A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

Stroke patients receiving thrombolysis do not appear to be at increased risk of symptomatic intracerebral hemorrhage (sICH) if they are taking direct oral anticoagulants (DOACs), a new study has found.

The study, the largest ever regarding the safety of thrombolysis in patients on DOACs, actually found a lower rate of sICH among patients taking DOACs than among those not taking anticoagulants.

“Thrombolysis is a backbone therapy in stroke, but the large population of patients who take DOACs are currently excluded from this treatment because DOAC use is a contraindication to treatment with thrombolysis. This is based on the presumption of an increased risk of sICH, but data to support or refute this presumption are lacking,” said senior author David J. Seiffge, MD, Bern University Hospital, Switzerland.

“Our results suggest that current guidelines need to be revised to remove the absolute contraindication of thrombolysis in patients on DOACs. The guidelines need to be more liberal on the use of thrombolysis in these patients,” he added.

“This study provides the basis for extending vital thrombolysis treatment to this substantial population of patients who take DOACs,” Dr. Seiffge said.

He estimates that 1 of every 6 stroke patients are taking a DOAC and that 1% to 2% of patients taking DOACs have a stroke each year. “As millions of patients are on DOACs, this is a large number of people who are not getting potentially life-saving thrombolysis therapy.”

Dr. Seiffge comments: “In our hospital we see at least one stroke patient on DOACs every day. It is a very frequent scenario. With this new data, we believe many of these patients could now benefit from thrombolysis without an increased bleeding risk.”

The study was published online  in JAMA Neurology.
 

An international investigation

While thrombolysis is currently contraindicated for patients taking DOACs, some clinicians still administer thrombolysis to these patients. Different selection strategies are used, including the use of DOAC reversal agents prior to thrombolysis or the selection of patients with low anticoagulant activity, the authors noted.

The current study involved an international collaboration. The investigators compared the risk of sICH among patients who had recently taken DOACs and who underwent thrombolysis as treatment for acute ischemic stroke with the risk among control stroke patients who underwent thrombolysis but who had not been taking DOACs.

Potential contributing centers were identified by a systematic search of the literature based on published studies on the use of thrombolysis for patients who had recently taken DOACs or prospective stroke registries that may include patients who had recently taken DOACs.

The study included 832 patients from 64 centers worldwide who were confirmed to have taken a DOAC within 48 hours of receiving thrombolysis for acute ischemic stroke. The comparison group was made up of 32,375 patients who had experienced ischemic stroke that was treated with thrombolysis but who had received no prior anticoagulation therapy.

Compared with control patients, patients who had recently taken DOACs were older; the incidence of hypertension among them was higher; they had a higher degree of prestroke disability; they were less likely to be smokers; the time from symptom onset to treatment was longer; they had experienced more severe stroke; and they were more likely to have a large-vessel occlusion.

Of the patients taking DOACs, 30.3% received DOAC reversal prior to thrombolysis. For 27.0%, DOAC plasma levels were measured. The remainder were treated with thrombolysis without either of these selection methods.

Results showed that the unadjusted rate of sICH was 2.5% among patients taking DOACs, compared with 4.1% among control patients who were not taking anticoagulants.

After adjustment for stroke severity and other baseline sICH predictors, patients who had recently taken DOACs and who received thrombolysis had lower odds of developing sICH (adjusted odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .02).

There was no difference between the selection strategies, and results were consistent in different sensitivity analyses.

The secondary outcome of any ICH occurred in 18.0% in patients taking DOACs, compared with 17.4% among control patients who used no anticoagulants. After adjustment, there was no difference in the odds for any ICH between the groups (aOR, 1.18; 95% CI, 0.95-1.45; P = .14).

The unadjusted rate of functional independence was 45% among patients taking DOACs, compared with 57% among control patients. After adjustment, patients who had recently taken DOACs and who underwent thrombolysis had numerically higher odds of being functionally independent than control patients, although this difference did not reach statistical significance (aOR, 1.13; 95% CI, 0.94-1.36; P = .20).

The association of DOAC therapy with lower odds of sICH remained when mechanical thrombectomy, large-vessel occlusion, or concomitant antiplatelet therapy was added to the model.

“This is by far the largest study to look at this issue of thrombolytic use in patients on DOACs, and we did not find any group on DOACs that had an excess ICH rate with thrombolysis,” Dr. Seiffge said,

He explained that receiving warfarin was at one time an absolute contraindication for thrombolysis, but after a 2014 study suggested that the risk was not increased for patients with an international normalized ratio below 117, this was downgraded to a relative contraindication.

“We think our study is comparable and should lead to a guideline change,” Dr. Seiffge commented.

“A relative contraindication allows clinicians the space to make a considered decision on an individual basis,” he added.

Dr. Seiffge said that at his hospital, local guidelines regarding this issue have already been changed on the basis of these data, and use of DOACs is now considered a relative contraindication.

“International guidelines can take years to update, so in the meantime, I think other centers will also go ahead with a more liberal approach. There are always some centers that are ahead of the guidelines,” he added.

Although the lower risk of sICH seen in patients who have recently used DOACs seems counterintuitive at first glance, there could be a pathophysiologic explanation for this finding, the authors suggest.

They point out that thrombin inhibition, either directly or via the coagulation cascade, might be protective against the occurrence of sICH.

“Anticoagulants may allow the clot to respond better to thrombolysis – the clot is not as solid and is easier to recanalize. This leads to smaller strokes and a lower bleeding risk. Thrombin generation is also a major driver for blood brain barrier breakdown. DOACs reduce thrombin generation, so reduce blood brain barrier breakdown and reduce bleeding,” Dr. Seiffge explained. “But these are hypotheses,” he added.
 

Study ‘meaningfully advances the field’

In an accompanying editorial, Eva A. Mistry, MBBS, University of Cincinnati, said the current study “meaningfully advances the field” and provides an estimation of safety of intravenous thrombolysis among patients who have taken DOACs within 48 hours of hospital admission.

She lists strengths of the study as inclusion of a large number of patients across several geographically diverse institutions with heterogeneous standard practices for thrombolysis with recent DOAC use and narrow confidence intervals regarding observed rates of sICH.

“Further, the upper bound of this confidence interval for the DOAC group is below 4%, which is a welcome result and provides supportive data for clinicians who already practice thrombolysis for patients with recent DOAC ingestion,” Dr. Mistry adds.

However, she points out several study limitations, which she says limit immediate, widespread clinical applicability.

These include use of a nonconcurrent control population, which included patients from centers that did not contribute to the DOAC group and the inclusion of Asian patients who likely received a lower thrombolytic dose.

Dr. Seiffge noted that the researchers did adjust for Asian patients but not for the thrombolytic dosage. “I personally do not think this affects the results, as Asian patients have a lower dosage because they have a higher bleeding risk. The lower bleeding risk with DOACs was seen in all continents.”

Dr. Mistry also suggests that the DOAC group itself is prone to selection bias from preferential thrombolysis of patients receiving DOAC who are at lower risk of sICH.

But Dr. Seiffge argued: “I think, actually, the opposite is true. The DOAC patients were older, had more severe comorbidities, and an increased bleeding risk.”

Dr. Mistry concluded, “Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population.”

The study was supported by a grant from the Bangerter-Rhyner Foundation. Dr. Seiffge received grants from Bangerter Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work. Dr. Mistry receives grant funding from the National Institute of Neurological Disorders and Stroke and serves as a consultant for RAPID AI.

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

Stroke patients receiving thrombolysis do not appear to be at increased risk of symptomatic intracerebral hemorrhage (sICH) if they are taking direct oral anticoagulants (DOACs), a new study has found.

The study, the largest ever regarding the safety of thrombolysis in patients on DOACs, actually found a lower rate of sICH among patients taking DOACs than among those not taking anticoagulants.

“Thrombolysis is a backbone therapy in stroke, but the large population of patients who take DOACs are currently excluded from this treatment because DOAC use is a contraindication to treatment with thrombolysis. This is based on the presumption of an increased risk of sICH, but data to support or refute this presumption are lacking,” said senior author David J. Seiffge, MD, Bern University Hospital, Switzerland.

“Our results suggest that current guidelines need to be revised to remove the absolute contraindication of thrombolysis in patients on DOACs. The guidelines need to be more liberal on the use of thrombolysis in these patients,” he added.

“This study provides the basis for extending vital thrombolysis treatment to this substantial population of patients who take DOACs,” Dr. Seiffge said.

He estimates that 1 of every 6 stroke patients are taking a DOAC and that 1% to 2% of patients taking DOACs have a stroke each year. “As millions of patients are on DOACs, this is a large number of people who are not getting potentially life-saving thrombolysis therapy.”

Dr. Seiffge comments: “In our hospital we see at least one stroke patient on DOACs every day. It is a very frequent scenario. With this new data, we believe many of these patients could now benefit from thrombolysis without an increased bleeding risk.”

The study was published online  in JAMA Neurology.
 

An international investigation

While thrombolysis is currently contraindicated for patients taking DOACs, some clinicians still administer thrombolysis to these patients. Different selection strategies are used, including the use of DOAC reversal agents prior to thrombolysis or the selection of patients with low anticoagulant activity, the authors noted.

The current study involved an international collaboration. The investigators compared the risk of sICH among patients who had recently taken DOACs and who underwent thrombolysis as treatment for acute ischemic stroke with the risk among control stroke patients who underwent thrombolysis but who had not been taking DOACs.

Potential contributing centers were identified by a systematic search of the literature based on published studies on the use of thrombolysis for patients who had recently taken DOACs or prospective stroke registries that may include patients who had recently taken DOACs.

The study included 832 patients from 64 centers worldwide who were confirmed to have taken a DOAC within 48 hours of receiving thrombolysis for acute ischemic stroke. The comparison group was made up of 32,375 patients who had experienced ischemic stroke that was treated with thrombolysis but who had received no prior anticoagulation therapy.

Compared with control patients, patients who had recently taken DOACs were older; the incidence of hypertension among them was higher; they had a higher degree of prestroke disability; they were less likely to be smokers; the time from symptom onset to treatment was longer; they had experienced more severe stroke; and they were more likely to have a large-vessel occlusion.

Of the patients taking DOACs, 30.3% received DOAC reversal prior to thrombolysis. For 27.0%, DOAC plasma levels were measured. The remainder were treated with thrombolysis without either of these selection methods.

Results showed that the unadjusted rate of sICH was 2.5% among patients taking DOACs, compared with 4.1% among control patients who were not taking anticoagulants.

After adjustment for stroke severity and other baseline sICH predictors, patients who had recently taken DOACs and who received thrombolysis had lower odds of developing sICH (adjusted odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .02).

There was no difference between the selection strategies, and results were consistent in different sensitivity analyses.

The secondary outcome of any ICH occurred in 18.0% in patients taking DOACs, compared with 17.4% among control patients who used no anticoagulants. After adjustment, there was no difference in the odds for any ICH between the groups (aOR, 1.18; 95% CI, 0.95-1.45; P = .14).

The unadjusted rate of functional independence was 45% among patients taking DOACs, compared with 57% among control patients. After adjustment, patients who had recently taken DOACs and who underwent thrombolysis had numerically higher odds of being functionally independent than control patients, although this difference did not reach statistical significance (aOR, 1.13; 95% CI, 0.94-1.36; P = .20).

The association of DOAC therapy with lower odds of sICH remained when mechanical thrombectomy, large-vessel occlusion, or concomitant antiplatelet therapy was added to the model.

“This is by far the largest study to look at this issue of thrombolytic use in patients on DOACs, and we did not find any group on DOACs that had an excess ICH rate with thrombolysis,” Dr. Seiffge said,

He explained that receiving warfarin was at one time an absolute contraindication for thrombolysis, but after a 2014 study suggested that the risk was not increased for patients with an international normalized ratio below 117, this was downgraded to a relative contraindication.

“We think our study is comparable and should lead to a guideline change,” Dr. Seiffge commented.

“A relative contraindication allows clinicians the space to make a considered decision on an individual basis,” he added.

Dr. Seiffge said that at his hospital, local guidelines regarding this issue have already been changed on the basis of these data, and use of DOACs is now considered a relative contraindication.

“International guidelines can take years to update, so in the meantime, I think other centers will also go ahead with a more liberal approach. There are always some centers that are ahead of the guidelines,” he added.

Although the lower risk of sICH seen in patients who have recently used DOACs seems counterintuitive at first glance, there could be a pathophysiologic explanation for this finding, the authors suggest.

They point out that thrombin inhibition, either directly or via the coagulation cascade, might be protective against the occurrence of sICH.

“Anticoagulants may allow the clot to respond better to thrombolysis – the clot is not as solid and is easier to recanalize. This leads to smaller strokes and a lower bleeding risk. Thrombin generation is also a major driver for blood brain barrier breakdown. DOACs reduce thrombin generation, so reduce blood brain barrier breakdown and reduce bleeding,” Dr. Seiffge explained. “But these are hypotheses,” he added.
 

Study ‘meaningfully advances the field’

In an accompanying editorial, Eva A. Mistry, MBBS, University of Cincinnati, said the current study “meaningfully advances the field” and provides an estimation of safety of intravenous thrombolysis among patients who have taken DOACs within 48 hours of hospital admission.

She lists strengths of the study as inclusion of a large number of patients across several geographically diverse institutions with heterogeneous standard practices for thrombolysis with recent DOAC use and narrow confidence intervals regarding observed rates of sICH.

“Further, the upper bound of this confidence interval for the DOAC group is below 4%, which is a welcome result and provides supportive data for clinicians who already practice thrombolysis for patients with recent DOAC ingestion,” Dr. Mistry adds.

However, she points out several study limitations, which she says limit immediate, widespread clinical applicability.

These include use of a nonconcurrent control population, which included patients from centers that did not contribute to the DOAC group and the inclusion of Asian patients who likely received a lower thrombolytic dose.

Dr. Seiffge noted that the researchers did adjust for Asian patients but not for the thrombolytic dosage. “I personally do not think this affects the results, as Asian patients have a lower dosage because they have a higher bleeding risk. The lower bleeding risk with DOACs was seen in all continents.”

Dr. Mistry also suggests that the DOAC group itself is prone to selection bias from preferential thrombolysis of patients receiving DOAC who are at lower risk of sICH.

But Dr. Seiffge argued: “I think, actually, the opposite is true. The DOAC patients were older, had more severe comorbidities, and an increased bleeding risk.”

Dr. Mistry concluded, “Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population.”

The study was supported by a grant from the Bangerter-Rhyner Foundation. Dr. Seiffge received grants from Bangerter Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work. Dr. Mistry receives grant funding from the National Institute of Neurological Disorders and Stroke and serves as a consultant for RAPID AI.

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

Stroke patients receiving thrombolysis do not appear to be at increased risk of symptomatic intracerebral hemorrhage (sICH) if they are taking direct oral anticoagulants (DOACs), a new study has found.

The study, the largest ever regarding the safety of thrombolysis in patients on DOACs, actually found a lower rate of sICH among patients taking DOACs than among those not taking anticoagulants.

“Thrombolysis is a backbone therapy in stroke, but the large population of patients who take DOACs are currently excluded from this treatment because DOAC use is a contraindication to treatment with thrombolysis. This is based on the presumption of an increased risk of sICH, but data to support or refute this presumption are lacking,” said senior author David J. Seiffge, MD, Bern University Hospital, Switzerland.

“Our results suggest that current guidelines need to be revised to remove the absolute contraindication of thrombolysis in patients on DOACs. The guidelines need to be more liberal on the use of thrombolysis in these patients,” he added.

“This study provides the basis for extending vital thrombolysis treatment to this substantial population of patients who take DOACs,” Dr. Seiffge said.

He estimates that 1 of every 6 stroke patients are taking a DOAC and that 1% to 2% of patients taking DOACs have a stroke each year. “As millions of patients are on DOACs, this is a large number of people who are not getting potentially life-saving thrombolysis therapy.”

Dr. Seiffge comments: “In our hospital we see at least one stroke patient on DOACs every day. It is a very frequent scenario. With this new data, we believe many of these patients could now benefit from thrombolysis without an increased bleeding risk.”

The study was published online  in JAMA Neurology.
 

An international investigation

While thrombolysis is currently contraindicated for patients taking DOACs, some clinicians still administer thrombolysis to these patients. Different selection strategies are used, including the use of DOAC reversal agents prior to thrombolysis or the selection of patients with low anticoagulant activity, the authors noted.

The current study involved an international collaboration. The investigators compared the risk of sICH among patients who had recently taken DOACs and who underwent thrombolysis as treatment for acute ischemic stroke with the risk among control stroke patients who underwent thrombolysis but who had not been taking DOACs.

Potential contributing centers were identified by a systematic search of the literature based on published studies on the use of thrombolysis for patients who had recently taken DOACs or prospective stroke registries that may include patients who had recently taken DOACs.

The study included 832 patients from 64 centers worldwide who were confirmed to have taken a DOAC within 48 hours of receiving thrombolysis for acute ischemic stroke. The comparison group was made up of 32,375 patients who had experienced ischemic stroke that was treated with thrombolysis but who had received no prior anticoagulation therapy.

Compared with control patients, patients who had recently taken DOACs were older; the incidence of hypertension among them was higher; they had a higher degree of prestroke disability; they were less likely to be smokers; the time from symptom onset to treatment was longer; they had experienced more severe stroke; and they were more likely to have a large-vessel occlusion.

Of the patients taking DOACs, 30.3% received DOAC reversal prior to thrombolysis. For 27.0%, DOAC plasma levels were measured. The remainder were treated with thrombolysis without either of these selection methods.

Results showed that the unadjusted rate of sICH was 2.5% among patients taking DOACs, compared with 4.1% among control patients who were not taking anticoagulants.

After adjustment for stroke severity and other baseline sICH predictors, patients who had recently taken DOACs and who received thrombolysis had lower odds of developing sICH (adjusted odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .02).

There was no difference between the selection strategies, and results were consistent in different sensitivity analyses.

The secondary outcome of any ICH occurred in 18.0% in patients taking DOACs, compared with 17.4% among control patients who used no anticoagulants. After adjustment, there was no difference in the odds for any ICH between the groups (aOR, 1.18; 95% CI, 0.95-1.45; P = .14).

The unadjusted rate of functional independence was 45% among patients taking DOACs, compared with 57% among control patients. After adjustment, patients who had recently taken DOACs and who underwent thrombolysis had numerically higher odds of being functionally independent than control patients, although this difference did not reach statistical significance (aOR, 1.13; 95% CI, 0.94-1.36; P = .20).

The association of DOAC therapy with lower odds of sICH remained when mechanical thrombectomy, large-vessel occlusion, or concomitant antiplatelet therapy was added to the model.

“This is by far the largest study to look at this issue of thrombolytic use in patients on DOACs, and we did not find any group on DOACs that had an excess ICH rate with thrombolysis,” Dr. Seiffge said,

He explained that receiving warfarin was at one time an absolute contraindication for thrombolysis, but after a 2014 study suggested that the risk was not increased for patients with an international normalized ratio below 117, this was downgraded to a relative contraindication.

“We think our study is comparable and should lead to a guideline change,” Dr. Seiffge commented.

“A relative contraindication allows clinicians the space to make a considered decision on an individual basis,” he added.

Dr. Seiffge said that at his hospital, local guidelines regarding this issue have already been changed on the basis of these data, and use of DOACs is now considered a relative contraindication.

“International guidelines can take years to update, so in the meantime, I think other centers will also go ahead with a more liberal approach. There are always some centers that are ahead of the guidelines,” he added.

Although the lower risk of sICH seen in patients who have recently used DOACs seems counterintuitive at first glance, there could be a pathophysiologic explanation for this finding, the authors suggest.

They point out that thrombin inhibition, either directly or via the coagulation cascade, might be protective against the occurrence of sICH.

“Anticoagulants may allow the clot to respond better to thrombolysis – the clot is not as solid and is easier to recanalize. This leads to smaller strokes and a lower bleeding risk. Thrombin generation is also a major driver for blood brain barrier breakdown. DOACs reduce thrombin generation, so reduce blood brain barrier breakdown and reduce bleeding,” Dr. Seiffge explained. “But these are hypotheses,” he added.
 

Study ‘meaningfully advances the field’

In an accompanying editorial, Eva A. Mistry, MBBS, University of Cincinnati, said the current study “meaningfully advances the field” and provides an estimation of safety of intravenous thrombolysis among patients who have taken DOACs within 48 hours of hospital admission.

She lists strengths of the study as inclusion of a large number of patients across several geographically diverse institutions with heterogeneous standard practices for thrombolysis with recent DOAC use and narrow confidence intervals regarding observed rates of sICH.

“Further, the upper bound of this confidence interval for the DOAC group is below 4%, which is a welcome result and provides supportive data for clinicians who already practice thrombolysis for patients with recent DOAC ingestion,” Dr. Mistry adds.

However, she points out several study limitations, which she says limit immediate, widespread clinical applicability.

These include use of a nonconcurrent control population, which included patients from centers that did not contribute to the DOAC group and the inclusion of Asian patients who likely received a lower thrombolytic dose.

Dr. Seiffge noted that the researchers did adjust for Asian patients but not for the thrombolytic dosage. “I personally do not think this affects the results, as Asian patients have a lower dosage because they have a higher bleeding risk. The lower bleeding risk with DOACs was seen in all continents.”

Dr. Mistry also suggests that the DOAC group itself is prone to selection bias from preferential thrombolysis of patients receiving DOAC who are at lower risk of sICH.

But Dr. Seiffge argued: “I think, actually, the opposite is true. The DOAC patients were older, had more severe comorbidities, and an increased bleeding risk.”

Dr. Mistry concluded, “Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population.”

The study was supported by a grant from the Bangerter-Rhyner Foundation. Dr. Seiffge received grants from Bangerter Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work. Dr. Mistry receives grant funding from the National Institute of Neurological Disorders and Stroke and serves as a consultant for RAPID AI.

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

U.S. News & World Report recently released its annual ratings of the best diets based on medical and nutritional data. It was the Mediterranean diet for the sixth year in a row.

Does this surprise anyone?

Although first publicized in 1975, the diet really didn’t gain attention until the 1990s. But, since then, the evidence in its favor has steadily grown.

Granted, while it was codified into a diet then, the benefits of fruits and vegetables weren’t exactly a secret beforehand. I’m pretty sure all of us remember being told to eat our vegetables (often repeatedly) while growing up.

So it’s not like we, both medical and nonmedical people, should be surprised at the results.

Is it really going to change anyone’s dietary habits?

Of course it will! It’s the beginning of the new year, and this time people are actually going to stick with their resolutions! For the first time they understand that ... who am I kidding?

For some people (hopefully myself included) there will be success at eating better and taking care of themselves. For most it will be Groundhog Day, both literally and figuratively, when February comes around.

It makes me wonder why this is. We all know what’s good for us. The evidence to support the Mediterranean diet is solid. The foods on it are widely available, often at lower cost than the usual American protein-heavy and processed foods habits. They’re flexible, and, generally taste good.

Yet, for all the evidence behind it, most won’t stick with it. Too many years of habits. Too many stressful days at work that lower our willpower to stick with it. Too many convenient reasons to count.

The question really isn’t “what’s the best diet?” That’s been answered. Realistically I don’t see that changing anytime soon.

The real question is “how do I stick with it?”

And another 5, 10, or 20 years of annually trying to figure out what the best diet is won’t change that.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

U.S. News & World Report recently released its annual ratings of the best diets based on medical and nutritional data. It was the Mediterranean diet for the sixth year in a row.

Does this surprise anyone?

Although first publicized in 1975, the diet really didn’t gain attention until the 1990s. But, since then, the evidence in its favor has steadily grown.

Granted, while it was codified into a diet then, the benefits of fruits and vegetables weren’t exactly a secret beforehand. I’m pretty sure all of us remember being told to eat our vegetables (often repeatedly) while growing up.

So it’s not like we, both medical and nonmedical people, should be surprised at the results.

Is it really going to change anyone’s dietary habits?

Of course it will! It’s the beginning of the new year, and this time people are actually going to stick with their resolutions! For the first time they understand that ... who am I kidding?

For some people (hopefully myself included) there will be success at eating better and taking care of themselves. For most it will be Groundhog Day, both literally and figuratively, when February comes around.

It makes me wonder why this is. We all know what’s good for us. The evidence to support the Mediterranean diet is solid. The foods on it are widely available, often at lower cost than the usual American protein-heavy and processed foods habits. They’re flexible, and, generally taste good.

Yet, for all the evidence behind it, most won’t stick with it. Too many years of habits. Too many stressful days at work that lower our willpower to stick with it. Too many convenient reasons to count.

The question really isn’t “what’s the best diet?” That’s been answered. Realistically I don’t see that changing anytime soon.

The real question is “how do I stick with it?”

And another 5, 10, or 20 years of annually trying to figure out what the best diet is won’t change that.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

U.S. News & World Report recently released its annual ratings of the best diets based on medical and nutritional data. It was the Mediterranean diet for the sixth year in a row.

Does this surprise anyone?

Although first publicized in 1975, the diet really didn’t gain attention until the 1990s. But, since then, the evidence in its favor has steadily grown.

Granted, while it was codified into a diet then, the benefits of fruits and vegetables weren’t exactly a secret beforehand. I’m pretty sure all of us remember being told to eat our vegetables (often repeatedly) while growing up.

So it’s not like we, both medical and nonmedical people, should be surprised at the results.

Is it really going to change anyone’s dietary habits?

Of course it will! It’s the beginning of the new year, and this time people are actually going to stick with their resolutions! For the first time they understand that ... who am I kidding?

For some people (hopefully myself included) there will be success at eating better and taking care of themselves. For most it will be Groundhog Day, both literally and figuratively, when February comes around.

It makes me wonder why this is. We all know what’s good for us. The evidence to support the Mediterranean diet is solid. The foods on it are widely available, often at lower cost than the usual American protein-heavy and processed foods habits. They’re flexible, and, generally taste good.

Yet, for all the evidence behind it, most won’t stick with it. Too many years of habits. Too many stressful days at work that lower our willpower to stick with it. Too many convenient reasons to count.

The question really isn’t “what’s the best diet?” That’s been answered. Realistically I don’t see that changing anytime soon.

The real question is “how do I stick with it?”

And another 5, 10, or 20 years of annually trying to figure out what the best diet is won’t change that.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A new consensus statement from the American Thyroid Association (ATA) and European Thyroid Association (ETA) offers recommendations for endocrinologists on the management of thyroid eye disease (TED), addressing key questions, including about important novel treatments, that transcend international borders.

The consensus statement is important as new therapies transform the treatment of TED that, notably, have even played a key role in simplifying the name of the disease, which has had numerous other, often confusing names over the years, ranging from thyrotropic exophthalmos to Graves ophthalmopathy, Terry F. Davies, MD, of the thyroid research unit, department of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an editorial published along with the statement in Thyroid.

“The emergence of novel therapies has changed the entire discussion concerning TED and not just its name,” he wrote. “These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.”

However, Dr. Davies stressed to this news organization that there are still a lot of unanswered questions, particularly when it comes to newer therapies. For example, teprotumumab can cost up to $300,000 for one course of treatment for one patient, the consensus statement notes.
 

When to consult an ophthalmologist

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the U.S. population. TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye-related signs and symptoms, which can be disfiguring and negatively affect quality of life, and in rare cases, threaten vision.

Key issues covered in the consensus statement include timely diagnosis of TED, assessment of disease activity and severity, initial care and referral for specialty care, and treatment recommendations for moderate to severe TED.

In terms of disease assessment, for instance, the statement authors noted the important distinction in TED “between the two interdependent components of inflammatory activity, manifested by pain, redness, and edema, and disease severity, including proptosis, lid malposition, exposure keratopathy, impaired ocular motility, and optic neuropathy.”

“The presence of multiple features of inflammation usually signifies active disease,” they explained.

For initial care, input from endocrinologists as well as ophthalmologists with experience in TED management is urged, and “an ophthalmologist should be consulted when the diagnosis of TED is uncertain, in cases of moderate to severe TED, and when surgical intervention needs to be considered.”

Furthermore, “urgent referral is required when sight-threatening TED is suspected or confirmed,” the authors noted.
 

Debate over some treatment recommendations

In terms of therapy, for initial care, “a single course of selenium selenite 100 mcg twice daily for 6 months may be considered for patients with mild, active TED, particularly in regions of selenium insufficiency,” the consensus statement recommends.

Intravenous glucocorticoid (IVGC) therapy is meanwhile recommended as a preferred treatment for active moderate to severe TED specifically when disease activity is the prominent feature in the absence of significant proptosis or diplopia.

For patients with active moderate to severe TED who are glucocorticoid-resistant, the authors noted that rituximab and tocilizumab may be considered and that teprotumumab has not been evaluated in this setting.

Teprotumumab, if available, is a preferred therapy for patients with active moderate to severe TED who have significant proptosis.

There is, however, some debate over the issue, editorial author Dr. Davies told this news organization.

“It is still argued over how bad the eyes need to be before recommending this new treatment,” he said. “I think the answer is in the proptosis – the amount of bulging present rather than just inflammation,” Dr. Davies said.

“There is also a real clinical problem in that we have no specific biomarker for the disease, however, high levels of TSH receptor antibody are often a good indicator of eye disease.”

The authors cautioned, however, that clinical trials with medical therapies have been limited by inclusion criteria and other factors, and biologics have meanwhile increased the cost of treatment “many-fold” compared with conventional agents.

Therefore, “clinicians should balance the demonstrated efficacy of recently introduced therapies [such as teprotumumab] against the absence of experience on sustained long-term efficacy, safety, and cost-effectiveness,” they noted.

Importantly, “one course consisting of eight infusions of teprotumumab has a retail cost of approximately $300,000, depending on patient weight, [which is] approximately 2,000 times that of IVGC,” they noted.

“The process involved in selecting therapy with these drugs and other drugs includes a consideration of both short- and long-term efficacy, adverse effects that are both known and unknown, the likelihood of disease aggravation or relapse after a previously beneficial response, and the relative cost and availability,” said Henry B. Burch, MD, who is at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Md., and is on the consensus statement task force.

To help with those decisions, the consensus statement provides comprehensive tables that compare drug efficacy for key outcomes including inflammation, proptosis, diplopia, and quality of life, and importantly, comparisons also of drug costs and potential adverse effects for each of the current TED therapies.
 

Consensus statement not a guideline

The groups noted that the consensus statement is not meant to be a clinical practice guideline and was not written to “establish a standard of care, replace sound clinical judgment, or capture all nuances likely to be present in any particular patient,” and “specific outcomes are not guaranteed.”

What the statement is intended for is to “provide a concise and timely appraisal of a rapidly changing therapeutic arena” for practicing endocrinologists, they explained.

Overall, the authors recommend an individualized management approach, based on factors ranging from disease severity, duration, its impact on daily living, patient age, comorbidities, and importantly, the costs of therapies.

Ultimately, patient satisfaction is essential in TED management, Dr. Burch added.

“Consideration of the impact of TED on patient’s satisfaction with their appearance and visual functioning is a key component in management decisions concerning TED.”A version of this article first appeared on Medscape.com.

A new consensus statement from the American Thyroid Association (ATA) and European Thyroid Association (ETA) offers recommendations for endocrinologists on the management of thyroid eye disease (TED), addressing key questions, including about important novel treatments, that transcend international borders.

The consensus statement is important as new therapies transform the treatment of TED that, notably, have even played a key role in simplifying the name of the disease, which has had numerous other, often confusing names over the years, ranging from thyrotropic exophthalmos to Graves ophthalmopathy, Terry F. Davies, MD, of the thyroid research unit, department of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an editorial published along with the statement in Thyroid.

“The emergence of novel therapies has changed the entire discussion concerning TED and not just its name,” he wrote. “These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.”

However, Dr. Davies stressed to this news organization that there are still a lot of unanswered questions, particularly when it comes to newer therapies. For example, teprotumumab can cost up to $300,000 for one course of treatment for one patient, the consensus statement notes.
 

When to consult an ophthalmologist

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the U.S. population. TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye-related signs and symptoms, which can be disfiguring and negatively affect quality of life, and in rare cases, threaten vision.

Key issues covered in the consensus statement include timely diagnosis of TED, assessment of disease activity and severity, initial care and referral for specialty care, and treatment recommendations for moderate to severe TED.

In terms of disease assessment, for instance, the statement authors noted the important distinction in TED “between the two interdependent components of inflammatory activity, manifested by pain, redness, and edema, and disease severity, including proptosis, lid malposition, exposure keratopathy, impaired ocular motility, and optic neuropathy.”

“The presence of multiple features of inflammation usually signifies active disease,” they explained.

For initial care, input from endocrinologists as well as ophthalmologists with experience in TED management is urged, and “an ophthalmologist should be consulted when the diagnosis of TED is uncertain, in cases of moderate to severe TED, and when surgical intervention needs to be considered.”

Furthermore, “urgent referral is required when sight-threatening TED is suspected or confirmed,” the authors noted.
 

Debate over some treatment recommendations

In terms of therapy, for initial care, “a single course of selenium selenite 100 mcg twice daily for 6 months may be considered for patients with mild, active TED, particularly in regions of selenium insufficiency,” the consensus statement recommends.

Intravenous glucocorticoid (IVGC) therapy is meanwhile recommended as a preferred treatment for active moderate to severe TED specifically when disease activity is the prominent feature in the absence of significant proptosis or diplopia.

For patients with active moderate to severe TED who are glucocorticoid-resistant, the authors noted that rituximab and tocilizumab may be considered and that teprotumumab has not been evaluated in this setting.

Teprotumumab, if available, is a preferred therapy for patients with active moderate to severe TED who have significant proptosis.

There is, however, some debate over the issue, editorial author Dr. Davies told this news organization.

“It is still argued over how bad the eyes need to be before recommending this new treatment,” he said. “I think the answer is in the proptosis – the amount of bulging present rather than just inflammation,” Dr. Davies said.

“There is also a real clinical problem in that we have no specific biomarker for the disease, however, high levels of TSH receptor antibody are often a good indicator of eye disease.”

The authors cautioned, however, that clinical trials with medical therapies have been limited by inclusion criteria and other factors, and biologics have meanwhile increased the cost of treatment “many-fold” compared with conventional agents.

Therefore, “clinicians should balance the demonstrated efficacy of recently introduced therapies [such as teprotumumab] against the absence of experience on sustained long-term efficacy, safety, and cost-effectiveness,” they noted.

Importantly, “one course consisting of eight infusions of teprotumumab has a retail cost of approximately $300,000, depending on patient weight, [which is] approximately 2,000 times that of IVGC,” they noted.

“The process involved in selecting therapy with these drugs and other drugs includes a consideration of both short- and long-term efficacy, adverse effects that are both known and unknown, the likelihood of disease aggravation or relapse after a previously beneficial response, and the relative cost and availability,” said Henry B. Burch, MD, who is at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Md., and is on the consensus statement task force.

To help with those decisions, the consensus statement provides comprehensive tables that compare drug efficacy for key outcomes including inflammation, proptosis, diplopia, and quality of life, and importantly, comparisons also of drug costs and potential adverse effects for each of the current TED therapies.
 

Consensus statement not a guideline

The groups noted that the consensus statement is not meant to be a clinical practice guideline and was not written to “establish a standard of care, replace sound clinical judgment, or capture all nuances likely to be present in any particular patient,” and “specific outcomes are not guaranteed.”

What the statement is intended for is to “provide a concise and timely appraisal of a rapidly changing therapeutic arena” for practicing endocrinologists, they explained.

Overall, the authors recommend an individualized management approach, based on factors ranging from disease severity, duration, its impact on daily living, patient age, comorbidities, and importantly, the costs of therapies.

Ultimately, patient satisfaction is essential in TED management, Dr. Burch added.

“Consideration of the impact of TED on patient’s satisfaction with their appearance and visual functioning is a key component in management decisions concerning TED.”A version of this article first appeared on Medscape.com.

A new consensus statement from the American Thyroid Association (ATA) and European Thyroid Association (ETA) offers recommendations for endocrinologists on the management of thyroid eye disease (TED), addressing key questions, including about important novel treatments, that transcend international borders.

The consensus statement is important as new therapies transform the treatment of TED that, notably, have even played a key role in simplifying the name of the disease, which has had numerous other, often confusing names over the years, ranging from thyrotropic exophthalmos to Graves ophthalmopathy, Terry F. Davies, MD, of the thyroid research unit, department of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an editorial published along with the statement in Thyroid.

“The emergence of novel therapies has changed the entire discussion concerning TED and not just its name,” he wrote. “These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.”

However, Dr. Davies stressed to this news organization that there are still a lot of unanswered questions, particularly when it comes to newer therapies. For example, teprotumumab can cost up to $300,000 for one course of treatment for one patient, the consensus statement notes.
 

When to consult an ophthalmologist

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the U.S. population. TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye-related signs and symptoms, which can be disfiguring and negatively affect quality of life, and in rare cases, threaten vision.

Key issues covered in the consensus statement include timely diagnosis of TED, assessment of disease activity and severity, initial care and referral for specialty care, and treatment recommendations for moderate to severe TED.

In terms of disease assessment, for instance, the statement authors noted the important distinction in TED “between the two interdependent components of inflammatory activity, manifested by pain, redness, and edema, and disease severity, including proptosis, lid malposition, exposure keratopathy, impaired ocular motility, and optic neuropathy.”

“The presence of multiple features of inflammation usually signifies active disease,” they explained.

For initial care, input from endocrinologists as well as ophthalmologists with experience in TED management is urged, and “an ophthalmologist should be consulted when the diagnosis of TED is uncertain, in cases of moderate to severe TED, and when surgical intervention needs to be considered.”

Furthermore, “urgent referral is required when sight-threatening TED is suspected or confirmed,” the authors noted.
 

Debate over some treatment recommendations

In terms of therapy, for initial care, “a single course of selenium selenite 100 mcg twice daily for 6 months may be considered for patients with mild, active TED, particularly in regions of selenium insufficiency,” the consensus statement recommends.

Intravenous glucocorticoid (IVGC) therapy is meanwhile recommended as a preferred treatment for active moderate to severe TED specifically when disease activity is the prominent feature in the absence of significant proptosis or diplopia.

For patients with active moderate to severe TED who are glucocorticoid-resistant, the authors noted that rituximab and tocilizumab may be considered and that teprotumumab has not been evaluated in this setting.

Teprotumumab, if available, is a preferred therapy for patients with active moderate to severe TED who have significant proptosis.

There is, however, some debate over the issue, editorial author Dr. Davies told this news organization.

“It is still argued over how bad the eyes need to be before recommending this new treatment,” he said. “I think the answer is in the proptosis – the amount of bulging present rather than just inflammation,” Dr. Davies said.

“There is also a real clinical problem in that we have no specific biomarker for the disease, however, high levels of TSH receptor antibody are often a good indicator of eye disease.”

The authors cautioned, however, that clinical trials with medical therapies have been limited by inclusion criteria and other factors, and biologics have meanwhile increased the cost of treatment “many-fold” compared with conventional agents.

Therefore, “clinicians should balance the demonstrated efficacy of recently introduced therapies [such as teprotumumab] against the absence of experience on sustained long-term efficacy, safety, and cost-effectiveness,” they noted.

Importantly, “one course consisting of eight infusions of teprotumumab has a retail cost of approximately $300,000, depending on patient weight, [which is] approximately 2,000 times that of IVGC,” they noted.

“The process involved in selecting therapy with these drugs and other drugs includes a consideration of both short- and long-term efficacy, adverse effects that are both known and unknown, the likelihood of disease aggravation or relapse after a previously beneficial response, and the relative cost and availability,” said Henry B. Burch, MD, who is at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Md., and is on the consensus statement task force.

To help with those decisions, the consensus statement provides comprehensive tables that compare drug efficacy for key outcomes including inflammation, proptosis, diplopia, and quality of life, and importantly, comparisons also of drug costs and potential adverse effects for each of the current TED therapies.
 

Consensus statement not a guideline

The groups noted that the consensus statement is not meant to be a clinical practice guideline and was not written to “establish a standard of care, replace sound clinical judgment, or capture all nuances likely to be present in any particular patient,” and “specific outcomes are not guaranteed.”

What the statement is intended for is to “provide a concise and timely appraisal of a rapidly changing therapeutic arena” for practicing endocrinologists, they explained.

Overall, the authors recommend an individualized management approach, based on factors ranging from disease severity, duration, its impact on daily living, patient age, comorbidities, and importantly, the costs of therapies.

Ultimately, patient satisfaction is essential in TED management, Dr. Burch added.

“Consideration of the impact of TED on patient’s satisfaction with their appearance and visual functioning is a key component in management decisions concerning TED.”A version of this article first appeared on Medscape.com.

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Participation in the first 2 years of Maryland’s Advanced Primary Care Program (MDPCP) was associated with better COVID-19 outcomes compared with a matched group not involved with the program, new data indicate.

The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.

The results were published online in JAMA Network Open.

The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
 

More vaccinations, more antibody treatments

Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).

Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.

Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
 

Program components

Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.

The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).

It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.

Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.

As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”

“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
 

Vaccines and testing made available to providers

Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.

The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.

“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
 

‘Innovative and important’

Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.

“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”

She said states can learn from each other and this model is an example.

Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.

“But they may be the key components to achieving these outcomes,” she said.
 

Take-home message

The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.

“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.

Authors report no relevant financial disclosures.

The study received financial support from the Maryland Department of Health.

Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
 

Participation in the first 2 years of Maryland’s Advanced Primary Care Program (MDPCP) was associated with better COVID-19 outcomes compared with a matched group not involved with the program, new data indicate.

The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.

The results were published online in JAMA Network Open.

The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
 

More vaccinations, more antibody treatments

Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).

Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.

Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
 

Program components

Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.

The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).

It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.

Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.

As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”

“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
 

Vaccines and testing made available to providers

Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.

The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.

“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
 

‘Innovative and important’

Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.

“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”

She said states can learn from each other and this model is an example.

Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.

“But they may be the key components to achieving these outcomes,” she said.
 

Take-home message

The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.

“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.

Authors report no relevant financial disclosures.

The study received financial support from the Maryland Department of Health.

Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
 

Participation in the first 2 years of Maryland’s Advanced Primary Care Program (MDPCP) was associated with better COVID-19 outcomes compared with a matched group not involved with the program, new data indicate.

The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.

The results were published online in JAMA Network Open.

The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
 

More vaccinations, more antibody treatments

Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).

Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.

Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
 

Program components

Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.

The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).

It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.

Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.

As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”

“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
 

Vaccines and testing made available to providers

Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.

The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.

“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
 

‘Innovative and important’

Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.

“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”

She said states can learn from each other and this model is an example.

Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.

“But they may be the key components to achieving these outcomes,” she said.
 

Take-home message

The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.

“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.

Authors report no relevant financial disclosures.

The study received financial support from the Maryland Department of Health.

Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
 

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

I guess we shouldn’t be surprised that vaccination rates in this country fell during the frenzy created by the COVID pandemic. We had a lot on our plates. Schools closed and many of us retreated into what seemed to be the safety of our homes. Parents were reluctant to take their children anywhere, let alone a pediatrician’s office. State health agencies wisely focused on collecting case figures and then shepherding the efforts to immunize against SARS-CoV-2 once vaccines were available. Tracking and promoting the existing children’s vaccinations fell off the priority list, even in places with exemplary vaccination rates.

Whether or not the pandemic is over continues to be a topic for debate, but there is clearly a general shift toward a new normalcy. However, vaccination rates of our children have not rebounded to prepandemic levels. In fact, in some areas they are continuing to fall.

In a recent guest essay in the New York Times, Ezekiel J. Emmanuel, MD, PhD, a physician and professor of medical ethics and health policy at the University of Pennsylvania, and Matthew Guido, his research assistant, explore the reasons for this lack of a significant rebound. The authors cite recent outbreaks of measles in Ohio and polio in New York City as examples of the peril we are facing if we fail to reverse the trend. In some areas measles vaccine rates alarmingly have dipped below the threshold for herd immunity.

While Dr. Emmanuel and Mr. Guido acknowledge that the pandemic was a major driver of the falling vaccination rates they lay blame on the persistent decline on three factors that they view as correctable: nonmedical exemptions, our failure to vigorously enforce existing vaccine requirements, and inadequate public health campaigns.

The authors underestimate the lingering effect of the pandemic on parents’ vaccine hesitancy. As a septuagenarian who often hangs out with other septuagenarians I view the rapid development and effectiveness of the COVID vaccine as astounding and a boost for vaccines in general. However, were I much younger I might treat the vaccine’s success with a shrug. After some initial concern, the younger half of the population didn’t seem to see the illness as much of a threat to themselves or their peers. This attitude was reinforced by the fact that few of their peers, including those who were unvaccinated, were getting seriously ill. Despite all the hype, most parents and their children never ended up getting seriously ill.

You can understand why many parents might be quick to toss what you and I consider a successful COVID vaccine onto what they view as a growing pile of vaccines for diseases that in their experience have never sickened or killed anyone they have known.

Let’s be honest: Over the last half century we have produced several generations of parents who have little knowledge and certainly no personal experience with a childhood disease on the order or magnitude of polio. The vaccines that we have developed during their lifetimes have been targeted at diseases such as haemophilus influenzae meningitis that, while serious and anxiety provoking for pediatricians, occur so sporadically that most parents have no personal experience to motivate them to vaccinate their children.

Dr. Emmanuel and Mr. Guido are correct in advocating for the broader elimination of nonmedical exemptions and urging us to find the political will to vigorously enforce the vaccine requirements we have already enacted. I agree that our promotional campaigns need to be more robust. But, this will be a difficult challenge unless we can impress our audience with our straight talk and honesty. We must acknowledge and then explain why all vaccines are not created equal and that some are of more critical importance than others.

We are slowly learning that education isn’t the cure-all for vaccine hesitancy we once thought it was. And using scare tactics can backfire and create dysfunctional anxiety. We must choosing our words and target audience carefully. And ... having the political will to force parents into doing the right thing will be critical if we wish to restore our vaccination rates.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

I guess we shouldn’t be surprised that vaccination rates in this country fell during the frenzy created by the COVID pandemic. We had a lot on our plates. Schools closed and many of us retreated into what seemed to be the safety of our homes. Parents were reluctant to take their children anywhere, let alone a pediatrician’s office. State health agencies wisely focused on collecting case figures and then shepherding the efforts to immunize against SARS-CoV-2 once vaccines were available. Tracking and promoting the existing children’s vaccinations fell off the priority list, even in places with exemplary vaccination rates.

Whether or not the pandemic is over continues to be a topic for debate, but there is clearly a general shift toward a new normalcy. However, vaccination rates of our children have not rebounded to prepandemic levels. In fact, in some areas they are continuing to fall.

In a recent guest essay in the New York Times, Ezekiel J. Emmanuel, MD, PhD, a physician and professor of medical ethics and health policy at the University of Pennsylvania, and Matthew Guido, his research assistant, explore the reasons for this lack of a significant rebound. The authors cite recent outbreaks of measles in Ohio and polio in New York City as examples of the peril we are facing if we fail to reverse the trend. In some areas measles vaccine rates alarmingly have dipped below the threshold for herd immunity.

While Dr. Emmanuel and Mr. Guido acknowledge that the pandemic was a major driver of the falling vaccination rates they lay blame on the persistent decline on three factors that they view as correctable: nonmedical exemptions, our failure to vigorously enforce existing vaccine requirements, and inadequate public health campaigns.

The authors underestimate the lingering effect of the pandemic on parents’ vaccine hesitancy. As a septuagenarian who often hangs out with other septuagenarians I view the rapid development and effectiveness of the COVID vaccine as astounding and a boost for vaccines in general. However, were I much younger I might treat the vaccine’s success with a shrug. After some initial concern, the younger half of the population didn’t seem to see the illness as much of a threat to themselves or their peers. This attitude was reinforced by the fact that few of their peers, including those who were unvaccinated, were getting seriously ill. Despite all the hype, most parents and their children never ended up getting seriously ill.

You can understand why many parents might be quick to toss what you and I consider a successful COVID vaccine onto what they view as a growing pile of vaccines for diseases that in their experience have never sickened or killed anyone they have known.

Let’s be honest: Over the last half century we have produced several generations of parents who have little knowledge and certainly no personal experience with a childhood disease on the order or magnitude of polio. The vaccines that we have developed during their lifetimes have been targeted at diseases such as haemophilus influenzae meningitis that, while serious and anxiety provoking for pediatricians, occur so sporadically that most parents have no personal experience to motivate them to vaccinate their children.

Dr. Emmanuel and Mr. Guido are correct in advocating for the broader elimination of nonmedical exemptions and urging us to find the political will to vigorously enforce the vaccine requirements we have already enacted. I agree that our promotional campaigns need to be more robust. But, this will be a difficult challenge unless we can impress our audience with our straight talk and honesty. We must acknowledge and then explain why all vaccines are not created equal and that some are of more critical importance than others.

We are slowly learning that education isn’t the cure-all for vaccine hesitancy we once thought it was. And using scare tactics can backfire and create dysfunctional anxiety. We must choosing our words and target audience carefully. And ... having the political will to force parents into doing the right thing will be critical if we wish to restore our vaccination rates.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

I guess we shouldn’t be surprised that vaccination rates in this country fell during the frenzy created by the COVID pandemic. We had a lot on our plates. Schools closed and many of us retreated into what seemed to be the safety of our homes. Parents were reluctant to take their children anywhere, let alone a pediatrician’s office. State health agencies wisely focused on collecting case figures and then shepherding the efforts to immunize against SARS-CoV-2 once vaccines were available. Tracking and promoting the existing children’s vaccinations fell off the priority list, even in places with exemplary vaccination rates.

Whether or not the pandemic is over continues to be a topic for debate, but there is clearly a general shift toward a new normalcy. However, vaccination rates of our children have not rebounded to prepandemic levels. In fact, in some areas they are continuing to fall.

In a recent guest essay in the New York Times, Ezekiel J. Emmanuel, MD, PhD, a physician and professor of medical ethics and health policy at the University of Pennsylvania, and Matthew Guido, his research assistant, explore the reasons for this lack of a significant rebound. The authors cite recent outbreaks of measles in Ohio and polio in New York City as examples of the peril we are facing if we fail to reverse the trend. In some areas measles vaccine rates alarmingly have dipped below the threshold for herd immunity.

While Dr. Emmanuel and Mr. Guido acknowledge that the pandemic was a major driver of the falling vaccination rates they lay blame on the persistent decline on three factors that they view as correctable: nonmedical exemptions, our failure to vigorously enforce existing vaccine requirements, and inadequate public health campaigns.

The authors underestimate the lingering effect of the pandemic on parents’ vaccine hesitancy. As a septuagenarian who often hangs out with other septuagenarians I view the rapid development and effectiveness of the COVID vaccine as astounding and a boost for vaccines in general. However, were I much younger I might treat the vaccine’s success with a shrug. After some initial concern, the younger half of the population didn’t seem to see the illness as much of a threat to themselves or their peers. This attitude was reinforced by the fact that few of their peers, including those who were unvaccinated, were getting seriously ill. Despite all the hype, most parents and their children never ended up getting seriously ill.

You can understand why many parents might be quick to toss what you and I consider a successful COVID vaccine onto what they view as a growing pile of vaccines for diseases that in their experience have never sickened or killed anyone they have known.

Let’s be honest: Over the last half century we have produced several generations of parents who have little knowledge and certainly no personal experience with a childhood disease on the order or magnitude of polio. The vaccines that we have developed during their lifetimes have been targeted at diseases such as haemophilus influenzae meningitis that, while serious and anxiety provoking for pediatricians, occur so sporadically that most parents have no personal experience to motivate them to vaccinate their children.

Dr. Emmanuel and Mr. Guido are correct in advocating for the broader elimination of nonmedical exemptions and urging us to find the political will to vigorously enforce the vaccine requirements we have already enacted. I agree that our promotional campaigns need to be more robust. But, this will be a difficult challenge unless we can impress our audience with our straight talk and honesty. We must acknowledge and then explain why all vaccines are not created equal and that some are of more critical importance than others.

We are slowly learning that education isn’t the cure-all for vaccine hesitancy we once thought it was. And using scare tactics can backfire and create dysfunctional anxiety. We must choosing our words and target audience carefully. And ... having the political will to force parents into doing the right thing will be critical if we wish to restore our vaccination rates.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

SAN DIEGO – When patients ask if collagen supplements can benefit their skin, what should you tell them?

According to Ava Shamban, MD, a dermatologist who practices in Santa Monica, Calif., limited data exist to suggest that consuming collagen-dense foods can directly benefit skin or joint health. And in her opinion, more research is needed to establish knowledge of the effects and physiologic mechanism of collagen supplementation.

“Collagen is the most abundant protein in the skin; it is found only in animal flesh like meat and fish that contain connective tissue,” she said at the annual Masters of Aesthetics Symposium. “We produce less collagen as we age. External factors can slow down our collagen production, including smoking, sun exposure, lack of sleep/exercise, and alcohol consumption.”

Though human studies are lacking, some trials have found that collagen supplements may improve skin hydration and elasticity. “Maybe there’s some benefit, but the digestive process breaks collagen down into amino acids, so I don’t buy it,” she said.

At the meeting, Dr. Shamban discussed other topics related to the effect of supplements and nutrition on the skin:

Can Nutrafol reverse permanent hair loss? “It definitely doesn’t do that,” she said. “Can it help regrow hair? Perhaps.” Nutrafol is an over-the-counter supplement that aims to relieve moderate hair thinning or strengthen hair to prevent breakage, and is physician-formulated with medical-grade ingredients that target root causes of thinning such as stress, lifestyle, hormones, and nutrition.

As for biotin, “we now know that high levels of biotin can actually cause hair loss,” she said. “If you have advanced hair loss, supplements may not work for you. There is no hair regrowth supplement that can bring back a dead hair follicle. Can it help a miniaturized hair follicle? Maybe. Platelet-rich plasma injections have been shown to stimulate hair growth, but only if the follicle is miniaturized, not if it’s totally gone.”

How does the human microbiome affect skin? In a review of sequencing surveys of healthy adults, “the composition of microbial communities was found to be primarily dependent on the physiology of the skin site, with changes in the relative abundance of bacterial taxa associated with moist, dry, and sebaceous environments,” the authors reported . “The microbiome is the genetic material of all the microbes that live inside the body, including bacteria, fungi, protozoa, and viruses,” Dr. Shamban said. “The more diverse the microbiota is, the healthier it’s considered. That diversity is enriched through a diet full of various vegetables and fruits.”

Nearly all adults are colonized with Cutibacterium acnes (formerly Propionibacterium acnes), but only a minority have acne, which highlights the importance of studying diseases in the broader context of host genetics, immune or barrier defects, the microbiome, and the environment, she added. For example, the decreased diversity of the skin microbiome in people with atopic dermatitis has been linked to a reduction in environmental biodiversity in the areas surrounding their homes.

Do adaptogens have a role in skin care? Adaptogens such as ashwagandha, elderberry, ginseng, licorice root, neem, moringa, and reishi mushrooms have been used in Chinese and Ayurvedic medicine for centuries and are purported to promote adaptability, resilience, and survival of living organisms in stress. They appear to affect the neuroendocrine immune system and at low doses may function as mild stress mimetics.

“The idea is that combining adaptogens into skin care can reinforce and support the skin’s resistance against stressors that can accelerate visible signs of aging,” said Dr. Shamban. “They share some similarities with antioxidants in that their main purpose is to protect the body from external stressors such as UV rays, oxidation, and pollution.” More studies should be conducted to verify effectiveness, she said, “but Eastern practices that have incorporated it for centuries shouldn’t be fully dismissed. Most doctors believe adaptogens are safe, but how they interact with the mechanics of the body’s stress response system remains a mystery.”

Embrace the consumption of micronutrients. Inspired by work from dermatologist Zoe Diana Draelos, MD, Dr. Shamban advises patients to eat a “rainbow of different colored foods” every day, especially those rich in vitamins A, C, and E. Green foods are generally rich in vitamin E, brown foods are rich in trace minerals, and blue/purple foods are rich in antioxidants. “It’s always best to get nutrients from a rich, healthy diet, but sometimes our skin requires extra help,” she said.

A randomized, placebo-controlled, double-blind study by French researchers, which showed that skin is prone to seasonal changes during the winter, particularly in exposed areas, also looked at whether a daily micronutrient supplement with ingredients that included green tea extract, blackcurrant seed oil, and magnesium, had an impact on the negative effects of winter weather on the skin. “The data indicate that oral micronutrient supplementation can be a safe treatment, with no serious side effects, and may prevent or even eliminate the negative effects of winter on the skin,” she said.

Dr. Shamban disclosed that she conducts clinical trials for many pharmaceutical and device companies.

SAN DIEGO – When patients ask if collagen supplements can benefit their skin, what should you tell them?

According to Ava Shamban, MD, a dermatologist who practices in Santa Monica, Calif., limited data exist to suggest that consuming collagen-dense foods can directly benefit skin or joint health. And in her opinion, more research is needed to establish knowledge of the effects and physiologic mechanism of collagen supplementation.

“Collagen is the most abundant protein in the skin; it is found only in animal flesh like meat and fish that contain connective tissue,” she said at the annual Masters of Aesthetics Symposium. “We produce less collagen as we age. External factors can slow down our collagen production, including smoking, sun exposure, lack of sleep/exercise, and alcohol consumption.”

Though human studies are lacking, some trials have found that collagen supplements may improve skin hydration and elasticity. “Maybe there’s some benefit, but the digestive process breaks collagen down into amino acids, so I don’t buy it,” she said.

At the meeting, Dr. Shamban discussed other topics related to the effect of supplements and nutrition on the skin:

Can Nutrafol reverse permanent hair loss? “It definitely doesn’t do that,” she said. “Can it help regrow hair? Perhaps.” Nutrafol is an over-the-counter supplement that aims to relieve moderate hair thinning or strengthen hair to prevent breakage, and is physician-formulated with medical-grade ingredients that target root causes of thinning such as stress, lifestyle, hormones, and nutrition.

As for biotin, “we now know that high levels of biotin can actually cause hair loss,” she said. “If you have advanced hair loss, supplements may not work for you. There is no hair regrowth supplement that can bring back a dead hair follicle. Can it help a miniaturized hair follicle? Maybe. Platelet-rich plasma injections have been shown to stimulate hair growth, but only if the follicle is miniaturized, not if it’s totally gone.”

How does the human microbiome affect skin? In a review of sequencing surveys of healthy adults, “the composition of microbial communities was found to be primarily dependent on the physiology of the skin site, with changes in the relative abundance of bacterial taxa associated with moist, dry, and sebaceous environments,” the authors reported . “The microbiome is the genetic material of all the microbes that live inside the body, including bacteria, fungi, protozoa, and viruses,” Dr. Shamban said. “The more diverse the microbiota is, the healthier it’s considered. That diversity is enriched through a diet full of various vegetables and fruits.”

Nearly all adults are colonized with Cutibacterium acnes (formerly Propionibacterium acnes), but only a minority have acne, which highlights the importance of studying diseases in the broader context of host genetics, immune or barrier defects, the microbiome, and the environment, she added. For example, the decreased diversity of the skin microbiome in people with atopic dermatitis has been linked to a reduction in environmental biodiversity in the areas surrounding their homes.

Do adaptogens have a role in skin care? Adaptogens such as ashwagandha, elderberry, ginseng, licorice root, neem, moringa, and reishi mushrooms have been used in Chinese and Ayurvedic medicine for centuries and are purported to promote adaptability, resilience, and survival of living organisms in stress. They appear to affect the neuroendocrine immune system and at low doses may function as mild stress mimetics.

“The idea is that combining adaptogens into skin care can reinforce and support the skin’s resistance against stressors that can accelerate visible signs of aging,” said Dr. Shamban. “They share some similarities with antioxidants in that their main purpose is to protect the body from external stressors such as UV rays, oxidation, and pollution.” More studies should be conducted to verify effectiveness, she said, “but Eastern practices that have incorporated it for centuries shouldn’t be fully dismissed. Most doctors believe adaptogens are safe, but how they interact with the mechanics of the body’s stress response system remains a mystery.”

Embrace the consumption of micronutrients. Inspired by work from dermatologist Zoe Diana Draelos, MD, Dr. Shamban advises patients to eat a “rainbow of different colored foods” every day, especially those rich in vitamins A, C, and E. Green foods are generally rich in vitamin E, brown foods are rich in trace minerals, and blue/purple foods are rich in antioxidants. “It’s always best to get nutrients from a rich, healthy diet, but sometimes our skin requires extra help,” she said.

A randomized, placebo-controlled, double-blind study by French researchers, which showed that skin is prone to seasonal changes during the winter, particularly in exposed areas, also looked at whether a daily micronutrient supplement with ingredients that included green tea extract, blackcurrant seed oil, and magnesium, had an impact on the negative effects of winter weather on the skin. “The data indicate that oral micronutrient supplementation can be a safe treatment, with no serious side effects, and may prevent or even eliminate the negative effects of winter on the skin,” she said.

Dr. Shamban disclosed that she conducts clinical trials for many pharmaceutical and device companies.

SAN DIEGO – When patients ask if collagen supplements can benefit their skin, what should you tell them?

According to Ava Shamban, MD, a dermatologist who practices in Santa Monica, Calif., limited data exist to suggest that consuming collagen-dense foods can directly benefit skin or joint health. And in her opinion, more research is needed to establish knowledge of the effects and physiologic mechanism of collagen supplementation.

“Collagen is the most abundant protein in the skin; it is found only in animal flesh like meat and fish that contain connective tissue,” she said at the annual Masters of Aesthetics Symposium. “We produce less collagen as we age. External factors can slow down our collagen production, including smoking, sun exposure, lack of sleep/exercise, and alcohol consumption.”

Though human studies are lacking, some trials have found that collagen supplements may improve skin hydration and elasticity. “Maybe there’s some benefit, but the digestive process breaks collagen down into amino acids, so I don’t buy it,” she said.

At the meeting, Dr. Shamban discussed other topics related to the effect of supplements and nutrition on the skin:

Can Nutrafol reverse permanent hair loss? “It definitely doesn’t do that,” she said. “Can it help regrow hair? Perhaps.” Nutrafol is an over-the-counter supplement that aims to relieve moderate hair thinning or strengthen hair to prevent breakage, and is physician-formulated with medical-grade ingredients that target root causes of thinning such as stress, lifestyle, hormones, and nutrition.

As for biotin, “we now know that high levels of biotin can actually cause hair loss,” she said. “If you have advanced hair loss, supplements may not work for you. There is no hair regrowth supplement that can bring back a dead hair follicle. Can it help a miniaturized hair follicle? Maybe. Platelet-rich plasma injections have been shown to stimulate hair growth, but only if the follicle is miniaturized, not if it’s totally gone.”

How does the human microbiome affect skin? In a review of sequencing surveys of healthy adults, “the composition of microbial communities was found to be primarily dependent on the physiology of the skin site, with changes in the relative abundance of bacterial taxa associated with moist, dry, and sebaceous environments,” the authors reported . “The microbiome is the genetic material of all the microbes that live inside the body, including bacteria, fungi, protozoa, and viruses,” Dr. Shamban said. “The more diverse the microbiota is, the healthier it’s considered. That diversity is enriched through a diet full of various vegetables and fruits.”

Nearly all adults are colonized with Cutibacterium acnes (formerly Propionibacterium acnes), but only a minority have acne, which highlights the importance of studying diseases in the broader context of host genetics, immune or barrier defects, the microbiome, and the environment, she added. For example, the decreased diversity of the skin microbiome in people with atopic dermatitis has been linked to a reduction in environmental biodiversity in the areas surrounding their homes.

Do adaptogens have a role in skin care? Adaptogens such as ashwagandha, elderberry, ginseng, licorice root, neem, moringa, and reishi mushrooms have been used in Chinese and Ayurvedic medicine for centuries and are purported to promote adaptability, resilience, and survival of living organisms in stress. They appear to affect the neuroendocrine immune system and at low doses may function as mild stress mimetics.

“The idea is that combining adaptogens into skin care can reinforce and support the skin’s resistance against stressors that can accelerate visible signs of aging,” said Dr. Shamban. “They share some similarities with antioxidants in that their main purpose is to protect the body from external stressors such as UV rays, oxidation, and pollution.” More studies should be conducted to verify effectiveness, she said, “but Eastern practices that have incorporated it for centuries shouldn’t be fully dismissed. Most doctors believe adaptogens are safe, but how they interact with the mechanics of the body’s stress response system remains a mystery.”

Embrace the consumption of micronutrients. Inspired by work from dermatologist Zoe Diana Draelos, MD, Dr. Shamban advises patients to eat a “rainbow of different colored foods” every day, especially those rich in vitamins A, C, and E. Green foods are generally rich in vitamin E, brown foods are rich in trace minerals, and blue/purple foods are rich in antioxidants. “It’s always best to get nutrients from a rich, healthy diet, but sometimes our skin requires extra help,” she said.

A randomized, placebo-controlled, double-blind study by French researchers, which showed that skin is prone to seasonal changes during the winter, particularly in exposed areas, also looked at whether a daily micronutrient supplement with ingredients that included green tea extract, blackcurrant seed oil, and magnesium, had an impact on the negative effects of winter weather on the skin. “The data indicate that oral micronutrient supplementation can be a safe treatment, with no serious side effects, and may prevent or even eliminate the negative effects of winter on the skin,” she said.

Dr. Shamban disclosed that she conducts clinical trials for many pharmaceutical and device companies.