Neurologic effects can be a significant part of COVID-19, but does the SARS-CoV-2 virus directly damage the central nervous system or are the neurologic symptoms attributable to secondary mechanisms? A new review article summarizes what is known so far, and what clinicians need to look out for.

“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.

“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.

The review was published online May 29 in JAMA Neurology.
 

Brain changes linked to loss of smell

In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.

“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
 

Can coronaviruses enter the CNS?

Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”

“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.

In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.

“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
 

Complications of other systemic effects?

Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.

“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.

Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”

Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”

On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”

There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”

Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.

“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
 

Much is still unknown

“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.

Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”

It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.

Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.

This article first appeared on Medscape.com.

Neurologic effects can be a significant part of COVID-19, but does the SARS-CoV-2 virus directly damage the central nervous system or are the neurologic symptoms attributable to secondary mechanisms? A new review article summarizes what is known so far, and what clinicians need to look out for.

“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.

“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.

The review was published online May 29 in JAMA Neurology.
 

Brain changes linked to loss of smell

In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.

“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
 

Can coronaviruses enter the CNS?

Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”

“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.

In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.

“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
 

Complications of other systemic effects?

Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.

“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.

Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”

Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”

On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”

There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”

Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.

“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
 

Much is still unknown

“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.

Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”

It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.

Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.

This article first appeared on Medscape.com.

Neurologic effects can be a significant part of COVID-19, but does the SARS-CoV-2 virus directly damage the central nervous system or are the neurologic symptoms attributable to secondary mechanisms? A new review article summarizes what is known so far, and what clinicians need to look out for.

“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.

“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.

The review was published online May 29 in JAMA Neurology.
 

Brain changes linked to loss of smell

In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.

“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
 

Can coronaviruses enter the CNS?

Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”

“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.

In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.

“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
 

Complications of other systemic effects?

Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.

“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.

Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”

Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”

On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”

There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”

Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.

“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
 

Much is still unknown

“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.

Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”

It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.

Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.

This article first appeared on Medscape.com.

The Food and Drug Administration has approved Recarbrio (imipenem-cilastatin and relebactam) for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia in people aged 18 years and older.

Approval for Recarbrio was based on results of a randomized, controlled clinical trial of 535 hospitalized adults with hospital-acquired and ventilator-associated bacterial pneumonia who received either Recarbrio or piperacillin-tazobactam. After 28 days, 16% of patients who received Recarbrio and 21% of patients who received piperacillin-tazobactam had died.

The most common adverse events associated with Recarbrio are increased alanine aminotransferase/ aspartate aminotransferase, anemia, diarrhea, hypokalemia, and hyponatremia. Recarbrio was previously approved by the FDA to treat patients with complicated urinary tract infections and complicated intra-abdominal infections who have limited or no alternative treatment options, according to an FDA press release.

“As a public health agency, the FDA addresses the threat of antimicrobial-resistant infections by facilitating the development of safe and effective new treatments. These efforts provide more options to fight serious bacterial infections and get new, safe and effective therapies to patients as soon as possible,” said Sumathi Nambiar, MD, MPH, director of the division of anti-infectives within the office of infectious disease at the Center for Drug Evaluation and Research.

lfranki@mdedge.com

The Food and Drug Administration has approved Recarbrio (imipenem-cilastatin and relebactam) for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia in people aged 18 years and older.

Approval for Recarbrio was based on results of a randomized, controlled clinical trial of 535 hospitalized adults with hospital-acquired and ventilator-associated bacterial pneumonia who received either Recarbrio or piperacillin-tazobactam. After 28 days, 16% of patients who received Recarbrio and 21% of patients who received piperacillin-tazobactam had died.

The most common adverse events associated with Recarbrio are increased alanine aminotransferase/ aspartate aminotransferase, anemia, diarrhea, hypokalemia, and hyponatremia. Recarbrio was previously approved by the FDA to treat patients with complicated urinary tract infections and complicated intra-abdominal infections who have limited or no alternative treatment options, according to an FDA press release.

“As a public health agency, the FDA addresses the threat of antimicrobial-resistant infections by facilitating the development of safe and effective new treatments. These efforts provide more options to fight serious bacterial infections and get new, safe and effective therapies to patients as soon as possible,” said Sumathi Nambiar, MD, MPH, director of the division of anti-infectives within the office of infectious disease at the Center for Drug Evaluation and Research.

lfranki@mdedge.com

The Food and Drug Administration has approved Recarbrio (imipenem-cilastatin and relebactam) for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia in people aged 18 years and older.

Approval for Recarbrio was based on results of a randomized, controlled clinical trial of 535 hospitalized adults with hospital-acquired and ventilator-associated bacterial pneumonia who received either Recarbrio or piperacillin-tazobactam. After 28 days, 16% of patients who received Recarbrio and 21% of patients who received piperacillin-tazobactam had died.

The most common adverse events associated with Recarbrio are increased alanine aminotransferase/ aspartate aminotransferase, anemia, diarrhea, hypokalemia, and hyponatremia. Recarbrio was previously approved by the FDA to treat patients with complicated urinary tract infections and complicated intra-abdominal infections who have limited or no alternative treatment options, according to an FDA press release.

“As a public health agency, the FDA addresses the threat of antimicrobial-resistant infections by facilitating the development of safe and effective new treatments. These efforts provide more options to fight serious bacterial infections and get new, safe and effective therapies to patients as soon as possible,” said Sumathi Nambiar, MD, MPH, director of the division of anti-infectives within the office of infectious disease at the Center for Drug Evaluation and Research.

lfranki@mdedge.com

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Reports of herpes zoster virus (HZV) among patients being treated with disease-modifying therapies (DMTs) for multiple sclerosis (MS) are nearly five times higher among women versus men and commonly occur in people under the age of 40, a new study of adverse event reports on a variety of DMTs suggests.

DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.

“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.

For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.

They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.

Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.

Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.

Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.

“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.

Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.

In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.

“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”

The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”

While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.

“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.

“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”

He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.

“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”

Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.

This article first appeared on Medscape.com.

Reports of herpes zoster virus (HZV) among patients being treated with disease-modifying therapies (DMTs) for multiple sclerosis (MS) are nearly five times higher among women versus men and commonly occur in people under the age of 40, a new study of adverse event reports on a variety of DMTs suggests.

DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.

“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.

For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.

They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.

Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.

Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.

Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.

“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.

Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.

In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.

“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”

The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”

While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.

“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.

“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”

He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.

“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”

Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.

This article first appeared on Medscape.com.

Reports of herpes zoster virus (HZV) among patients being treated with disease-modifying therapies (DMTs) for multiple sclerosis (MS) are nearly five times higher among women versus men and commonly occur in people under the age of 40, a new study of adverse event reports on a variety of DMTs suggests.

DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.

“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.

For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.

They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.

Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.

Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.

Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.

“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.

Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.

In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.

“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”

The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”

While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.

“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.

“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”

He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.

“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”

Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.

This article first appeared on Medscape.com.

Among patients with ankylosing spondylitis or undifferentiated spondyloarthritis, risk for anterior uveitis may hinge on the choice of biologic disease-modifying antirheumatic drug (bDMARD), a large Swedish cohort study suggests.

Study results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“Randomized, controlled trials indicate that compared to tumor necrosis factor (TNF) inhibitors, secukinumab has similar efficacy regarding axial inflammation in spondyloarthritis and better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease,” noted lead investigator Ulf Lindström, MD, PhD, of the department of rheumatology and inflammation research in the Institute of Medicine at the University of Gothenburg (Sweden). “However, the efficacy of secukinumab, compared to TNF inhibitors, in anterior uveitis has not been extensively studied.”

The investigators used national registry data to study 3,568 patients with ankylosing spondylitis or undifferentiated spondyloarthritis who started bDMARDs in 2005-2018. They considered four agents: the anti–interleukin-17A antibody secukinumab (Cosentyx) and the TNF inhibitors etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade).

Analyses based on 4,523 treatment episodes showed that after excluding the 23% of patients who had previously experienced anterior uveitis, merely 0.9% of patients experienced new-onset anterior uveitis while on their bDMARD, Dr. Lindström reported.

There was confounding by indication, whereby patients with previous anterior uveitis were channeled toward adalimumab and infliximab, and away from secukinumab and etanercept. In addition, there was confounding by line of treatment, with secukinumab usually used in the third line.

After excluding patients who had experienced anterior uveitis in the past year to partly address confounding, the adjusted risk for first on-treatment anterior uveitis was about twice as high with secukinumab and with etanercept as compared with adalimumab. After additionally excluding all biologic treatment episodes beyond the third line, elevation of risk remained significant only for etanercept.

“There is probably a higher occurrence of anterior uveitis on treatment with secukinumab, compared to adalimumab, but there may still be residual confounding and bias that we need to consider,” Dr. Lindström concluded. “As seen previously, there is a higher occurrence of anterior uveitis on etanercept compared to adalimumab or infliximab.”

Findings in context

“These results are not surprising as we have known that secukinumab and etanercept are not good for controlling recurrent and chronic uveitis,” Nigil Haroon MD, PhD, DM, commented in an interview. However, “a single episode of uveitis or infrequent episodes are not usually considered a contraindication to starting these drugs.”

Study caveats included lack of adjustment for uveitis severity and potentially missed uveitis episodes in patients who treated it themselves with steroid eyedrops, he said. “Standard practice is to keep drops with them to start at the earliest possible time point.”

“It would be useful to know the number of patients who stopped medications as a result of uveitis,” added Dr. Haroon, who is codirector of the spondylitis program at the University Health Network and associate professor of medicine and rheumatology at the University of Toronto. “Time-to-event analysis may also be interesting.”

“The study raises an important point regarding channeling bias, and this is important to consider when interpreting clinical trial data as well. Investigators are unlikely to include patients with history of uveitis (or strong family history of inflammatory bowel disease or personal history of gut symptoms) in studies with IL-17 inhibitors and etanercept. Hence, the results have to be interpreted with caution.”
 

Study details

Dr. Lindström and coinvestigators assessed incidences of any anterior uveitis (ascertained from outpatient ophthalmology visits having this diagnostic code) and of anterior uveitis flares (the subset occurring after a gap of at least 90 days without the diagnosis).

When they excluded patients who had experienced anterior uveitis in the year before starting therapy, secukinumab and etanercept carried the highest incidences of anterior uveitis (6.8 and 7.5 per 100 patient-years, respectively) and anterior uveitis flares (2.8 per 100 patient-years for each), he reported.

With adalimumab as the comparator, adjusted risk for first on-treatment anterior uveitis in this population was significantly higher with secukinumab (hazard ratio, 2.23) and etanercept (hazard ratio, 1.80).

When the investigators additionally excluded episodes of therapy beyond the third line, only etanercept carried notably higher incidences of anterior uveitis (7.0 per 100 patient-years) and anterior uveitis flares (2.6 per 100 patient-years). “This could imply that some of the higher incidence rate seen for secukinumab could be due to the fact that these patients are harder to treat and have received more biologics before,” Dr. Lindström proposed.

With adalimumab again as the comparator, the adjusted risk for first on-treatment anterior uveitis in this population was significantly higher only with etanercept (hazard ratio, 1.85).

A final analysis included all patients who started adalimumab in 2004-2018 and then switched to one of the other agents, dramatically reducing confounding by indication. In this population, the incidence rate ratio of anterior uveitis flares was 3.05 for secukinumab, 1.79 for etanercept, and 0.53 for infliximab, compared with adalimumab.

Dr. Lindström disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding. Dr. Haroon disclosed consulting for Amgen, Abbvie, Eli Lilly, Janssen, Novartis, and UCB.

SOURCE: Lindström U et al. Ann Rheum Dis. 2020;79[suppl 1]:9, Abstract OP0014.

Among patients with ankylosing spondylitis or undifferentiated spondyloarthritis, risk for anterior uveitis may hinge on the choice of biologic disease-modifying antirheumatic drug (bDMARD), a large Swedish cohort study suggests.

Study results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“Randomized, controlled trials indicate that compared to tumor necrosis factor (TNF) inhibitors, secukinumab has similar efficacy regarding axial inflammation in spondyloarthritis and better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease,” noted lead investigator Ulf Lindström, MD, PhD, of the department of rheumatology and inflammation research in the Institute of Medicine at the University of Gothenburg (Sweden). “However, the efficacy of secukinumab, compared to TNF inhibitors, in anterior uveitis has not been extensively studied.”

The investigators used national registry data to study 3,568 patients with ankylosing spondylitis or undifferentiated spondyloarthritis who started bDMARDs in 2005-2018. They considered four agents: the anti–interleukin-17A antibody secukinumab (Cosentyx) and the TNF inhibitors etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade).

Analyses based on 4,523 treatment episodes showed that after excluding the 23% of patients who had previously experienced anterior uveitis, merely 0.9% of patients experienced new-onset anterior uveitis while on their bDMARD, Dr. Lindström reported.

There was confounding by indication, whereby patients with previous anterior uveitis were channeled toward adalimumab and infliximab, and away from secukinumab and etanercept. In addition, there was confounding by line of treatment, with secukinumab usually used in the third line.

After excluding patients who had experienced anterior uveitis in the past year to partly address confounding, the adjusted risk for first on-treatment anterior uveitis was about twice as high with secukinumab and with etanercept as compared with adalimumab. After additionally excluding all biologic treatment episodes beyond the third line, elevation of risk remained significant only for etanercept.

“There is probably a higher occurrence of anterior uveitis on treatment with secukinumab, compared to adalimumab, but there may still be residual confounding and bias that we need to consider,” Dr. Lindström concluded. “As seen previously, there is a higher occurrence of anterior uveitis on etanercept compared to adalimumab or infliximab.”

Findings in context

“These results are not surprising as we have known that secukinumab and etanercept are not good for controlling recurrent and chronic uveitis,” Nigil Haroon MD, PhD, DM, commented in an interview. However, “a single episode of uveitis or infrequent episodes are not usually considered a contraindication to starting these drugs.”

Study caveats included lack of adjustment for uveitis severity and potentially missed uveitis episodes in patients who treated it themselves with steroid eyedrops, he said. “Standard practice is to keep drops with them to start at the earliest possible time point.”

“It would be useful to know the number of patients who stopped medications as a result of uveitis,” added Dr. Haroon, who is codirector of the spondylitis program at the University Health Network and associate professor of medicine and rheumatology at the University of Toronto. “Time-to-event analysis may also be interesting.”

“The study raises an important point regarding channeling bias, and this is important to consider when interpreting clinical trial data as well. Investigators are unlikely to include patients with history of uveitis (or strong family history of inflammatory bowel disease or personal history of gut symptoms) in studies with IL-17 inhibitors and etanercept. Hence, the results have to be interpreted with caution.”
 

Study details

Dr. Lindström and coinvestigators assessed incidences of any anterior uveitis (ascertained from outpatient ophthalmology visits having this diagnostic code) and of anterior uveitis flares (the subset occurring after a gap of at least 90 days without the diagnosis).

When they excluded patients who had experienced anterior uveitis in the year before starting therapy, secukinumab and etanercept carried the highest incidences of anterior uveitis (6.8 and 7.5 per 100 patient-years, respectively) and anterior uveitis flares (2.8 per 100 patient-years for each), he reported.

With adalimumab as the comparator, adjusted risk for first on-treatment anterior uveitis in this population was significantly higher with secukinumab (hazard ratio, 2.23) and etanercept (hazard ratio, 1.80).

When the investigators additionally excluded episodes of therapy beyond the third line, only etanercept carried notably higher incidences of anterior uveitis (7.0 per 100 patient-years) and anterior uveitis flares (2.6 per 100 patient-years). “This could imply that some of the higher incidence rate seen for secukinumab could be due to the fact that these patients are harder to treat and have received more biologics before,” Dr. Lindström proposed.

With adalimumab again as the comparator, the adjusted risk for first on-treatment anterior uveitis in this population was significantly higher only with etanercept (hazard ratio, 1.85).

A final analysis included all patients who started adalimumab in 2004-2018 and then switched to one of the other agents, dramatically reducing confounding by indication. In this population, the incidence rate ratio of anterior uveitis flares was 3.05 for secukinumab, 1.79 for etanercept, and 0.53 for infliximab, compared with adalimumab.

Dr. Lindström disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding. Dr. Haroon disclosed consulting for Amgen, Abbvie, Eli Lilly, Janssen, Novartis, and UCB.

SOURCE: Lindström U et al. Ann Rheum Dis. 2020;79[suppl 1]:9, Abstract OP0014.

Among patients with ankylosing spondylitis or undifferentiated spondyloarthritis, risk for anterior uveitis may hinge on the choice of biologic disease-modifying antirheumatic drug (bDMARD), a large Swedish cohort study suggests.

Study results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“Randomized, controlled trials indicate that compared to tumor necrosis factor (TNF) inhibitors, secukinumab has similar efficacy regarding axial inflammation in spondyloarthritis and better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease,” noted lead investigator Ulf Lindström, MD, PhD, of the department of rheumatology and inflammation research in the Institute of Medicine at the University of Gothenburg (Sweden). “However, the efficacy of secukinumab, compared to TNF inhibitors, in anterior uveitis has not been extensively studied.”

The investigators used national registry data to study 3,568 patients with ankylosing spondylitis or undifferentiated spondyloarthritis who started bDMARDs in 2005-2018. They considered four agents: the anti–interleukin-17A antibody secukinumab (Cosentyx) and the TNF inhibitors etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade).

Analyses based on 4,523 treatment episodes showed that after excluding the 23% of patients who had previously experienced anterior uveitis, merely 0.9% of patients experienced new-onset anterior uveitis while on their bDMARD, Dr. Lindström reported.

There was confounding by indication, whereby patients with previous anterior uveitis were channeled toward adalimumab and infliximab, and away from secukinumab and etanercept. In addition, there was confounding by line of treatment, with secukinumab usually used in the third line.

After excluding patients who had experienced anterior uveitis in the past year to partly address confounding, the adjusted risk for first on-treatment anterior uveitis was about twice as high with secukinumab and with etanercept as compared with adalimumab. After additionally excluding all biologic treatment episodes beyond the third line, elevation of risk remained significant only for etanercept.

“There is probably a higher occurrence of anterior uveitis on treatment with secukinumab, compared to adalimumab, but there may still be residual confounding and bias that we need to consider,” Dr. Lindström concluded. “As seen previously, there is a higher occurrence of anterior uveitis on etanercept compared to adalimumab or infliximab.”

Findings in context

“These results are not surprising as we have known that secukinumab and etanercept are not good for controlling recurrent and chronic uveitis,” Nigil Haroon MD, PhD, DM, commented in an interview. However, “a single episode of uveitis or infrequent episodes are not usually considered a contraindication to starting these drugs.”

Study caveats included lack of adjustment for uveitis severity and potentially missed uveitis episodes in patients who treated it themselves with steroid eyedrops, he said. “Standard practice is to keep drops with them to start at the earliest possible time point.”

“It would be useful to know the number of patients who stopped medications as a result of uveitis,” added Dr. Haroon, who is codirector of the spondylitis program at the University Health Network and associate professor of medicine and rheumatology at the University of Toronto. “Time-to-event analysis may also be interesting.”

“The study raises an important point regarding channeling bias, and this is important to consider when interpreting clinical trial data as well. Investigators are unlikely to include patients with history of uveitis (or strong family history of inflammatory bowel disease or personal history of gut symptoms) in studies with IL-17 inhibitors and etanercept. Hence, the results have to be interpreted with caution.”
 

Study details

Dr. Lindström and coinvestigators assessed incidences of any anterior uveitis (ascertained from outpatient ophthalmology visits having this diagnostic code) and of anterior uveitis flares (the subset occurring after a gap of at least 90 days without the diagnosis).

When they excluded patients who had experienced anterior uveitis in the year before starting therapy, secukinumab and etanercept carried the highest incidences of anterior uveitis (6.8 and 7.5 per 100 patient-years, respectively) and anterior uveitis flares (2.8 per 100 patient-years for each), he reported.

With adalimumab as the comparator, adjusted risk for first on-treatment anterior uveitis in this population was significantly higher with secukinumab (hazard ratio, 2.23) and etanercept (hazard ratio, 1.80).

When the investigators additionally excluded episodes of therapy beyond the third line, only etanercept carried notably higher incidences of anterior uveitis (7.0 per 100 patient-years) and anterior uveitis flares (2.6 per 100 patient-years). “This could imply that some of the higher incidence rate seen for secukinumab could be due to the fact that these patients are harder to treat and have received more biologics before,” Dr. Lindström proposed.

With adalimumab again as the comparator, the adjusted risk for first on-treatment anterior uveitis in this population was significantly higher only with etanercept (hazard ratio, 1.85).

A final analysis included all patients who started adalimumab in 2004-2018 and then switched to one of the other agents, dramatically reducing confounding by indication. In this population, the incidence rate ratio of anterior uveitis flares was 3.05 for secukinumab, 1.79 for etanercept, and 0.53 for infliximab, compared with adalimumab.

Dr. Lindström disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding. Dr. Haroon disclosed consulting for Amgen, Abbvie, Eli Lilly, Janssen, Novartis, and UCB.

SOURCE: Lindström U et al. Ann Rheum Dis. 2020;79[suppl 1]:9, Abstract OP0014.

As the rigor of COVID-19 research comes under increasing scrutiny, a deep dive into contemporary trials of invasive cardiovascular interventions finds intricate ties with industry and the art of spin on full display.

After examining 216 randomized, controlled trials published in the past decade, researchers found that more than half (53.2%) were commercially funded. In 18.3% of these trials, the sponsor was involved with the trial conduct and reporting.

Commercially sponsored trials were significantly more likely to report results that favored the experimental therapy than trials without commercial sponsorship (64.3% vs. 48.5%; P = .02).

The association remained statistically significant after adjustment for differences in trial characteristics (exponent of regression coefficient beta, 2.80; 95% confidence interval, 1.09-7.18; P = .03), the authors reported in JAMA Internal Medicine.

“To make this clear, this is not an attack on industry-sponsored trials,” study author and cardiac surgeon Mario Gaudino, MD, of New York–Presbyterian and Weill Cornell Medical Center, New York, said in an interview. “Because industry has more money, they have the best trialists, the best research organization. So they generally do a pretty good trial; they’re larger, they have a higher Fragility Index, which means they’re more solid.

“And, most importantly, more than half of the trials were sponsored by industry,” he said. “So without industry, there wouldn’t be half the research in that 10-year period we explored.”

Previous research in cardiology and in other fields has shown that trials supported by for-profit organizations are more likely to report positive findings. The explanations often focus on bias and differential quality in how the trials were designed and reported.

In the present analysis, however, the authors found no difference between trials with and without industry funding in terms of estimated treatment effect, length of follow-up, use of composite or clinically significant outcomes, or outcome modification, compared with the published protocol.

Part of the explanation may be that industry-sponsored trials more often used a noninferiority design (26.1% vs. 14.9%) and had a higher loss of patients to follow-up (median of sample, 1.0% vs. 0.1%), Dr. Gaudino said. “But I think more, in general, it’s not so much a difference in the measurable characteristics of the trial. It’s the selection of the sites that participate, the patient population that is targeted that makes the trial very likely to get the result that industry would like to see.”

“Just think of the differences in the transcatheter MitraClip results between MITRA-FR and COAPT – basically they were related to the fact they enrolled different patients,” he said.
 

Significant spin

The analysis included 216 coronary, vascular, and structural interventional cardiology and vascular and cardiac surgical randomized, controlled trials published from January 2008 to May 31, 2019. Most were multicenter trials (78.7%); 58% originated from Europe, 12% from North America, and 10.6% from Asia.

One in six trials (16.2%) were not prospectively registered before the start of enrollment, and at least one major discrepancy existed between the registered and published primary outcome in 38% of registered trials.

“If you don’t register the trial then you can make all the changes you want to the protocol up until the moment you publish,” Dr. Gaudino observed. “There really is no rational justification for not registering a trial.”

Overall, the trials were not particularly robust, he noted. In 62 trials in which the Fragility Index was measured, only a median of five patients experiencing a different outcome in a commercially sponsored trial would change statistically significant results to nonsignificant. For noncommercially sponsored trials, that number was 4.5 and in four trials; the change in condition of only one patient was needed to switch the statistical significance.

“This finding is concerning given the substantial role that [randomized, controlled trials] results play in federal device approvals, payer criteria, and clinical consensus guidelines,” the authors wrote.

The authors also looked for interpretation bias in the trials. In the 84 trials with nonsignificant differences in the primary outcomes, 65.5% contained spin, such as focusing on statistically significant secondary outcomes or interpreting nonsignificant primary outcomes as showing treatment equivalence or comparable effectiveness. Spin was present in 80.6% of the trials with commercial sponsorship and in 54.2% without (P = .02) – a finding that remained significant after trial differences were controlled for (beta, 4.64; 95% CI, 1.05-20.54; P = .04).
 

A pivot point

“It’s just another paper showing there are issues with conflicts of interest in industry trials. I’m not particularly surprised,” said David Moher, PhD, MSc, director of the Centre for Journalology, based at the Ottawa Hospital Research Institute.

“It’s sort of high time people from all sides sat down together and tried to resolve how to actually move forward with industry wanting to do trials,” he said. “They are hugely important in drug development. How can these trials be done where the impact of industry and, for that matter, academia is minimized?”

Dr. Gaudino suggested the “ideal situation” would be to have industry put its funding into an existing funding organization, such as the National Institutes of Health or a newly created independent organization – a concept that has been floated before without much forward movement.

“We may be at a pivot point,” Dr. Moher said. “It’s quite clear that COVID has indicated some serious problems with how trials are done, how they’re disseminated, the notion of open science. I think this could be an opportunity. Whether there is so much noise, whether anybody will be able to take any of these initiative forward, I don’t know.”

No matter how trial funding is revised, patients must be brought to the table, he said.

“What frustrates me quite a bit is this almost parental view of all of this – the scientists know best, industry knows best,” Dr. Moher said. “We actually need the most important groups: patients and the public. They need to have an enormous amount of say in how this actually is formed.”

Commenting further, Dr. Moher said that “industry and academia can only do trials when they have patients willing to participate, and yet in the discussions you and I are having, what do patients think about spin in trials? I would imagine they would be horrified that they are going into studies – in a sense in many cases risking their lives – and yet people are spinning the results.”

Dr. Gaudino and Dr. Moher reported having no relevant conflicts of interest.

A version of this story originally appeared on Medscape.com.

As the rigor of COVID-19 research comes under increasing scrutiny, a deep dive into contemporary trials of invasive cardiovascular interventions finds intricate ties with industry and the art of spin on full display.

After examining 216 randomized, controlled trials published in the past decade, researchers found that more than half (53.2%) were commercially funded. In 18.3% of these trials, the sponsor was involved with the trial conduct and reporting.

Commercially sponsored trials were significantly more likely to report results that favored the experimental therapy than trials without commercial sponsorship (64.3% vs. 48.5%; P = .02).

The association remained statistically significant after adjustment for differences in trial characteristics (exponent of regression coefficient beta, 2.80; 95% confidence interval, 1.09-7.18; P = .03), the authors reported in JAMA Internal Medicine.

“To make this clear, this is not an attack on industry-sponsored trials,” study author and cardiac surgeon Mario Gaudino, MD, of New York–Presbyterian and Weill Cornell Medical Center, New York, said in an interview. “Because industry has more money, they have the best trialists, the best research organization. So they generally do a pretty good trial; they’re larger, they have a higher Fragility Index, which means they’re more solid.

“And, most importantly, more than half of the trials were sponsored by industry,” he said. “So without industry, there wouldn’t be half the research in that 10-year period we explored.”

Previous research in cardiology and in other fields has shown that trials supported by for-profit organizations are more likely to report positive findings. The explanations often focus on bias and differential quality in how the trials were designed and reported.

In the present analysis, however, the authors found no difference between trials with and without industry funding in terms of estimated treatment effect, length of follow-up, use of composite or clinically significant outcomes, or outcome modification, compared with the published protocol.

Part of the explanation may be that industry-sponsored trials more often used a noninferiority design (26.1% vs. 14.9%) and had a higher loss of patients to follow-up (median of sample, 1.0% vs. 0.1%), Dr. Gaudino said. “But I think more, in general, it’s not so much a difference in the measurable characteristics of the trial. It’s the selection of the sites that participate, the patient population that is targeted that makes the trial very likely to get the result that industry would like to see.”

“Just think of the differences in the transcatheter MitraClip results between MITRA-FR and COAPT – basically they were related to the fact they enrolled different patients,” he said.
 

Significant spin

The analysis included 216 coronary, vascular, and structural interventional cardiology and vascular and cardiac surgical randomized, controlled trials published from January 2008 to May 31, 2019. Most were multicenter trials (78.7%); 58% originated from Europe, 12% from North America, and 10.6% from Asia.

One in six trials (16.2%) were not prospectively registered before the start of enrollment, and at least one major discrepancy existed between the registered and published primary outcome in 38% of registered trials.

“If you don’t register the trial then you can make all the changes you want to the protocol up until the moment you publish,” Dr. Gaudino observed. “There really is no rational justification for not registering a trial.”

Overall, the trials were not particularly robust, he noted. In 62 trials in which the Fragility Index was measured, only a median of five patients experiencing a different outcome in a commercially sponsored trial would change statistically significant results to nonsignificant. For noncommercially sponsored trials, that number was 4.5 and in four trials; the change in condition of only one patient was needed to switch the statistical significance.

“This finding is concerning given the substantial role that [randomized, controlled trials] results play in federal device approvals, payer criteria, and clinical consensus guidelines,” the authors wrote.

The authors also looked for interpretation bias in the trials. In the 84 trials with nonsignificant differences in the primary outcomes, 65.5% contained spin, such as focusing on statistically significant secondary outcomes or interpreting nonsignificant primary outcomes as showing treatment equivalence or comparable effectiveness. Spin was present in 80.6% of the trials with commercial sponsorship and in 54.2% without (P = .02) – a finding that remained significant after trial differences were controlled for (beta, 4.64; 95% CI, 1.05-20.54; P = .04).
 

A pivot point

“It’s just another paper showing there are issues with conflicts of interest in industry trials. I’m not particularly surprised,” said David Moher, PhD, MSc, director of the Centre for Journalology, based at the Ottawa Hospital Research Institute.

“It’s sort of high time people from all sides sat down together and tried to resolve how to actually move forward with industry wanting to do trials,” he said. “They are hugely important in drug development. How can these trials be done where the impact of industry and, for that matter, academia is minimized?”

Dr. Gaudino suggested the “ideal situation” would be to have industry put its funding into an existing funding organization, such as the National Institutes of Health or a newly created independent organization – a concept that has been floated before without much forward movement.

“We may be at a pivot point,” Dr. Moher said. “It’s quite clear that COVID has indicated some serious problems with how trials are done, how they’re disseminated, the notion of open science. I think this could be an opportunity. Whether there is so much noise, whether anybody will be able to take any of these initiative forward, I don’t know.”

No matter how trial funding is revised, patients must be brought to the table, he said.

“What frustrates me quite a bit is this almost parental view of all of this – the scientists know best, industry knows best,” Dr. Moher said. “We actually need the most important groups: patients and the public. They need to have an enormous amount of say in how this actually is formed.”

Commenting further, Dr. Moher said that “industry and academia can only do trials when they have patients willing to participate, and yet in the discussions you and I are having, what do patients think about spin in trials? I would imagine they would be horrified that they are going into studies – in a sense in many cases risking their lives – and yet people are spinning the results.”

Dr. Gaudino and Dr. Moher reported having no relevant conflicts of interest.

A version of this story originally appeared on Medscape.com.

As the rigor of COVID-19 research comes under increasing scrutiny, a deep dive into contemporary trials of invasive cardiovascular interventions finds intricate ties with industry and the art of spin on full display.

After examining 216 randomized, controlled trials published in the past decade, researchers found that more than half (53.2%) were commercially funded. In 18.3% of these trials, the sponsor was involved with the trial conduct and reporting.

Commercially sponsored trials were significantly more likely to report results that favored the experimental therapy than trials without commercial sponsorship (64.3% vs. 48.5%; P = .02).

The association remained statistically significant after adjustment for differences in trial characteristics (exponent of regression coefficient beta, 2.80; 95% confidence interval, 1.09-7.18; P = .03), the authors reported in JAMA Internal Medicine.

“To make this clear, this is not an attack on industry-sponsored trials,” study author and cardiac surgeon Mario Gaudino, MD, of New York–Presbyterian and Weill Cornell Medical Center, New York, said in an interview. “Because industry has more money, they have the best trialists, the best research organization. So they generally do a pretty good trial; they’re larger, they have a higher Fragility Index, which means they’re more solid.

“And, most importantly, more than half of the trials were sponsored by industry,” he said. “So without industry, there wouldn’t be half the research in that 10-year period we explored.”

Previous research in cardiology and in other fields has shown that trials supported by for-profit organizations are more likely to report positive findings. The explanations often focus on bias and differential quality in how the trials were designed and reported.

In the present analysis, however, the authors found no difference between trials with and without industry funding in terms of estimated treatment effect, length of follow-up, use of composite or clinically significant outcomes, or outcome modification, compared with the published protocol.

Part of the explanation may be that industry-sponsored trials more often used a noninferiority design (26.1% vs. 14.9%) and had a higher loss of patients to follow-up (median of sample, 1.0% vs. 0.1%), Dr. Gaudino said. “But I think more, in general, it’s not so much a difference in the measurable characteristics of the trial. It’s the selection of the sites that participate, the patient population that is targeted that makes the trial very likely to get the result that industry would like to see.”

“Just think of the differences in the transcatheter MitraClip results between MITRA-FR and COAPT – basically they were related to the fact they enrolled different patients,” he said.
 

Significant spin

The analysis included 216 coronary, vascular, and structural interventional cardiology and vascular and cardiac surgical randomized, controlled trials published from January 2008 to May 31, 2019. Most were multicenter trials (78.7%); 58% originated from Europe, 12% from North America, and 10.6% from Asia.

One in six trials (16.2%) were not prospectively registered before the start of enrollment, and at least one major discrepancy existed between the registered and published primary outcome in 38% of registered trials.

“If you don’t register the trial then you can make all the changes you want to the protocol up until the moment you publish,” Dr. Gaudino observed. “There really is no rational justification for not registering a trial.”

Overall, the trials were not particularly robust, he noted. In 62 trials in which the Fragility Index was measured, only a median of five patients experiencing a different outcome in a commercially sponsored trial would change statistically significant results to nonsignificant. For noncommercially sponsored trials, that number was 4.5 and in four trials; the change in condition of only one patient was needed to switch the statistical significance.

“This finding is concerning given the substantial role that [randomized, controlled trials] results play in federal device approvals, payer criteria, and clinical consensus guidelines,” the authors wrote.

The authors also looked for interpretation bias in the trials. In the 84 trials with nonsignificant differences in the primary outcomes, 65.5% contained spin, such as focusing on statistically significant secondary outcomes or interpreting nonsignificant primary outcomes as showing treatment equivalence or comparable effectiveness. Spin was present in 80.6% of the trials with commercial sponsorship and in 54.2% without (P = .02) – a finding that remained significant after trial differences were controlled for (beta, 4.64; 95% CI, 1.05-20.54; P = .04).
 

A pivot point

“It’s just another paper showing there are issues with conflicts of interest in industry trials. I’m not particularly surprised,” said David Moher, PhD, MSc, director of the Centre for Journalology, based at the Ottawa Hospital Research Institute.

“It’s sort of high time people from all sides sat down together and tried to resolve how to actually move forward with industry wanting to do trials,” he said. “They are hugely important in drug development. How can these trials be done where the impact of industry and, for that matter, academia is minimized?”

Dr. Gaudino suggested the “ideal situation” would be to have industry put its funding into an existing funding organization, such as the National Institutes of Health or a newly created independent organization – a concept that has been floated before without much forward movement.

“We may be at a pivot point,” Dr. Moher said. “It’s quite clear that COVID has indicated some serious problems with how trials are done, how they’re disseminated, the notion of open science. I think this could be an opportunity. Whether there is so much noise, whether anybody will be able to take any of these initiative forward, I don’t know.”

No matter how trial funding is revised, patients must be brought to the table, he said.

“What frustrates me quite a bit is this almost parental view of all of this – the scientists know best, industry knows best,” Dr. Moher said. “We actually need the most important groups: patients and the public. They need to have an enormous amount of say in how this actually is formed.”

Commenting further, Dr. Moher said that “industry and academia can only do trials when they have patients willing to participate, and yet in the discussions you and I are having, what do patients think about spin in trials? I would imagine they would be horrified that they are going into studies – in a sense in many cases risking their lives – and yet people are spinning the results.”

Dr. Gaudino and Dr. Moher reported having no relevant conflicts of interest.

A version of this story originally appeared on Medscape.com.

Most people can cope, to some degree, with the multiple weeks of social distancing and stressors related to the pandemic. But what if those stressors became a way of life for a year – or longer? What sorts of skills would be essential not only to survive but to have a renewed sense of resilience?

I know of one group that has had experiences that mirror the challenges faced by the parents of children: the parents of special needs children. As I argued previously, those parents have faced many of the challenges presented by COVID-19. Among those challenges are social distancing and difficulty accessing everyday common experiences. These parents know that they have to manage more areas of their children’s rearing than do their counterparts.

In addition to having to plan for how to deal with acute urgent or emergent medical situations involving their special needs children, these parents also must prepare for the long-term effects of managing children who require ongoing daily care, attention, and dedication.

As psychiatrists, we can teach patients several strategies that can serve as basic building blocks. These strategies can help the parents of special needs kids find a sense of mastery and comfort. The hope is that, after practicing them for long periods of time, the strategies become second nature.

Here are several strategies that might help patients with children during this pandemic:

• Take time to reset: Sometimes it is helpful for parents to take a minute away from a difficult impasse with their kids to reset and take their own “time out.” A few seconds of mental time away from the “scene” provides space and a mental reminder that the minute that just happened is finite, and that a whole new one is coming up next. The break provides a sense of hope. This cognitive reframing could be practiced often.
• Re-enter the challenging scene with a warm voice: Parents model for their children, but they also are telling their own brains that they, too, can calm down. This approach also de-escalates the situation and allows children to get used to hearing directions from someone who is in control – without hostility or irritability.
• Keep a sense of humor; it might come in handy: This is especially the case when tension is in the home, or when facing a set of challenging bad news. As an example, consider how some situations are so repetitive that they border on the ridiculous – such as a grown child having a tantrum at a store. Encourage the children to give themselves permission to cry first so they can laugh second, and then move on.
• Establish a routine for children that is self-reinforcing, and allows for together and separate times: They can, as an example: A) Get ready for the day all by themselves, or as much as they can do independently, before they come down and then B) have breakfast. Then, the child can C) do homework, and then D) go play outside. The routine would then continue on its own without outside reinforcers.
• Tell the children that they can get to the reinforcing activity only after completing the previous one. Over time, they learn to take pride in completing the first activity and doing so more independently. Not having to wait to be told what to do all the time fosters a sense of independence.
• Plan for meals and fun tasks together, and separate for individual work. This creates a sense of change and gives the day a certain flow. Establish routines that are predictable for the children that can be easily documented for the whole family on a calendar. Establish a beginning and an end time to the work day. Mark the end of the day with a chalk line establishing when the family can engage in a certain activity, for example, going for a family bike ride. Let the routine honor healthy circadian rhythms for sleep/wakeful times, and be consistent.
• Feed the brain and body the “good stuff”: Limit negative news, and surround the children with people who bring them joy or provide hope. Listen to inspirational messages and uplifting music. Give the children food that nourishes and energizes their bodies. Take in the view outside, the greenery, or the sky if there is no green around. Connect with family/friends who are far away.
• Make time to replenish with something that is meaningful/productive/helpful: Parents have very little time for themselves when they are “on,” so when they can actually take a little time to recharge, the activity should check many boxes. For example, encourage them to go for a walk (exercise) while listening to music (relax), make a phone call to someone who can relate to their situation (socialize), pray with someone (be spiritual), or sit in their rooms to get some alone quiet time (meditate). Reach out to those who are lonely. Network. Mentor. Volunteer.
• Develop an eye for noticing the positive: Instead of hoping for things to go back to the way they were, tell your patients to practice embracing without judgment the new norm. Get them to notice the time they spend with their families. Break all tasks into many smaller tasks, so there is more possibility of observing progress, and it is evident for everyone to see. Learn to notice the small changes that they want to see in their children. Celebrate all that can be celebrated by stating the obvious: “You wiped your face after eating. You are observant; you are noticing when you have something on your face.”
• State when a child is forgiving, helpful, or puts forward some effort. Label the growth witnessed. The child will learn that that is who they are over time (“observant”). Verbalizing these behaviors also will provide patients with a sense of mastery over parenting, because they are driving the emotional and behavioral development of their children in a way that also complements their family values.
• Make everyone in the family a contributor and foster a sense of gratitude: Give everyone a reason to claim that their collaboration and effort are a big part of the plan’s success. Take turns to lessen everyone’s burden and to thank them for their contributions. Older children can take on leadership roles, even in small ways. Younger children can practice being good listeners, following directions, and helping. Reverse the roles when possible.

Special needs families sometimes have to work harder than others to overcome obstacles, grow, and learn to support one another. Since the pandemic, many parents have been just as challenged. Mastering the above skills might provide a sense of fulfillment and agency, as well as an appreciation for the unexpected gifts that special children – and all children – have to offer.
 

Dr. Sotir is a psychiatrist with a private practice in Wheaton, Ill. As a parent of three children, one with special needs, she has extensive experience helping parents challenged by having special needs children find balance, support, direction, and joy in all dimensions of individual and family life. This area is the focus of her practice and public speaking. She has no disclosures.

Most people can cope, to some degree, with the multiple weeks of social distancing and stressors related to the pandemic. But what if those stressors became a way of life for a year – or longer? What sorts of skills would be essential not only to survive but to have a renewed sense of resilience?

I know of one group that has had experiences that mirror the challenges faced by the parents of children: the parents of special needs children. As I argued previously, those parents have faced many of the challenges presented by COVID-19. Among those challenges are social distancing and difficulty accessing everyday common experiences. These parents know that they have to manage more areas of their children’s rearing than do their counterparts.

In addition to having to plan for how to deal with acute urgent or emergent medical situations involving their special needs children, these parents also must prepare for the long-term effects of managing children who require ongoing daily care, attention, and dedication.

As psychiatrists, we can teach patients several strategies that can serve as basic building blocks. These strategies can help the parents of special needs kids find a sense of mastery and comfort. The hope is that, after practicing them for long periods of time, the strategies become second nature.

Here are several strategies that might help patients with children during this pandemic:

• Take time to reset: Sometimes it is helpful for parents to take a minute away from a difficult impasse with their kids to reset and take their own “time out.” A few seconds of mental time away from the “scene” provides space and a mental reminder that the minute that just happened is finite, and that a whole new one is coming up next. The break provides a sense of hope. This cognitive reframing could be practiced often.
• Re-enter the challenging scene with a warm voice: Parents model for their children, but they also are telling their own brains that they, too, can calm down. This approach also de-escalates the situation and allows children to get used to hearing directions from someone who is in control – without hostility or irritability.
• Keep a sense of humor; it might come in handy: This is especially the case when tension is in the home, or when facing a set of challenging bad news. As an example, consider how some situations are so repetitive that they border on the ridiculous – such as a grown child having a tantrum at a store. Encourage the children to give themselves permission to cry first so they can laugh second, and then move on.
• Establish a routine for children that is self-reinforcing, and allows for together and separate times: They can, as an example: A) Get ready for the day all by themselves, or as much as they can do independently, before they come down and then B) have breakfast. Then, the child can C) do homework, and then D) go play outside. The routine would then continue on its own without outside reinforcers.
• Tell the children that they can get to the reinforcing activity only after completing the previous one. Over time, they learn to take pride in completing the first activity and doing so more independently. Not having to wait to be told what to do all the time fosters a sense of independence.
• Plan for meals and fun tasks together, and separate for individual work. This creates a sense of change and gives the day a certain flow. Establish routines that are predictable for the children that can be easily documented for the whole family on a calendar. Establish a beginning and an end time to the work day. Mark the end of the day with a chalk line establishing when the family can engage in a certain activity, for example, going for a family bike ride. Let the routine honor healthy circadian rhythms for sleep/wakeful times, and be consistent.
• Feed the brain and body the “good stuff”: Limit negative news, and surround the children with people who bring them joy or provide hope. Listen to inspirational messages and uplifting music. Give the children food that nourishes and energizes their bodies. Take in the view outside, the greenery, or the sky if there is no green around. Connect with family/friends who are far away.
• Make time to replenish with something that is meaningful/productive/helpful: Parents have very little time for themselves when they are “on,” so when they can actually take a little time to recharge, the activity should check many boxes. For example, encourage them to go for a walk (exercise) while listening to music (relax), make a phone call to someone who can relate to their situation (socialize), pray with someone (be spiritual), or sit in their rooms to get some alone quiet time (meditate). Reach out to those who are lonely. Network. Mentor. Volunteer.
• Develop an eye for noticing the positive: Instead of hoping for things to go back to the way they were, tell your patients to practice embracing without judgment the new norm. Get them to notice the time they spend with their families. Break all tasks into many smaller tasks, so there is more possibility of observing progress, and it is evident for everyone to see. Learn to notice the small changes that they want to see in their children. Celebrate all that can be celebrated by stating the obvious: “You wiped your face after eating. You are observant; you are noticing when you have something on your face.”
• State when a child is forgiving, helpful, or puts forward some effort. Label the growth witnessed. The child will learn that that is who they are over time (“observant”). Verbalizing these behaviors also will provide patients with a sense of mastery over parenting, because they are driving the emotional and behavioral development of their children in a way that also complements their family values.
• Make everyone in the family a contributor and foster a sense of gratitude: Give everyone a reason to claim that their collaboration and effort are a big part of the plan’s success. Take turns to lessen everyone’s burden and to thank them for their contributions. Older children can take on leadership roles, even in small ways. Younger children can practice being good listeners, following directions, and helping. Reverse the roles when possible.

Special needs families sometimes have to work harder than others to overcome obstacles, grow, and learn to support one another. Since the pandemic, many parents have been just as challenged. Mastering the above skills might provide a sense of fulfillment and agency, as well as an appreciation for the unexpected gifts that special children – and all children – have to offer.
 

Dr. Sotir is a psychiatrist with a private practice in Wheaton, Ill. As a parent of three children, one with special needs, she has extensive experience helping parents challenged by having special needs children find balance, support, direction, and joy in all dimensions of individual and family life. This area is the focus of her practice and public speaking. She has no disclosures.

Most people can cope, to some degree, with the multiple weeks of social distancing and stressors related to the pandemic. But what if those stressors became a way of life for a year – or longer? What sorts of skills would be essential not only to survive but to have a renewed sense of resilience?

I know of one group that has had experiences that mirror the challenges faced by the parents of children: the parents of special needs children. As I argued previously, those parents have faced many of the challenges presented by COVID-19. Among those challenges are social distancing and difficulty accessing everyday common experiences. These parents know that they have to manage more areas of their children’s rearing than do their counterparts.

In addition to having to plan for how to deal with acute urgent or emergent medical situations involving their special needs children, these parents also must prepare for the long-term effects of managing children who require ongoing daily care, attention, and dedication.

As psychiatrists, we can teach patients several strategies that can serve as basic building blocks. These strategies can help the parents of special needs kids find a sense of mastery and comfort. The hope is that, after practicing them for long periods of time, the strategies become second nature.

Here are several strategies that might help patients with children during this pandemic:

• Take time to reset: Sometimes it is helpful for parents to take a minute away from a difficult impasse with their kids to reset and take their own “time out.” A few seconds of mental time away from the “scene” provides space and a mental reminder that the minute that just happened is finite, and that a whole new one is coming up next. The break provides a sense of hope. This cognitive reframing could be practiced often.
• Re-enter the challenging scene with a warm voice: Parents model for their children, but they also are telling their own brains that they, too, can calm down. This approach also de-escalates the situation and allows children to get used to hearing directions from someone who is in control – without hostility or irritability.
• Keep a sense of humor; it might come in handy: This is especially the case when tension is in the home, or when facing a set of challenging bad news. As an example, consider how some situations are so repetitive that they border on the ridiculous – such as a grown child having a tantrum at a store. Encourage the children to give themselves permission to cry first so they can laugh second, and then move on.
• Establish a routine for children that is self-reinforcing, and allows for together and separate times: They can, as an example: A) Get ready for the day all by themselves, or as much as they can do independently, before they come down and then B) have breakfast. Then, the child can C) do homework, and then D) go play outside. The routine would then continue on its own without outside reinforcers.
• Tell the children that they can get to the reinforcing activity only after completing the previous one. Over time, they learn to take pride in completing the first activity and doing so more independently. Not having to wait to be told what to do all the time fosters a sense of independence.
• Plan for meals and fun tasks together, and separate for individual work. This creates a sense of change and gives the day a certain flow. Establish routines that are predictable for the children that can be easily documented for the whole family on a calendar. Establish a beginning and an end time to the work day. Mark the end of the day with a chalk line establishing when the family can engage in a certain activity, for example, going for a family bike ride. Let the routine honor healthy circadian rhythms for sleep/wakeful times, and be consistent.
• Feed the brain and body the “good stuff”: Limit negative news, and surround the children with people who bring them joy or provide hope. Listen to inspirational messages and uplifting music. Give the children food that nourishes and energizes their bodies. Take in the view outside, the greenery, or the sky if there is no green around. Connect with family/friends who are far away.
• Make time to replenish with something that is meaningful/productive/helpful: Parents have very little time for themselves when they are “on,” so when they can actually take a little time to recharge, the activity should check many boxes. For example, encourage them to go for a walk (exercise) while listening to music (relax), make a phone call to someone who can relate to their situation (socialize), pray with someone (be spiritual), or sit in their rooms to get some alone quiet time (meditate). Reach out to those who are lonely. Network. Mentor. Volunteer.
• Develop an eye for noticing the positive: Instead of hoping for things to go back to the way they were, tell your patients to practice embracing without judgment the new norm. Get them to notice the time they spend with their families. Break all tasks into many smaller tasks, so there is more possibility of observing progress, and it is evident for everyone to see. Learn to notice the small changes that they want to see in their children. Celebrate all that can be celebrated by stating the obvious: “You wiped your face after eating. You are observant; you are noticing when you have something on your face.”
• State when a child is forgiving, helpful, or puts forward some effort. Label the growth witnessed. The child will learn that that is who they are over time (“observant”). Verbalizing these behaviors also will provide patients with a sense of mastery over parenting, because they are driving the emotional and behavioral development of their children in a way that also complements their family values.
• Make everyone in the family a contributor and foster a sense of gratitude: Give everyone a reason to claim that their collaboration and effort are a big part of the plan’s success. Take turns to lessen everyone’s burden and to thank them for their contributions. Older children can take on leadership roles, even in small ways. Younger children can practice being good listeners, following directions, and helping. Reverse the roles when possible.

Special needs families sometimes have to work harder than others to overcome obstacles, grow, and learn to support one another. Since the pandemic, many parents have been just as challenged. Mastering the above skills might provide a sense of fulfillment and agency, as well as an appreciation for the unexpected gifts that special children – and all children – have to offer.
 

Dr. Sotir is a psychiatrist with a private practice in Wheaton, Ill. As a parent of three children, one with special needs, she has extensive experience helping parents challenged by having special needs children find balance, support, direction, and joy in all dimensions of individual and family life. This area is the focus of her practice and public speaking. She has no disclosures.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

A recently approved first-in-class antipsychotic appears to have fewer adverse cardiometabolic effects than standard care with risperidone, new research suggests.

In post hoc analyses of two short-term randomized controlled trials plus an open-label long-term study, patients with schizophrenia on lumateperone (Caplyta, Intra-Cellular Therapies) had reduced rates of metabolic syndrome, compared with their counterparts taking placebo or the antipsychotic risperidone.

In the short-term studies, rates of metabolic syndrome were similar between groups at baseline, but by the end of 4 and 6 weeks of treatment, 25% of patients taking lumateperone no longer met criteria for metabolic syndrome. A similar finding occurred in 36% of patients in the 1-year open label study.

“One of the major advantages that we found during the drug’s development was that it has a very favorable profile with regard to changes in weight, and other [parameters] associated with cardiovascular disease risk, such as elevated glucose and lipids,” study investigator Andrew Satlin, MD, chief medical officer at Intra-Cellular Therapies, New York, told this news organization.

“So we went back to our data and looked to see whether the changes that we saw had an impact on either the development or the resolution of metabolic syndrome in the patients who came into our studies,” he said.

The findings were presented at the American Society of Clinical Psychopharmacology 2020 Virtual Conference.
 

Reduced cholesterol

Lumateperone was approved in December by the Food and Drug Administration. The drug acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

The short-term studies included 511 patients randomly assigned to receive lumateperone 42 mg (n = 256 patients) or risperidone 4 mg (n = 255 patients).

At baseline, rates of metabolic syndrome were 16% in the lumateperone group and 19% in the risperidone group. At the end of treatment, metabolic syndrome was less common in the lumateperone group (13%) vs. those receiving risperidone (25%).

In addition, 46% of lumateperone patients with metabolic syndrome at baseline no longer had it at the end of the study period. This compared with 25% of patients on risperidone.

More patients taking risperidone than on lumateperone developed metabolic syndrome during treatment (13% vs. 5%).

The differences in metabolic syndrome conversion rates appeared to be driven by greater reductions in total cholesterol with lumateperone, compared with risperidone (­–2.8 mg/dL with lumateperone vs. 4.8 mg/dL with risperidone) and triglycerides (–0.7 mg/dL with lumateperone vs. 20.4 mg/dL with risperidone).

Greater increases in blood glucose were also seen with risperidone (7.7 mg/dL) than with lumateperone (0.9 mg/dL).

The long-term study included 602 patients with stable schizophrenia. All received lumateperone 42 mg, and 197 patients (33%) had metabolic syndrome at baseline.

At the end of the 1-year study, 72 of these patients (36%) no longer met criteria for metabolic syndrome.
 

“Safest antipsychotic so far”

“Lumateperone seems to be the safest antipsychotic we have seen so far,” Christoph U. Correll, MD, professor of child and adolescent psychiatry, Charité Universitatsmedizin, Berlin, who was also involved in clinical trials of lumateperone, told this news organization.

“It seems to be very safe when it comes to cardiometabolic parameters, and it shows similar reduction in symptoms as risperidone. It is certainly an agent one should consider, particularly when a patient cannot tolerate other medications or may not be in full adherence,” said Dr. Correll, who has a joint appointment as professor of psychiatry and molecular medicine at the Zucker School of Medicine at Hofstra University in Hempstead, New York.

The drug’s safety and efficacy profile would make it a good candidate in patients initiating antipsychotic treatment, but reimbursement issues may be a barrier, at least for now, he added.

He said that the drug may prevent the onset of metabolic side effects and added that once payers are willing to reimburse the drug it should become the “first-line standard of care.”

It is well known that atypical antipsychotics are associated with adverse and rapid metabolic changes. Dr. Correll noted that particularly early-phase and first-episode patients can be “very sensitive” to the side effects of these drugs and often experience rapid weight gain and other adverse metabolic changes. Lumateperone, he added, may help avoid some of this cardiometabolic risk.
 

Time will tell

Jessica M. Gannon, MD, a psychiatrist at the University of Pittsburgh said in commenting on the findings that the drug’s favorable metabolic profile has previously been reported.

She also noted that there has been some interest in lumateperone because of possible “downstream effects on NMDA-type glutamate receptor activity, a larger binding ratio at dopamine-2:5HT1A receptors than other atypical antipsychotics, and presynaptic D2 partial agonism and a postsynaptic D2 antagonism.”

“This latter feature may explain the reported low extrapyramidal symptom incidence in the clinical trials,” she said .

“While I think future studies and clinical use can help determine how clinically efficacious this medication will be for our patients when compared to others on the market, its favorable metabolic and EPS profile do make it of interest,” added Gannon, who was not involved in researching the drug.

The study was funded by Intra-Cellular Therapies. Dr. Satlin is chief medical officer of Intracellular Therapies. Dr. Correll has been a consultant or advisor to and has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva.

A version of this article originally appeared on Medscape.com.

A recently approved first-in-class antipsychotic appears to have fewer adverse cardiometabolic effects than standard care with risperidone, new research suggests.

In post hoc analyses of two short-term randomized controlled trials plus an open-label long-term study, patients with schizophrenia on lumateperone (Caplyta, Intra-Cellular Therapies) had reduced rates of metabolic syndrome, compared with their counterparts taking placebo or the antipsychotic risperidone.

In the short-term studies, rates of metabolic syndrome were similar between groups at baseline, but by the end of 4 and 6 weeks of treatment, 25% of patients taking lumateperone no longer met criteria for metabolic syndrome. A similar finding occurred in 36% of patients in the 1-year open label study.

“One of the major advantages that we found during the drug’s development was that it has a very favorable profile with regard to changes in weight, and other [parameters] associated with cardiovascular disease risk, such as elevated glucose and lipids,” study investigator Andrew Satlin, MD, chief medical officer at Intra-Cellular Therapies, New York, told this news organization.

“So we went back to our data and looked to see whether the changes that we saw had an impact on either the development or the resolution of metabolic syndrome in the patients who came into our studies,” he said.

The findings were presented at the American Society of Clinical Psychopharmacology 2020 Virtual Conference.
 

Reduced cholesterol

Lumateperone was approved in December by the Food and Drug Administration. The drug acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

The short-term studies included 511 patients randomly assigned to receive lumateperone 42 mg (n = 256 patients) or risperidone 4 mg (n = 255 patients).

At baseline, rates of metabolic syndrome were 16% in the lumateperone group and 19% in the risperidone group. At the end of treatment, metabolic syndrome was less common in the lumateperone group (13%) vs. those receiving risperidone (25%).

In addition, 46% of lumateperone patients with metabolic syndrome at baseline no longer had it at the end of the study period. This compared with 25% of patients on risperidone.

More patients taking risperidone than on lumateperone developed metabolic syndrome during treatment (13% vs. 5%).

The differences in metabolic syndrome conversion rates appeared to be driven by greater reductions in total cholesterol with lumateperone, compared with risperidone (­–2.8 mg/dL with lumateperone vs. 4.8 mg/dL with risperidone) and triglycerides (–0.7 mg/dL with lumateperone vs. 20.4 mg/dL with risperidone).

Greater increases in blood glucose were also seen with risperidone (7.7 mg/dL) than with lumateperone (0.9 mg/dL).

The long-term study included 602 patients with stable schizophrenia. All received lumateperone 42 mg, and 197 patients (33%) had metabolic syndrome at baseline.

At the end of the 1-year study, 72 of these patients (36%) no longer met criteria for metabolic syndrome.
 

“Safest antipsychotic so far”

“Lumateperone seems to be the safest antipsychotic we have seen so far,” Christoph U. Correll, MD, professor of child and adolescent psychiatry, Charité Universitatsmedizin, Berlin, who was also involved in clinical trials of lumateperone, told this news organization.

“It seems to be very safe when it comes to cardiometabolic parameters, and it shows similar reduction in symptoms as risperidone. It is certainly an agent one should consider, particularly when a patient cannot tolerate other medications or may not be in full adherence,” said Dr. Correll, who has a joint appointment as professor of psychiatry and molecular medicine at the Zucker School of Medicine at Hofstra University in Hempstead, New York.

The drug’s safety and efficacy profile would make it a good candidate in patients initiating antipsychotic treatment, but reimbursement issues may be a barrier, at least for now, he added.

He said that the drug may prevent the onset of metabolic side effects and added that once payers are willing to reimburse the drug it should become the “first-line standard of care.”

It is well known that atypical antipsychotics are associated with adverse and rapid metabolic changes. Dr. Correll noted that particularly early-phase and first-episode patients can be “very sensitive” to the side effects of these drugs and often experience rapid weight gain and other adverse metabolic changes. Lumateperone, he added, may help avoid some of this cardiometabolic risk.
 

Time will tell

Jessica M. Gannon, MD, a psychiatrist at the University of Pittsburgh said in commenting on the findings that the drug’s favorable metabolic profile has previously been reported.

She also noted that there has been some interest in lumateperone because of possible “downstream effects on NMDA-type glutamate receptor activity, a larger binding ratio at dopamine-2:5HT1A receptors than other atypical antipsychotics, and presynaptic D2 partial agonism and a postsynaptic D2 antagonism.”

“This latter feature may explain the reported low extrapyramidal symptom incidence in the clinical trials,” she said .

“While I think future studies and clinical use can help determine how clinically efficacious this medication will be for our patients when compared to others on the market, its favorable metabolic and EPS profile do make it of interest,” added Gannon, who was not involved in researching the drug.

The study was funded by Intra-Cellular Therapies. Dr. Satlin is chief medical officer of Intracellular Therapies. Dr. Correll has been a consultant or advisor to and has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva.

A version of this article originally appeared on Medscape.com.

A recently approved first-in-class antipsychotic appears to have fewer adverse cardiometabolic effects than standard care with risperidone, new research suggests.

In post hoc analyses of two short-term randomized controlled trials plus an open-label long-term study, patients with schizophrenia on lumateperone (Caplyta, Intra-Cellular Therapies) had reduced rates of metabolic syndrome, compared with their counterparts taking placebo or the antipsychotic risperidone.

In the short-term studies, rates of metabolic syndrome were similar between groups at baseline, but by the end of 4 and 6 weeks of treatment, 25% of patients taking lumateperone no longer met criteria for metabolic syndrome. A similar finding occurred in 36% of patients in the 1-year open label study.

“One of the major advantages that we found during the drug’s development was that it has a very favorable profile with regard to changes in weight, and other [parameters] associated with cardiovascular disease risk, such as elevated glucose and lipids,” study investigator Andrew Satlin, MD, chief medical officer at Intra-Cellular Therapies, New York, told this news organization.

“So we went back to our data and looked to see whether the changes that we saw had an impact on either the development or the resolution of metabolic syndrome in the patients who came into our studies,” he said.

The findings were presented at the American Society of Clinical Psychopharmacology 2020 Virtual Conference.
 

Reduced cholesterol

Lumateperone was approved in December by the Food and Drug Administration. The drug acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

The short-term studies included 511 patients randomly assigned to receive lumateperone 42 mg (n = 256 patients) or risperidone 4 mg (n = 255 patients).

At baseline, rates of metabolic syndrome were 16% in the lumateperone group and 19% in the risperidone group. At the end of treatment, metabolic syndrome was less common in the lumateperone group (13%) vs. those receiving risperidone (25%).

In addition, 46% of lumateperone patients with metabolic syndrome at baseline no longer had it at the end of the study period. This compared with 25% of patients on risperidone.

More patients taking risperidone than on lumateperone developed metabolic syndrome during treatment (13% vs. 5%).

The differences in metabolic syndrome conversion rates appeared to be driven by greater reductions in total cholesterol with lumateperone, compared with risperidone (­–2.8 mg/dL with lumateperone vs. 4.8 mg/dL with risperidone) and triglycerides (–0.7 mg/dL with lumateperone vs. 20.4 mg/dL with risperidone).

Greater increases in blood glucose were also seen with risperidone (7.7 mg/dL) than with lumateperone (0.9 mg/dL).

The long-term study included 602 patients with stable schizophrenia. All received lumateperone 42 mg, and 197 patients (33%) had metabolic syndrome at baseline.

At the end of the 1-year study, 72 of these patients (36%) no longer met criteria for metabolic syndrome.
 

“Safest antipsychotic so far”

“Lumateperone seems to be the safest antipsychotic we have seen so far,” Christoph U. Correll, MD, professor of child and adolescent psychiatry, Charité Universitatsmedizin, Berlin, who was also involved in clinical trials of lumateperone, told this news organization.

“It seems to be very safe when it comes to cardiometabolic parameters, and it shows similar reduction in symptoms as risperidone. It is certainly an agent one should consider, particularly when a patient cannot tolerate other medications or may not be in full adherence,” said Dr. Correll, who has a joint appointment as professor of psychiatry and molecular medicine at the Zucker School of Medicine at Hofstra University in Hempstead, New York.

The drug’s safety and efficacy profile would make it a good candidate in patients initiating antipsychotic treatment, but reimbursement issues may be a barrier, at least for now, he added.

He said that the drug may prevent the onset of metabolic side effects and added that once payers are willing to reimburse the drug it should become the “first-line standard of care.”

It is well known that atypical antipsychotics are associated with adverse and rapid metabolic changes. Dr. Correll noted that particularly early-phase and first-episode patients can be “very sensitive” to the side effects of these drugs and often experience rapid weight gain and other adverse metabolic changes. Lumateperone, he added, may help avoid some of this cardiometabolic risk.
 

Time will tell

Jessica M. Gannon, MD, a psychiatrist at the University of Pittsburgh said in commenting on the findings that the drug’s favorable metabolic profile has previously been reported.

She also noted that there has been some interest in lumateperone because of possible “downstream effects on NMDA-type glutamate receptor activity, a larger binding ratio at dopamine-2:5HT1A receptors than other atypical antipsychotics, and presynaptic D2 partial agonism and a postsynaptic D2 antagonism.”

“This latter feature may explain the reported low extrapyramidal symptom incidence in the clinical trials,” she said .

“While I think future studies and clinical use can help determine how clinically efficacious this medication will be for our patients when compared to others on the market, its favorable metabolic and EPS profile do make it of interest,” added Gannon, who was not involved in researching the drug.

The study was funded by Intra-Cellular Therapies. Dr. Satlin is chief medical officer of Intracellular Therapies. Dr. Correll has been a consultant or advisor to and has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva.

A version of this article originally appeared on Medscape.com.

A significant number of teenage blood donors already have low iron stores before they donate blood, and approximately 15% of males and one-third of females may be iron depleted 1 year after a red blood cell donation, according to a study published online in Pediatrics.

copyrightSaipg/iStockphoto

“Our findings ... support the strong encouragement of postdonation low-dose iron supplements, at least in teenagers with already low or borderline iron stores,” said Ralph R. Vassallo, MD and colleagues. An increased interdonation interval for teenage blood donors may need to be considered. Dr. Vassallo is executive vice president and chief medical and scientific officer at Vitalant, a community blood service provider based in Scottsdale, Ariz., that collects approximately 14% of the U.S. blood supply.
 

Data from a safety initiative

Iron deficiency may erode exercise performance, lead to pica, and have subtle cognitive effects. Iron that is lost during blood donation may be difficult to replace on an average Western diet, the researchers said. Knowledge of the time course of iron recovery is limited, and recent studies have found high rates of mild iron depletion or absent stores in teenage blood donors.

As a safety initiative, Vitalant began serum ferritin testing of predonation specimens from successful donations by 16- to 18-year-old donors to identify iron deficiency. The researchers defined inadequate iron stores as ferritin values less than 20 ng/mL in female donors and less than 30 ng/mL in male donors.

While whole-blood donors generally were deferred from red blood cell donation for 56 days and double red blood cell donors were deferred from any donation for 112 days, teenagers found to have low ferritin were deferred longer: 12 months for females and 6 months for males. Teenagers with low ferritin also were counseled by letter to take low-dose (18-28 mg) iron for 60 days.

Vitalant began conducting serum ferritin tests on Dec. 19, 2016, and the researchers analyzed data that were available through Dec. 31, 2018. The study included data from teen donors aged 16-18 years from 24 states.

In all, 125,384 teenagers donated whole blood or double red blood cells at least once, and 39% of females and 12% of males had a low-index ferritin value. The researchers focused on 30,806 teenagers (24.6%) who returned and successfully donated again within 25 months. In this cohort, 11% of female donors and 10% of male donors had a low-index ferritin value.

Twelve months after the first whole-blood donation, 80%-90% of males and 60%-70% of females had adequate iron stores. These proportions were about 10% lower for double red blood cell donors.

Among whole-blood donors, the percentage of donors with adequate iron stores at a follow-up donation “is highly dependent on index ferritin,” Dr. Vassallo and colleagues reported. For 90% of donors to have adequate iron stores within 3-9 months of index donation, index ferritin values had to be at least 47 ng/mL for males and 53 ng/mL for females, according to their analysis.

“At least 12 months are required for a sizeable proportion to reach next-donation ferritin values indicative of adequate iron stores,” the researchers said. “However, donor sex, donation type, first-time versus repeat status, and ferritin level at index were significant determinants of iron stores at the follow-up donation.”

“The enthusiasm of altruistic, highly motivated young donors makes large high school and college blood drives efficient and productive,” but these donors may be at increased risk for donation-related iron depletion, they said.

The estimated intervals needed to replenish iron stores represent best-case scenarios, the authors noted. The cohort did not include individuals deferred for low hemoglobin, likely due to iron deficiency, and these donors probably require more time to replenish iron stores.

The data suggest that health care providers should consider blood donation as a possible cause of low hemoglobin, Dr. Vassallo and colleagues said. Before prescribing higher doses of iron, however, physicians should assess a patient’s risk for other causes of iron deficiency such as gastrointestinal blood loss or celiac disease.
 

Shift collection efforts away from teenagers?

Vitalant’s findings “are of considerable value to other organizations collecting blood from teenagers,” Alan E. Mast, MD, PhD, said in an accompanying editorial. Dr. Mast is medical director and senior investigator at Versiti Blood Research Institute and associate professor of cell biology, neurobiology, and anatomy at Medical College of Wisconsin in Milwaukee. “The data presented confirm the high baseline level of iron deficiency in teenagers and its increase after blood donation. Pediatricians should be aware of the large number of teenagers donating blood in the United States, consider routinely asking about blood donation during routine physical examinations, and perform appropriate laboratory screening and treatment of iron deficiency.”

High school blood drives are a cost-effective way to collect blood, and stricter regulations on the collection of blood from teenagers may “have a detrimental effect on the blood supply,” Dr. Mast said. Nevertheless, “efforts should be made to reverse the trend of increasing collections from teenagers with increased emphasis on collection from adults.”

AABB (previously known as the American Association of Blood Banks), an organization of professionals who practice transfusion medicine, recommended in 2017 that blood collection agencies limit donors aged 16-18 years to one whole-blood donation per year, dispense iron supplements, or perform ferritin testing to advise donors about further steps, Dr. Mast noted.

“In the absence of other interventions, 1 year should be the minimum interdonation interval for teenagers,” said Dr. Mast. “If ferritin testing is performed, teenagers with ferritin levels [greater than] 50 ng/mL at index donation could perhaps donate twice per year.”

Dr. Vassallo has received payment from Fresenius Kabi and HemaStrat for scientific advisory board membership. Dr. Mast receives research funding from Novo Nordisk and has received honoraria for serving on Novo Nordisk advisory boards. He received no external funding for his commentary.

jremaly@mdedge.com

SOURCE: Vassallo RR et al. Pediatrics. 2020 Jun 5. doi: 10.1542/peds.2019-3316.

A significant number of teenage blood donors already have low iron stores before they donate blood, and approximately 15% of males and one-third of females may be iron depleted 1 year after a red blood cell donation, according to a study published online in Pediatrics.

copyrightSaipg/iStockphoto

“Our findings ... support the strong encouragement of postdonation low-dose iron supplements, at least in teenagers with already low or borderline iron stores,” said Ralph R. Vassallo, MD and colleagues. An increased interdonation interval for teenage blood donors may need to be considered. Dr. Vassallo is executive vice president and chief medical and scientific officer at Vitalant, a community blood service provider based in Scottsdale, Ariz., that collects approximately 14% of the U.S. blood supply.
 

Data from a safety initiative

Iron deficiency may erode exercise performance, lead to pica, and have subtle cognitive effects. Iron that is lost during blood donation may be difficult to replace on an average Western diet, the researchers said. Knowledge of the time course of iron recovery is limited, and recent studies have found high rates of mild iron depletion or absent stores in teenage blood donors.

As a safety initiative, Vitalant began serum ferritin testing of predonation specimens from successful donations by 16- to 18-year-old donors to identify iron deficiency. The researchers defined inadequate iron stores as ferritin values less than 20 ng/mL in female donors and less than 30 ng/mL in male donors.

While whole-blood donors generally were deferred from red blood cell donation for 56 days and double red blood cell donors were deferred from any donation for 112 days, teenagers found to have low ferritin were deferred longer: 12 months for females and 6 months for males. Teenagers with low ferritin also were counseled by letter to take low-dose (18-28 mg) iron for 60 days.

Vitalant began conducting serum ferritin tests on Dec. 19, 2016, and the researchers analyzed data that were available through Dec. 31, 2018. The study included data from teen donors aged 16-18 years from 24 states.

In all, 125,384 teenagers donated whole blood or double red blood cells at least once, and 39% of females and 12% of males had a low-index ferritin value. The researchers focused on 30,806 teenagers (24.6%) who returned and successfully donated again within 25 months. In this cohort, 11% of female donors and 10% of male donors had a low-index ferritin value.

Twelve months after the first whole-blood donation, 80%-90% of males and 60%-70% of females had adequate iron stores. These proportions were about 10% lower for double red blood cell donors.

Among whole-blood donors, the percentage of donors with adequate iron stores at a follow-up donation “is highly dependent on index ferritin,” Dr. Vassallo and colleagues reported. For 90% of donors to have adequate iron stores within 3-9 months of index donation, index ferritin values had to be at least 47 ng/mL for males and 53 ng/mL for females, according to their analysis.

“At least 12 months are required for a sizeable proportion to reach next-donation ferritin values indicative of adequate iron stores,” the researchers said. “However, donor sex, donation type, first-time versus repeat status, and ferritin level at index were significant determinants of iron stores at the follow-up donation.”

“The enthusiasm of altruistic, highly motivated young donors makes large high school and college blood drives efficient and productive,” but these donors may be at increased risk for donation-related iron depletion, they said.

The estimated intervals needed to replenish iron stores represent best-case scenarios, the authors noted. The cohort did not include individuals deferred for low hemoglobin, likely due to iron deficiency, and these donors probably require more time to replenish iron stores.

The data suggest that health care providers should consider blood donation as a possible cause of low hemoglobin, Dr. Vassallo and colleagues said. Before prescribing higher doses of iron, however, physicians should assess a patient’s risk for other causes of iron deficiency such as gastrointestinal blood loss or celiac disease.
 

Shift collection efforts away from teenagers?

Vitalant’s findings “are of considerable value to other organizations collecting blood from teenagers,” Alan E. Mast, MD, PhD, said in an accompanying editorial. Dr. Mast is medical director and senior investigator at Versiti Blood Research Institute and associate professor of cell biology, neurobiology, and anatomy at Medical College of Wisconsin in Milwaukee. “The data presented confirm the high baseline level of iron deficiency in teenagers and its increase after blood donation. Pediatricians should be aware of the large number of teenagers donating blood in the United States, consider routinely asking about blood donation during routine physical examinations, and perform appropriate laboratory screening and treatment of iron deficiency.”

High school blood drives are a cost-effective way to collect blood, and stricter regulations on the collection of blood from teenagers may “have a detrimental effect on the blood supply,” Dr. Mast said. Nevertheless, “efforts should be made to reverse the trend of increasing collections from teenagers with increased emphasis on collection from adults.”

AABB (previously known as the American Association of Blood Banks), an organization of professionals who practice transfusion medicine, recommended in 2017 that blood collection agencies limit donors aged 16-18 years to one whole-blood donation per year, dispense iron supplements, or perform ferritin testing to advise donors about further steps, Dr. Mast noted.

“In the absence of other interventions, 1 year should be the minimum interdonation interval for teenagers,” said Dr. Mast. “If ferritin testing is performed, teenagers with ferritin levels [greater than] 50 ng/mL at index donation could perhaps donate twice per year.”

Dr. Vassallo has received payment from Fresenius Kabi and HemaStrat for scientific advisory board membership. Dr. Mast receives research funding from Novo Nordisk and has received honoraria for serving on Novo Nordisk advisory boards. He received no external funding for his commentary.

jremaly@mdedge.com

SOURCE: Vassallo RR et al. Pediatrics. 2020 Jun 5. doi: 10.1542/peds.2019-3316.

A significant number of teenage blood donors already have low iron stores before they donate blood, and approximately 15% of males and one-third of females may be iron depleted 1 year after a red blood cell donation, according to a study published online in Pediatrics.

copyrightSaipg/iStockphoto

“Our findings ... support the strong encouragement of postdonation low-dose iron supplements, at least in teenagers with already low or borderline iron stores,” said Ralph R. Vassallo, MD and colleagues. An increased interdonation interval for teenage blood donors may need to be considered. Dr. Vassallo is executive vice president and chief medical and scientific officer at Vitalant, a community blood service provider based in Scottsdale, Ariz., that collects approximately 14% of the U.S. blood supply.
 

Data from a safety initiative

Iron deficiency may erode exercise performance, lead to pica, and have subtle cognitive effects. Iron that is lost during blood donation may be difficult to replace on an average Western diet, the researchers said. Knowledge of the time course of iron recovery is limited, and recent studies have found high rates of mild iron depletion or absent stores in teenage blood donors.

As a safety initiative, Vitalant began serum ferritin testing of predonation specimens from successful donations by 16- to 18-year-old donors to identify iron deficiency. The researchers defined inadequate iron stores as ferritin values less than 20 ng/mL in female donors and less than 30 ng/mL in male donors.

While whole-blood donors generally were deferred from red blood cell donation for 56 days and double red blood cell donors were deferred from any donation for 112 days, teenagers found to have low ferritin were deferred longer: 12 months for females and 6 months for males. Teenagers with low ferritin also were counseled by letter to take low-dose (18-28 mg) iron for 60 days.

Vitalant began conducting serum ferritin tests on Dec. 19, 2016, and the researchers analyzed data that were available through Dec. 31, 2018. The study included data from teen donors aged 16-18 years from 24 states.

In all, 125,384 teenagers donated whole blood or double red blood cells at least once, and 39% of females and 12% of males had a low-index ferritin value. The researchers focused on 30,806 teenagers (24.6%) who returned and successfully donated again within 25 months. In this cohort, 11% of female donors and 10% of male donors had a low-index ferritin value.

Twelve months after the first whole-blood donation, 80%-90% of males and 60%-70% of females had adequate iron stores. These proportions were about 10% lower for double red blood cell donors.

Among whole-blood donors, the percentage of donors with adequate iron stores at a follow-up donation “is highly dependent on index ferritin,” Dr. Vassallo and colleagues reported. For 90% of donors to have adequate iron stores within 3-9 months of index donation, index ferritin values had to be at least 47 ng/mL for males and 53 ng/mL for females, according to their analysis.

“At least 12 months are required for a sizeable proportion to reach next-donation ferritin values indicative of adequate iron stores,” the researchers said. “However, donor sex, donation type, first-time versus repeat status, and ferritin level at index were significant determinants of iron stores at the follow-up donation.”

“The enthusiasm of altruistic, highly motivated young donors makes large high school and college blood drives efficient and productive,” but these donors may be at increased risk for donation-related iron depletion, they said.

The estimated intervals needed to replenish iron stores represent best-case scenarios, the authors noted. The cohort did not include individuals deferred for low hemoglobin, likely due to iron deficiency, and these donors probably require more time to replenish iron stores.

The data suggest that health care providers should consider blood donation as a possible cause of low hemoglobin, Dr. Vassallo and colleagues said. Before prescribing higher doses of iron, however, physicians should assess a patient’s risk for other causes of iron deficiency such as gastrointestinal blood loss or celiac disease.
 

Shift collection efforts away from teenagers?

Vitalant’s findings “are of considerable value to other organizations collecting blood from teenagers,” Alan E. Mast, MD, PhD, said in an accompanying editorial. Dr. Mast is medical director and senior investigator at Versiti Blood Research Institute and associate professor of cell biology, neurobiology, and anatomy at Medical College of Wisconsin in Milwaukee. “The data presented confirm the high baseline level of iron deficiency in teenagers and its increase after blood donation. Pediatricians should be aware of the large number of teenagers donating blood in the United States, consider routinely asking about blood donation during routine physical examinations, and perform appropriate laboratory screening and treatment of iron deficiency.”

High school blood drives are a cost-effective way to collect blood, and stricter regulations on the collection of blood from teenagers may “have a detrimental effect on the blood supply,” Dr. Mast said. Nevertheless, “efforts should be made to reverse the trend of increasing collections from teenagers with increased emphasis on collection from adults.”

AABB (previously known as the American Association of Blood Banks), an organization of professionals who practice transfusion medicine, recommended in 2017 that blood collection agencies limit donors aged 16-18 years to one whole-blood donation per year, dispense iron supplements, or perform ferritin testing to advise donors about further steps, Dr. Mast noted.

“In the absence of other interventions, 1 year should be the minimum interdonation interval for teenagers,” said Dr. Mast. “If ferritin testing is performed, teenagers with ferritin levels [greater than] 50 ng/mL at index donation could perhaps donate twice per year.”

Dr. Vassallo has received payment from Fresenius Kabi and HemaStrat for scientific advisory board membership. Dr. Mast receives research funding from Novo Nordisk and has received honoraria for serving on Novo Nordisk advisory boards. He received no external funding for his commentary.

jremaly@mdedge.com

SOURCE: Vassallo RR et al. Pediatrics. 2020 Jun 5. doi: 10.1542/peds.2019-3316.