apple iPhone. For the main outcomes of interest, the researchers collected the total sleep time, sleep efficiency, and apnea-hypopnea index (AHI) from the PSG and compared them with their equivalents from Fitbit and smartphone applications. For statistical analysis, they performed Bland-Altman plots, paired t-tests, and regression lines to assess R2, slope, and Y-intercept.

Dr. Chung and his colleagues found that both Fitbit Alta HR (P = .0014) and smartphone applications (P less than .0001) significantly overestimated the total sleep time, compared with PSG, while moderate correlation for sleep efficiency was observed between PSG and Fitbit (r = 0.38). Other findings of note were that the number of times awake recorded by Fitbit significantly underestimated the PSG AHI (P less than .0001), the snoring noise measurements from Sleep as Android had strong associations with PSG AHI (R2 = 0.43), and those from Sleep Cycle had modest associations with PSG AHI (R2 = 0.12). However, Bland-Altman plots showed wide limits of agreement for total sleep time and sleep efficiency, though as sleep efficiency approached 100%, the discrepancy between the PSG and Fitbit decreased.

“While there are various tools out right now that claim to measure sleep in a more comforting setting, we cannot recommend any product to act as a screening device or replacement for the PSG at this time,” Dr. Chung said.

He acknowledged certain limitations of the study, including the fact that Fitbit is unable to fully record sleep data if the wearer is asleep for fewer than 3 hours, which can happen in patients with severe OSA. In addition, the smartphone applications require the user to begin and conclude the recording. “This was performed only by the sleep technicians and not the patients, and can be a significant source of error, particularly with the Sleep as Android application, as it had a less intuitive interface,” he noted. “This lead to multiple unusable data points. There were also incidences where the Fitbit Alta HR failed to record sleep data even though it was fully charged and correctly placed, which led to only a smaller number of patients having both measurements at the same time.”

Dr. Chung reported having no financial disclosures. The meeting was jointly sponsored by the Triological Society and the American College of Surgeons.
 

[email protected]

SOURCE: Chung D et al. Triological CSM, Abstracts.

CORONADO, CALIF. – Raw data from the Fitbit and sleep applications for smartphones should not be recommended as screening tools for obstructive sleep apnea, results from a single-center study suggest.

Doug Brunk/MDedge News

“Currently, the gold standard for diagnosis is a polysomnography (PSG), which is basically a sleep study test,” one of the study authors, Daniel Chung, MD, said in an interview in advance of the Triological Society’s Combined Sections Meeting. “While it is very thorough, it is expensive, intrusive, and gives data on only 1 night of sleep and cannot give information on a patient’s sleep pattern over several days. Using wrist-worn devices such as Fitbit products or smartphone applications such as Sleep Cycle would be much cheaper alternatives with little distraction that can provide continuous data over several days if accurate.”

According to Dr. Chung, an otolaryngology head and neck surgery resident in the department of surgery at the George Washington University, Washington, previous studies about this topic are inconclusive.

“Most have been studied only in the pediatric population, and in general, show that Fitbit overestimates PSG measurements,” he said. “Also, prior studies have looked into 20-60 patients, depending on the study.”

In an effort to address these limitations, he and his colleagues prospectively evaluated 180 adult patients who were already scheduled to undergo a PSG with or without CPAP testing from the sleep lab. The overnight test was performed with a Fitbit Alta HR on their wrist of choice and a smartphone at their bedside. Each smartphone was randomly assigned and had a popular sleep application installed, with Sleep as Android on the Android phone and Sleep Cycle on the Apple iPhone. For the main outcomes of interest, the researchers collected the total sleep time, sleep efficiency, and apnea-hypopnea index (AHI) from the PSG and compared them with their equivalents from Fitbit and smartphone applications. For statistical analysis, they performed Bland-Altman plots, paired t-tests, and regression lines to assess R2, slope, and Y-intercept.

Dr. Chung and his colleagues found that both Fitbit Alta HR (P = .0014) and smartphone applications (P less than .0001) significantly overestimated the total sleep time, compared with PSG, while moderate correlation for sleep efficiency was observed between PSG and Fitbit (r = 0.38). Other findings of note were that the number of times awake recorded by Fitbit significantly underestimated the PSG AHI (P less than .0001), the snoring noise measurements from Sleep as Android had strong associations with PSG AHI (R2 = 0.43), and those from Sleep Cycle had modest associations with PSG AHI (R2 = 0.12). However, Bland-Altman plots showed wide limits of agreement for total sleep time and sleep efficiency, though as sleep efficiency approached 100%, the discrepancy between the PSG and Fitbit decreased.

“While there are various tools out right now that claim to measure sleep in a more comforting setting, we cannot recommend any product to act as a screening device or replacement for the PSG at this time,” Dr. Chung said.

He acknowledged certain limitations of the study, including the fact that Fitbit is unable to fully record sleep data if the wearer is asleep for fewer than 3 hours, which can happen in patients with severe OSA. In addition, the smartphone applications require the user to begin and conclude the recording. “This was performed only by the sleep technicians and not the patients, and can be a significant source of error, particularly with the Sleep as Android application, as it had a less intuitive interface,” he noted. “This lead to multiple unusable data points. There were also incidences where the Fitbit Alta HR failed to record sleep data even though it was fully charged and correctly placed, which led to only a smaller number of patients having both measurements at the same time.”

Dr. Chung reported having no financial disclosures. The meeting was jointly sponsored by the Triological Society and the American College of Surgeons.
 

[email protected]

SOURCE: Chung D et al. Triological CSM, Abstracts.

Clinical question: What are the causes and risks of mortality in the first year after nonfatal opioid overdose?

Background: The current opioid epidemic has led to increasing hospitalizations and ED presentations for nonfatal opioid overdose. Despite this, little is known about the subsequent causes of mortality in these patients. Additional information could suggest potential interventions to decrease subsequent risk of death.

Study design: Retrospective cohort study.

Setting: U.S. national cohort of Medicaid beneficiaries, aged 18-64 years, during 2001-2007.

Dr. Breviu is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: What are the causes and risks of mortality in the first year after nonfatal opioid overdose?

Background: The current opioid epidemic has led to increasing hospitalizations and ED presentations for nonfatal opioid overdose. Despite this, little is known about the subsequent causes of mortality in these patients. Additional information could suggest potential interventions to decrease subsequent risk of death.

Study design: Retrospective cohort study.

Setting: U.S. national cohort of Medicaid beneficiaries, aged 18-64 years, during 2001-2007.

Dr. Breviu is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: What are the causes and risks of mortality in the first year after nonfatal opioid overdose?

Background: The current opioid epidemic has led to increasing hospitalizations and ED presentations for nonfatal opioid overdose. Despite this, little is known about the subsequent causes of mortality in these patients. Additional information could suggest potential interventions to decrease subsequent risk of death.

Study design: Retrospective cohort study.

Setting: U.S. national cohort of Medicaid beneficiaries, aged 18-64 years, during 2001-2007.

Dr. Breviu is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.