Pseudomonas aeruginosa persisted in the airways of patients with chronic obstructive pulmonary disease (COPD), based on data from 23 patients over a 1-year period.

P. aeruginosa is cultured in as many as 20% of bacterial exacerbations and has been linked to increased morbidity and mortality in patients with COPD, wrote Josefin Eklöf, MD, of the University of Copenhagen and colleagues. However, its patterns and characteristics have not been well studied, and researchers proposed that P. aerunginosa persists in COPD patients in part because of genetic adaptations in the genes related to antibiotic resistance.

In a study published in Clinical Microbiology and Infection, the researchers identified 23 consecutive patients enrolled in an ongoing randomized clinical trial at four sites in Denmark between Jan. 2018 and Jan. 2020. Participants were randomized 1:1 to targeted antipseudomonal antibiotic treatment for 14 days (between visit day 1 and visit day 14) or no antipseudomonal treatment. Sputum samples were collected at baseline on day 1 and on days 14, 30, 60, 90, and 365.

The researchers sequenced isolates from 23 adult patients over 365 days of follow-up. The recurrence of P. aeruginosa occurred in 19 patients (83%) during this period. Ultimately, a total of 153 isolates were analyzed. The researchers found that each patient carried their own unique lineage, with the except of one patient in whom two distinct lineages were identified.

“Independent mutation of the same gene across multiple lineages may be the result of positive selection of adaptive mutations,” Dr. Eklöf and colleagues wrote. They found 38 genes for P. aeruginosa that were mutated in at least two lineages, which suggested adaptive mutations. Some of the more frequently mutated genes were those important to antibiotic resistance and chronic infections, the researchers said. Specifically, mutations occurred in 40 of 140 pathoadaptive genes, compared with 265 of 5,572 other genes (P < .001). In addition, the 24 total lineages carried 4-6 antibiotic resistance genes, and no evidence suggested that lineages acquired or lost these genes during carriage.

Overall, the results indicate that the recurrence of P. aeruginosa was caused by persistence of the same clonal lineage in each patient. “This pattern of persistence was associated with genetic adaptation related to phenotypes considered important for P. aeruginosa infections,” the researchers said.

The study findings were limited by the relatively small number of samples and isolates per sample, the follow-up of only 1 year, and the inability to account for mutations in the early stage because few patients were naive to P. aeruginosa at the start of the study, the researchers noted. However, the results were strengthened by the relatively large and well-defined study population and high rate of sampling compliance, they said.

Overall, “the findings warrant research to improve therapy, including trial data on possible clinical benefits of attempting antibiotic eradication of P. aeruginosa in this vulnerable group of patients,” they concluded.

The study was supported by the Independent Research Fund Denmark and the Research committee at Copenhagen University Hospital-Herlev and Gentofte Hospital. The researchers had no financial conflicts to disclose.

Pseudomonas aeruginosa persisted in the airways of patients with chronic obstructive pulmonary disease (COPD), based on data from 23 patients over a 1-year period.

P. aeruginosa is cultured in as many as 20% of bacterial exacerbations and has been linked to increased morbidity and mortality in patients with COPD, wrote Josefin Eklöf, MD, of the University of Copenhagen and colleagues. However, its patterns and characteristics have not been well studied, and researchers proposed that P. aerunginosa persists in COPD patients in part because of genetic adaptations in the genes related to antibiotic resistance.

In a study published in Clinical Microbiology and Infection, the researchers identified 23 consecutive patients enrolled in an ongoing randomized clinical trial at four sites in Denmark between Jan. 2018 and Jan. 2020. Participants were randomized 1:1 to targeted antipseudomonal antibiotic treatment for 14 days (between visit day 1 and visit day 14) or no antipseudomonal treatment. Sputum samples were collected at baseline on day 1 and on days 14, 30, 60, 90, and 365.

The researchers sequenced isolates from 23 adult patients over 365 days of follow-up. The recurrence of P. aeruginosa occurred in 19 patients (83%) during this period. Ultimately, a total of 153 isolates were analyzed. The researchers found that each patient carried their own unique lineage, with the except of one patient in whom two distinct lineages were identified.

“Independent mutation of the same gene across multiple lineages may be the result of positive selection of adaptive mutations,” Dr. Eklöf and colleagues wrote. They found 38 genes for P. aeruginosa that were mutated in at least two lineages, which suggested adaptive mutations. Some of the more frequently mutated genes were those important to antibiotic resistance and chronic infections, the researchers said. Specifically, mutations occurred in 40 of 140 pathoadaptive genes, compared with 265 of 5,572 other genes (P < .001). In addition, the 24 total lineages carried 4-6 antibiotic resistance genes, and no evidence suggested that lineages acquired or lost these genes during carriage.

Overall, the results indicate that the recurrence of P. aeruginosa was caused by persistence of the same clonal lineage in each patient. “This pattern of persistence was associated with genetic adaptation related to phenotypes considered important for P. aeruginosa infections,” the researchers said.

The study findings were limited by the relatively small number of samples and isolates per sample, the follow-up of only 1 year, and the inability to account for mutations in the early stage because few patients were naive to P. aeruginosa at the start of the study, the researchers noted. However, the results were strengthened by the relatively large and well-defined study population and high rate of sampling compliance, they said.

Overall, “the findings warrant research to improve therapy, including trial data on possible clinical benefits of attempting antibiotic eradication of P. aeruginosa in this vulnerable group of patients,” they concluded.

The study was supported by the Independent Research Fund Denmark and the Research committee at Copenhagen University Hospital-Herlev and Gentofte Hospital. The researchers had no financial conflicts to disclose.

Pseudomonas aeruginosa persisted in the airways of patients with chronic obstructive pulmonary disease (COPD), based on data from 23 patients over a 1-year period.

P. aeruginosa is cultured in as many as 20% of bacterial exacerbations and has been linked to increased morbidity and mortality in patients with COPD, wrote Josefin Eklöf, MD, of the University of Copenhagen and colleagues. However, its patterns and characteristics have not been well studied, and researchers proposed that P. aerunginosa persists in COPD patients in part because of genetic adaptations in the genes related to antibiotic resistance.

In a study published in Clinical Microbiology and Infection, the researchers identified 23 consecutive patients enrolled in an ongoing randomized clinical trial at four sites in Denmark between Jan. 2018 and Jan. 2020. Participants were randomized 1:1 to targeted antipseudomonal antibiotic treatment for 14 days (between visit day 1 and visit day 14) or no antipseudomonal treatment. Sputum samples were collected at baseline on day 1 and on days 14, 30, 60, 90, and 365.

The researchers sequenced isolates from 23 adult patients over 365 days of follow-up. The recurrence of P. aeruginosa occurred in 19 patients (83%) during this period. Ultimately, a total of 153 isolates were analyzed. The researchers found that each patient carried their own unique lineage, with the except of one patient in whom two distinct lineages were identified.

“Independent mutation of the same gene across multiple lineages may be the result of positive selection of adaptive mutations,” Dr. Eklöf and colleagues wrote. They found 38 genes for P. aeruginosa that were mutated in at least two lineages, which suggested adaptive mutations. Some of the more frequently mutated genes were those important to antibiotic resistance and chronic infections, the researchers said. Specifically, mutations occurred in 40 of 140 pathoadaptive genes, compared with 265 of 5,572 other genes (P < .001). In addition, the 24 total lineages carried 4-6 antibiotic resistance genes, and no evidence suggested that lineages acquired or lost these genes during carriage.

Overall, the results indicate that the recurrence of P. aeruginosa was caused by persistence of the same clonal lineage in each patient. “This pattern of persistence was associated with genetic adaptation related to phenotypes considered important for P. aeruginosa infections,” the researchers said.

The study findings were limited by the relatively small number of samples and isolates per sample, the follow-up of only 1 year, and the inability to account for mutations in the early stage because few patients were naive to P. aeruginosa at the start of the study, the researchers noted. However, the results were strengthened by the relatively large and well-defined study population and high rate of sampling compliance, they said.

Overall, “the findings warrant research to improve therapy, including trial data on possible clinical benefits of attempting antibiotic eradication of P. aeruginosa in this vulnerable group of patients,” they concluded.

The study was supported by the Independent Research Fund Denmark and the Research committee at Copenhagen University Hospital-Herlev and Gentofte Hospital. The researchers had no financial conflicts to disclose.

Even mild cases of COVID-19 are associated with brain changes, including decreased gray matter, an overall reduction in brain volume, and cognitive decline, a new imaging study shows.

In the first study to use magnetic resonance brain imaging, before and after COVID-19, investigators found “greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, greater changes in markers of tissue damage in regions functionally connected to the primary olfactory cortex and greater reduction in global brain size.” However, the researchers urge caution when interpreting the findings.

Gwenaëlle Douaud, PhD, Wellcome Center for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, England, and colleagues describe these brain changes as “modest.”

“Whether these abnormal changes are the hallmark of the spread of the pathogenic effects in the brain, or of the virus itself, and whether these may prefigure a future vulnerability of the limbic system in particular, including memory, for these participants, remains to be investigated,” the researchers wrote.

The findings were published online March 7 in the journal Nature.
 

Gray matter loss

The investigators analyzed data from the UK Biobank, a large-scale biomedical database with genetic and health information for about 500,000 individuals living in the UK. They identified 785 adults aged 51-81 years who had undergone two brain MRIs about 3 years apart. Of these, 401 tested positive for SARS-CoV-2 before the second scan.

Participants also completed cognitive tests at the time of both scans.

Biobank centers use identical MRI scans and scanning methods, including six types of MRI scans, to image distinct regions of the brain and brain function. Results showed that although some loss of gray matter over time is normal, individuals who were infected with SARS-CoV-2 showed a 0.2% to 2% brain tissue loss in the parahippocampal gyrus, the orbitofrontal cortex, and the insula – all of which are largely involved in the sense of smell.

Participants who had contracted COVID-19 also showed a greater reduction in overall brain volume and a decrease in cognitive function.

Most of those with COVID-19 had only mild or moderate symptoms. However, the findings held even after the researchers excluded patients who had been hospitalized.
 

More research needed

“These findings might help explain why some people experience brain symptoms long after the acute infection,” Max Taquet, PhD, National Institute for Health Research Oxford Health BRC senior research fellow, University of Oxford, said in a press release.

Dr. Taquet, who was not a part of the study, noted the causes of these brain changes remain to be determined. Questions remain as to “whether they can be prevented or even reverted, as well as whether similar changes are observed in hospitalized patients,” children, younger adults, and minority groups.

“It is possible that these brain changes are not caused by COVID-19 but represent the natural progression of a disease that itself increased the risk of COVID-19,” Dr. Taquet said.

Other experts expressed concern over the findings and emphasized the need for more research.

“I am very concerned by the alarming use of language in the report with terms such as ‘neurodegenerative,’ “ Alan Carson, MD, professor of neuropsychiatry at the Center for Clinical Brain Sciences at the University of Edinburgh, Scotland, said in a press release. “The size and magnitude of brain changes found is very modest and such changes can be caused by a simple change in mental experience,” Dr. Carson said.

“What this study almost certainly shows is the impact, in terms of neural changes, of being disconnected from one’s sense of smell,” he added.

The study was funded by the Wellcome Trust Collaborative. Full financial conflict information for the study authors is included in the original article. Dr. Taquet has collaborated previously with some of the investigators.

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

Even mild cases of COVID-19 are associated with brain changes, including decreased gray matter, an overall reduction in brain volume, and cognitive decline, a new imaging study shows.

In the first study to use magnetic resonance brain imaging, before and after COVID-19, investigators found “greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, greater changes in markers of tissue damage in regions functionally connected to the primary olfactory cortex and greater reduction in global brain size.” However, the researchers urge caution when interpreting the findings.

Gwenaëlle Douaud, PhD, Wellcome Center for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, England, and colleagues describe these brain changes as “modest.”

“Whether these abnormal changes are the hallmark of the spread of the pathogenic effects in the brain, or of the virus itself, and whether these may prefigure a future vulnerability of the limbic system in particular, including memory, for these participants, remains to be investigated,” the researchers wrote.

The findings were published online March 7 in the journal Nature.
 

Gray matter loss

The investigators analyzed data from the UK Biobank, a large-scale biomedical database with genetic and health information for about 500,000 individuals living in the UK. They identified 785 adults aged 51-81 years who had undergone two brain MRIs about 3 years apart. Of these, 401 tested positive for SARS-CoV-2 before the second scan.

Participants also completed cognitive tests at the time of both scans.

Biobank centers use identical MRI scans and scanning methods, including six types of MRI scans, to image distinct regions of the brain and brain function. Results showed that although some loss of gray matter over time is normal, individuals who were infected with SARS-CoV-2 showed a 0.2% to 2% brain tissue loss in the parahippocampal gyrus, the orbitofrontal cortex, and the insula – all of which are largely involved in the sense of smell.

Participants who had contracted COVID-19 also showed a greater reduction in overall brain volume and a decrease in cognitive function.

Most of those with COVID-19 had only mild or moderate symptoms. However, the findings held even after the researchers excluded patients who had been hospitalized.
 

More research needed

“These findings might help explain why some people experience brain symptoms long after the acute infection,” Max Taquet, PhD, National Institute for Health Research Oxford Health BRC senior research fellow, University of Oxford, said in a press release.

Dr. Taquet, who was not a part of the study, noted the causes of these brain changes remain to be determined. Questions remain as to “whether they can be prevented or even reverted, as well as whether similar changes are observed in hospitalized patients,” children, younger adults, and minority groups.

“It is possible that these brain changes are not caused by COVID-19 but represent the natural progression of a disease that itself increased the risk of COVID-19,” Dr. Taquet said.

Other experts expressed concern over the findings and emphasized the need for more research.

“I am very concerned by the alarming use of language in the report with terms such as ‘neurodegenerative,’ “ Alan Carson, MD, professor of neuropsychiatry at the Center for Clinical Brain Sciences at the University of Edinburgh, Scotland, said in a press release. “The size and magnitude of brain changes found is very modest and such changes can be caused by a simple change in mental experience,” Dr. Carson said.

“What this study almost certainly shows is the impact, in terms of neural changes, of being disconnected from one’s sense of smell,” he added.

The study was funded by the Wellcome Trust Collaborative. Full financial conflict information for the study authors is included in the original article. Dr. Taquet has collaborated previously with some of the investigators.

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

Even mild cases of COVID-19 are associated with brain changes, including decreased gray matter, an overall reduction in brain volume, and cognitive decline, a new imaging study shows.

In the first study to use magnetic resonance brain imaging, before and after COVID-19, investigators found “greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, greater changes in markers of tissue damage in regions functionally connected to the primary olfactory cortex and greater reduction in global brain size.” However, the researchers urge caution when interpreting the findings.

Gwenaëlle Douaud, PhD, Wellcome Center for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, England, and colleagues describe these brain changes as “modest.”

“Whether these abnormal changes are the hallmark of the spread of the pathogenic effects in the brain, or of the virus itself, and whether these may prefigure a future vulnerability of the limbic system in particular, including memory, for these participants, remains to be investigated,” the researchers wrote.

The findings were published online March 7 in the journal Nature.
 

Gray matter loss

The investigators analyzed data from the UK Biobank, a large-scale biomedical database with genetic and health information for about 500,000 individuals living in the UK. They identified 785 adults aged 51-81 years who had undergone two brain MRIs about 3 years apart. Of these, 401 tested positive for SARS-CoV-2 before the second scan.

Participants also completed cognitive tests at the time of both scans.

Biobank centers use identical MRI scans and scanning methods, including six types of MRI scans, to image distinct regions of the brain and brain function. Results showed that although some loss of gray matter over time is normal, individuals who were infected with SARS-CoV-2 showed a 0.2% to 2% brain tissue loss in the parahippocampal gyrus, the orbitofrontal cortex, and the insula – all of which are largely involved in the sense of smell.

Participants who had contracted COVID-19 also showed a greater reduction in overall brain volume and a decrease in cognitive function.

Most of those with COVID-19 had only mild or moderate symptoms. However, the findings held even after the researchers excluded patients who had been hospitalized.
 

More research needed

“These findings might help explain why some people experience brain symptoms long after the acute infection,” Max Taquet, PhD, National Institute for Health Research Oxford Health BRC senior research fellow, University of Oxford, said in a press release.

Dr. Taquet, who was not a part of the study, noted the causes of these brain changes remain to be determined. Questions remain as to “whether they can be prevented or even reverted, as well as whether similar changes are observed in hospitalized patients,” children, younger adults, and minority groups.

“It is possible that these brain changes are not caused by COVID-19 but represent the natural progression of a disease that itself increased the risk of COVID-19,” Dr. Taquet said.

Other experts expressed concern over the findings and emphasized the need for more research.

“I am very concerned by the alarming use of language in the report with terms such as ‘neurodegenerative,’ “ Alan Carson, MD, professor of neuropsychiatry at the Center for Clinical Brain Sciences at the University of Edinburgh, Scotland, said in a press release. “The size and magnitude of brain changes found is very modest and such changes can be caused by a simple change in mental experience,” Dr. Carson said.

“What this study almost certainly shows is the impact, in terms of neural changes, of being disconnected from one’s sense of smell,” he added.

The study was funded by the Wellcome Trust Collaborative. Full financial conflict information for the study authors is included in the original article. Dr. Taquet has collaborated previously with some of the investigators.

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

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

Pain management is a huge part of how we in palliative care help patients – and most of the time, I think we do it well, but in the regulatory environment of the opioid epidemic, getting opioid prescriptions filled in a timely manner with the clinician’s drug of choice can feel like a Sisyphean task.

A patient – let’s call her Joan – calls me in distress. She is a 62-year-old woman with widespread metastatic breast cancer. Her pain is mainly due to bone metastases, but she also has discomfort due to the cancer’s invasion of the thin membranes that line her lungs and abdomen.

She was started on a combination opioid and acetaminophen tablet about 2 months ago by her oncologist, but is now requiring it around the clock, nearing the ceiling dose for this particular medication.

Given that her pain is escalating, Joan and I discuss starting a long-acting opioid to better manage the peak and trough effect of short-acting opioids, which can make a patient feel that the pain is relieved only for a few hours at a time, with sharp spikes throughout the day that mandate the next dose of short-acting opioid. This tethers the patient to the clock, having to take as many as six or eight doses of medication per day, and can be very disruptive to daily life.

Sarah F. D’Ambruoso, NP, is a palliative care nurse practitioner in Santa Monica, Calif.

Pain management is a huge part of how we in palliative care help patients – and most of the time, I think we do it well, but in the regulatory environment of the opioid epidemic, getting opioid prescriptions filled in a timely manner with the clinician’s drug of choice can feel like a Sisyphean task.

A patient – let’s call her Joan – calls me in distress. She is a 62-year-old woman with widespread metastatic breast cancer. Her pain is mainly due to bone metastases, but she also has discomfort due to the cancer’s invasion of the thin membranes that line her lungs and abdomen.

She was started on a combination opioid and acetaminophen tablet about 2 months ago by her oncologist, but is now requiring it around the clock, nearing the ceiling dose for this particular medication.

Given that her pain is escalating, Joan and I discuss starting a long-acting opioid to better manage the peak and trough effect of short-acting opioids, which can make a patient feel that the pain is relieved only for a few hours at a time, with sharp spikes throughout the day that mandate the next dose of short-acting opioid. This tethers the patient to the clock, having to take as many as six or eight doses of medication per day, and can be very disruptive to daily life.

Sarah F. D’Ambruoso, NP, is a palliative care nurse practitioner in Santa Monica, Calif.

Pain management is a huge part of how we in palliative care help patients – and most of the time, I think we do it well, but in the regulatory environment of the opioid epidemic, getting opioid prescriptions filled in a timely manner with the clinician’s drug of choice can feel like a Sisyphean task.

A patient – let’s call her Joan – calls me in distress. She is a 62-year-old woman with widespread metastatic breast cancer. Her pain is mainly due to bone metastases, but she also has discomfort due to the cancer’s invasion of the thin membranes that line her lungs and abdomen.

She was started on a combination opioid and acetaminophen tablet about 2 months ago by her oncologist, but is now requiring it around the clock, nearing the ceiling dose for this particular medication.

Given that her pain is escalating, Joan and I discuss starting a long-acting opioid to better manage the peak and trough effect of short-acting opioids, which can make a patient feel that the pain is relieved only for a few hours at a time, with sharp spikes throughout the day that mandate the next dose of short-acting opioid. This tethers the patient to the clock, having to take as many as six or eight doses of medication per day, and can be very disruptive to daily life.

Sarah F. D’Ambruoso, NP, is a palliative care nurse practitioner in Santa Monica, Calif.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

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.

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

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.

This has been an unfortunate, but not an atypical year, for the children in Maine whose lives have intersected with the state’s Department of Health and Human Services. In 2021, 25 children died of abuse and neglect or in homes with prior involvement with the child protective system. Four cases not included in that number are currently listed as homicides. At a recent legislative hearing the grandmother of one of those victims told her story to the lawmaker.

Her grandson was removed from his mother’s custody at 3 months of age after a 2-year-old sibling overdosed on methadone. Father and grandmother became his caregivers but when the father was arrested the child was returned to the mother’s custody by a judge despite the pleas of the child’s court-appointed guardian. The child eventually returned to the care of his paternal aunt and father, but when the father was arrested again the then 3-year-old was returned to his mother. Within months he was dead with multiple fractures, including to his spine and with internal and intracranial bleeding (Overton P. Maine’s child welfare system failed a 3-year old who died, grandmother tells lawmakers. 2022 Feb 11. Portland Press Herald).

The grandmother questioned the legislators why a vulnerable child would be returned to the care of a woman with such an extensive history of involvement with the Department of Health and Human Services. While there may have been errors of judgment on the part of department staff, in large part the answer lies in the system’s emphasis on reunification. Like apple pie, motherhood, and more recently fatherhood, have been viewed as something deserving of our unquestioning efforts to preserve.

This is not a recent trend. Some of the most frustrating cases over my 40 years of practice involved the failure of the courts and in some cases social workers to place a child’s welfare in the proper perspective as court schedules and custody decisions were made. Too often the reunification of “the family” seemed to trump the needs of the child. Fortunately, I’m unaware of any of my patients who died as the result of these untimely and poorly made decisions. However, many of my patients lived in unsettled conditions never sure what the next week would bring while the system focused on giving an adult whose life was a mess one more chance to demonstrate his or her ability to parent.

Of course, there are occasions in which child protective workers have been too hasty in pulling a child from his or her parents. But, in my experience those cases pale next to the number of times in which children were exposed to home environments that threatened their psychological health and development. Yes, there are bad foster homes. Many foster homes might do a better job if they were working in a system that put a higher value on the emotional needs and safety of the children in making its custody decisions.

We have a governor here in Maine who has worked hard to do the right thing during the pandemic and has made child health a focus. However, her recent proposed appropriations bill appears to continue the focus on reunification by funneling money into programs such as family reunion training and coaching as well as a parent mentorship program. Certainly, one can’t argue that these kind of programs might be helpful to some families. On the other hand, we can’t let these programs create the impression that an intact family is our primary goal. Not every family is repairable, at least on a time schedule compatible with the emotional and health needs of the children.

I wouldn’t be surprised to learn that many of you have experienced a similar frustration when decisions based on an unrealistic goal of family reunification have put your patients at risk.

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.

Long-term results from the Dutch PREOPANC randomized, controlled trial confirm that neoadjuvant chemoradiotherapy conveys a survival advantage to patients with resectable and borderline resectable pancreatic cancer.

Neoadjuvant therapy remains controversial in this patient population, which makes up 15% of pancreatic cancer cases. Historically, these patients have been treated with surgery followed by adjuvant chemotherapy, but only about half of patients ever receive adjuvant chemotherapy due to early recurrence, surgical complication, or worsening disease. Neoadjuvant chemoradiotherapy is thought to increase the fraction of patients who receive chemotherapy. Improved exposure to chemotherapy could increase survival, and may also increase the rate of microscopically margin-negative resections.

Neoadjuvant chemoradiotherapy has become increasingly common, but the practice is based on retrospective analysis and small, phase II trials.

“This phase III, randomized trial demonstrates a long-term survival benefit with neoadjuvant treatment compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer,” the researchers wrote in the study, published online Jan. 27 in the Journal of Clinical Oncology. “The effect of neoadjuvant chemoradiotherapy was consistent across subgroups, including resectable and borderline resectable disease,” they added.

The new data represent long-term follow-up of 246 patients who had been randomized to neoadjuvant chemoradiotherapy or upfront surgery. Short-term data, published in 2020, showed trends toward improved survival but no statistically significant difference at a median of 27 months of follow-up. In the update, after a median follow-up of 59 months, patients in the neoadjuvant chemoradiotherapy group had better overall survival (hazard ratio [HR], 0.73; P = .025) and the 5-year overall survival was higher in the neoadjuvant chemoradiotherapy group (20.5%; 95% confidence interval [CI], 14.2%-29.8%) than the upfront surgery group (6.5%; 95% CI, 3.1%-13.7%).

Subgroup analyses found a survival advantage for upfront chemoradiotherapy among patients with borderline resectable tumors (HR, 0.67; P = .045), and a trend toward improved survival among patients with resectable tumors (HR, 0.79; P = .23). There was a trend toward more serious adverse events in the upfront chemoradiotherapy group (52% versus 41%; P = .096). There was no difference in major surgical complications or postoperative mortality.

The study found high progression rates within the first year in both the neoadjuvant chemoradiotherapy group and the upfront surgery group. “Apparently, our neoadjuvant schedule was not able to prevent many of these early progressions, and more effective schedules are warranted,” the authors wrote.

The survival outcomes were lower than those found in adjuvant trials, likely because of differences in patient populations. Adjuvant studies generally recruit patients who have recovered well from resection and have no early signs of recurrence, and therefore have a more favorable prognosis.

The long-term results from PREOPANC are in agreement with four previous studies that compared neoadjuvant chemoradiotherapy to upfront surgery.

A limitation of the study was that gemcitabine monotherapy was used in the adjuvant setting, and this regimen is now considered out of date.

The study was funded by the Dutch Cancer Foundation.

Long-term results from the Dutch PREOPANC randomized, controlled trial confirm that neoadjuvant chemoradiotherapy conveys a survival advantage to patients with resectable and borderline resectable pancreatic cancer.

Neoadjuvant therapy remains controversial in this patient population, which makes up 15% of pancreatic cancer cases. Historically, these patients have been treated with surgery followed by adjuvant chemotherapy, but only about half of patients ever receive adjuvant chemotherapy due to early recurrence, surgical complication, or worsening disease. Neoadjuvant chemoradiotherapy is thought to increase the fraction of patients who receive chemotherapy. Improved exposure to chemotherapy could increase survival, and may also increase the rate of microscopically margin-negative resections.

Neoadjuvant chemoradiotherapy has become increasingly common, but the practice is based on retrospective analysis and small, phase II trials.

“This phase III, randomized trial demonstrates a long-term survival benefit with neoadjuvant treatment compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer,” the researchers wrote in the study, published online Jan. 27 in the Journal of Clinical Oncology. “The effect of neoadjuvant chemoradiotherapy was consistent across subgroups, including resectable and borderline resectable disease,” they added.

The new data represent long-term follow-up of 246 patients who had been randomized to neoadjuvant chemoradiotherapy or upfront surgery. Short-term data, published in 2020, showed trends toward improved survival but no statistically significant difference at a median of 27 months of follow-up. In the update, after a median follow-up of 59 months, patients in the neoadjuvant chemoradiotherapy group had better overall survival (hazard ratio [HR], 0.73; P = .025) and the 5-year overall survival was higher in the neoadjuvant chemoradiotherapy group (20.5%; 95% confidence interval [CI], 14.2%-29.8%) than the upfront surgery group (6.5%; 95% CI, 3.1%-13.7%).

Subgroup analyses found a survival advantage for upfront chemoradiotherapy among patients with borderline resectable tumors (HR, 0.67; P = .045), and a trend toward improved survival among patients with resectable tumors (HR, 0.79; P = .23). There was a trend toward more serious adverse events in the upfront chemoradiotherapy group (52% versus 41%; P = .096). There was no difference in major surgical complications or postoperative mortality.

The study found high progression rates within the first year in both the neoadjuvant chemoradiotherapy group and the upfront surgery group. “Apparently, our neoadjuvant schedule was not able to prevent many of these early progressions, and more effective schedules are warranted,” the authors wrote.

The survival outcomes were lower than those found in adjuvant trials, likely because of differences in patient populations. Adjuvant studies generally recruit patients who have recovered well from resection and have no early signs of recurrence, and therefore have a more favorable prognosis.

The long-term results from PREOPANC are in agreement with four previous studies that compared neoadjuvant chemoradiotherapy to upfront surgery.

A limitation of the study was that gemcitabine monotherapy was used in the adjuvant setting, and this regimen is now considered out of date.

The study was funded by the Dutch Cancer Foundation.

Long-term results from the Dutch PREOPANC randomized, controlled trial confirm that neoadjuvant chemoradiotherapy conveys a survival advantage to patients with resectable and borderline resectable pancreatic cancer.

Neoadjuvant therapy remains controversial in this patient population, which makes up 15% of pancreatic cancer cases. Historically, these patients have been treated with surgery followed by adjuvant chemotherapy, but only about half of patients ever receive adjuvant chemotherapy due to early recurrence, surgical complication, or worsening disease. Neoadjuvant chemoradiotherapy is thought to increase the fraction of patients who receive chemotherapy. Improved exposure to chemotherapy could increase survival, and may also increase the rate of microscopically margin-negative resections.

Neoadjuvant chemoradiotherapy has become increasingly common, but the practice is based on retrospective analysis and small, phase II trials.

“This phase III, randomized trial demonstrates a long-term survival benefit with neoadjuvant treatment compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer,” the researchers wrote in the study, published online Jan. 27 in the Journal of Clinical Oncology. “The effect of neoadjuvant chemoradiotherapy was consistent across subgroups, including resectable and borderline resectable disease,” they added.

The new data represent long-term follow-up of 246 patients who had been randomized to neoadjuvant chemoradiotherapy or upfront surgery. Short-term data, published in 2020, showed trends toward improved survival but no statistically significant difference at a median of 27 months of follow-up. In the update, after a median follow-up of 59 months, patients in the neoadjuvant chemoradiotherapy group had better overall survival (hazard ratio [HR], 0.73; P = .025) and the 5-year overall survival was higher in the neoadjuvant chemoradiotherapy group (20.5%; 95% confidence interval [CI], 14.2%-29.8%) than the upfront surgery group (6.5%; 95% CI, 3.1%-13.7%).

Subgroup analyses found a survival advantage for upfront chemoradiotherapy among patients with borderline resectable tumors (HR, 0.67; P = .045), and a trend toward improved survival among patients with resectable tumors (HR, 0.79; P = .23). There was a trend toward more serious adverse events in the upfront chemoradiotherapy group (52% versus 41%; P = .096). There was no difference in major surgical complications or postoperative mortality.

The study found high progression rates within the first year in both the neoadjuvant chemoradiotherapy group and the upfront surgery group. “Apparently, our neoadjuvant schedule was not able to prevent many of these early progressions, and more effective schedules are warranted,” the authors wrote.

The survival outcomes were lower than those found in adjuvant trials, likely because of differences in patient populations. Adjuvant studies generally recruit patients who have recovered well from resection and have no early signs of recurrence, and therefore have a more favorable prognosis.

The long-term results from PREOPANC are in agreement with four previous studies that compared neoadjuvant chemoradiotherapy to upfront surgery.

A limitation of the study was that gemcitabine monotherapy was used in the adjuvant setting, and this regimen is now considered out of date.

The study was funded by the Dutch Cancer Foundation.

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

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

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

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

Mr. Jones has had multiple sclerosis (MS) since 2008. Initially it was pretty active, though I was able to bring it under control with drug A. He didn’t like the side effects, or the shots, but at that time options for MS treatment were kind of limited.

When the oral agents came out he switched to drug B. He still had some side effects on it, which he didn’t like, but his insurance didn’t cover the other oral agent that was available. So he soldiered on.

Then, in late 2019, he had an episode of optic neuritis, and a repeat MRI showed that in the last 2 years he’d had an uptick in demyelinating plaques. So, in early 2020, he switched to drug C.

Drug C has, to date, been pretty good. He’s had no side effects or relapses, and a recent brain MRI was stable.

Of course, drug C ain’t cheap. Its price isn’t even listed on ePocrates or GoodRx. So my staff and I have to do all kinds of paperwork and hoop-jumping to get it covered each year.

So in late 2021 we started the annual process, which doesn’t happen overnight. We finally received notice he’d been approved – until March 1, 2022. Only 3 months.

Given the alacrity with which these companies seem to work, we began the new authorization paperwork almost as soon as we got the last one in mid-January. This time we didn’t hear back, and every time we called they told us the application was “under review.” In the meantime, Mr. Jones’ supply of pills, which are pretty critical to his health and well-being, was gradually decreasing.

Recently, out of the blue, a 1-month supply of drug C showed up in his mailbox, along with a bill for $3,000. Mr. Jones is a career waiter at a local restaurant, and had no way to pay for this. So my staff went to work on the phones, and after a few hours got it in writing that it was being covered as a bridging supply under the manufacturer’s assistance program. Okay. That crises was averted. (I have no idea if the insurance really pays $3,000/month. Like buying a car, there can be a big difference between a drug’s asking price and what’s really paid for it).

The next morning, however, we got a note from his insurance company saying the medical reviewer had decided he didn’t need drug C, and wanted him to go back to drug B. After all, it was cheaper. I called the reviewer and argued with him. I told him he’d clinically worsened on drug B, not to mention the side effects. The reviewer said I should have mentioned that in my notes. I pointed out that it was in my notes, which had been sent along with the forms I’d filled out. He didn’t answer that, just said he’d have them fax me an appeal form.

The appeal form showed up about an hour later, so I took some time out of my weekend to fill it out. Then I faxed it back, along with (as they requested) chart notes and MRI reports dating back to 2008. Which was a lot.

So now we’ll see what happens.

Do other countries have this sort of thing? Or is this a product of the bizarre patchwork that makes up the American health care system? Different insurance companies, different subplans, and regional sub-subplans, and so on, each with a different set of rules, forms, and obstacle courses to navigate.

For all their glitzy TV commercials showing smiling, happy, multigenerational families, all looking to be in glowing health from the medical care they’re receiving, they seem to be pretty determined to keep Mr. Jones from receiving a drug that’s allowing him to continue working as a waiter 50-60 hours per week. Without it, he’d likely be unable to work and, at some point, would have to file for disability. Probably would eventually need increasingly high-cost items, going to a cane, then a walker, then a wheelchair, then a power wheelchair. ER visits, things that. In the long run, those would cost a helluva lot more than drug C.

Of course, that may be part of their game, too. Maybe they figure he’ll end up dropping off their insurance as he worsens, and then their shareholders don’t have to pay for his bad luck. I hope I’m wrong in thinking that, but such is the nature of business. And health insurance is a HUGE business.

So now I’ve faxed in the appeal forms, and can move on, for the time being, to the needs of other patients (not to mention spending time with my family). But Mr. Jones’ pill supply will run out on April 1, 2022, and I still have no idea what will happen then.

Neither does he. And for him, that’s pretty scary.

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

Computed tomographic angiography (CTA) appears preferable to standard cath-based angiography for the initial evaluation of most stable, intermediate-risk patients with angina-like symptoms, researchers say, based on their study conducted at centers across Europe.

Clinical outcomes over several years in the randomized trial – called DISCHARGE, with an enrollment of more than 3,500 – were statistically similar whether the patients were assigned to CTA or invasive coronary angiography (ICA) as their initial evaluation. Symptoms and quality-of-life measures were also similar.

But the patients assigned to the initial-CTA strategy, of whom fewer than a fourth went on to cardiac cath, showed far fewer procedure-related complications and less often went to coronary revascularization during the median follow-up of 3.5 years, the group reported March 4 in the New England Journal of Medicine.

Based on the findings, CTA “is a safe alternative to cardiac catheterization for patients with suspected CAD [coronary artery disease] that will likely change clinical practice worldwide by replacing invasive testing in patients with stable chest pain who can be expected to benefit” those with an intermediate pretest probability for obstructive disease, principal investigator Marc Dewey, MD, Charité – Universitätsmedizin Berlin, told this news organization.

None of the patient subgroups explored in the trial showed a significant clinical benefit from one strategy over the other, Dr. Dewey commented in an email.

The trial’s results don’t apply to patients unlike those entered, and in particular, he said, “ICA should remain the first test option in patients with high clinical pretest probability of obstructive CAD.”

Dr. Dewey is senior author on the study’s publication, which was timed to coincide with his presentation of the results at ECR 2022 Overture, an all-virtual scientific session of the European Congress of Radiology.

“This is the definitive study,” Matthew Budoff, MD, Lundquist Institute at Harbor-UCLA, Torrance, California, said in an interview. It suggests in a large population that the initial CTA strategy “is as good and maybe safer” in stable patients at intermediate risk compared with initial ICA. “I would say close to 75% or 80% of the patients that we see would fall into that range of risk” and be suitable for the testing algorithm used in the study, said Dr. Budoff, who was not part of the trial.

Invasive angiography would generally still be the initial approach for patients at greater than intermediate risk, such as those with breakthrough angina or electrocardiographic changes, he said. “I still think there’s a huge role for invasive angiography. It’s just a bit smaller now than it used to be for the lower-risk patient.”  

The DISCHARGE trial, agreed cardiothoracic radiology specialist Rozemarijn Vliegenthart, MD, PhD, University of Groningen, the Netherlands, “shows that in patients with intermediate pretest probability, CTA should be used as a gatekeeper before invasive coronary angiography, instead of directly referring for invasive coronary angiography.”

It shows that “a CT-first approach” is both safe and clinically effective and even a trend suggesting better clinical outcomes, compared with ICA. And it demonstrates that “still, many diagnostic invasive coronary angiographies are performed unnecessarily,” Dr. Vliegenthart said as the invited discussant following Dr. Dewey’s presentation.

DISCOVER is only the latest in a series of major studies to explore how CTA best fits in with ICA, stress imaging, and other tests for evaluating patients with chest pain. For example, “the PROMISE trial and the SCOT-HEART trial found that CT was as good as or even better than functional testing. DISCHARGE, I think, confirms the safety of the CT strategy” and reaffirms that it is “at least as good” as an ICA-first approach, cardiologist Klaus F. Kofoed, MD, PhD, DMSc, Rigshospitalet University of Copenhagen, said when co-presenting the trial’s results with Dr. Dewey.

“We can now say CT may be suitable in intermediate-risk patients referred for ICA, particularly those with a clinical constellation suggesting a higher event risk, with abnormal or inconclusive functional test results, or with persistent symptoms despite medical treatment,” said Dr. Kofoed, who is on the DISCOVER steering committee.

The trial’s 3,561 patients with stable chest pain – at 26 experienced centers in 16 countries – were randomly assigned to undergo CTA or ICA as their initial diagnostic imaging approach. Entry required them to be at intermediate risk, defined as an estimated 10% to 60% probability of having obstructive CAD. Of note, women made up about 56% of both groups.

Imaging was positive for obstructive disease in 26% of the 1,808 patients in the CTA group and in the same proportion of the 1,753 who were assigned to ICA. Nonobstructive CAD was identified in 36% and 22%, respectively.

Importantly, 404 (22.3%) patients in the CTA group then underwent ICA, which identified obstructive CAD in 293 (72.5%).

With a complete follow-up in about 99% of patients, the report notes, the rate of the primary endpoint of major adverse cardiac events, or MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 2.1% in the CTA group and in 3.0% in the ICA group. The adjusted hazard ratio of 0.70 (95% confidence interval, 0.46-1.07; P = .10) fell short of significance.

The corresponding HR for an “expanded primary outcome” that also included transient ischemic attack or major procedure-related complications was 0.60 (95% CI, 0.42-0.85) in favor of the CTA group.

As a “pragmatic trial,” DISCHARGE relied on clinically identified events for the endpoint assessments and did not require, for example, laboratory biomarker or neurologic imaging for confirmation, the report notes.

Major procedure-related complications during the initial management phase occurred in 0.5% of the CTA group, and 1.9% of those assigned to initial ICA (HR, 0.26; 95% CI, 0.13-0.55).

Coronary revascularization was less common in the CTA group during the trial’s follow-up, 14.2% versus 18.0% for those assigned to ICA (HR, 0.76; 95% CI, 0.65-0.90).

But the prevalences of angina during the final 4 weeks of follow-up, the group reported, were statistically similar at 8.8% and 7.5% for patients assigned to CTA and ICA, respectively.

The trial showed “no material difference” between the initial CTA versus ICA strategies for its MACE primary endpoint, observed Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., in an accompanying editorial.

“This result is probably a consequence of the lack of effect of revascularization on cardiovascular events among most patients with stable angina and the limited number of those with high-risk anatomy who would benefit from revascularization in the trial,” he writes.

That CTA was performed “significantly earlier than angiography, 3 days versus 12 days after enrollment,” may have led to earlier coronary revascularization in that group, and therefore is “a better outcome in patients whose anatomy would benefit from it.”

Dr. Loscalzo questioned several aspects of the trial design, which, for example, led to a more than 35% prevalence of patients with nonanginal chest pain among those randomized. Different criteria for classifying patients as “intermediate risk” might also have contributed to the fairly low prevalence of patients in either group ultimately identified with obstructive CAD, he proposes. That low prevalence “suggests that the overall trial population had a low risk of obstructive CAD rather than an intermediate risk.”

DISCHARGE was supported by grants from the European Union Seventh Framework Program, the Berlin Institute of Health, Rigshospitalet of the University of Copenhagen, the British Heart Foundation, and the German Research Foundation. Disclosures for the authors and editorialist are available at NEJM.org. Dr. Budoff has disclosed receiving grant support from General Electric. Dr. Vliegenthart discloses receiving grants from Siemens Healthineers and honorarium for speaking from Siemens Healthineers and Bayer.

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

Computed tomographic angiography (CTA) appears preferable to standard cath-based angiography for the initial evaluation of most stable, intermediate-risk patients with angina-like symptoms, researchers say, based on their study conducted at centers across Europe.

Clinical outcomes over several years in the randomized trial – called DISCHARGE, with an enrollment of more than 3,500 – were statistically similar whether the patients were assigned to CTA or invasive coronary angiography (ICA) as their initial evaluation. Symptoms and quality-of-life measures were also similar.

But the patients assigned to the initial-CTA strategy, of whom fewer than a fourth went on to cardiac cath, showed far fewer procedure-related complications and less often went to coronary revascularization during the median follow-up of 3.5 years, the group reported March 4 in the New England Journal of Medicine.

Based on the findings, CTA “is a safe alternative to cardiac catheterization for patients with suspected CAD [coronary artery disease] that will likely change clinical practice worldwide by replacing invasive testing in patients with stable chest pain who can be expected to benefit” those with an intermediate pretest probability for obstructive disease, principal investigator Marc Dewey, MD, Charité – Universitätsmedizin Berlin, told this news organization.

None of the patient subgroups explored in the trial showed a significant clinical benefit from one strategy over the other, Dr. Dewey commented in an email.

The trial’s results don’t apply to patients unlike those entered, and in particular, he said, “ICA should remain the first test option in patients with high clinical pretest probability of obstructive CAD.”

Dr. Dewey is senior author on the study’s publication, which was timed to coincide with his presentation of the results at ECR 2022 Overture, an all-virtual scientific session of the European Congress of Radiology.

“This is the definitive study,” Matthew Budoff, MD, Lundquist Institute at Harbor-UCLA, Torrance, California, said in an interview. It suggests in a large population that the initial CTA strategy “is as good and maybe safer” in stable patients at intermediate risk compared with initial ICA. “I would say close to 75% or 80% of the patients that we see would fall into that range of risk” and be suitable for the testing algorithm used in the study, said Dr. Budoff, who was not part of the trial.

Invasive angiography would generally still be the initial approach for patients at greater than intermediate risk, such as those with breakthrough angina or electrocardiographic changes, he said. “I still think there’s a huge role for invasive angiography. It’s just a bit smaller now than it used to be for the lower-risk patient.”  

The DISCHARGE trial, agreed cardiothoracic radiology specialist Rozemarijn Vliegenthart, MD, PhD, University of Groningen, the Netherlands, “shows that in patients with intermediate pretest probability, CTA should be used as a gatekeeper before invasive coronary angiography, instead of directly referring for invasive coronary angiography.”

It shows that “a CT-first approach” is both safe and clinically effective and even a trend suggesting better clinical outcomes, compared with ICA. And it demonstrates that “still, many diagnostic invasive coronary angiographies are performed unnecessarily,” Dr. Vliegenthart said as the invited discussant following Dr. Dewey’s presentation.

DISCOVER is only the latest in a series of major studies to explore how CTA best fits in with ICA, stress imaging, and other tests for evaluating patients with chest pain. For example, “the PROMISE trial and the SCOT-HEART trial found that CT was as good as or even better than functional testing. DISCHARGE, I think, confirms the safety of the CT strategy” and reaffirms that it is “at least as good” as an ICA-first approach, cardiologist Klaus F. Kofoed, MD, PhD, DMSc, Rigshospitalet University of Copenhagen, said when co-presenting the trial’s results with Dr. Dewey.

“We can now say CT may be suitable in intermediate-risk patients referred for ICA, particularly those with a clinical constellation suggesting a higher event risk, with abnormal or inconclusive functional test results, or with persistent symptoms despite medical treatment,” said Dr. Kofoed, who is on the DISCOVER steering committee.

The trial’s 3,561 patients with stable chest pain – at 26 experienced centers in 16 countries – were randomly assigned to undergo CTA or ICA as their initial diagnostic imaging approach. Entry required them to be at intermediate risk, defined as an estimated 10% to 60% probability of having obstructive CAD. Of note, women made up about 56% of both groups.

Imaging was positive for obstructive disease in 26% of the 1,808 patients in the CTA group and in the same proportion of the 1,753 who were assigned to ICA. Nonobstructive CAD was identified in 36% and 22%, respectively.

Importantly, 404 (22.3%) patients in the CTA group then underwent ICA, which identified obstructive CAD in 293 (72.5%).

With a complete follow-up in about 99% of patients, the report notes, the rate of the primary endpoint of major adverse cardiac events, or MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 2.1% in the CTA group and in 3.0% in the ICA group. The adjusted hazard ratio of 0.70 (95% confidence interval, 0.46-1.07; P = .10) fell short of significance.

The corresponding HR for an “expanded primary outcome” that also included transient ischemic attack or major procedure-related complications was 0.60 (95% CI, 0.42-0.85) in favor of the CTA group.

As a “pragmatic trial,” DISCHARGE relied on clinically identified events for the endpoint assessments and did not require, for example, laboratory biomarker or neurologic imaging for confirmation, the report notes.

Major procedure-related complications during the initial management phase occurred in 0.5% of the CTA group, and 1.9% of those assigned to initial ICA (HR, 0.26; 95% CI, 0.13-0.55).

Coronary revascularization was less common in the CTA group during the trial’s follow-up, 14.2% versus 18.0% for those assigned to ICA (HR, 0.76; 95% CI, 0.65-0.90).

But the prevalences of angina during the final 4 weeks of follow-up, the group reported, were statistically similar at 8.8% and 7.5% for patients assigned to CTA and ICA, respectively.

The trial showed “no material difference” between the initial CTA versus ICA strategies for its MACE primary endpoint, observed Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., in an accompanying editorial.

“This result is probably a consequence of the lack of effect of revascularization on cardiovascular events among most patients with stable angina and the limited number of those with high-risk anatomy who would benefit from revascularization in the trial,” he writes.

That CTA was performed “significantly earlier than angiography, 3 days versus 12 days after enrollment,” may have led to earlier coronary revascularization in that group, and therefore is “a better outcome in patients whose anatomy would benefit from it.”

Dr. Loscalzo questioned several aspects of the trial design, which, for example, led to a more than 35% prevalence of patients with nonanginal chest pain among those randomized. Different criteria for classifying patients as “intermediate risk” might also have contributed to the fairly low prevalence of patients in either group ultimately identified with obstructive CAD, he proposes. That low prevalence “suggests that the overall trial population had a low risk of obstructive CAD rather than an intermediate risk.”

DISCHARGE was supported by grants from the European Union Seventh Framework Program, the Berlin Institute of Health, Rigshospitalet of the University of Copenhagen, the British Heart Foundation, and the German Research Foundation. Disclosures for the authors and editorialist are available at NEJM.org. Dr. Budoff has disclosed receiving grant support from General Electric. Dr. Vliegenthart discloses receiving grants from Siemens Healthineers and honorarium for speaking from Siemens Healthineers and Bayer.

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

Computed tomographic angiography (CTA) appears preferable to standard cath-based angiography for the initial evaluation of most stable, intermediate-risk patients with angina-like symptoms, researchers say, based on their study conducted at centers across Europe.

Clinical outcomes over several years in the randomized trial – called DISCHARGE, with an enrollment of more than 3,500 – were statistically similar whether the patients were assigned to CTA or invasive coronary angiography (ICA) as their initial evaluation. Symptoms and quality-of-life measures were also similar.

But the patients assigned to the initial-CTA strategy, of whom fewer than a fourth went on to cardiac cath, showed far fewer procedure-related complications and less often went to coronary revascularization during the median follow-up of 3.5 years, the group reported March 4 in the New England Journal of Medicine.

Based on the findings, CTA “is a safe alternative to cardiac catheterization for patients with suspected CAD [coronary artery disease] that will likely change clinical practice worldwide by replacing invasive testing in patients with stable chest pain who can be expected to benefit” those with an intermediate pretest probability for obstructive disease, principal investigator Marc Dewey, MD, Charité – Universitätsmedizin Berlin, told this news organization.

None of the patient subgroups explored in the trial showed a significant clinical benefit from one strategy over the other, Dr. Dewey commented in an email.

The trial’s results don’t apply to patients unlike those entered, and in particular, he said, “ICA should remain the first test option in patients with high clinical pretest probability of obstructive CAD.”

Dr. Dewey is senior author on the study’s publication, which was timed to coincide with his presentation of the results at ECR 2022 Overture, an all-virtual scientific session of the European Congress of Radiology.

“This is the definitive study,” Matthew Budoff, MD, Lundquist Institute at Harbor-UCLA, Torrance, California, said in an interview. It suggests in a large population that the initial CTA strategy “is as good and maybe safer” in stable patients at intermediate risk compared with initial ICA. “I would say close to 75% or 80% of the patients that we see would fall into that range of risk” and be suitable for the testing algorithm used in the study, said Dr. Budoff, who was not part of the trial.

Invasive angiography would generally still be the initial approach for patients at greater than intermediate risk, such as those with breakthrough angina or electrocardiographic changes, he said. “I still think there’s a huge role for invasive angiography. It’s just a bit smaller now than it used to be for the lower-risk patient.”  

The DISCHARGE trial, agreed cardiothoracic radiology specialist Rozemarijn Vliegenthart, MD, PhD, University of Groningen, the Netherlands, “shows that in patients with intermediate pretest probability, CTA should be used as a gatekeeper before invasive coronary angiography, instead of directly referring for invasive coronary angiography.”

It shows that “a CT-first approach” is both safe and clinically effective and even a trend suggesting better clinical outcomes, compared with ICA. And it demonstrates that “still, many diagnostic invasive coronary angiographies are performed unnecessarily,” Dr. Vliegenthart said as the invited discussant following Dr. Dewey’s presentation.

DISCOVER is only the latest in a series of major studies to explore how CTA best fits in with ICA, stress imaging, and other tests for evaluating patients with chest pain. For example, “the PROMISE trial and the SCOT-HEART trial found that CT was as good as or even better than functional testing. DISCHARGE, I think, confirms the safety of the CT strategy” and reaffirms that it is “at least as good” as an ICA-first approach, cardiologist Klaus F. Kofoed, MD, PhD, DMSc, Rigshospitalet University of Copenhagen, said when co-presenting the trial’s results with Dr. Dewey.

“We can now say CT may be suitable in intermediate-risk patients referred for ICA, particularly those with a clinical constellation suggesting a higher event risk, with abnormal or inconclusive functional test results, or with persistent symptoms despite medical treatment,” said Dr. Kofoed, who is on the DISCOVER steering committee.

The trial’s 3,561 patients with stable chest pain – at 26 experienced centers in 16 countries – were randomly assigned to undergo CTA or ICA as their initial diagnostic imaging approach. Entry required them to be at intermediate risk, defined as an estimated 10% to 60% probability of having obstructive CAD. Of note, women made up about 56% of both groups.

Imaging was positive for obstructive disease in 26% of the 1,808 patients in the CTA group and in the same proportion of the 1,753 who were assigned to ICA. Nonobstructive CAD was identified in 36% and 22%, respectively.

Importantly, 404 (22.3%) patients in the CTA group then underwent ICA, which identified obstructive CAD in 293 (72.5%).

With a complete follow-up in about 99% of patients, the report notes, the rate of the primary endpoint of major adverse cardiac events, or MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 2.1% in the CTA group and in 3.0% in the ICA group. The adjusted hazard ratio of 0.70 (95% confidence interval, 0.46-1.07; P = .10) fell short of significance.

The corresponding HR for an “expanded primary outcome” that also included transient ischemic attack or major procedure-related complications was 0.60 (95% CI, 0.42-0.85) in favor of the CTA group.

As a “pragmatic trial,” DISCHARGE relied on clinically identified events for the endpoint assessments and did not require, for example, laboratory biomarker or neurologic imaging for confirmation, the report notes.

Major procedure-related complications during the initial management phase occurred in 0.5% of the CTA group, and 1.9% of those assigned to initial ICA (HR, 0.26; 95% CI, 0.13-0.55).

Coronary revascularization was less common in the CTA group during the trial’s follow-up, 14.2% versus 18.0% for those assigned to ICA (HR, 0.76; 95% CI, 0.65-0.90).

But the prevalences of angina during the final 4 weeks of follow-up, the group reported, were statistically similar at 8.8% and 7.5% for patients assigned to CTA and ICA, respectively.

The trial showed “no material difference” between the initial CTA versus ICA strategies for its MACE primary endpoint, observed Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., in an accompanying editorial.

“This result is probably a consequence of the lack of effect of revascularization on cardiovascular events among most patients with stable angina and the limited number of those with high-risk anatomy who would benefit from revascularization in the trial,” he writes.

That CTA was performed “significantly earlier than angiography, 3 days versus 12 days after enrollment,” may have led to earlier coronary revascularization in that group, and therefore is “a better outcome in patients whose anatomy would benefit from it.”

Dr. Loscalzo questioned several aspects of the trial design, which, for example, led to a more than 35% prevalence of patients with nonanginal chest pain among those randomized. Different criteria for classifying patients as “intermediate risk” might also have contributed to the fairly low prevalence of patients in either group ultimately identified with obstructive CAD, he proposes. That low prevalence “suggests that the overall trial population had a low risk of obstructive CAD rather than an intermediate risk.”

DISCHARGE was supported by grants from the European Union Seventh Framework Program, the Berlin Institute of Health, Rigshospitalet of the University of Copenhagen, the British Heart Foundation, and the German Research Foundation. Disclosures for the authors and editorialist are available at NEJM.org. Dr. Budoff has disclosed receiving grant support from General Electric. Dr. Vliegenthart discloses receiving grants from Siemens Healthineers and honorarium for speaking from Siemens Healthineers and Bayer.

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