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Ketamine versus ECT for depression: First head-to-head results
Intravenous ketamine is effective for treating depression but is inferior to electroconvulsive therapy (ECT), new research suggests.
In the first head-to-head trial, ECT was more effective than intravenous ketamine in hospitalized patients with severe depression, with higher remission rates and a greater reduction in symptoms.
However, ketamine led to remission in nearly half of participants and is a “valuable” option for treating severe depression, particularly in younger patients, the investigators noted.
The high rate of remission for ketamine infusion “indicates that it definitely can be used in a clinical setting, but it is more probable that a patient will achieve remission with ECT compared to ketamine,” principal investigator Pouya Movahed Rad, MD, PhD (pharmacology), senior consultant and researcher in psychiatry, Lund (Sweden) University, said in an interview.
Results of the KetECT study were recently published online in the International Journal of Neuropsychopharmacology.
Primary focus on remission
The parallel, open-label, noninferiority study included 186 patients aged 18-85 years who were hospitalized with severe unipolar depression and had a score of at least 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
Participants were randomly allocated (1:1) to thrice-weekly infusions of racemic ketamine (0.5 mg/kg over 40 minutes) or ECT. All patients continued to take their antidepressant medication during the study. The primary outcome was remission, defined as a MADRS score of 10 or less.
Results showed the remission rate was significantly higher in the ECT group than in the ketamine group (63% vs. 46%, respectively; P = .026). The 95% confidence interval of the difference in remission rates was estimated between 2% and 30%.
Both ketamine and ECT required a median of six treatment sessions to induce remission.
Post-hoc analysis indicated that age was a factor in the findings. In the ECT group, remission was significantly more likely in older patients (51-85 years), compared with younger patients (18-50 years), with remission rates of 77% and 50%, respectively.
But the opposite was true in the ketamine group, with significantly higher remission rates in younger versus older patients (61% vs. 37%).
The study results also support the safety and efficacy of ketamine in patients with psychotic depression, which was present in 15% of patients in the ECT group and 18% of those in the ketamine group.
In this subgroup, half of patients with psychotic depression remitted after ketamine, with no indications of adverse reactions particular for these patients. The remission rate with ECT was 79%.
During the 12-month follow-up period, rate of relapse among remitters was similar at 64% in the ECT group and 70% in the ketamine group (log rank P = .44).
Let the patient decide
As expected, ECT and ketamine had distinct side effect profiles. Subjectively reported prolonged amnesia was more common with ECT and reports of dissociative side effects, anxiety, blurred vision, euphoria, vertigo, and diplopia (double vision) were more common with ketamine.
“Dissociative symptoms were, as expected, observed during treatment with ketamine, but they were brief and in the majority of cases mild and tolerable,” Dr. Movahed Rad said.
The investigators noted that participating study sites all had long-time experience with ECT but no experience administering ketamine.
“Staffs, and some patients, were familiar with side effects common to ECT but were less prepared for the adverse psychological effects of ketamine. This, and knowing ECT was available after the study, probably contributed to the higher dropout rate in the ketamine group,” they wrote.
If both ECT and ketamine are available, “the patient’s preference should, of course, be taken in account when choosing treatment,” said Dr. Movahed Rad.
“ or other somatic risk factor. Patients who have not responded to ECT or have had unacceptable side effects should be offered ketamine infusion and vice versa,” he added.
A good alternative
Commenting on the findings, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said the data confirm ECT is highly effective for treatment-resistant depression and show that “newcomer” intravenous ketamine also performs “exceptionally well.”
“This is an extremely important study that really establishes the efficacy of ketamine in a very difficult to treat population,” added Dr. McIntyre, who was not involved in the research.
He added that this “rigorous, well-designed study addresses a critical question” about the comparative efficacy of ECT and intravenous ketamine. It also makes “quite a strong statement about the efficacy of ketamine in younger people.”
He cautioned, however, that this study represents the “first data point and, of course, is not the final word on the topic. There are other studies currently still ongoing that are also comparing ECT to IV ketamine and we’ll look forward to seeing the results.”
The fact that 15%-20% of the study patients had psychotic depression is also noteworthy, said Dr. McIntyre.
“We’ve been hesitant to use ketamine in these patients, I think for obvious reasons, but we recently published a paper showing that it is safe and very effective in these patients,” he said.
Having ketamine as a treatment option is important because the majority of patients who could benefit from ECT decline it, often because of the stigma associated with the procedure, which is often portrayed negatively in films and other media.
“I have been recommending ECT almost every day of my professional life and 98 times out of 100 people say: ‘Thanks but no thanks.’ That’s a problem because ECT is so effective,” Dr. McIntyre said.
The study was funded by the Swedish Research Council, Crafoord Foundation, Skåne Regional Council, Königska Foundation, Lions Forskningsfond Skåne, and the OM Perssons donation foundation. Dr. Movahed Rad has received lecturer honoraria from Lundbeck. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, and other companies. McIntyre is also CEO of AltMed.
A version of this article first appeared on Medscape.com.
Intravenous ketamine is effective for treating depression but is inferior to electroconvulsive therapy (ECT), new research suggests.
In the first head-to-head trial, ECT was more effective than intravenous ketamine in hospitalized patients with severe depression, with higher remission rates and a greater reduction in symptoms.
However, ketamine led to remission in nearly half of participants and is a “valuable” option for treating severe depression, particularly in younger patients, the investigators noted.
The high rate of remission for ketamine infusion “indicates that it definitely can be used in a clinical setting, but it is more probable that a patient will achieve remission with ECT compared to ketamine,” principal investigator Pouya Movahed Rad, MD, PhD (pharmacology), senior consultant and researcher in psychiatry, Lund (Sweden) University, said in an interview.
Results of the KetECT study were recently published online in the International Journal of Neuropsychopharmacology.
Primary focus on remission
The parallel, open-label, noninferiority study included 186 patients aged 18-85 years who were hospitalized with severe unipolar depression and had a score of at least 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
Participants were randomly allocated (1:1) to thrice-weekly infusions of racemic ketamine (0.5 mg/kg over 40 minutes) or ECT. All patients continued to take their antidepressant medication during the study. The primary outcome was remission, defined as a MADRS score of 10 or less.
Results showed the remission rate was significantly higher in the ECT group than in the ketamine group (63% vs. 46%, respectively; P = .026). The 95% confidence interval of the difference in remission rates was estimated between 2% and 30%.
Both ketamine and ECT required a median of six treatment sessions to induce remission.
Post-hoc analysis indicated that age was a factor in the findings. In the ECT group, remission was significantly more likely in older patients (51-85 years), compared with younger patients (18-50 years), with remission rates of 77% and 50%, respectively.
But the opposite was true in the ketamine group, with significantly higher remission rates in younger versus older patients (61% vs. 37%).
The study results also support the safety and efficacy of ketamine in patients with psychotic depression, which was present in 15% of patients in the ECT group and 18% of those in the ketamine group.
In this subgroup, half of patients with psychotic depression remitted after ketamine, with no indications of adverse reactions particular for these patients. The remission rate with ECT was 79%.
During the 12-month follow-up period, rate of relapse among remitters was similar at 64% in the ECT group and 70% in the ketamine group (log rank P = .44).
Let the patient decide
As expected, ECT and ketamine had distinct side effect profiles. Subjectively reported prolonged amnesia was more common with ECT and reports of dissociative side effects, anxiety, blurred vision, euphoria, vertigo, and diplopia (double vision) were more common with ketamine.
“Dissociative symptoms were, as expected, observed during treatment with ketamine, but they were brief and in the majority of cases mild and tolerable,” Dr. Movahed Rad said.
The investigators noted that participating study sites all had long-time experience with ECT but no experience administering ketamine.
“Staffs, and some patients, were familiar with side effects common to ECT but were less prepared for the adverse psychological effects of ketamine. This, and knowing ECT was available after the study, probably contributed to the higher dropout rate in the ketamine group,” they wrote.
If both ECT and ketamine are available, “the patient’s preference should, of course, be taken in account when choosing treatment,” said Dr. Movahed Rad.
“ or other somatic risk factor. Patients who have not responded to ECT or have had unacceptable side effects should be offered ketamine infusion and vice versa,” he added.
A good alternative
Commenting on the findings, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said the data confirm ECT is highly effective for treatment-resistant depression and show that “newcomer” intravenous ketamine also performs “exceptionally well.”
“This is an extremely important study that really establishes the efficacy of ketamine in a very difficult to treat population,” added Dr. McIntyre, who was not involved in the research.
He added that this “rigorous, well-designed study addresses a critical question” about the comparative efficacy of ECT and intravenous ketamine. It also makes “quite a strong statement about the efficacy of ketamine in younger people.”
He cautioned, however, that this study represents the “first data point and, of course, is not the final word on the topic. There are other studies currently still ongoing that are also comparing ECT to IV ketamine and we’ll look forward to seeing the results.”
The fact that 15%-20% of the study patients had psychotic depression is also noteworthy, said Dr. McIntyre.
“We’ve been hesitant to use ketamine in these patients, I think for obvious reasons, but we recently published a paper showing that it is safe and very effective in these patients,” he said.
Having ketamine as a treatment option is important because the majority of patients who could benefit from ECT decline it, often because of the stigma associated with the procedure, which is often portrayed negatively in films and other media.
“I have been recommending ECT almost every day of my professional life and 98 times out of 100 people say: ‘Thanks but no thanks.’ That’s a problem because ECT is so effective,” Dr. McIntyre said.
The study was funded by the Swedish Research Council, Crafoord Foundation, Skåne Regional Council, Königska Foundation, Lions Forskningsfond Skåne, and the OM Perssons donation foundation. Dr. Movahed Rad has received lecturer honoraria from Lundbeck. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, and other companies. McIntyre is also CEO of AltMed.
A version of this article first appeared on Medscape.com.
Intravenous ketamine is effective for treating depression but is inferior to electroconvulsive therapy (ECT), new research suggests.
In the first head-to-head trial, ECT was more effective than intravenous ketamine in hospitalized patients with severe depression, with higher remission rates and a greater reduction in symptoms.
However, ketamine led to remission in nearly half of participants and is a “valuable” option for treating severe depression, particularly in younger patients, the investigators noted.
The high rate of remission for ketamine infusion “indicates that it definitely can be used in a clinical setting, but it is more probable that a patient will achieve remission with ECT compared to ketamine,” principal investigator Pouya Movahed Rad, MD, PhD (pharmacology), senior consultant and researcher in psychiatry, Lund (Sweden) University, said in an interview.
Results of the KetECT study were recently published online in the International Journal of Neuropsychopharmacology.
Primary focus on remission
The parallel, open-label, noninferiority study included 186 patients aged 18-85 years who were hospitalized with severe unipolar depression and had a score of at least 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
Participants were randomly allocated (1:1) to thrice-weekly infusions of racemic ketamine (0.5 mg/kg over 40 minutes) or ECT. All patients continued to take their antidepressant medication during the study. The primary outcome was remission, defined as a MADRS score of 10 or less.
Results showed the remission rate was significantly higher in the ECT group than in the ketamine group (63% vs. 46%, respectively; P = .026). The 95% confidence interval of the difference in remission rates was estimated between 2% and 30%.
Both ketamine and ECT required a median of six treatment sessions to induce remission.
Post-hoc analysis indicated that age was a factor in the findings. In the ECT group, remission was significantly more likely in older patients (51-85 years), compared with younger patients (18-50 years), with remission rates of 77% and 50%, respectively.
But the opposite was true in the ketamine group, with significantly higher remission rates in younger versus older patients (61% vs. 37%).
The study results also support the safety and efficacy of ketamine in patients with psychotic depression, which was present in 15% of patients in the ECT group and 18% of those in the ketamine group.
In this subgroup, half of patients with psychotic depression remitted after ketamine, with no indications of adverse reactions particular for these patients. The remission rate with ECT was 79%.
During the 12-month follow-up period, rate of relapse among remitters was similar at 64% in the ECT group and 70% in the ketamine group (log rank P = .44).
Let the patient decide
As expected, ECT and ketamine had distinct side effect profiles. Subjectively reported prolonged amnesia was more common with ECT and reports of dissociative side effects, anxiety, blurred vision, euphoria, vertigo, and diplopia (double vision) were more common with ketamine.
“Dissociative symptoms were, as expected, observed during treatment with ketamine, but they were brief and in the majority of cases mild and tolerable,” Dr. Movahed Rad said.
The investigators noted that participating study sites all had long-time experience with ECT but no experience administering ketamine.
“Staffs, and some patients, were familiar with side effects common to ECT but were less prepared for the adverse psychological effects of ketamine. This, and knowing ECT was available after the study, probably contributed to the higher dropout rate in the ketamine group,” they wrote.
If both ECT and ketamine are available, “the patient’s preference should, of course, be taken in account when choosing treatment,” said Dr. Movahed Rad.
“ or other somatic risk factor. Patients who have not responded to ECT or have had unacceptable side effects should be offered ketamine infusion and vice versa,” he added.
A good alternative
Commenting on the findings, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said the data confirm ECT is highly effective for treatment-resistant depression and show that “newcomer” intravenous ketamine also performs “exceptionally well.”
“This is an extremely important study that really establishes the efficacy of ketamine in a very difficult to treat population,” added Dr. McIntyre, who was not involved in the research.
He added that this “rigorous, well-designed study addresses a critical question” about the comparative efficacy of ECT and intravenous ketamine. It also makes “quite a strong statement about the efficacy of ketamine in younger people.”
He cautioned, however, that this study represents the “first data point and, of course, is not the final word on the topic. There are other studies currently still ongoing that are also comparing ECT to IV ketamine and we’ll look forward to seeing the results.”
The fact that 15%-20% of the study patients had psychotic depression is also noteworthy, said Dr. McIntyre.
“We’ve been hesitant to use ketamine in these patients, I think for obvious reasons, but we recently published a paper showing that it is safe and very effective in these patients,” he said.
Having ketamine as a treatment option is important because the majority of patients who could benefit from ECT decline it, often because of the stigma associated with the procedure, which is often portrayed negatively in films and other media.
“I have been recommending ECT almost every day of my professional life and 98 times out of 100 people say: ‘Thanks but no thanks.’ That’s a problem because ECT is so effective,” Dr. McIntyre said.
The study was funded by the Swedish Research Council, Crafoord Foundation, Skåne Regional Council, Königska Foundation, Lions Forskningsfond Skåne, and the OM Perssons donation foundation. Dr. Movahed Rad has received lecturer honoraria from Lundbeck. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, and other companies. McIntyre is also CEO of AltMed.
A version of this article first appeared on Medscape.com.
FROM THE INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
Ketamine an ‘intriguing new therapy’ for alcoholism
Three weekly infusions of the dissociative anesthetic ketamine coupled with mindfulness-based relapse prevention therapy may help adults with alcohol use disorder (AUD) maintain abstinence, new research suggests.
Preliminary results from a phase 2, double-blind, placebo-controlled trial show ketamine was well tolerated and, compared with placebo, associated with more days of abstinence from alcohol at 6 months.
The results suggest ketamine plus psychological therapy may be a “new, relatively brief treatment that has long lasting effects in AUD,” Celia Morgan, PhD, professor of psychopharmacology, University of Exeter, United Kingdom, told this news organization.
The study was published online Jan. 11 in the American Journal of Psychiatry.
Target depression
Depressive symptoms are common in patients under treatment for AUD and increase relapse risk.
“Ketamine may support alcohol abstinence by temporarily alleviating depressive symptoms during the high-risk relapse period in the weeks after detoxification,” the investigators note.
Ketamine may also provide a “temporary boost to synaptogenesis and neurogenesis, which may allow psychological therapies and new strategies for managing addiction to embed more readily,” they add.
To test these theories, the researchers recruited 96 adults (mean age, 44 years, 35 women) with severe AUD to participate in the trial.
All participants had to abstain from alcohol for at least 24 hours before the trial started and have a reading of 0.0 on a breath alcohol test at the baseline visit.
Participants were randomly allocated to one of four groups:
1. three weekly ketamine infusions of 0.8 mg/kg IV over 40 minutes plus psychological therapy
2. three saline infusions plus psychological therapy
3. three ketamine infusions plus alcohol education
4. three saline infusions plus alcohol education
The primary outcome was self-reported percentage of days abstinent, as well as confirmed alcohol relapse at 6-month follow-up.
(mean difference, 10.1%; 95% confidence interval, 1.1-19.0), “although confidence intervals were wide, consistent with a proof-of-concept study,” the authors note.
The greatest reduction in total days off alcohol occurred in the ketamine plus relapse-prevention therapy group compared with the saline plus alcohol education group (mean difference, 15.9%; 95% CI, 3.8-28.1).
There was no significant difference in relapse rate between the ketamine and placebo groups. No serious adverse effects were reported in any participant.
Growing evidence
These findings support some other studies that have also suggested a benefit of ketamine in AUD.
As reported by this news organization, one recent study found a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.
A separate study showed that a single dose of ketamine plus therapy that focused on reactivating drinking-related “maladaptive reward memories” reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.
“That ketamine can reduce both alcohol use and depression in AUD is encouraging therapeutically,” the researchers write.
“While a clear link between depression and AUD is acknowledged, alcohol and mental health services still struggle to meet the needs of dual-diagnosis patients, so ketamine may represent a solution to this long-standing comorbidity,” they add.
Dr. Morgan said in an interview that adjunctive ketamine with relapse-prevention therapy is “currently being delivered in Awakn Clinics in the U.K. and Norway, but we need to conduct the phase 3 trial in order to make the treatment more widely accessible.”
An ‘Intriguing new therapy’
Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services, Addiction Institute of Mount Sinai, New York, said ketamine “continues to be an intriguing new therapy for a variety of mental health conditions.”
“Unfortunately, the study did not show any difference in rates of relapse to alcohol, though an improvement in days of abstinence is certainly noteworthy,” Dr. Brennan said in an interview.
“Because this was just a proof-of-concept study and did not compare ketamine to any FDA-approved pharmacotherapy for alcohol, it remains too early to recommend ketamine infusions to those suffering from alcohol use disorder,” he cautioned.
The study was supported by the Medical Research Council. Dr. Morgan has received royalties for KARE (Ketamine for Reduction of Alcoholic Relapse) therapy license distribution. KARE therapy is licensed from University of Exeter to Awakn Life Sciences. Dr. Morgan has received research funding from Awakn Life Sciences and has served as a consultant for Janssen Pharmaceuticals. Other coauthors have disclosed relationships with industry; the full list can be found with the original article. Dr. Brennan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Three weekly infusions of the dissociative anesthetic ketamine coupled with mindfulness-based relapse prevention therapy may help adults with alcohol use disorder (AUD) maintain abstinence, new research suggests.
Preliminary results from a phase 2, double-blind, placebo-controlled trial show ketamine was well tolerated and, compared with placebo, associated with more days of abstinence from alcohol at 6 months.
The results suggest ketamine plus psychological therapy may be a “new, relatively brief treatment that has long lasting effects in AUD,” Celia Morgan, PhD, professor of psychopharmacology, University of Exeter, United Kingdom, told this news organization.
The study was published online Jan. 11 in the American Journal of Psychiatry.
Target depression
Depressive symptoms are common in patients under treatment for AUD and increase relapse risk.
“Ketamine may support alcohol abstinence by temporarily alleviating depressive symptoms during the high-risk relapse period in the weeks after detoxification,” the investigators note.
Ketamine may also provide a “temporary boost to synaptogenesis and neurogenesis, which may allow psychological therapies and new strategies for managing addiction to embed more readily,” they add.
To test these theories, the researchers recruited 96 adults (mean age, 44 years, 35 women) with severe AUD to participate in the trial.
All participants had to abstain from alcohol for at least 24 hours before the trial started and have a reading of 0.0 on a breath alcohol test at the baseline visit.
Participants were randomly allocated to one of four groups:
1. three weekly ketamine infusions of 0.8 mg/kg IV over 40 minutes plus psychological therapy
2. three saline infusions plus psychological therapy
3. three ketamine infusions plus alcohol education
4. three saline infusions plus alcohol education
The primary outcome was self-reported percentage of days abstinent, as well as confirmed alcohol relapse at 6-month follow-up.
(mean difference, 10.1%; 95% confidence interval, 1.1-19.0), “although confidence intervals were wide, consistent with a proof-of-concept study,” the authors note.
The greatest reduction in total days off alcohol occurred in the ketamine plus relapse-prevention therapy group compared with the saline plus alcohol education group (mean difference, 15.9%; 95% CI, 3.8-28.1).
There was no significant difference in relapse rate between the ketamine and placebo groups. No serious adverse effects were reported in any participant.
Growing evidence
These findings support some other studies that have also suggested a benefit of ketamine in AUD.
As reported by this news organization, one recent study found a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.
A separate study showed that a single dose of ketamine plus therapy that focused on reactivating drinking-related “maladaptive reward memories” reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.
“That ketamine can reduce both alcohol use and depression in AUD is encouraging therapeutically,” the researchers write.
“While a clear link between depression and AUD is acknowledged, alcohol and mental health services still struggle to meet the needs of dual-diagnosis patients, so ketamine may represent a solution to this long-standing comorbidity,” they add.
Dr. Morgan said in an interview that adjunctive ketamine with relapse-prevention therapy is “currently being delivered in Awakn Clinics in the U.K. and Norway, but we need to conduct the phase 3 trial in order to make the treatment more widely accessible.”
An ‘Intriguing new therapy’
Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services, Addiction Institute of Mount Sinai, New York, said ketamine “continues to be an intriguing new therapy for a variety of mental health conditions.”
“Unfortunately, the study did not show any difference in rates of relapse to alcohol, though an improvement in days of abstinence is certainly noteworthy,” Dr. Brennan said in an interview.
“Because this was just a proof-of-concept study and did not compare ketamine to any FDA-approved pharmacotherapy for alcohol, it remains too early to recommend ketamine infusions to those suffering from alcohol use disorder,” he cautioned.
The study was supported by the Medical Research Council. Dr. Morgan has received royalties for KARE (Ketamine for Reduction of Alcoholic Relapse) therapy license distribution. KARE therapy is licensed from University of Exeter to Awakn Life Sciences. Dr. Morgan has received research funding from Awakn Life Sciences and has served as a consultant for Janssen Pharmaceuticals. Other coauthors have disclosed relationships with industry; the full list can be found with the original article. Dr. Brennan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Three weekly infusions of the dissociative anesthetic ketamine coupled with mindfulness-based relapse prevention therapy may help adults with alcohol use disorder (AUD) maintain abstinence, new research suggests.
Preliminary results from a phase 2, double-blind, placebo-controlled trial show ketamine was well tolerated and, compared with placebo, associated with more days of abstinence from alcohol at 6 months.
The results suggest ketamine plus psychological therapy may be a “new, relatively brief treatment that has long lasting effects in AUD,” Celia Morgan, PhD, professor of psychopharmacology, University of Exeter, United Kingdom, told this news organization.
The study was published online Jan. 11 in the American Journal of Psychiatry.
Target depression
Depressive symptoms are common in patients under treatment for AUD and increase relapse risk.
“Ketamine may support alcohol abstinence by temporarily alleviating depressive symptoms during the high-risk relapse period in the weeks after detoxification,” the investigators note.
Ketamine may also provide a “temporary boost to synaptogenesis and neurogenesis, which may allow psychological therapies and new strategies for managing addiction to embed more readily,” they add.
To test these theories, the researchers recruited 96 adults (mean age, 44 years, 35 women) with severe AUD to participate in the trial.
All participants had to abstain from alcohol for at least 24 hours before the trial started and have a reading of 0.0 on a breath alcohol test at the baseline visit.
Participants were randomly allocated to one of four groups:
1. three weekly ketamine infusions of 0.8 mg/kg IV over 40 minutes plus psychological therapy
2. three saline infusions plus psychological therapy
3. three ketamine infusions plus alcohol education
4. three saline infusions plus alcohol education
The primary outcome was self-reported percentage of days abstinent, as well as confirmed alcohol relapse at 6-month follow-up.
(mean difference, 10.1%; 95% confidence interval, 1.1-19.0), “although confidence intervals were wide, consistent with a proof-of-concept study,” the authors note.
The greatest reduction in total days off alcohol occurred in the ketamine plus relapse-prevention therapy group compared with the saline plus alcohol education group (mean difference, 15.9%; 95% CI, 3.8-28.1).
There was no significant difference in relapse rate between the ketamine and placebo groups. No serious adverse effects were reported in any participant.
Growing evidence
These findings support some other studies that have also suggested a benefit of ketamine in AUD.
As reported by this news organization, one recent study found a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.
A separate study showed that a single dose of ketamine plus therapy that focused on reactivating drinking-related “maladaptive reward memories” reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.
“That ketamine can reduce both alcohol use and depression in AUD is encouraging therapeutically,” the researchers write.
“While a clear link between depression and AUD is acknowledged, alcohol and mental health services still struggle to meet the needs of dual-diagnosis patients, so ketamine may represent a solution to this long-standing comorbidity,” they add.
Dr. Morgan said in an interview that adjunctive ketamine with relapse-prevention therapy is “currently being delivered in Awakn Clinics in the U.K. and Norway, but we need to conduct the phase 3 trial in order to make the treatment more widely accessible.”
An ‘Intriguing new therapy’
Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services, Addiction Institute of Mount Sinai, New York, said ketamine “continues to be an intriguing new therapy for a variety of mental health conditions.”
“Unfortunately, the study did not show any difference in rates of relapse to alcohol, though an improvement in days of abstinence is certainly noteworthy,” Dr. Brennan said in an interview.
“Because this was just a proof-of-concept study and did not compare ketamine to any FDA-approved pharmacotherapy for alcohol, it remains too early to recommend ketamine infusions to those suffering from alcohol use disorder,” he cautioned.
The study was supported by the Medical Research Council. Dr. Morgan has received royalties for KARE (Ketamine for Reduction of Alcoholic Relapse) therapy license distribution. KARE therapy is licensed from University of Exeter to Awakn Life Sciences. Dr. Morgan has received research funding from Awakn Life Sciences and has served as a consultant for Janssen Pharmaceuticals. Other coauthors have disclosed relationships with industry; the full list can be found with the original article. Dr. Brennan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Expert views diverge on adding chemotherapy to EGFR TKIs in EGFR-mutant NSCLC
One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.
In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.
Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.
Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.
While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.
The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.
In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.
Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”
Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.
“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.
No conflicts of interest were reported by the authors of either study.
One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.
In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.
Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.
Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.
While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.
The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.
In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.
Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”
Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.
“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.
No conflicts of interest were reported by the authors of either study.
One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.
In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.
Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.
Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.
While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.
The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.
In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.
Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”
Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.
“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.
No conflicts of interest were reported by the authors of either study.
FROM THE JOURNAL OF THORACIC ONCOLOGY
Abraxane still in short supply for cancer patients
forcing physicians to find alternatives for a drug once lauded for being easier to tolerate.
Abraxane (Bristol-Myers Squibb) is a paclitaxel albumin-bound injectable. It is different from alternative chemotherapy treatments like Taxol (paclitaxel) because it doesn’t use the solvents that can make Taxol difficult to tolerate. It was described as a “next-generation taxane” because it didn’t rely on solvents. It was approved in 2005 for metastatic breast cancer, then in 2012 for advanced non–small cell lung cancer, in 2013 for late-stage pancreatic cancer and in 2019 for people with PD-L1–positive metastatic triple-negative breast cancer.
The shortage, which was announced on Oct. 5, 2021, by the Food and Drug Administration, has led to some difficult decisions for patients and physicians. How long the shortage will last isn’t clear.
“I printed out [an] allotment sheet 2 days ago, and all it says [for Abraxane] is allocated,” said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center, Hammond, La. “Everyone is keeping what they’ve got for their own patients, so there really isn’t anything available.”
The Pontchartrain Cancer Center sent two patients to the University of Texas MD Anderson Cancer Center, Houston, for continued treatment with Abraxane, but that option is costly and time consuming for patients. The two patients had the means to travel, but Ms. Oubre said that many others cannot afford to travel for treatment. “Everyone has patients who are living paycheck to paycheck who certainly couldn’t afford to do that. There are going to be patients across the nation that are not going to be able to have care as a result of these things.”
The supply problems are causing difficult decisions for physicians, who may have to switch a patient from an unavailable drug to an alternative that isn’t as effective, Ms. Oubre said. “I can’t imagine the stress and the sadness that the physicians have to feel when they have to go explain that to a patient. That runs counter to everything they are as physicians.”
Other strategies include chemo holidays and rounding down doses in patients with metastatic cancer, according to Camille Hill, PharmD, vice president of oncology pharmacy services, West Cancer Center, Germantown, Tenn.
Shortages and allocations are growing at an alarming rate, Ms. Oubre said. In her 15 years of working in the industry, “I don’t recall it ever being this challenging.” During a Zoom interview, she held up a lengthy list of drugs on allocation or unavailable that her pharmacy group purchasing organization sent her the previous week. “I don’t ever recall getting this kind of list. Every 3 days, I’m getting this. If it were just that one product, I can live with that. We figure it out. But it’s bigger than that.”
Worker shortages are exacerbating the issue. Ms. Oubre received a letter from a drug company describing its employee issues, which included chemists, plant workers, and loading dock staff. On top of that, delivery companies are experiencing staff shortages, which can result in more delays and complicate matters further. “It’s just compounding. These things can get really difficult very quickly. I don’t want to say we’re in crisis, and we’re not rationing care. We’re not in those buckets yet. But I would say that if these things don’t get better, it’s the first time in my work career that we are having those conversations of: ‘How we are going to plan for that it does come to that?’ ” she said.
“In general, with the pandemic, we have seen all sorts of just disruptions to the supply chain. So, I think you just do your best, you find alternatives for those patients that you can, and you come up with strategies. I don’t know that for Abraxane, or any other product, that I’d be particularly confident that we may not see another shortage,” Dr. Hill said.
forcing physicians to find alternatives for a drug once lauded for being easier to tolerate.
Abraxane (Bristol-Myers Squibb) is a paclitaxel albumin-bound injectable. It is different from alternative chemotherapy treatments like Taxol (paclitaxel) because it doesn’t use the solvents that can make Taxol difficult to tolerate. It was described as a “next-generation taxane” because it didn’t rely on solvents. It was approved in 2005 for metastatic breast cancer, then in 2012 for advanced non–small cell lung cancer, in 2013 for late-stage pancreatic cancer and in 2019 for people with PD-L1–positive metastatic triple-negative breast cancer.
The shortage, which was announced on Oct. 5, 2021, by the Food and Drug Administration, has led to some difficult decisions for patients and physicians. How long the shortage will last isn’t clear.
“I printed out [an] allotment sheet 2 days ago, and all it says [for Abraxane] is allocated,” said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center, Hammond, La. “Everyone is keeping what they’ve got for their own patients, so there really isn’t anything available.”
The Pontchartrain Cancer Center sent two patients to the University of Texas MD Anderson Cancer Center, Houston, for continued treatment with Abraxane, but that option is costly and time consuming for patients. The two patients had the means to travel, but Ms. Oubre said that many others cannot afford to travel for treatment. “Everyone has patients who are living paycheck to paycheck who certainly couldn’t afford to do that. There are going to be patients across the nation that are not going to be able to have care as a result of these things.”
The supply problems are causing difficult decisions for physicians, who may have to switch a patient from an unavailable drug to an alternative that isn’t as effective, Ms. Oubre said. “I can’t imagine the stress and the sadness that the physicians have to feel when they have to go explain that to a patient. That runs counter to everything they are as physicians.”
Other strategies include chemo holidays and rounding down doses in patients with metastatic cancer, according to Camille Hill, PharmD, vice president of oncology pharmacy services, West Cancer Center, Germantown, Tenn.
Shortages and allocations are growing at an alarming rate, Ms. Oubre said. In her 15 years of working in the industry, “I don’t recall it ever being this challenging.” During a Zoom interview, she held up a lengthy list of drugs on allocation or unavailable that her pharmacy group purchasing organization sent her the previous week. “I don’t ever recall getting this kind of list. Every 3 days, I’m getting this. If it were just that one product, I can live with that. We figure it out. But it’s bigger than that.”
Worker shortages are exacerbating the issue. Ms. Oubre received a letter from a drug company describing its employee issues, which included chemists, plant workers, and loading dock staff. On top of that, delivery companies are experiencing staff shortages, which can result in more delays and complicate matters further. “It’s just compounding. These things can get really difficult very quickly. I don’t want to say we’re in crisis, and we’re not rationing care. We’re not in those buckets yet. But I would say that if these things don’t get better, it’s the first time in my work career that we are having those conversations of: ‘How we are going to plan for that it does come to that?’ ” she said.
“In general, with the pandemic, we have seen all sorts of just disruptions to the supply chain. So, I think you just do your best, you find alternatives for those patients that you can, and you come up with strategies. I don’t know that for Abraxane, or any other product, that I’d be particularly confident that we may not see another shortage,” Dr. Hill said.
forcing physicians to find alternatives for a drug once lauded for being easier to tolerate.
Abraxane (Bristol-Myers Squibb) is a paclitaxel albumin-bound injectable. It is different from alternative chemotherapy treatments like Taxol (paclitaxel) because it doesn’t use the solvents that can make Taxol difficult to tolerate. It was described as a “next-generation taxane” because it didn’t rely on solvents. It was approved in 2005 for metastatic breast cancer, then in 2012 for advanced non–small cell lung cancer, in 2013 for late-stage pancreatic cancer and in 2019 for people with PD-L1–positive metastatic triple-negative breast cancer.
The shortage, which was announced on Oct. 5, 2021, by the Food and Drug Administration, has led to some difficult decisions for patients and physicians. How long the shortage will last isn’t clear.
“I printed out [an] allotment sheet 2 days ago, and all it says [for Abraxane] is allocated,” said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center, Hammond, La. “Everyone is keeping what they’ve got for their own patients, so there really isn’t anything available.”
The Pontchartrain Cancer Center sent two patients to the University of Texas MD Anderson Cancer Center, Houston, for continued treatment with Abraxane, but that option is costly and time consuming for patients. The two patients had the means to travel, but Ms. Oubre said that many others cannot afford to travel for treatment. “Everyone has patients who are living paycheck to paycheck who certainly couldn’t afford to do that. There are going to be patients across the nation that are not going to be able to have care as a result of these things.”
The supply problems are causing difficult decisions for physicians, who may have to switch a patient from an unavailable drug to an alternative that isn’t as effective, Ms. Oubre said. “I can’t imagine the stress and the sadness that the physicians have to feel when they have to go explain that to a patient. That runs counter to everything they are as physicians.”
Other strategies include chemo holidays and rounding down doses in patients with metastatic cancer, according to Camille Hill, PharmD, vice president of oncology pharmacy services, West Cancer Center, Germantown, Tenn.
Shortages and allocations are growing at an alarming rate, Ms. Oubre said. In her 15 years of working in the industry, “I don’t recall it ever being this challenging.” During a Zoom interview, she held up a lengthy list of drugs on allocation or unavailable that her pharmacy group purchasing organization sent her the previous week. “I don’t ever recall getting this kind of list. Every 3 days, I’m getting this. If it were just that one product, I can live with that. We figure it out. But it’s bigger than that.”
Worker shortages are exacerbating the issue. Ms. Oubre received a letter from a drug company describing its employee issues, which included chemists, plant workers, and loading dock staff. On top of that, delivery companies are experiencing staff shortages, which can result in more delays and complicate matters further. “It’s just compounding. These things can get really difficult very quickly. I don’t want to say we’re in crisis, and we’re not rationing care. We’re not in those buckets yet. But I would say that if these things don’t get better, it’s the first time in my work career that we are having those conversations of: ‘How we are going to plan for that it does come to that?’ ” she said.
“In general, with the pandemic, we have seen all sorts of just disruptions to the supply chain. So, I think you just do your best, you find alternatives for those patients that you can, and you come up with strategies. I don’t know that for Abraxane, or any other product, that I’d be particularly confident that we may not see another shortage,” Dr. Hill said.
How safe is a drug holiday from bisphosphonates for osteoporosis?
Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.
The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.
These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.
The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.
“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.
“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting.
“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.
Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.
“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
Hip fracture risk with risedronate vs. alendronate drug holiday
Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.
Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.
Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.
They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.
Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.
Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.
Most of the patients were women (82%) and were White.
They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.
During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.
This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).
The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).
However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34).
There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).
The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.
The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.
These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.
The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.
“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.
“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting.
“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.
Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.
“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
Hip fracture risk with risedronate vs. alendronate drug holiday
Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.
Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.
Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.
They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.
Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.
Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.
Most of the patients were women (82%) and were White.
They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.
During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.
This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).
The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).
However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34).
There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).
The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.
The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.
These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.
The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.
“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.
“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting.
“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.
Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.
“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
Hip fracture risk with risedronate vs. alendronate drug holiday
Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.
Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.
Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.
They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.
Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.
Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.
Most of the patients were women (82%) and were White.
They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.
During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.
This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).
The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).
However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34).
There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).
The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Orally dissolving buprenorphine tied to severe tooth decay, FDA warns
Orally dissolving medications containing buprenorphine are linked to severe dental problems, including total tooth loss, the U.S. Food and Drug Administration warns in a safety communication.
The oral side effects of these medications, which are used to treat opioid use disorder (OUD) and pain, include cavities/tooth decay, including rampant caries; dental abscesses/infection; tooth erosion; fillings falling out; and, in some cases, total tooth loss.
Multiple cases have been reported even in patients with no history of dental problems.
The FDA is adding a warning about the risk of dental problems to the prescribing information and the patient medication guide for all buprenorphine-containing medicines dissolved in the mouth.
The FDA emphasizes, however, that buprenorphine remains “an important treatment option for OUD and pain, and the benefits of these medicines clearly outweigh the risks.”
More than 300 reported cases
Buprenorphine was approved in 2002 as a sublingual tablet, and in 2015 as a film to be placed inside the cheek to treat pain. Both delivery methods have been associated with dental problems.
Since buprenorphine was approved, the FDA has identified 305 cases of dental problems associated with orally dissolving buprenorphine, including 131 classified as serious.
There may be other cases, the FDA says, as this represents only cases reported to the FDA or published in the medical literature.
, but those as young as 18 years old were also affected.
Most cases occurred in patients using the medicines for OUD; however, 28 cases of dental problems occurred in patients using it to treat pain.
In 26 cases, patients had no prior history of dental problems. Some dental problems developed as soon as 2 weeks after treatment began; the median time to diagnosis was about 2 years after starting treatment.
Among all 305 cases reported, 113 involved two or more teeth.
The most common treatment for the dental problems was tooth extraction/removal, which was reported in 71 cases. Other cases required root canals, dental surgery, and other procedures such as crowns and implants.
Recommendations
The FDA says health care providers should counsel patients that severe and extensive tooth decay, tooth loss, and tooth fracture have been reported with the use of transmucosal buprenorphine-containing medicines and emphasize the importance of visiting their dentist to closely monitor their teeth.
Patients should be counseled to continue taking buprenorphine medications as prescribed and not stop suddenly without first talking to their health care provider, as this could lead to serious consequences, including relapse, misuse or abuse of other opioids, overdose, and death.
Patients are also being advised to take extra steps to help lessen the risk of serious dental problems.
Patients should also be educated on strategies to maintain or improve oral health while taking transmucosal buprenorphine medicines.
Counsel them that after the medicine is completely dissolved, the patient should take a large sip of water, swish it gently around the teeth and gums, swallow, and wait at least 1 hour before brushing their teeth, as the FDA advises. This will allow time for the mouth to gradually return to oral homeostasis and avoid any mechanical damage that may occur due to brushing.
The FDA also advises that patients tell their provider about any history of tooth problems, including cavities, and schedule a dentist visit soon after starting the medicine.
Dental problems related to transmucosal buprenorphine-containing medicines should be reported to the FDA’s MedWatch program.
A version of this article first appeared on Medscape.com.
Orally dissolving medications containing buprenorphine are linked to severe dental problems, including total tooth loss, the U.S. Food and Drug Administration warns in a safety communication.
The oral side effects of these medications, which are used to treat opioid use disorder (OUD) and pain, include cavities/tooth decay, including rampant caries; dental abscesses/infection; tooth erosion; fillings falling out; and, in some cases, total tooth loss.
Multiple cases have been reported even in patients with no history of dental problems.
The FDA is adding a warning about the risk of dental problems to the prescribing information and the patient medication guide for all buprenorphine-containing medicines dissolved in the mouth.
The FDA emphasizes, however, that buprenorphine remains “an important treatment option for OUD and pain, and the benefits of these medicines clearly outweigh the risks.”
More than 300 reported cases
Buprenorphine was approved in 2002 as a sublingual tablet, and in 2015 as a film to be placed inside the cheek to treat pain. Both delivery methods have been associated with dental problems.
Since buprenorphine was approved, the FDA has identified 305 cases of dental problems associated with orally dissolving buprenorphine, including 131 classified as serious.
There may be other cases, the FDA says, as this represents only cases reported to the FDA or published in the medical literature.
, but those as young as 18 years old were also affected.
Most cases occurred in patients using the medicines for OUD; however, 28 cases of dental problems occurred in patients using it to treat pain.
In 26 cases, patients had no prior history of dental problems. Some dental problems developed as soon as 2 weeks after treatment began; the median time to diagnosis was about 2 years after starting treatment.
Among all 305 cases reported, 113 involved two or more teeth.
The most common treatment for the dental problems was tooth extraction/removal, which was reported in 71 cases. Other cases required root canals, dental surgery, and other procedures such as crowns and implants.
Recommendations
The FDA says health care providers should counsel patients that severe and extensive tooth decay, tooth loss, and tooth fracture have been reported with the use of transmucosal buprenorphine-containing medicines and emphasize the importance of visiting their dentist to closely monitor their teeth.
Patients should be counseled to continue taking buprenorphine medications as prescribed and not stop suddenly without first talking to their health care provider, as this could lead to serious consequences, including relapse, misuse or abuse of other opioids, overdose, and death.
Patients are also being advised to take extra steps to help lessen the risk of serious dental problems.
Patients should also be educated on strategies to maintain or improve oral health while taking transmucosal buprenorphine medicines.
Counsel them that after the medicine is completely dissolved, the patient should take a large sip of water, swish it gently around the teeth and gums, swallow, and wait at least 1 hour before brushing their teeth, as the FDA advises. This will allow time for the mouth to gradually return to oral homeostasis and avoid any mechanical damage that may occur due to brushing.
The FDA also advises that patients tell their provider about any history of tooth problems, including cavities, and schedule a dentist visit soon after starting the medicine.
Dental problems related to transmucosal buprenorphine-containing medicines should be reported to the FDA’s MedWatch program.
A version of this article first appeared on Medscape.com.
Orally dissolving medications containing buprenorphine are linked to severe dental problems, including total tooth loss, the U.S. Food and Drug Administration warns in a safety communication.
The oral side effects of these medications, which are used to treat opioid use disorder (OUD) and pain, include cavities/tooth decay, including rampant caries; dental abscesses/infection; tooth erosion; fillings falling out; and, in some cases, total tooth loss.
Multiple cases have been reported even in patients with no history of dental problems.
The FDA is adding a warning about the risk of dental problems to the prescribing information and the patient medication guide for all buprenorphine-containing medicines dissolved in the mouth.
The FDA emphasizes, however, that buprenorphine remains “an important treatment option for OUD and pain, and the benefits of these medicines clearly outweigh the risks.”
More than 300 reported cases
Buprenorphine was approved in 2002 as a sublingual tablet, and in 2015 as a film to be placed inside the cheek to treat pain. Both delivery methods have been associated with dental problems.
Since buprenorphine was approved, the FDA has identified 305 cases of dental problems associated with orally dissolving buprenorphine, including 131 classified as serious.
There may be other cases, the FDA says, as this represents only cases reported to the FDA or published in the medical literature.
, but those as young as 18 years old were also affected.
Most cases occurred in patients using the medicines for OUD; however, 28 cases of dental problems occurred in patients using it to treat pain.
In 26 cases, patients had no prior history of dental problems. Some dental problems developed as soon as 2 weeks after treatment began; the median time to diagnosis was about 2 years after starting treatment.
Among all 305 cases reported, 113 involved two or more teeth.
The most common treatment for the dental problems was tooth extraction/removal, which was reported in 71 cases. Other cases required root canals, dental surgery, and other procedures such as crowns and implants.
Recommendations
The FDA says health care providers should counsel patients that severe and extensive tooth decay, tooth loss, and tooth fracture have been reported with the use of transmucosal buprenorphine-containing medicines and emphasize the importance of visiting their dentist to closely monitor their teeth.
Patients should be counseled to continue taking buprenorphine medications as prescribed and not stop suddenly without first talking to their health care provider, as this could lead to serious consequences, including relapse, misuse or abuse of other opioids, overdose, and death.
Patients are also being advised to take extra steps to help lessen the risk of serious dental problems.
Patients should also be educated on strategies to maintain or improve oral health while taking transmucosal buprenorphine medicines.
Counsel them that after the medicine is completely dissolved, the patient should take a large sip of water, swish it gently around the teeth and gums, swallow, and wait at least 1 hour before brushing their teeth, as the FDA advises. This will allow time for the mouth to gradually return to oral homeostasis and avoid any mechanical damage that may occur due to brushing.
The FDA also advises that patients tell their provider about any history of tooth problems, including cavities, and schedule a dentist visit soon after starting the medicine.
Dental problems related to transmucosal buprenorphine-containing medicines should be reported to the FDA’s MedWatch program.
A version of this article first appeared on Medscape.com.
‘Highly encouraging’ MRD results for zanubrutinib add-on in CLL
Treatment was stopped in the single-arm phase 2 trial when patients reached undetectable MRD, a novel use of MRD to guide treatment duration. At a median of 16 months after discontinuation, MRD remained undetectable in 31 of 33 patients (94%).
The team also found that a reduction to 1/400 of baseline MRD (delta-MRD400) by day 1 of cycle five predicted undetectable bone marrow MRD within eight treatment cycles.
delta-MRD400 is “a potential biomarker” to identify patients who’ll do well with a shorter treatment and flag others who require longer courses of therapy, said investigators led by Jacob Soumerai, MD, a hematologist/oncologist at Massachusetts General Hospital, Boston.
Overall, the results “are highly encouraging,” they said, with efficacy and safety comparing favorably to trials that added other BTK inhibitors – namely ibrutinib and acalabrutinib – to the standard obinutuzumab/venetoclax backbone, with a shorter treatment duration.
They said the novel triplet warrants further study in the first line and noted that they also “plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration.” The study was published recently in The Lancet Haematology.
Two editorialists – Davide Rossi, MD, PhD, and Joyce Marques De Almeida, both of the of the Oncology Institute of Southern Switzerland, Bellinzona – were encouraged by the findings and wanted future research to assess how well MRD-guided treatment duration works in patients with tumor protein p53-disrupted disease, who “benefit less from time-limited therapies” then patients with wild-type TP53; the trial was too small to address the issue.
There was a two-cycle lead-in with zanubrutinib and obinutuzumab then venetoclax ramp-up starting at cycle 3, with each cycle running 28 days.
Zanubrutinib is approved in the U.S. for mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.
In a previous phase 2 trial of ibrutinib add-on to venetoclax-obinutuzumab for 14 cycles followed by ibrutinib monotherapy, the rate of undetectable MRD in both peripheral blood and bone marrow was 67%. The rate of bone marrow undetectable MRD was 77% in another phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab for at least 15 cycles.
Dr. Soumerai and his team cautioned, however, that “comparisons across trials are fraught with selection bias resulting in differences in treated patient populations, and randomized data are needed to establish the optimal BTK inhibitor to combine with venetoclax with or without obinutuzumab, and to establish whether” the zanubrutinib triplet “improves progression-free survival and overall survival compared with current standard first-line therapy.”
There was grade 3 or worse neutropenia in 18% of subjects (7/39), one episode of febrile neutropenia (3%), lung infections in three patients (8%) patients, and five cases of hypertension (13%).
The editorialists characterized the numbers as low and the regimen as well tolerated. Past studies of ibrutinib, a first generation BTK, with venetoclax and obinutuzumab have pegged grade 3 or worse neutropenia at 56% and the hypertension incidence at 48%.
Granulocyte colony-stimulating factor administration “could partially account for the low incidence of severe neutropenia” in the trial, the investigators said.
The study was funded by zanubrutinib marketer Beigene as well as Genentech, the National Cancer Institute, and others. Many of the authors had industry ties, including Dr. Soumerai who reported being a consultant and researcher for Beigene and other companies. Dr. Rossi reported honoraria and research grants from AbbVie, AstraZeneca, and Janssen.
Treatment was stopped in the single-arm phase 2 trial when patients reached undetectable MRD, a novel use of MRD to guide treatment duration. At a median of 16 months after discontinuation, MRD remained undetectable in 31 of 33 patients (94%).
The team also found that a reduction to 1/400 of baseline MRD (delta-MRD400) by day 1 of cycle five predicted undetectable bone marrow MRD within eight treatment cycles.
delta-MRD400 is “a potential biomarker” to identify patients who’ll do well with a shorter treatment and flag others who require longer courses of therapy, said investigators led by Jacob Soumerai, MD, a hematologist/oncologist at Massachusetts General Hospital, Boston.
Overall, the results “are highly encouraging,” they said, with efficacy and safety comparing favorably to trials that added other BTK inhibitors – namely ibrutinib and acalabrutinib – to the standard obinutuzumab/venetoclax backbone, with a shorter treatment duration.
They said the novel triplet warrants further study in the first line and noted that they also “plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration.” The study was published recently in The Lancet Haematology.
Two editorialists – Davide Rossi, MD, PhD, and Joyce Marques De Almeida, both of the of the Oncology Institute of Southern Switzerland, Bellinzona – were encouraged by the findings and wanted future research to assess how well MRD-guided treatment duration works in patients with tumor protein p53-disrupted disease, who “benefit less from time-limited therapies” then patients with wild-type TP53; the trial was too small to address the issue.
There was a two-cycle lead-in with zanubrutinib and obinutuzumab then venetoclax ramp-up starting at cycle 3, with each cycle running 28 days.
Zanubrutinib is approved in the U.S. for mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.
In a previous phase 2 trial of ibrutinib add-on to venetoclax-obinutuzumab for 14 cycles followed by ibrutinib monotherapy, the rate of undetectable MRD in both peripheral blood and bone marrow was 67%. The rate of bone marrow undetectable MRD was 77% in another phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab for at least 15 cycles.
Dr. Soumerai and his team cautioned, however, that “comparisons across trials are fraught with selection bias resulting in differences in treated patient populations, and randomized data are needed to establish the optimal BTK inhibitor to combine with venetoclax with or without obinutuzumab, and to establish whether” the zanubrutinib triplet “improves progression-free survival and overall survival compared with current standard first-line therapy.”
There was grade 3 or worse neutropenia in 18% of subjects (7/39), one episode of febrile neutropenia (3%), lung infections in three patients (8%) patients, and five cases of hypertension (13%).
The editorialists characterized the numbers as low and the regimen as well tolerated. Past studies of ibrutinib, a first generation BTK, with venetoclax and obinutuzumab have pegged grade 3 or worse neutropenia at 56% and the hypertension incidence at 48%.
Granulocyte colony-stimulating factor administration “could partially account for the low incidence of severe neutropenia” in the trial, the investigators said.
The study was funded by zanubrutinib marketer Beigene as well as Genentech, the National Cancer Institute, and others. Many of the authors had industry ties, including Dr. Soumerai who reported being a consultant and researcher for Beigene and other companies. Dr. Rossi reported honoraria and research grants from AbbVie, AstraZeneca, and Janssen.
Treatment was stopped in the single-arm phase 2 trial when patients reached undetectable MRD, a novel use of MRD to guide treatment duration. At a median of 16 months after discontinuation, MRD remained undetectable in 31 of 33 patients (94%).
The team also found that a reduction to 1/400 of baseline MRD (delta-MRD400) by day 1 of cycle five predicted undetectable bone marrow MRD within eight treatment cycles.
delta-MRD400 is “a potential biomarker” to identify patients who’ll do well with a shorter treatment and flag others who require longer courses of therapy, said investigators led by Jacob Soumerai, MD, a hematologist/oncologist at Massachusetts General Hospital, Boston.
Overall, the results “are highly encouraging,” they said, with efficacy and safety comparing favorably to trials that added other BTK inhibitors – namely ibrutinib and acalabrutinib – to the standard obinutuzumab/venetoclax backbone, with a shorter treatment duration.
They said the novel triplet warrants further study in the first line and noted that they also “plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration.” The study was published recently in The Lancet Haematology.
Two editorialists – Davide Rossi, MD, PhD, and Joyce Marques De Almeida, both of the of the Oncology Institute of Southern Switzerland, Bellinzona – were encouraged by the findings and wanted future research to assess how well MRD-guided treatment duration works in patients with tumor protein p53-disrupted disease, who “benefit less from time-limited therapies” then patients with wild-type TP53; the trial was too small to address the issue.
There was a two-cycle lead-in with zanubrutinib and obinutuzumab then venetoclax ramp-up starting at cycle 3, with each cycle running 28 days.
Zanubrutinib is approved in the U.S. for mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.
In a previous phase 2 trial of ibrutinib add-on to venetoclax-obinutuzumab for 14 cycles followed by ibrutinib monotherapy, the rate of undetectable MRD in both peripheral blood and bone marrow was 67%. The rate of bone marrow undetectable MRD was 77% in another phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab for at least 15 cycles.
Dr. Soumerai and his team cautioned, however, that “comparisons across trials are fraught with selection bias resulting in differences in treated patient populations, and randomized data are needed to establish the optimal BTK inhibitor to combine with venetoclax with or without obinutuzumab, and to establish whether” the zanubrutinib triplet “improves progression-free survival and overall survival compared with current standard first-line therapy.”
There was grade 3 or worse neutropenia in 18% of subjects (7/39), one episode of febrile neutropenia (3%), lung infections in three patients (8%) patients, and five cases of hypertension (13%).
The editorialists characterized the numbers as low and the regimen as well tolerated. Past studies of ibrutinib, a first generation BTK, with venetoclax and obinutuzumab have pegged grade 3 or worse neutropenia at 56% and the hypertension incidence at 48%.
Granulocyte colony-stimulating factor administration “could partially account for the low incidence of severe neutropenia” in the trial, the investigators said.
The study was funded by zanubrutinib marketer Beigene as well as Genentech, the National Cancer Institute, and others. Many of the authors had industry ties, including Dr. Soumerai who reported being a consultant and researcher for Beigene and other companies. Dr. Rossi reported honoraria and research grants from AbbVie, AstraZeneca, and Janssen.
FROM THE LANCET HEMATOLOGY
COVID-vaccine myocarditis: Rare, mild, and usually in young men
The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”
The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.
That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
Unlikely, brief, and ‘benign’
“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.
In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”
Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.
And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.
Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.
And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.
In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
Modulation of immune responses
Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.
“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.
But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”
“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.
Prospects for younger children
Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?
Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.
It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”
A version of this article first appeared on Medscape.com.
The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”
The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.
That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
Unlikely, brief, and ‘benign’
“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.
In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”
Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.
And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.
Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.
And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.
In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
Modulation of immune responses
Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.
“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.
But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”
“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.
Prospects for younger children
Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?
Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.
It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”
A version of this article first appeared on Medscape.com.
The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”
The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.
That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
Unlikely, brief, and ‘benign’
“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.
In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”
Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.
And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.
Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.
And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.
In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
Modulation of immune responses
Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.
“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.
But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”
“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.
Prospects for younger children
Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?
Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.
It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”
A version of this article first appeared on Medscape.com.
SGLT2 inhibitors improve cardiovascular outcomes across groups
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.
The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.
“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.
The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”
However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
Ten trials, consistent cardiovascular benefits
Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.
The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).
Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).
Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.
On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.
All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
Benefits seen across age, sex, and race/ethnicity subgroups
While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).
By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).
And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.
“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.
The authors have no disclosures.
A version of this article first appeared on Medscape.com.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.
The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.
“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.
The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”
However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
Ten trials, consistent cardiovascular benefits
Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.
The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).
Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).
Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.
On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.
All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
Benefits seen across age, sex, and race/ethnicity subgroups
While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).
By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).
And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.
“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.
The authors have no disclosures.
A version of this article first appeared on Medscape.com.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.
The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.
“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.
The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”
However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
Ten trials, consistent cardiovascular benefits
Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.
The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).
Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).
Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.
On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.
All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
Benefits seen across age, sex, and race/ethnicity subgroups
While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).
By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).
And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.
“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.
The authors have no disclosures.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Pill not enough for ‘sexual problems’ female cancer patients face
The antidepressant bupropion failed to improve sexual dysfunction in female cancer survivors, according to new findings published online in the Journal of Clinical Oncology.
Using the Female Sexual Function Index (FSFI) as a measurement tool, investigators found that desire scores were not significantly different for participants who received bupropion versus a placebo over the 9-week study period.
“Sexual health is a complex phenomenon and [our results suggest that] no one intervention is going to solve the broader issue,” lead author Debra Barton, RN, PhD, FAAN, professor in the School of Nursing at the University of Michigan, Ann Arbor, told this news organization.
Sexual dysfunction is common among cancer survivors and experienced across multiple cancer types and stages of disease. Research shows that as many as 70% of female cancer survivors report loss of desire, compared with up to one-third of the general population.
Common sexual concerns among female cancer survivors include low desire, arousal issues, lack of appropriate lubrication, difficulty in achieving orgasm, and pain with penetrative sexual activity. Additionally, these women may experience significant overlap of symptoms, and often encounter multiple sexual issues that are exacerbated by a range of cancer treatments.
“It’s a huge problem,” Maryam B. Lustberg, MD, MPH, from Yale Cancer Center, New Haven, Conn., and colleagues wrote in an accompanying editorial.
Despite the prevalence of sexual dysfunction among cancer survivors, effective treatments remain elusive. Preliminary evidence suggests that bupropion, already approved for seasonal affective disorder, major depressive disorder, and smoking cessation, may also enhance libido.
Dr. Barton and colleagues conducted this phase 2 trial to determine whether bupropion can improve sexual desire in female cancer survivors without undesirable side effects.
In the study, Dr. Barton and colleagues compared two dose levels of extended-release bupropion in a cohort of 230 postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (<3.3), who had completed definitive cancer therapy.
Participants were randomized to receive either 150 mg (79 patients) or 300 mg (74 patients) once daily of extended-release bupropion, or placebo (77 patients).
Barton and colleagues then evaluated whether sexual desire significantly improved over the 9-week study period comparing the bupropion arms and the placebo group.
Overall, the authors found no significant differences (mean between-arm change for 150 mg once daily and placebo of 0.02; P = .93; mean between-arm change for 300 mg once daily and placebo of –0.02; P = .92). Mean scores at 9 weeks on the desire subscale were 2.17, 2.27, and 2.30 for 150 mg, 300 mg, and the placebo group, respectively.
In addition, none of the subscales – which included arousal, lubrication, and orgasm – or the total score showed a significant difference between arms at either 5 or 9 weeks.
Bupropion did, however, appear to be well tolerated. No grade 4-5 treatment-related adverse events occurred. In the 150-mg bupropion arm, two patients (2.6%) experienced a grade 3 event (insomnia and headache) and one patient in the 300-mg bupropion arm (1.4%) and placebo arm (1.3%) experienced a grade 3 event related to treatment (hypertension and headache, respectively).
In the accompanying editorial, Dr. Lustberg and colleagues “applaud the authors for conducting a study in this population of cancer survivors,” noting that “evidenced-based approaches have not been extensively studied.”
Dr. Lustberg and colleagues also commented that other randomized controlled clinical trials evaluating sexual desire disorder assessed outcomes using additional metrics, such as the Female Sexual Distress Scale–Revised questionnaire, which measures distress related to sexual dysfunction and low desire, in particular.
“The use of specific validated instruments for libido in place of the FSFI might have helped determine the effect of the study intervention in this reported trial,” they wrote.
Overall, according to Dr. Lustberg and colleagues, the negative results of this study indicate that a multidisciplinary clinical approach may be needed.
“As much as we would like to have one intervention that addresses this prominent issue, the evidence strongly suggests that cancer-related sexual problems may need an integrative biopsychosocial model that intervenes on biologic, psychologic, interpersonal, and social-cultural factors, not just on one factor, such as libido,” they wrote. “Such work may require access to multidisciplinary care with specialists in women’s health, pelvic floor rehabilitation, and psychosocial oncology.”
Dr. Barton said she has been developing a multicomponent approach to addressing sexual health in female cancer survivors.
However, she noted, “there is still much we do not fully understand about the broader impact of the degree of hormone deprivation in the population of female cancer survivors. A better understanding would provide clearer targets for interventions.”
The study was supported by the National Cancer Institute and Breast Cancer Research Foundation. Dr. Barton has disclosed research funding from Merck. Dr. Lustberg reported receiving honoraria from Novartis and Biotheranostics; consulting or advising with PledPharma, Disarm Therapeutics, Pfizer; and other relationships with Cynosure/Hologic.
A version of this article first appeared on Medscape.com.
The antidepressant bupropion failed to improve sexual dysfunction in female cancer survivors, according to new findings published online in the Journal of Clinical Oncology.
Using the Female Sexual Function Index (FSFI) as a measurement tool, investigators found that desire scores were not significantly different for participants who received bupropion versus a placebo over the 9-week study period.
“Sexual health is a complex phenomenon and [our results suggest that] no one intervention is going to solve the broader issue,” lead author Debra Barton, RN, PhD, FAAN, professor in the School of Nursing at the University of Michigan, Ann Arbor, told this news organization.
Sexual dysfunction is common among cancer survivors and experienced across multiple cancer types and stages of disease. Research shows that as many as 70% of female cancer survivors report loss of desire, compared with up to one-third of the general population.
Common sexual concerns among female cancer survivors include low desire, arousal issues, lack of appropriate lubrication, difficulty in achieving orgasm, and pain with penetrative sexual activity. Additionally, these women may experience significant overlap of symptoms, and often encounter multiple sexual issues that are exacerbated by a range of cancer treatments.
“It’s a huge problem,” Maryam B. Lustberg, MD, MPH, from Yale Cancer Center, New Haven, Conn., and colleagues wrote in an accompanying editorial.
Despite the prevalence of sexual dysfunction among cancer survivors, effective treatments remain elusive. Preliminary evidence suggests that bupropion, already approved for seasonal affective disorder, major depressive disorder, and smoking cessation, may also enhance libido.
Dr. Barton and colleagues conducted this phase 2 trial to determine whether bupropion can improve sexual desire in female cancer survivors without undesirable side effects.
In the study, Dr. Barton and colleagues compared two dose levels of extended-release bupropion in a cohort of 230 postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (<3.3), who had completed definitive cancer therapy.
Participants were randomized to receive either 150 mg (79 patients) or 300 mg (74 patients) once daily of extended-release bupropion, or placebo (77 patients).
Barton and colleagues then evaluated whether sexual desire significantly improved over the 9-week study period comparing the bupropion arms and the placebo group.
Overall, the authors found no significant differences (mean between-arm change for 150 mg once daily and placebo of 0.02; P = .93; mean between-arm change for 300 mg once daily and placebo of –0.02; P = .92). Mean scores at 9 weeks on the desire subscale were 2.17, 2.27, and 2.30 for 150 mg, 300 mg, and the placebo group, respectively.
In addition, none of the subscales – which included arousal, lubrication, and orgasm – or the total score showed a significant difference between arms at either 5 or 9 weeks.
Bupropion did, however, appear to be well tolerated. No grade 4-5 treatment-related adverse events occurred. In the 150-mg bupropion arm, two patients (2.6%) experienced a grade 3 event (insomnia and headache) and one patient in the 300-mg bupropion arm (1.4%) and placebo arm (1.3%) experienced a grade 3 event related to treatment (hypertension and headache, respectively).
In the accompanying editorial, Dr. Lustberg and colleagues “applaud the authors for conducting a study in this population of cancer survivors,” noting that “evidenced-based approaches have not been extensively studied.”
Dr. Lustberg and colleagues also commented that other randomized controlled clinical trials evaluating sexual desire disorder assessed outcomes using additional metrics, such as the Female Sexual Distress Scale–Revised questionnaire, which measures distress related to sexual dysfunction and low desire, in particular.
“The use of specific validated instruments for libido in place of the FSFI might have helped determine the effect of the study intervention in this reported trial,” they wrote.
Overall, according to Dr. Lustberg and colleagues, the negative results of this study indicate that a multidisciplinary clinical approach may be needed.
“As much as we would like to have one intervention that addresses this prominent issue, the evidence strongly suggests that cancer-related sexual problems may need an integrative biopsychosocial model that intervenes on biologic, psychologic, interpersonal, and social-cultural factors, not just on one factor, such as libido,” they wrote. “Such work may require access to multidisciplinary care with specialists in women’s health, pelvic floor rehabilitation, and psychosocial oncology.”
Dr. Barton said she has been developing a multicomponent approach to addressing sexual health in female cancer survivors.
However, she noted, “there is still much we do not fully understand about the broader impact of the degree of hormone deprivation in the population of female cancer survivors. A better understanding would provide clearer targets for interventions.”
The study was supported by the National Cancer Institute and Breast Cancer Research Foundation. Dr. Barton has disclosed research funding from Merck. Dr. Lustberg reported receiving honoraria from Novartis and Biotheranostics; consulting or advising with PledPharma, Disarm Therapeutics, Pfizer; and other relationships with Cynosure/Hologic.
A version of this article first appeared on Medscape.com.
The antidepressant bupropion failed to improve sexual dysfunction in female cancer survivors, according to new findings published online in the Journal of Clinical Oncology.
Using the Female Sexual Function Index (FSFI) as a measurement tool, investigators found that desire scores were not significantly different for participants who received bupropion versus a placebo over the 9-week study period.
“Sexual health is a complex phenomenon and [our results suggest that] no one intervention is going to solve the broader issue,” lead author Debra Barton, RN, PhD, FAAN, professor in the School of Nursing at the University of Michigan, Ann Arbor, told this news organization.
Sexual dysfunction is common among cancer survivors and experienced across multiple cancer types and stages of disease. Research shows that as many as 70% of female cancer survivors report loss of desire, compared with up to one-third of the general population.
Common sexual concerns among female cancer survivors include low desire, arousal issues, lack of appropriate lubrication, difficulty in achieving orgasm, and pain with penetrative sexual activity. Additionally, these women may experience significant overlap of symptoms, and often encounter multiple sexual issues that are exacerbated by a range of cancer treatments.
“It’s a huge problem,” Maryam B. Lustberg, MD, MPH, from Yale Cancer Center, New Haven, Conn., and colleagues wrote in an accompanying editorial.
Despite the prevalence of sexual dysfunction among cancer survivors, effective treatments remain elusive. Preliminary evidence suggests that bupropion, already approved for seasonal affective disorder, major depressive disorder, and smoking cessation, may also enhance libido.
Dr. Barton and colleagues conducted this phase 2 trial to determine whether bupropion can improve sexual desire in female cancer survivors without undesirable side effects.
In the study, Dr. Barton and colleagues compared two dose levels of extended-release bupropion in a cohort of 230 postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (<3.3), who had completed definitive cancer therapy.
Participants were randomized to receive either 150 mg (79 patients) or 300 mg (74 patients) once daily of extended-release bupropion, or placebo (77 patients).
Barton and colleagues then evaluated whether sexual desire significantly improved over the 9-week study period comparing the bupropion arms and the placebo group.
Overall, the authors found no significant differences (mean between-arm change for 150 mg once daily and placebo of 0.02; P = .93; mean between-arm change for 300 mg once daily and placebo of –0.02; P = .92). Mean scores at 9 weeks on the desire subscale were 2.17, 2.27, and 2.30 for 150 mg, 300 mg, and the placebo group, respectively.
In addition, none of the subscales – which included arousal, lubrication, and orgasm – or the total score showed a significant difference between arms at either 5 or 9 weeks.
Bupropion did, however, appear to be well tolerated. No grade 4-5 treatment-related adverse events occurred. In the 150-mg bupropion arm, two patients (2.6%) experienced a grade 3 event (insomnia and headache) and one patient in the 300-mg bupropion arm (1.4%) and placebo arm (1.3%) experienced a grade 3 event related to treatment (hypertension and headache, respectively).
In the accompanying editorial, Dr. Lustberg and colleagues “applaud the authors for conducting a study in this population of cancer survivors,” noting that “evidenced-based approaches have not been extensively studied.”
Dr. Lustberg and colleagues also commented that other randomized controlled clinical trials evaluating sexual desire disorder assessed outcomes using additional metrics, such as the Female Sexual Distress Scale–Revised questionnaire, which measures distress related to sexual dysfunction and low desire, in particular.
“The use of specific validated instruments for libido in place of the FSFI might have helped determine the effect of the study intervention in this reported trial,” they wrote.
Overall, according to Dr. Lustberg and colleagues, the negative results of this study indicate that a multidisciplinary clinical approach may be needed.
“As much as we would like to have one intervention that addresses this prominent issue, the evidence strongly suggests that cancer-related sexual problems may need an integrative biopsychosocial model that intervenes on biologic, psychologic, interpersonal, and social-cultural factors, not just on one factor, such as libido,” they wrote. “Such work may require access to multidisciplinary care with specialists in women’s health, pelvic floor rehabilitation, and psychosocial oncology.”
Dr. Barton said she has been developing a multicomponent approach to addressing sexual health in female cancer survivors.
However, she noted, “there is still much we do not fully understand about the broader impact of the degree of hormone deprivation in the population of female cancer survivors. A better understanding would provide clearer targets for interventions.”
The study was supported by the National Cancer Institute and Breast Cancer Research Foundation. Dr. Barton has disclosed research funding from Merck. Dr. Lustberg reported receiving honoraria from Novartis and Biotheranostics; consulting or advising with PledPharma, Disarm Therapeutics, Pfizer; and other relationships with Cynosure/Hologic.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL ONCOLOGY