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APOE genotype directly regulates alpha-synuclein accumulation
Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.
These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.
“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.
According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.
“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”
The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.
“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.
Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.
“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”
The study at the Mayo Clinic echoed these findings.
“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”
Both studies found that the exacerbating effect of APOE4 translated to human patients.
Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.
Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).
According to the investigators, these findings could have both prognostic and therapeutic implications.
“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.
According to Dr. Masliah, several treatment strategies are under investigation.
“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.
“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.
Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.
“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”
The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.
SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.
Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.
These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.
“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.
According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.
“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”
The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.
“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.
Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.
“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”
The study at the Mayo Clinic echoed these findings.
“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”
Both studies found that the exacerbating effect of APOE4 translated to human patients.
Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.
Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).
According to the investigators, these findings could have both prognostic and therapeutic implications.
“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.
According to Dr. Masliah, several treatment strategies are under investigation.
“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.
“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.
Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.
“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”
The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.
SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.
Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.
These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.
“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.
According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.
“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”
The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.
“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.
Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.
“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”
The study at the Mayo Clinic echoed these findings.
“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”
Both studies found that the exacerbating effect of APOE4 translated to human patients.
Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.
Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).
According to the investigators, these findings could have both prognostic and therapeutic implications.
“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.
According to Dr. Masliah, several treatment strategies are under investigation.
“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.
“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.
Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.
“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”
The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.
SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.
FROM SCIENCE TRANSLATIONAL MEDICINE
Glioma trials should track living well, not just longer
Neuro-oncology working group backs focus on how patients feel, function
Glioma treatment goals traditionally have focused on tumor shrinkage or prolonging survival, but it’s time for those endpoints to be supplemented by clinical outcomes that are meaningful to the patient, according to a recently published report from a neuro-oncology working group.
The group, which includes representatives of previous oncology working groups, the Food and Drug Administration, and observers from the European Medicines Agency, has established a core set of symptoms and functional points that they say could be used in clinical trials and clinical care for patients with high-grade gliomas.
“Patients want to live longer, but they also want to continue to function as well as possible for as long as possible,” said Terri S. Armstrong, PhD, of the National Cancer Institute (NCI), and coauthors in a report that sums up the work to date of the Fast Track COA Group.
That work, while specific to gliomas, echoes results from broader initiatives that seek to standardize patient-reported outcomes in oncology trials, Dr. Armstrong and coauthors wrote. The report was published in the Lancet Oncology.
The core set of symptom constructs and functional issues identified by the work group are represented already in patient-reported outcome measures, according to the authors.
The symptoms worth measuring fall into five categories, including pain, difficulty communicating, perceived cognition, seizures, and symptomatic adverse events. The functional issues were divided into two categories, physical functioning, including weakness or walking, and role functioning, which they defined as the ability to work or participate in social or leisure activities.
Some of those outcomes can be challenging or cumbersome to track, Dr. Armstrong and coauthors said.
Pain has “many dimensions“ and is important to track, the group wrote. Likewise, patients’ concerns related to language function also are important, but are very “noisy“ as a variable and can be specific to tumor location.
Collecting data on seizure frequency and severity is important yet complicated, because of the variability in seizures and considerable difference between focal and generalized seizures. Assessment of cognitive functioning can be lengthy and burdensome to patients.
Adverse events of relevance will vary, depending on the drug used, its mechanism of action, and available data, though some allowance needs to be made for the possibility of “overlap“ with disease-related symptoms, the report said.
Physical functioning, including walking and weakness, should be evaluated. It also would be useful to distinguish the duration of time that patients have deficits in physical functioning in the later stages of their disease progression, authors said.
Role and social functioning should be assessed in most patients with high-grade gliomas, who will have symptoms and deficits that prevent returning to a job. “Patients might spend a substantial portion of their lives feeling ill, unable to do usual activities, or meet occupational, social, financial, and family obligations,” said Dr. Armstrong and coauthors in the report.
The scales and tools used to measure symptoms and functional concerns need to be those that best fit a particular clinical trial or clinical practice scenario. Several instruments that would be appropriate are discussed in the report, including the NCI Patient-Reported Outcome of the Common Toxicity Criteria Adverse Events (NCI PRO-CTCAE) and symptom and function scales or items in the Patient-Reported Outcomes Measurement System (PROMIS).
, such as time to recurrence or survival.
“Strategies for introducing these constructs to clinical trial cooperative groups and sponsors will be necessary,” they concluded.
Dr. Armstrong reported employment as a senior investigator and deputy chief of the neuro-oncology branch of the Center for Cancer Research at the NCI. His coauthors reported disclosures related to several companies and interests, including AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Taiho, and Tocagen.
SOURCE: Armstrong TS et al. Lancet Oncol. 2020;21(2):e97-103.
Neuro-oncology working group backs focus on how patients feel, function
Neuro-oncology working group backs focus on how patients feel, function
Glioma treatment goals traditionally have focused on tumor shrinkage or prolonging survival, but it’s time for those endpoints to be supplemented by clinical outcomes that are meaningful to the patient, according to a recently published report from a neuro-oncology working group.
The group, which includes representatives of previous oncology working groups, the Food and Drug Administration, and observers from the European Medicines Agency, has established a core set of symptoms and functional points that they say could be used in clinical trials and clinical care for patients with high-grade gliomas.
“Patients want to live longer, but they also want to continue to function as well as possible for as long as possible,” said Terri S. Armstrong, PhD, of the National Cancer Institute (NCI), and coauthors in a report that sums up the work to date of the Fast Track COA Group.
That work, while specific to gliomas, echoes results from broader initiatives that seek to standardize patient-reported outcomes in oncology trials, Dr. Armstrong and coauthors wrote. The report was published in the Lancet Oncology.
The core set of symptom constructs and functional issues identified by the work group are represented already in patient-reported outcome measures, according to the authors.
The symptoms worth measuring fall into five categories, including pain, difficulty communicating, perceived cognition, seizures, and symptomatic adverse events. The functional issues were divided into two categories, physical functioning, including weakness or walking, and role functioning, which they defined as the ability to work or participate in social or leisure activities.
Some of those outcomes can be challenging or cumbersome to track, Dr. Armstrong and coauthors said.
Pain has “many dimensions“ and is important to track, the group wrote. Likewise, patients’ concerns related to language function also are important, but are very “noisy“ as a variable and can be specific to tumor location.
Collecting data on seizure frequency and severity is important yet complicated, because of the variability in seizures and considerable difference between focal and generalized seizures. Assessment of cognitive functioning can be lengthy and burdensome to patients.
Adverse events of relevance will vary, depending on the drug used, its mechanism of action, and available data, though some allowance needs to be made for the possibility of “overlap“ with disease-related symptoms, the report said.
Physical functioning, including walking and weakness, should be evaluated. It also would be useful to distinguish the duration of time that patients have deficits in physical functioning in the later stages of their disease progression, authors said.
Role and social functioning should be assessed in most patients with high-grade gliomas, who will have symptoms and deficits that prevent returning to a job. “Patients might spend a substantial portion of their lives feeling ill, unable to do usual activities, or meet occupational, social, financial, and family obligations,” said Dr. Armstrong and coauthors in the report.
The scales and tools used to measure symptoms and functional concerns need to be those that best fit a particular clinical trial or clinical practice scenario. Several instruments that would be appropriate are discussed in the report, including the NCI Patient-Reported Outcome of the Common Toxicity Criteria Adverse Events (NCI PRO-CTCAE) and symptom and function scales or items in the Patient-Reported Outcomes Measurement System (PROMIS).
, such as time to recurrence or survival.
“Strategies for introducing these constructs to clinical trial cooperative groups and sponsors will be necessary,” they concluded.
Dr. Armstrong reported employment as a senior investigator and deputy chief of the neuro-oncology branch of the Center for Cancer Research at the NCI. His coauthors reported disclosures related to several companies and interests, including AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Taiho, and Tocagen.
SOURCE: Armstrong TS et al. Lancet Oncol. 2020;21(2):e97-103.
Glioma treatment goals traditionally have focused on tumor shrinkage or prolonging survival, but it’s time for those endpoints to be supplemented by clinical outcomes that are meaningful to the patient, according to a recently published report from a neuro-oncology working group.
The group, which includes representatives of previous oncology working groups, the Food and Drug Administration, and observers from the European Medicines Agency, has established a core set of symptoms and functional points that they say could be used in clinical trials and clinical care for patients with high-grade gliomas.
“Patients want to live longer, but they also want to continue to function as well as possible for as long as possible,” said Terri S. Armstrong, PhD, of the National Cancer Institute (NCI), and coauthors in a report that sums up the work to date of the Fast Track COA Group.
That work, while specific to gliomas, echoes results from broader initiatives that seek to standardize patient-reported outcomes in oncology trials, Dr. Armstrong and coauthors wrote. The report was published in the Lancet Oncology.
The core set of symptom constructs and functional issues identified by the work group are represented already in patient-reported outcome measures, according to the authors.
The symptoms worth measuring fall into five categories, including pain, difficulty communicating, perceived cognition, seizures, and symptomatic adverse events. The functional issues were divided into two categories, physical functioning, including weakness or walking, and role functioning, which they defined as the ability to work or participate in social or leisure activities.
Some of those outcomes can be challenging or cumbersome to track, Dr. Armstrong and coauthors said.
Pain has “many dimensions“ and is important to track, the group wrote. Likewise, patients’ concerns related to language function also are important, but are very “noisy“ as a variable and can be specific to tumor location.
Collecting data on seizure frequency and severity is important yet complicated, because of the variability in seizures and considerable difference between focal and generalized seizures. Assessment of cognitive functioning can be lengthy and burdensome to patients.
Adverse events of relevance will vary, depending on the drug used, its mechanism of action, and available data, though some allowance needs to be made for the possibility of “overlap“ with disease-related symptoms, the report said.
Physical functioning, including walking and weakness, should be evaluated. It also would be useful to distinguish the duration of time that patients have deficits in physical functioning in the later stages of their disease progression, authors said.
Role and social functioning should be assessed in most patients with high-grade gliomas, who will have symptoms and deficits that prevent returning to a job. “Patients might spend a substantial portion of their lives feeling ill, unable to do usual activities, or meet occupational, social, financial, and family obligations,” said Dr. Armstrong and coauthors in the report.
The scales and tools used to measure symptoms and functional concerns need to be those that best fit a particular clinical trial or clinical practice scenario. Several instruments that would be appropriate are discussed in the report, including the NCI Patient-Reported Outcome of the Common Toxicity Criteria Adverse Events (NCI PRO-CTCAE) and symptom and function scales or items in the Patient-Reported Outcomes Measurement System (PROMIS).
, such as time to recurrence or survival.
“Strategies for introducing these constructs to clinical trial cooperative groups and sponsors will be necessary,” they concluded.
Dr. Armstrong reported employment as a senior investigator and deputy chief of the neuro-oncology branch of the Center for Cancer Research at the NCI. His coauthors reported disclosures related to several companies and interests, including AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Taiho, and Tocagen.
SOURCE: Armstrong TS et al. Lancet Oncol. 2020;21(2):e97-103.
FROM THE LANCET ONCOLOGY
Shift in approach is encouraged in assessing chronic pain
In many cases, dietary interventions can lead to less inflammation
SAN DIEGO – When clinicians ask patients to quantify their level of chronic pain on a scale of 1-10, and they rate it as a 7, what does that really mean?
Robert A. Bonakdar, MD, said posing such a question as the main determinator of the treatment approach during a pain assessment “depersonalizes medicine to the point where you’re making a patient a number.” Dr. Bonakdar spoke at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
“It considers areas that are often overlooked, such as the role of the gut microbiome, mood, and epigenetics.”
Over the past two decades, the number of American adults suffering from pain has increased from 120 million to 178 million, or to 41% of the adult population, said Dr. Bonakdar, a family physician who is director of pain management at the Scripps Center for Integrative Medicine. Data from the National Institutes of Health estimate that Americans spend more than $600 billion each year on the treatment of pain, which surpasses monies spent on cancer, heart disease, and diabetes. According to a 2016 report from the United States Bone and Joint Initiative, arthritis and rheumatologic conditions resulted in an estimated 6.7 million annual hospitalizations, and the average annual cost per person for treatment of a musculoskeletal condition is $7,800.
“If we continue on our current trajectory, we are choosing to accept more prevalence and incidence of these disorders, spiraling costs, restricted access to needed services, and less success in alleviating pain and suffering – a high cost,” Edward H. Yelin, PhD, cochair of the report’s steering committee, and professor of medicine and health policy at the University of California, San Francisco, said in a prepared statement in 2016. That same year, Brian F. Mandell, MD, PhD, editor of the Cleveland Clinic Journal of Medicine, penned an editorial in which he stated that “The time has come to move past using a one-size-fits-all fifth vital sign . . . and reflexively prescribing an opioid when pain is characterized as severe” (Clev Clin J Med. 2016. Jun;83[6]:400-1). A decade earlier, authors of a cross-sectional review at a single Department of Veterans Affairs medical center set out to assess the impact of the VA’s “Pain as the 5th Vital Sign” initiative on the quality of pain management (J Gen Intern Med. 2006;21[6]:607–12). They found that patients with substantial pain documented by the fifth vital sign often had inadequate pain management. The preponderance of existing evidence suggests that a different approach is needed to prescribing opioids, Dr. Bonakdar said. “It’s coming from every voice in pain care: that what we are doing is not working,” he said. “It’s not only not working; it’s dangerous. That’s the consequence of depersonalized medicine. What’s the consequence of depersonalized nutrition? It’s the same industrialized approach.”
The typical American diet, he continued, is rife with processed foods and lacks an adequate proportion of plant-based products. “It’s basically a setup for inflammation,” Dr. Bonakdar said. “Most people who come into our clinic are eating 63% processed foods, 25% animal foods, and 12% plant foods. When we are eating, we’re oversizing it because that’s the American thing to do. At the end of the day, this process is not only killing us from heart disease and stroke as causes of death, but it’s also killing us as far as pain. The same diet that’s causing heart disease is the same diet that’s increasing pain.”
Dr. Bonakdar said that the ingestion of ultra-processed foods over time jumpstarts the process of dysbiosis, which increases gut permeability. “When gut permeability happens, and you have high levels of polysaccharides and inflammatory markers such as zonulin and lipopolysaccharide (LPS), it not only goes on to affect adipose tissue and insulin resistance, it can affect the muscle and joints,” he explained. “That is a setup for sarcopenia, or muscle loss, which then makes it harder for patients to be fully functional and active. It goes on to cause joint problems as well.”
He likened an increase in gut permeability to “a bomb going off in the gut.” Routine consumption of highly processed foods “creates this wave of inflammation that goes throughout your body affecting joints and muscles, and causes an increased amount of pain. Over time, patients make the connection but it’s much easier to say, ‘take this NSAID’ or ‘take this Cox-2 inhibitor’ to suppress the pain. But if all you’re doing is suppressing, you’re not going to the source of the pain.”
Dr. Bonakdar cited several recent articles that help to make the connection between dysbiosis and pain, including a review that concluded that dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases (Nutrients. 2019;11[8]:1707). Authors of a separate review concluded that human microbiome studies strongly suggest an incriminating role of microbes in the pathophysiology and progression of RA. Lastly, several studies have noted that pain conditions such as fibromyalgia may have microbiome “signatures” related to dysbiosis, which may pave the way for interventions, such as dietary shifting and probiotics that target individuals with microbiome abnormalities (Pain. 2019 Nov;160[11]:2589-602 and EBioMedicine. 2019 Aug 1;46:499-511).
Clinicians can begin to help patients who present with pain complaints “by listening to what their current pattern is: strategies that have worked, and those that haven’t,” he said. “If we’re not understanding the person and we’re just ordering genetic studies or microbiome studies and going off of the assessment, we sometime miss what interventions to start. In many cases, a simple intervention like a dietary shift is all that’s required.”
A survey of more than 1 million individuals found that BMI and daily pain are positively correlated in the United States (Obesity 2012;20[7]:1491-5). “This is increased more significantly for women and the elderly,” said Dr. Bonakdar, who was not affiliated with the study. “If we can change the diet that person is taking, that’s going to begin the process of reversing this to the point where they’re having less pain from inflammation that’s affecting the adipose tissue and adipokines traveling to their joints, which can cause less dysbiosis. It is very much a vicious cycle that patients follow, but if you begin to unwind it, it’s going to help multiple areas.”
In the Intensive Diet and Exercise for Arthritis (IDEA) trial, researchers randomized 450 patients with osteoarthritis to intensive dietary restriction only, exercise only, or a combination of both (BMC Musculoskelet Disord. 2009;10:93). They found that a 5% weight loss over the course of 18 months led to a 30% reduction in pain and a 24% improvement in function.
Inspired by the IDEA trial design, Dr. Bonakdar and his colleagues completed an unpublished 12-week pilot program with 12 patients with a BMI of 27 kg/m2 or greater plus comorbidities. The program consisted of weekly group meetings, including a lecture by team clinicians, dietician, and fitness staff; group support sessions with a behavioral counselor; and a group exercise session. It also included weekly 1:1 personal training sessions and biweekly 1:1 dietitian meetings. The researchers also evaluated several deficiencies linked to pain, including magnesium, vitamin D, vitamins B1, B2, and B12, folate, calcium, amino acids, omega 3s, zinc, coenzyme Q10, carnitine, and vitamin C. The goal was a weight reduction of 5%.
The intervention consisted of a 28-day detox/protein shake consumed 1-3 times per day, which contained 17 g of protein per serving. Nutritional supplementation was added based on results of individual diagnostics.
According to preliminary results from the trial, the intended weight goal was achieved. “More importantly, there were significant improvements in markers of dysbiosis, including zonulin and lipopolysaccharide, as well as the adipokine leptin, which appeared to be associated with improvement in quality of life measures and pain,” Dr. Bonakdar said.
He concluded his presentation by highlighting a pilot study conducted in an Australian tertiary pain clinic. It found that a personalized dietitian-delivered dietary intervention can improve pain scores, quality of life, and dietary intake of people experiencing chronic pain (Nutrients. 2019 Jan 16;11[1] pii: E181). “This is another piece of the puzzle showing that these dietary interventions can be done in multiple settings, including tertiary centers with nutrition staff, and that this important step can improve pain and quality of life,” he said.
Dr. Bonakdar disclosed that he receives royalties from Oxford University Press, Lippincott, and Elsevier. He is also a consultant to Standard Process.
dbrunk@mdedge.com
In many cases, dietary interventions can lead to less inflammation
In many cases, dietary interventions can lead to less inflammation
SAN DIEGO – When clinicians ask patients to quantify their level of chronic pain on a scale of 1-10, and they rate it as a 7, what does that really mean?
Robert A. Bonakdar, MD, said posing such a question as the main determinator of the treatment approach during a pain assessment “depersonalizes medicine to the point where you’re making a patient a number.” Dr. Bonakdar spoke at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
“It considers areas that are often overlooked, such as the role of the gut microbiome, mood, and epigenetics.”
Over the past two decades, the number of American adults suffering from pain has increased from 120 million to 178 million, or to 41% of the adult population, said Dr. Bonakdar, a family physician who is director of pain management at the Scripps Center for Integrative Medicine. Data from the National Institutes of Health estimate that Americans spend more than $600 billion each year on the treatment of pain, which surpasses monies spent on cancer, heart disease, and diabetes. According to a 2016 report from the United States Bone and Joint Initiative, arthritis and rheumatologic conditions resulted in an estimated 6.7 million annual hospitalizations, and the average annual cost per person for treatment of a musculoskeletal condition is $7,800.
“If we continue on our current trajectory, we are choosing to accept more prevalence and incidence of these disorders, spiraling costs, restricted access to needed services, and less success in alleviating pain and suffering – a high cost,” Edward H. Yelin, PhD, cochair of the report’s steering committee, and professor of medicine and health policy at the University of California, San Francisco, said in a prepared statement in 2016. That same year, Brian F. Mandell, MD, PhD, editor of the Cleveland Clinic Journal of Medicine, penned an editorial in which he stated that “The time has come to move past using a one-size-fits-all fifth vital sign . . . and reflexively prescribing an opioid when pain is characterized as severe” (Clev Clin J Med. 2016. Jun;83[6]:400-1). A decade earlier, authors of a cross-sectional review at a single Department of Veterans Affairs medical center set out to assess the impact of the VA’s “Pain as the 5th Vital Sign” initiative on the quality of pain management (J Gen Intern Med. 2006;21[6]:607–12). They found that patients with substantial pain documented by the fifth vital sign often had inadequate pain management. The preponderance of existing evidence suggests that a different approach is needed to prescribing opioids, Dr. Bonakdar said. “It’s coming from every voice in pain care: that what we are doing is not working,” he said. “It’s not only not working; it’s dangerous. That’s the consequence of depersonalized medicine. What’s the consequence of depersonalized nutrition? It’s the same industrialized approach.”
The typical American diet, he continued, is rife with processed foods and lacks an adequate proportion of plant-based products. “It’s basically a setup for inflammation,” Dr. Bonakdar said. “Most people who come into our clinic are eating 63% processed foods, 25% animal foods, and 12% plant foods. When we are eating, we’re oversizing it because that’s the American thing to do. At the end of the day, this process is not only killing us from heart disease and stroke as causes of death, but it’s also killing us as far as pain. The same diet that’s causing heart disease is the same diet that’s increasing pain.”
Dr. Bonakdar said that the ingestion of ultra-processed foods over time jumpstarts the process of dysbiosis, which increases gut permeability. “When gut permeability happens, and you have high levels of polysaccharides and inflammatory markers such as zonulin and lipopolysaccharide (LPS), it not only goes on to affect adipose tissue and insulin resistance, it can affect the muscle and joints,” he explained. “That is a setup for sarcopenia, or muscle loss, which then makes it harder for patients to be fully functional and active. It goes on to cause joint problems as well.”
He likened an increase in gut permeability to “a bomb going off in the gut.” Routine consumption of highly processed foods “creates this wave of inflammation that goes throughout your body affecting joints and muscles, and causes an increased amount of pain. Over time, patients make the connection but it’s much easier to say, ‘take this NSAID’ or ‘take this Cox-2 inhibitor’ to suppress the pain. But if all you’re doing is suppressing, you’re not going to the source of the pain.”
Dr. Bonakdar cited several recent articles that help to make the connection between dysbiosis and pain, including a review that concluded that dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases (Nutrients. 2019;11[8]:1707). Authors of a separate review concluded that human microbiome studies strongly suggest an incriminating role of microbes in the pathophysiology and progression of RA. Lastly, several studies have noted that pain conditions such as fibromyalgia may have microbiome “signatures” related to dysbiosis, which may pave the way for interventions, such as dietary shifting and probiotics that target individuals with microbiome abnormalities (Pain. 2019 Nov;160[11]:2589-602 and EBioMedicine. 2019 Aug 1;46:499-511).
Clinicians can begin to help patients who present with pain complaints “by listening to what their current pattern is: strategies that have worked, and those that haven’t,” he said. “If we’re not understanding the person and we’re just ordering genetic studies or microbiome studies and going off of the assessment, we sometime miss what interventions to start. In many cases, a simple intervention like a dietary shift is all that’s required.”
A survey of more than 1 million individuals found that BMI and daily pain are positively correlated in the United States (Obesity 2012;20[7]:1491-5). “This is increased more significantly for women and the elderly,” said Dr. Bonakdar, who was not affiliated with the study. “If we can change the diet that person is taking, that’s going to begin the process of reversing this to the point where they’re having less pain from inflammation that’s affecting the adipose tissue and adipokines traveling to their joints, which can cause less dysbiosis. It is very much a vicious cycle that patients follow, but if you begin to unwind it, it’s going to help multiple areas.”
In the Intensive Diet and Exercise for Arthritis (IDEA) trial, researchers randomized 450 patients with osteoarthritis to intensive dietary restriction only, exercise only, or a combination of both (BMC Musculoskelet Disord. 2009;10:93). They found that a 5% weight loss over the course of 18 months led to a 30% reduction in pain and a 24% improvement in function.
Inspired by the IDEA trial design, Dr. Bonakdar and his colleagues completed an unpublished 12-week pilot program with 12 patients with a BMI of 27 kg/m2 or greater plus comorbidities. The program consisted of weekly group meetings, including a lecture by team clinicians, dietician, and fitness staff; group support sessions with a behavioral counselor; and a group exercise session. It also included weekly 1:1 personal training sessions and biweekly 1:1 dietitian meetings. The researchers also evaluated several deficiencies linked to pain, including magnesium, vitamin D, vitamins B1, B2, and B12, folate, calcium, amino acids, omega 3s, zinc, coenzyme Q10, carnitine, and vitamin C. The goal was a weight reduction of 5%.
The intervention consisted of a 28-day detox/protein shake consumed 1-3 times per day, which contained 17 g of protein per serving. Nutritional supplementation was added based on results of individual diagnostics.
According to preliminary results from the trial, the intended weight goal was achieved. “More importantly, there were significant improvements in markers of dysbiosis, including zonulin and lipopolysaccharide, as well as the adipokine leptin, which appeared to be associated with improvement in quality of life measures and pain,” Dr. Bonakdar said.
He concluded his presentation by highlighting a pilot study conducted in an Australian tertiary pain clinic. It found that a personalized dietitian-delivered dietary intervention can improve pain scores, quality of life, and dietary intake of people experiencing chronic pain (Nutrients. 2019 Jan 16;11[1] pii: E181). “This is another piece of the puzzle showing that these dietary interventions can be done in multiple settings, including tertiary centers with nutrition staff, and that this important step can improve pain and quality of life,” he said.
Dr. Bonakdar disclosed that he receives royalties from Oxford University Press, Lippincott, and Elsevier. He is also a consultant to Standard Process.
dbrunk@mdedge.com
SAN DIEGO – When clinicians ask patients to quantify their level of chronic pain on a scale of 1-10, and they rate it as a 7, what does that really mean?
Robert A. Bonakdar, MD, said posing such a question as the main determinator of the treatment approach during a pain assessment “depersonalizes medicine to the point where you’re making a patient a number.” Dr. Bonakdar spoke at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
“It considers areas that are often overlooked, such as the role of the gut microbiome, mood, and epigenetics.”
Over the past two decades, the number of American adults suffering from pain has increased from 120 million to 178 million, or to 41% of the adult population, said Dr. Bonakdar, a family physician who is director of pain management at the Scripps Center for Integrative Medicine. Data from the National Institutes of Health estimate that Americans spend more than $600 billion each year on the treatment of pain, which surpasses monies spent on cancer, heart disease, and diabetes. According to a 2016 report from the United States Bone and Joint Initiative, arthritis and rheumatologic conditions resulted in an estimated 6.7 million annual hospitalizations, and the average annual cost per person for treatment of a musculoskeletal condition is $7,800.
“If we continue on our current trajectory, we are choosing to accept more prevalence and incidence of these disorders, spiraling costs, restricted access to needed services, and less success in alleviating pain and suffering – a high cost,” Edward H. Yelin, PhD, cochair of the report’s steering committee, and professor of medicine and health policy at the University of California, San Francisco, said in a prepared statement in 2016. That same year, Brian F. Mandell, MD, PhD, editor of the Cleveland Clinic Journal of Medicine, penned an editorial in which he stated that “The time has come to move past using a one-size-fits-all fifth vital sign . . . and reflexively prescribing an opioid when pain is characterized as severe” (Clev Clin J Med. 2016. Jun;83[6]:400-1). A decade earlier, authors of a cross-sectional review at a single Department of Veterans Affairs medical center set out to assess the impact of the VA’s “Pain as the 5th Vital Sign” initiative on the quality of pain management (J Gen Intern Med. 2006;21[6]:607–12). They found that patients with substantial pain documented by the fifth vital sign often had inadequate pain management. The preponderance of existing evidence suggests that a different approach is needed to prescribing opioids, Dr. Bonakdar said. “It’s coming from every voice in pain care: that what we are doing is not working,” he said. “It’s not only not working; it’s dangerous. That’s the consequence of depersonalized medicine. What’s the consequence of depersonalized nutrition? It’s the same industrialized approach.”
The typical American diet, he continued, is rife with processed foods and lacks an adequate proportion of plant-based products. “It’s basically a setup for inflammation,” Dr. Bonakdar said. “Most people who come into our clinic are eating 63% processed foods, 25% animal foods, and 12% plant foods. When we are eating, we’re oversizing it because that’s the American thing to do. At the end of the day, this process is not only killing us from heart disease and stroke as causes of death, but it’s also killing us as far as pain. The same diet that’s causing heart disease is the same diet that’s increasing pain.”
Dr. Bonakdar said that the ingestion of ultra-processed foods over time jumpstarts the process of dysbiosis, which increases gut permeability. “When gut permeability happens, and you have high levels of polysaccharides and inflammatory markers such as zonulin and lipopolysaccharide (LPS), it not only goes on to affect adipose tissue and insulin resistance, it can affect the muscle and joints,” he explained. “That is a setup for sarcopenia, or muscle loss, which then makes it harder for patients to be fully functional and active. It goes on to cause joint problems as well.”
He likened an increase in gut permeability to “a bomb going off in the gut.” Routine consumption of highly processed foods “creates this wave of inflammation that goes throughout your body affecting joints and muscles, and causes an increased amount of pain. Over time, patients make the connection but it’s much easier to say, ‘take this NSAID’ or ‘take this Cox-2 inhibitor’ to suppress the pain. But if all you’re doing is suppressing, you’re not going to the source of the pain.”
Dr. Bonakdar cited several recent articles that help to make the connection between dysbiosis and pain, including a review that concluded that dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases (Nutrients. 2019;11[8]:1707). Authors of a separate review concluded that human microbiome studies strongly suggest an incriminating role of microbes in the pathophysiology and progression of RA. Lastly, several studies have noted that pain conditions such as fibromyalgia may have microbiome “signatures” related to dysbiosis, which may pave the way for interventions, such as dietary shifting and probiotics that target individuals with microbiome abnormalities (Pain. 2019 Nov;160[11]:2589-602 and EBioMedicine. 2019 Aug 1;46:499-511).
Clinicians can begin to help patients who present with pain complaints “by listening to what their current pattern is: strategies that have worked, and those that haven’t,” he said. “If we’re not understanding the person and we’re just ordering genetic studies or microbiome studies and going off of the assessment, we sometime miss what interventions to start. In many cases, a simple intervention like a dietary shift is all that’s required.”
A survey of more than 1 million individuals found that BMI and daily pain are positively correlated in the United States (Obesity 2012;20[7]:1491-5). “This is increased more significantly for women and the elderly,” said Dr. Bonakdar, who was not affiliated with the study. “If we can change the diet that person is taking, that’s going to begin the process of reversing this to the point where they’re having less pain from inflammation that’s affecting the adipose tissue and adipokines traveling to their joints, which can cause less dysbiosis. It is very much a vicious cycle that patients follow, but if you begin to unwind it, it’s going to help multiple areas.”
In the Intensive Diet and Exercise for Arthritis (IDEA) trial, researchers randomized 450 patients with osteoarthritis to intensive dietary restriction only, exercise only, or a combination of both (BMC Musculoskelet Disord. 2009;10:93). They found that a 5% weight loss over the course of 18 months led to a 30% reduction in pain and a 24% improvement in function.
Inspired by the IDEA trial design, Dr. Bonakdar and his colleagues completed an unpublished 12-week pilot program with 12 patients with a BMI of 27 kg/m2 or greater plus comorbidities. The program consisted of weekly group meetings, including a lecture by team clinicians, dietician, and fitness staff; group support sessions with a behavioral counselor; and a group exercise session. It also included weekly 1:1 personal training sessions and biweekly 1:1 dietitian meetings. The researchers also evaluated several deficiencies linked to pain, including magnesium, vitamin D, vitamins B1, B2, and B12, folate, calcium, amino acids, omega 3s, zinc, coenzyme Q10, carnitine, and vitamin C. The goal was a weight reduction of 5%.
The intervention consisted of a 28-day detox/protein shake consumed 1-3 times per day, which contained 17 g of protein per serving. Nutritional supplementation was added based on results of individual diagnostics.
According to preliminary results from the trial, the intended weight goal was achieved. “More importantly, there were significant improvements in markers of dysbiosis, including zonulin and lipopolysaccharide, as well as the adipokine leptin, which appeared to be associated with improvement in quality of life measures and pain,” Dr. Bonakdar said.
He concluded his presentation by highlighting a pilot study conducted in an Australian tertiary pain clinic. It found that a personalized dietitian-delivered dietary intervention can improve pain scores, quality of life, and dietary intake of people experiencing chronic pain (Nutrients. 2019 Jan 16;11[1] pii: E181). “This is another piece of the puzzle showing that these dietary interventions can be done in multiple settings, including tertiary centers with nutrition staff, and that this important step can improve pain and quality of life,” he said.
Dr. Bonakdar disclosed that he receives royalties from Oxford University Press, Lippincott, and Elsevier. He is also a consultant to Standard Process.
dbrunk@mdedge.com
REPORTING FROM A NATURAL SUPPLEMENTS UPDATE
CMS proposes second specialty tier for Medicare drugs
The Centers for Medicare & Medicaid Services’ latest maneuver to combat rising drug prices is the proposed addition of a second specialty drug tier for the Medicare Part D prescription drug benefit.
The proposal is part of a broader proposed update to Medicare Parts C and D for contract years 2021 and 2022.
In a fact sheet highlighting various elements of the overall proposal, CMS noted that Part D plan sponsors and pharmacy benefit managers have been requesting the option to add a second “preferred” specialty tier that would “encourage the use of more preferred, less expensive agents, reduce enrollee cost sharing, and reduce costs to CMS.”
Currently, all pharmaceuticals with a cost greater than $670 are placed in a single specialty tier.
During a Feb. 5 press briefing, CMS Administrator Seema Verma described this change as “giving plans more negotiating power so they can lower prices for beneficiaries even further.”
Ms. Verma used a hypothetical example of two rheumatoid arthritis drugs to illustrate how the change will work. Currently, if both are over the $670 threshold, they would both be on the specialty tier with the same cost sharing. “Creating a second preferred specialty tier would allow for a different copay and fosters a more competitive environment that places Part D plans in a better position to negotiate the price of similar drugs and pass those savings onto the patient through lower cost sharing,” she said.
CMS is proposing to allow plans to implement a preferred specialty tier for the 2021 plan year.
The agency is also seeking to drive more generic drug use as a means of lowering costs.
Ms. Verma noted that, typically, even after a generic drug is launched, health plan sponsors prefer to drive patients to the brand name product, if they can secure a greater rebate from the manufacturer.
In a separate Feb. 5 blog post, Ms. Verma noted that when a brand was included on a formulary, the generic was also on the formulary 91.8% of the time. For the times in which the generic was not, it was typically because the wholesale cost of the generic was only 5%-15% lower than the brand wholesale cost.
In an effort to encourage use of generics, CMS is seeking comment on the development of measures of generic and biosimilar use in Medicare Part D that could be incorporated in health plan star ratings.
Some of the measures proposed in the blog post include the generic substitution rate, the generic therapeutic alternative opportunity rate (which measures the number of brand fills divided by the sum of the brand and generic fills when both are available), and the biosimilar utilization rate.
gtwachtman@mdedge.com
The Centers for Medicare & Medicaid Services’ latest maneuver to combat rising drug prices is the proposed addition of a second specialty drug tier for the Medicare Part D prescription drug benefit.
The proposal is part of a broader proposed update to Medicare Parts C and D for contract years 2021 and 2022.
In a fact sheet highlighting various elements of the overall proposal, CMS noted that Part D plan sponsors and pharmacy benefit managers have been requesting the option to add a second “preferred” specialty tier that would “encourage the use of more preferred, less expensive agents, reduce enrollee cost sharing, and reduce costs to CMS.”
Currently, all pharmaceuticals with a cost greater than $670 are placed in a single specialty tier.
During a Feb. 5 press briefing, CMS Administrator Seema Verma described this change as “giving plans more negotiating power so they can lower prices for beneficiaries even further.”
Ms. Verma used a hypothetical example of two rheumatoid arthritis drugs to illustrate how the change will work. Currently, if both are over the $670 threshold, they would both be on the specialty tier with the same cost sharing. “Creating a second preferred specialty tier would allow for a different copay and fosters a more competitive environment that places Part D plans in a better position to negotiate the price of similar drugs and pass those savings onto the patient through lower cost sharing,” she said.
CMS is proposing to allow plans to implement a preferred specialty tier for the 2021 plan year.
The agency is also seeking to drive more generic drug use as a means of lowering costs.
Ms. Verma noted that, typically, even after a generic drug is launched, health plan sponsors prefer to drive patients to the brand name product, if they can secure a greater rebate from the manufacturer.
In a separate Feb. 5 blog post, Ms. Verma noted that when a brand was included on a formulary, the generic was also on the formulary 91.8% of the time. For the times in which the generic was not, it was typically because the wholesale cost of the generic was only 5%-15% lower than the brand wholesale cost.
In an effort to encourage use of generics, CMS is seeking comment on the development of measures of generic and biosimilar use in Medicare Part D that could be incorporated in health plan star ratings.
Some of the measures proposed in the blog post include the generic substitution rate, the generic therapeutic alternative opportunity rate (which measures the number of brand fills divided by the sum of the brand and generic fills when both are available), and the biosimilar utilization rate.
gtwachtman@mdedge.com
The Centers for Medicare & Medicaid Services’ latest maneuver to combat rising drug prices is the proposed addition of a second specialty drug tier for the Medicare Part D prescription drug benefit.
The proposal is part of a broader proposed update to Medicare Parts C and D for contract years 2021 and 2022.
In a fact sheet highlighting various elements of the overall proposal, CMS noted that Part D plan sponsors and pharmacy benefit managers have been requesting the option to add a second “preferred” specialty tier that would “encourage the use of more preferred, less expensive agents, reduce enrollee cost sharing, and reduce costs to CMS.”
Currently, all pharmaceuticals with a cost greater than $670 are placed in a single specialty tier.
During a Feb. 5 press briefing, CMS Administrator Seema Verma described this change as “giving plans more negotiating power so they can lower prices for beneficiaries even further.”
Ms. Verma used a hypothetical example of two rheumatoid arthritis drugs to illustrate how the change will work. Currently, if both are over the $670 threshold, they would both be on the specialty tier with the same cost sharing. “Creating a second preferred specialty tier would allow for a different copay and fosters a more competitive environment that places Part D plans in a better position to negotiate the price of similar drugs and pass those savings onto the patient through lower cost sharing,” she said.
CMS is proposing to allow plans to implement a preferred specialty tier for the 2021 plan year.
The agency is also seeking to drive more generic drug use as a means of lowering costs.
Ms. Verma noted that, typically, even after a generic drug is launched, health plan sponsors prefer to drive patients to the brand name product, if they can secure a greater rebate from the manufacturer.
In a separate Feb. 5 blog post, Ms. Verma noted that when a brand was included on a formulary, the generic was also on the formulary 91.8% of the time. For the times in which the generic was not, it was typically because the wholesale cost of the generic was only 5%-15% lower than the brand wholesale cost.
In an effort to encourage use of generics, CMS is seeking comment on the development of measures of generic and biosimilar use in Medicare Part D that could be incorporated in health plan star ratings.
Some of the measures proposed in the blog post include the generic substitution rate, the generic therapeutic alternative opportunity rate (which measures the number of brand fills divided by the sum of the brand and generic fills when both are available), and the biosimilar utilization rate.
gtwachtman@mdedge.com
Treating those who taught us
I was surprised when the name came up on my hospital census as a new consult.
Many years ago he’d been one of my attendings in residency. Someone I’d trained under. He’d been patient, almost grandfatherly, in the way he taught residents on his service. Never angry or impatient. I’d genuinely liked him as a person and respected him as a teacher.
And here he was now, a new consult on my daily hospital patient list.
A quick look at his chart brought the irony that I’m the same age now that he was when I worked under him. Time flies.
He didn’t remember me, nor did I expect him to. In my training from 1993 to 1997, I’d only dealt with him directly for a few months here and there. He’d seen a lot of residents come and go over his career.
He was, like me, older now. I wouldn’t have recognized him if I didn’t know the name in advance. He was frail now, seemingly smaller than I remembered, his mind and health damaged by his own neurologic issues.
Like all of us, I’ve taken care of other physicians, but this was the first time I’d encountered one of my former teachers in that role, and felt bad that he was in a situation I really couldn’t do much about.
I wrote some orders and moved on to the next consult, but haven’t stopped thinking about him.
Time comes for all of us sooner or later, though it’s never easy to reflect on. I’d certainly do what I could to help him, but was well aware (as I’m sure he was) that there was only so much I could.
When I came back the next day he’d left. At his own insistence, he wanted us to stop what we were doing and opted to be kept comfortable. It was certainly not an easy choice to make for any of us, but in character with the person and physician I still liked and respected.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I was surprised when the name came up on my hospital census as a new consult.
Many years ago he’d been one of my attendings in residency. Someone I’d trained under. He’d been patient, almost grandfatherly, in the way he taught residents on his service. Never angry or impatient. I’d genuinely liked him as a person and respected him as a teacher.
And here he was now, a new consult on my daily hospital patient list.
A quick look at his chart brought the irony that I’m the same age now that he was when I worked under him. Time flies.
He didn’t remember me, nor did I expect him to. In my training from 1993 to 1997, I’d only dealt with him directly for a few months here and there. He’d seen a lot of residents come and go over his career.
He was, like me, older now. I wouldn’t have recognized him if I didn’t know the name in advance. He was frail now, seemingly smaller than I remembered, his mind and health damaged by his own neurologic issues.
Like all of us, I’ve taken care of other physicians, but this was the first time I’d encountered one of my former teachers in that role, and felt bad that he was in a situation I really couldn’t do much about.
I wrote some orders and moved on to the next consult, but haven’t stopped thinking about him.
Time comes for all of us sooner or later, though it’s never easy to reflect on. I’d certainly do what I could to help him, but was well aware (as I’m sure he was) that there was only so much I could.
When I came back the next day he’d left. At his own insistence, he wanted us to stop what we were doing and opted to be kept comfortable. It was certainly not an easy choice to make for any of us, but in character with the person and physician I still liked and respected.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I was surprised when the name came up on my hospital census as a new consult.
Many years ago he’d been one of my attendings in residency. Someone I’d trained under. He’d been patient, almost grandfatherly, in the way he taught residents on his service. Never angry or impatient. I’d genuinely liked him as a person and respected him as a teacher.
And here he was now, a new consult on my daily hospital patient list.
A quick look at his chart brought the irony that I’m the same age now that he was when I worked under him. Time flies.
He didn’t remember me, nor did I expect him to. In my training from 1993 to 1997, I’d only dealt with him directly for a few months here and there. He’d seen a lot of residents come and go over his career.
He was, like me, older now. I wouldn’t have recognized him if I didn’t know the name in advance. He was frail now, seemingly smaller than I remembered, his mind and health damaged by his own neurologic issues.
Like all of us, I’ve taken care of other physicians, but this was the first time I’d encountered one of my former teachers in that role, and felt bad that he was in a situation I really couldn’t do much about.
I wrote some orders and moved on to the next consult, but haven’t stopped thinking about him.
Time comes for all of us sooner or later, though it’s never easy to reflect on. I’d certainly do what I could to help him, but was well aware (as I’m sure he was) that there was only so much I could.
When I came back the next day he’d left. At his own insistence, he wanted us to stop what we were doing and opted to be kept comfortable. It was certainly not an easy choice to make for any of us, but in character with the person and physician I still liked and respected.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
EEG abnormalities may indicate increased risk for epilepsy in patients with autism
BALTIMORE – , according to research presented at the annual meeting of the American Epilepsy Society. In addition, a positive family history of febrile seizures also is associated with an increased risk of epilepsy in this population.
The literature suggests that the prevalence of epilepsy in patients with ASD ranges from 5% to 40%. This broad range may result from the heterogeneity of epilepsy risk factors among patients with ASD. These risk factors include intellectual disability, age, and syndromic forms of ASD such as tuberous sclerosis complex. Regardless of whether they have epilepsy, approximately 60% of patients with ASD have EEG abnormalities. The prognostic implications of these abnormalities are uncertain.
Investigators reviewed patients’ charts retrospectively
Divya Nadkarni, MD, a neurologist at Ronald Reagan UCLA Medical Center in Los Angeles, and colleagues sought to clarify the relationship between risk factors such as EEG abnormalities and subsequent epilepsy in patients with ASD. They retrospectively identified patients who were followed jointly at UCLA and at Pediatric Minds, a neurodevelopmental clinic in Torrance, Calif. Eligible patients had a diagnosis of ASD, based on criteria from DSM-IV, DSM-5, or the Autism Diagnostic Observation Schedule. In addition, patients had overnight, continuous video EEG evaluation and a minimum follow-up of 1 week after EEG. Patients with a history of epilepsy before the initial EEG evaluation were excluded. Dr. Nadkarni and colleagues collected clinical and electrographic data by chart review.
The study’s primary outcome was time to onset of epilepsy. Among the variables that the investigators analyzed were EEG abnormalities, which they defined as focal slowing or generalized or focal epileptiform discharges. The other variables were history of febrile seizures, family history of epilepsy, family history of febrile seizures, and family history of ASD. Dr. Nadkarni and colleagues analyzed the data using the Kaplan–Meier method and Cox proportional hazards models.
In all, 164 patients met the study’s inclusion criteria. The population’s median age at the initial EEG evaluation was 4.5 years. The median follow-up after this evaluation was 2.4 years. The investigators found 63 patients (38.4%) with abnormal EEGs, and 18 patients (11%) subsequently developed epilepsy after a median of 1.9 years.
Family history of febrile seizures was associated with time to epilepsy onset
The time to epilepsy onset was associated with abnormalities on the initial overnight continuous EEG. The hazard ratio of epilepsy among patients with EEG abnormalities was 8.0. Approximately one-third of patients with EEG abnormalities developed subsequent epilepsy, compared with approximately 5% of patients without EEG abnormalities, said Dr. Nadkarni.
In addition, time to epilepsy onset was independently associated with a positive family history of febrile seizures. This finding was unexpected, said Dr. Nadkarni. The hazard ratio of epilepsy among patients with a positive family history of febrile seizures was 12.6.
The patient’s own history of febrile seizures was not associated with time to epilepsy onset. One potential explanation for this result is that it is difficult to distinguish between febrile seizure and seizure with fever in the general pediatric population. Making this distinction in children with ASD, who may have atypical febrile seizures, might be still more difficult, said Dr. Nadkarni.
Time for guideline updates?
“Statements from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Neurology, and the Child Neurology Society do not currently recommend routine EEG screening for all children with ASD,” said Dr. Nadkarni. Investigators are suggesting that the guidelines should be reevaluated, however. “Research shows that EEG abnormalities, particularly epileptiform abnormalities, are associated with worse outcome, in terms of developmental and adaptive functioning. EEG endophenotypes in ASD are starting to be elucidated ... That’s one reason to consider EEG screening.” Furthermore, preliminary connectivity research suggests that EEG screening of high-risk siblings of children with ASD may predict the development of ASD.
The small cohort and retrospective design were among the study’s limitations, said Dr. Nadkarni. Some patients were lost to follow-up, and some data were missing from patients’ charts.
“In our opinion, further study – ideally, a prospective, observational cohort study – might be warranted to determine whether overnight continuous EEG monitoring might be useful as a screening tool for epilepsy in patients with ASD,” Dr. Nadkarni concluded.
The study was conducted without external funding, and the investigators had no disclosures.
SOURCE: Nadkarni D et al. AES 2019. Abstract 1.29.
BALTIMORE – , according to research presented at the annual meeting of the American Epilepsy Society. In addition, a positive family history of febrile seizures also is associated with an increased risk of epilepsy in this population.
The literature suggests that the prevalence of epilepsy in patients with ASD ranges from 5% to 40%. This broad range may result from the heterogeneity of epilepsy risk factors among patients with ASD. These risk factors include intellectual disability, age, and syndromic forms of ASD such as tuberous sclerosis complex. Regardless of whether they have epilepsy, approximately 60% of patients with ASD have EEG abnormalities. The prognostic implications of these abnormalities are uncertain.
Investigators reviewed patients’ charts retrospectively
Divya Nadkarni, MD, a neurologist at Ronald Reagan UCLA Medical Center in Los Angeles, and colleagues sought to clarify the relationship between risk factors such as EEG abnormalities and subsequent epilepsy in patients with ASD. They retrospectively identified patients who were followed jointly at UCLA and at Pediatric Minds, a neurodevelopmental clinic in Torrance, Calif. Eligible patients had a diagnosis of ASD, based on criteria from DSM-IV, DSM-5, or the Autism Diagnostic Observation Schedule. In addition, patients had overnight, continuous video EEG evaluation and a minimum follow-up of 1 week after EEG. Patients with a history of epilepsy before the initial EEG evaluation were excluded. Dr. Nadkarni and colleagues collected clinical and electrographic data by chart review.
The study’s primary outcome was time to onset of epilepsy. Among the variables that the investigators analyzed were EEG abnormalities, which they defined as focal slowing or generalized or focal epileptiform discharges. The other variables were history of febrile seizures, family history of epilepsy, family history of febrile seizures, and family history of ASD. Dr. Nadkarni and colleagues analyzed the data using the Kaplan–Meier method and Cox proportional hazards models.
In all, 164 patients met the study’s inclusion criteria. The population’s median age at the initial EEG evaluation was 4.5 years. The median follow-up after this evaluation was 2.4 years. The investigators found 63 patients (38.4%) with abnormal EEGs, and 18 patients (11%) subsequently developed epilepsy after a median of 1.9 years.
Family history of febrile seizures was associated with time to epilepsy onset
The time to epilepsy onset was associated with abnormalities on the initial overnight continuous EEG. The hazard ratio of epilepsy among patients with EEG abnormalities was 8.0. Approximately one-third of patients with EEG abnormalities developed subsequent epilepsy, compared with approximately 5% of patients without EEG abnormalities, said Dr. Nadkarni.
In addition, time to epilepsy onset was independently associated with a positive family history of febrile seizures. This finding was unexpected, said Dr. Nadkarni. The hazard ratio of epilepsy among patients with a positive family history of febrile seizures was 12.6.
The patient’s own history of febrile seizures was not associated with time to epilepsy onset. One potential explanation for this result is that it is difficult to distinguish between febrile seizure and seizure with fever in the general pediatric population. Making this distinction in children with ASD, who may have atypical febrile seizures, might be still more difficult, said Dr. Nadkarni.
Time for guideline updates?
“Statements from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Neurology, and the Child Neurology Society do not currently recommend routine EEG screening for all children with ASD,” said Dr. Nadkarni. Investigators are suggesting that the guidelines should be reevaluated, however. “Research shows that EEG abnormalities, particularly epileptiform abnormalities, are associated with worse outcome, in terms of developmental and adaptive functioning. EEG endophenotypes in ASD are starting to be elucidated ... That’s one reason to consider EEG screening.” Furthermore, preliminary connectivity research suggests that EEG screening of high-risk siblings of children with ASD may predict the development of ASD.
The small cohort and retrospective design were among the study’s limitations, said Dr. Nadkarni. Some patients were lost to follow-up, and some data were missing from patients’ charts.
“In our opinion, further study – ideally, a prospective, observational cohort study – might be warranted to determine whether overnight continuous EEG monitoring might be useful as a screening tool for epilepsy in patients with ASD,” Dr. Nadkarni concluded.
The study was conducted without external funding, and the investigators had no disclosures.
SOURCE: Nadkarni D et al. AES 2019. Abstract 1.29.
BALTIMORE – , according to research presented at the annual meeting of the American Epilepsy Society. In addition, a positive family history of febrile seizures also is associated with an increased risk of epilepsy in this population.
The literature suggests that the prevalence of epilepsy in patients with ASD ranges from 5% to 40%. This broad range may result from the heterogeneity of epilepsy risk factors among patients with ASD. These risk factors include intellectual disability, age, and syndromic forms of ASD such as tuberous sclerosis complex. Regardless of whether they have epilepsy, approximately 60% of patients with ASD have EEG abnormalities. The prognostic implications of these abnormalities are uncertain.
Investigators reviewed patients’ charts retrospectively
Divya Nadkarni, MD, a neurologist at Ronald Reagan UCLA Medical Center in Los Angeles, and colleagues sought to clarify the relationship between risk factors such as EEG abnormalities and subsequent epilepsy in patients with ASD. They retrospectively identified patients who were followed jointly at UCLA and at Pediatric Minds, a neurodevelopmental clinic in Torrance, Calif. Eligible patients had a diagnosis of ASD, based on criteria from DSM-IV, DSM-5, or the Autism Diagnostic Observation Schedule. In addition, patients had overnight, continuous video EEG evaluation and a minimum follow-up of 1 week after EEG. Patients with a history of epilepsy before the initial EEG evaluation were excluded. Dr. Nadkarni and colleagues collected clinical and electrographic data by chart review.
The study’s primary outcome was time to onset of epilepsy. Among the variables that the investigators analyzed were EEG abnormalities, which they defined as focal slowing or generalized or focal epileptiform discharges. The other variables were history of febrile seizures, family history of epilepsy, family history of febrile seizures, and family history of ASD. Dr. Nadkarni and colleagues analyzed the data using the Kaplan–Meier method and Cox proportional hazards models.
In all, 164 patients met the study’s inclusion criteria. The population’s median age at the initial EEG evaluation was 4.5 years. The median follow-up after this evaluation was 2.4 years. The investigators found 63 patients (38.4%) with abnormal EEGs, and 18 patients (11%) subsequently developed epilepsy after a median of 1.9 years.
Family history of febrile seizures was associated with time to epilepsy onset
The time to epilepsy onset was associated with abnormalities on the initial overnight continuous EEG. The hazard ratio of epilepsy among patients with EEG abnormalities was 8.0. Approximately one-third of patients with EEG abnormalities developed subsequent epilepsy, compared with approximately 5% of patients without EEG abnormalities, said Dr. Nadkarni.
In addition, time to epilepsy onset was independently associated with a positive family history of febrile seizures. This finding was unexpected, said Dr. Nadkarni. The hazard ratio of epilepsy among patients with a positive family history of febrile seizures was 12.6.
The patient’s own history of febrile seizures was not associated with time to epilepsy onset. One potential explanation for this result is that it is difficult to distinguish between febrile seizure and seizure with fever in the general pediatric population. Making this distinction in children with ASD, who may have atypical febrile seizures, might be still more difficult, said Dr. Nadkarni.
Time for guideline updates?
“Statements from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Neurology, and the Child Neurology Society do not currently recommend routine EEG screening for all children with ASD,” said Dr. Nadkarni. Investigators are suggesting that the guidelines should be reevaluated, however. “Research shows that EEG abnormalities, particularly epileptiform abnormalities, are associated with worse outcome, in terms of developmental and adaptive functioning. EEG endophenotypes in ASD are starting to be elucidated ... That’s one reason to consider EEG screening.” Furthermore, preliminary connectivity research suggests that EEG screening of high-risk siblings of children with ASD may predict the development of ASD.
The small cohort and retrospective design were among the study’s limitations, said Dr. Nadkarni. Some patients were lost to follow-up, and some data were missing from patients’ charts.
“In our opinion, further study – ideally, a prospective, observational cohort study – might be warranted to determine whether overnight continuous EEG monitoring might be useful as a screening tool for epilepsy in patients with ASD,” Dr. Nadkarni concluded.
The study was conducted without external funding, and the investigators had no disclosures.
SOURCE: Nadkarni D et al. AES 2019. Abstract 1.29.
REPORTING FROM AES 2019
Serum levels of neurofilament light are increased before clinical onset of MS
(MS), according to research published in the January issue of JAMA Neurology. These results lend weight to the idea that MS has a prodromal phase, and this phase appears to be associated with neurodegeneration, according to the authors.
Patients often have CNS lesions of various stages of development at the time of their first demyelinating event, and this finding was one basis for neurologists’ hypothesis of a prodromal phase of MS. The finding that one-third of patients with radiologically isolated syndrome develop MS within 5 years also lends credence to this idea. Diagnosing MS early would enable early treatment that could prevent demyelination and the progression of neurodegeneration.
Researchers compared presymptomatic and symptomatic samples
With this idea in mind, Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard TH Chan School of Public Health in Boston, and colleagues evaluated whether serum levels of NfL, a marker of ongoing neuroaxonal degeneration, were increased in the years before and around the time of clinical onset of MS. For their study population, the investigators chose active-duty U.S. military personnel who have at least one serum sample stored in the U.S. Department of Defense Serum Repository. Samples are collected after routine HIV type 1 antibody testing.
Within this population, Dr. Bjornevik and colleagues identified patients with MS who had at least one presymptomatic serum sample. The date of clinical MS onset was defined as the date of the first neurologic symptoms attributable to MS documented in the medical record. The investigators randomly selected two control individuals from the population and matched them to each case by age, sex, race or ethnicity, and dates of sample collection. Eligible controls were on active duty on the date of onset of the matched case.
Dr. Bjornevik and colleagues identified 245 patients with MS. Among this sample, the researchers selected two groups that each included 30 cases and 30 controls. The first group included patients who had provided at least one serum sample before MS onset and one sample within 2 years after MS onset. The second group included cases with at least two presymptomatic serum samples, one of which was collected more than 5 years before MS diagnosis, and the other of which was collected between 2 and 5 years before diagnosis. The investigators handled pairs of serum samples in the same way and assayed them in the same batch. The order of the samples in each pair was arranged at random.
Levels were higher in cases than in controls
About 77% of the population was male. Sixty percent of participants were white, 28% were black, and 6.7% were Hispanic. The population’s mean age at first sample collection was approximately 27 years. Mean age at MS onset was approximately 31 years.
For patients who provided samples before and after the clinical onset of MS, serum NfL levels were higher than in matched controls at both points. Most patients who passed from the presymptomatic stage to the symptomatic stage had a significant increase in serum NfL level (i.e., from a median of 25.0 pg/mL to a median of 45.1 pg/mL). Serum NfL levels at the two time points in controls did not differ significantly. For any given patient, an increase in serum NfL level from the presymptomatic measurement to the symptomatic measurement was associated with an increased risk of MS.
In patients with two presymptomatic samples, serum NfL levels were significantly higher in both samples than in the corresponding samples from matched controls. In cases, the earlier sample was collected at a median of 6 years before clinical onset of MS, and the later sample was collected at a median of 1 year before clinical onset. The serum NfL levels increased significantly between the two points for cases (i.e., a median increase of 1.3 pg/mL per year), but there was no significant difference in serum NfL level between the two samples in controls. A within-patient increase in presymptomatic serum NfL level was associated with an increased risk of MS.
Population included few women
“Our study differs from previous studies on the prodromal phase of MS because these have used indirect markers of this phase, which included unspecific symptoms or disturbances occurring before the clinical onset, compared with a marker of neurodegeneration,” wrote Dr. Bjornevik and colleagues. Initiation of treatment with disease-modifying therapy is associated with reductions in serum NfL levels, and this association could explain why some patients in the current study had higher NfL levels before MS onset than afterward. Furthermore, serum NfL levels are highly associated with levels of NfL in cerebrospinal fluid. “Thus, our findings of a presymptomatic increase in serum NfL not only suggest the presence of a prodromal phase in MS, but also that this phase is associated with neurodegeneration,” wrote the investigators.
The study’s well-defined population helped to minimize selection bias, and the blinded, randomized method of analyzing the serum samples eliminated artifactual differences in serum NfL concentrations. But the small sample size precluded analyses that could have influenced clinical practice, wrote Dr. Bjornevik and colleagues. For example, the researchers could not evaluate distinct cutoffs in serum NfL level that could mark the beginning of the prodromal phase of MS. Nor could they determine whether presymptomatic serum NfL levels varied with age at clinical onset, sex, or race. The small number of women in the sample was another limitation of the study.
The Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke funded the study. Several of the investigators received fees from various drug companies that were unrelated to the study, and one researcher received grants from the National Institutes of Health during the study.
SOURCE: Bjornevik K et al. JAMA Neurol. 2020;77(1):58-64.
(MS), according to research published in the January issue of JAMA Neurology. These results lend weight to the idea that MS has a prodromal phase, and this phase appears to be associated with neurodegeneration, according to the authors.
Patients often have CNS lesions of various stages of development at the time of their first demyelinating event, and this finding was one basis for neurologists’ hypothesis of a prodromal phase of MS. The finding that one-third of patients with radiologically isolated syndrome develop MS within 5 years also lends credence to this idea. Diagnosing MS early would enable early treatment that could prevent demyelination and the progression of neurodegeneration.
Researchers compared presymptomatic and symptomatic samples
With this idea in mind, Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard TH Chan School of Public Health in Boston, and colleagues evaluated whether serum levels of NfL, a marker of ongoing neuroaxonal degeneration, were increased in the years before and around the time of clinical onset of MS. For their study population, the investigators chose active-duty U.S. military personnel who have at least one serum sample stored in the U.S. Department of Defense Serum Repository. Samples are collected after routine HIV type 1 antibody testing.
Within this population, Dr. Bjornevik and colleagues identified patients with MS who had at least one presymptomatic serum sample. The date of clinical MS onset was defined as the date of the first neurologic symptoms attributable to MS documented in the medical record. The investigators randomly selected two control individuals from the population and matched them to each case by age, sex, race or ethnicity, and dates of sample collection. Eligible controls were on active duty on the date of onset of the matched case.
Dr. Bjornevik and colleagues identified 245 patients with MS. Among this sample, the researchers selected two groups that each included 30 cases and 30 controls. The first group included patients who had provided at least one serum sample before MS onset and one sample within 2 years after MS onset. The second group included cases with at least two presymptomatic serum samples, one of which was collected more than 5 years before MS diagnosis, and the other of which was collected between 2 and 5 years before diagnosis. The investigators handled pairs of serum samples in the same way and assayed them in the same batch. The order of the samples in each pair was arranged at random.
Levels were higher in cases than in controls
About 77% of the population was male. Sixty percent of participants were white, 28% were black, and 6.7% were Hispanic. The population’s mean age at first sample collection was approximately 27 years. Mean age at MS onset was approximately 31 years.
For patients who provided samples before and after the clinical onset of MS, serum NfL levels were higher than in matched controls at both points. Most patients who passed from the presymptomatic stage to the symptomatic stage had a significant increase in serum NfL level (i.e., from a median of 25.0 pg/mL to a median of 45.1 pg/mL). Serum NfL levels at the two time points in controls did not differ significantly. For any given patient, an increase in serum NfL level from the presymptomatic measurement to the symptomatic measurement was associated with an increased risk of MS.
In patients with two presymptomatic samples, serum NfL levels were significantly higher in both samples than in the corresponding samples from matched controls. In cases, the earlier sample was collected at a median of 6 years before clinical onset of MS, and the later sample was collected at a median of 1 year before clinical onset. The serum NfL levels increased significantly between the two points for cases (i.e., a median increase of 1.3 pg/mL per year), but there was no significant difference in serum NfL level between the two samples in controls. A within-patient increase in presymptomatic serum NfL level was associated with an increased risk of MS.
Population included few women
“Our study differs from previous studies on the prodromal phase of MS because these have used indirect markers of this phase, which included unspecific symptoms or disturbances occurring before the clinical onset, compared with a marker of neurodegeneration,” wrote Dr. Bjornevik and colleagues. Initiation of treatment with disease-modifying therapy is associated with reductions in serum NfL levels, and this association could explain why some patients in the current study had higher NfL levels before MS onset than afterward. Furthermore, serum NfL levels are highly associated with levels of NfL in cerebrospinal fluid. “Thus, our findings of a presymptomatic increase in serum NfL not only suggest the presence of a prodromal phase in MS, but also that this phase is associated with neurodegeneration,” wrote the investigators.
The study’s well-defined population helped to minimize selection bias, and the blinded, randomized method of analyzing the serum samples eliminated artifactual differences in serum NfL concentrations. But the small sample size precluded analyses that could have influenced clinical practice, wrote Dr. Bjornevik and colleagues. For example, the researchers could not evaluate distinct cutoffs in serum NfL level that could mark the beginning of the prodromal phase of MS. Nor could they determine whether presymptomatic serum NfL levels varied with age at clinical onset, sex, or race. The small number of women in the sample was another limitation of the study.
The Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke funded the study. Several of the investigators received fees from various drug companies that were unrelated to the study, and one researcher received grants from the National Institutes of Health during the study.
SOURCE: Bjornevik K et al. JAMA Neurol. 2020;77(1):58-64.
(MS), according to research published in the January issue of JAMA Neurology. These results lend weight to the idea that MS has a prodromal phase, and this phase appears to be associated with neurodegeneration, according to the authors.
Patients often have CNS lesions of various stages of development at the time of their first demyelinating event, and this finding was one basis for neurologists’ hypothesis of a prodromal phase of MS. The finding that one-third of patients with radiologically isolated syndrome develop MS within 5 years also lends credence to this idea. Diagnosing MS early would enable early treatment that could prevent demyelination and the progression of neurodegeneration.
Researchers compared presymptomatic and symptomatic samples
With this idea in mind, Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard TH Chan School of Public Health in Boston, and colleagues evaluated whether serum levels of NfL, a marker of ongoing neuroaxonal degeneration, were increased in the years before and around the time of clinical onset of MS. For their study population, the investigators chose active-duty U.S. military personnel who have at least one serum sample stored in the U.S. Department of Defense Serum Repository. Samples are collected after routine HIV type 1 antibody testing.
Within this population, Dr. Bjornevik and colleagues identified patients with MS who had at least one presymptomatic serum sample. The date of clinical MS onset was defined as the date of the first neurologic symptoms attributable to MS documented in the medical record. The investigators randomly selected two control individuals from the population and matched them to each case by age, sex, race or ethnicity, and dates of sample collection. Eligible controls were on active duty on the date of onset of the matched case.
Dr. Bjornevik and colleagues identified 245 patients with MS. Among this sample, the researchers selected two groups that each included 30 cases and 30 controls. The first group included patients who had provided at least one serum sample before MS onset and one sample within 2 years after MS onset. The second group included cases with at least two presymptomatic serum samples, one of which was collected more than 5 years before MS diagnosis, and the other of which was collected between 2 and 5 years before diagnosis. The investigators handled pairs of serum samples in the same way and assayed them in the same batch. The order of the samples in each pair was arranged at random.
Levels were higher in cases than in controls
About 77% of the population was male. Sixty percent of participants were white, 28% were black, and 6.7% were Hispanic. The population’s mean age at first sample collection was approximately 27 years. Mean age at MS onset was approximately 31 years.
For patients who provided samples before and after the clinical onset of MS, serum NfL levels were higher than in matched controls at both points. Most patients who passed from the presymptomatic stage to the symptomatic stage had a significant increase in serum NfL level (i.e., from a median of 25.0 pg/mL to a median of 45.1 pg/mL). Serum NfL levels at the two time points in controls did not differ significantly. For any given patient, an increase in serum NfL level from the presymptomatic measurement to the symptomatic measurement was associated with an increased risk of MS.
In patients with two presymptomatic samples, serum NfL levels were significantly higher in both samples than in the corresponding samples from matched controls. In cases, the earlier sample was collected at a median of 6 years before clinical onset of MS, and the later sample was collected at a median of 1 year before clinical onset. The serum NfL levels increased significantly between the two points for cases (i.e., a median increase of 1.3 pg/mL per year), but there was no significant difference in serum NfL level between the two samples in controls. A within-patient increase in presymptomatic serum NfL level was associated with an increased risk of MS.
Population included few women
“Our study differs from previous studies on the prodromal phase of MS because these have used indirect markers of this phase, which included unspecific symptoms or disturbances occurring before the clinical onset, compared with a marker of neurodegeneration,” wrote Dr. Bjornevik and colleagues. Initiation of treatment with disease-modifying therapy is associated with reductions in serum NfL levels, and this association could explain why some patients in the current study had higher NfL levels before MS onset than afterward. Furthermore, serum NfL levels are highly associated with levels of NfL in cerebrospinal fluid. “Thus, our findings of a presymptomatic increase in serum NfL not only suggest the presence of a prodromal phase in MS, but also that this phase is associated with neurodegeneration,” wrote the investigators.
The study’s well-defined population helped to minimize selection bias, and the blinded, randomized method of analyzing the serum samples eliminated artifactual differences in serum NfL concentrations. But the small sample size precluded analyses that could have influenced clinical practice, wrote Dr. Bjornevik and colleagues. For example, the researchers could not evaluate distinct cutoffs in serum NfL level that could mark the beginning of the prodromal phase of MS. Nor could they determine whether presymptomatic serum NfL levels varied with age at clinical onset, sex, or race. The small number of women in the sample was another limitation of the study.
The Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke funded the study. Several of the investigators received fees from various drug companies that were unrelated to the study, and one researcher received grants from the National Institutes of Health during the study.
SOURCE: Bjornevik K et al. JAMA Neurol. 2020;77(1):58-64.
FROM JAMA NEUROLOGY
The power of an odd couple
The time has come for good men and women to unite and rise up against a common foe. For too long nurses and doctors have labored under the tyranny of a dictator who claimed to help them provide high-quality care for their patients while at the same time cutting their paperwork to nil. But like most autocrats he failed to engage his subjects in a meaningful dialogue as each new version of his promised improvements rolled off the drawing board. When the caregivers were slow to adopt these new nonsystems he offered them financial incentives and issued threats to their survival. Although they were warned that there might be uncomfortable adjustment periods, the caregivers were promised that the steep learning curves would level out and their professional lives would again be valued and productive.
Of course, the dictator is not a single person but a motley and disorganized conglomerate of user- and patient-unfriendly electronic health record nonsystems. Ask almost any nurse or physician for her feelings about computer-based medical record systems, and you will hear tales of long hours, disengagement, and frustration. Caregivers are unhappy at all levels, and patients have grown tired of their nurses and physicians spending most of their time looking at computer screens.
You certainly have heard this all before. But you are hearing it in hospital hallways and grocery store checkout lines as a low rumble of discontent emerging from separate individuals, not as a well-articulated and widely distributed voice of physicians as a group. To some extent this relative silence is because there is no such group, at least not in same mold as a labor union. The term “labor union” may make you uncomfortable. But given the current climate in medicine, unionizing may be the best and only way to effect change.
But organizing to effect change in the workplace isn’t part of the physician genome. In the 1960s, a group of house officers in Boston engaged in a heal-in to successfully improve their salaries and working conditions. But over the ensuing half century physicians have remained tragically silent in the face of a changing workplace landscape in which they have gone from being independent owner operators in control of their destinies to becoming employees feeling powerless to improve their working conditions. This perceived impotence has escalated in the face of the challenge posed by the introduction of dysfunctional EHRs.
Ironically, a solution is at almost every physician’s elbow. In a recent New York Times opinion piece Theresa Brown and Stephen Bergman acknowledge that physicians don’t seem prepared to mount a meaningful response to the challenge to the failed promise of EHRs (“Doctors, Nurses and the Paperwork Crisis That Could Unite Them,” Dec. 31, 2019). They point out that, over the last half century, physicians have remained isolated on the sidelines, finding just enough voice to grumble. Nurses have in a variety of situations organized to effect change in their working conditions – in some cases by forming labor unions.
The authors of this op-ed piece, a physician and a nurse, make a strong argument that the time has come for nurses and doctors shake off the shackles of their stereotypic roles and join in creating a loud, forceful, and effective voice to demand a working environment in which the computer functions as an asset and no longer as the terrible burden it has become. Neither group has the power to do it alone, but together they may be able to turn the tide. For physicians it will probably mean venturing several steps outside of their comfort zone. But working shoulder to shoulder with nurses may provide the courage to speak out.
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.” Email him at pdnews@mdedge.com.
The time has come for good men and women to unite and rise up against a common foe. For too long nurses and doctors have labored under the tyranny of a dictator who claimed to help them provide high-quality care for their patients while at the same time cutting their paperwork to nil. But like most autocrats he failed to engage his subjects in a meaningful dialogue as each new version of his promised improvements rolled off the drawing board. When the caregivers were slow to adopt these new nonsystems he offered them financial incentives and issued threats to their survival. Although they were warned that there might be uncomfortable adjustment periods, the caregivers were promised that the steep learning curves would level out and their professional lives would again be valued and productive.
Of course, the dictator is not a single person but a motley and disorganized conglomerate of user- and patient-unfriendly electronic health record nonsystems. Ask almost any nurse or physician for her feelings about computer-based medical record systems, and you will hear tales of long hours, disengagement, and frustration. Caregivers are unhappy at all levels, and patients have grown tired of their nurses and physicians spending most of their time looking at computer screens.
You certainly have heard this all before. But you are hearing it in hospital hallways and grocery store checkout lines as a low rumble of discontent emerging from separate individuals, not as a well-articulated and widely distributed voice of physicians as a group. To some extent this relative silence is because there is no such group, at least not in same mold as a labor union. The term “labor union” may make you uncomfortable. But given the current climate in medicine, unionizing may be the best and only way to effect change.
But organizing to effect change in the workplace isn’t part of the physician genome. In the 1960s, a group of house officers in Boston engaged in a heal-in to successfully improve their salaries and working conditions. But over the ensuing half century physicians have remained tragically silent in the face of a changing workplace landscape in which they have gone from being independent owner operators in control of their destinies to becoming employees feeling powerless to improve their working conditions. This perceived impotence has escalated in the face of the challenge posed by the introduction of dysfunctional EHRs.
Ironically, a solution is at almost every physician’s elbow. In a recent New York Times opinion piece Theresa Brown and Stephen Bergman acknowledge that physicians don’t seem prepared to mount a meaningful response to the challenge to the failed promise of EHRs (“Doctors, Nurses and the Paperwork Crisis That Could Unite Them,” Dec. 31, 2019). They point out that, over the last half century, physicians have remained isolated on the sidelines, finding just enough voice to grumble. Nurses have in a variety of situations organized to effect change in their working conditions – in some cases by forming labor unions.
The authors of this op-ed piece, a physician and a nurse, make a strong argument that the time has come for nurses and doctors shake off the shackles of their stereotypic roles and join in creating a loud, forceful, and effective voice to demand a working environment in which the computer functions as an asset and no longer as the terrible burden it has become. Neither group has the power to do it alone, but together they may be able to turn the tide. For physicians it will probably mean venturing several steps outside of their comfort zone. But working shoulder to shoulder with nurses may provide the courage to speak out.
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.” Email him at pdnews@mdedge.com.
The time has come for good men and women to unite and rise up against a common foe. For too long nurses and doctors have labored under the tyranny of a dictator who claimed to help them provide high-quality care for their patients while at the same time cutting their paperwork to nil. But like most autocrats he failed to engage his subjects in a meaningful dialogue as each new version of his promised improvements rolled off the drawing board. When the caregivers were slow to adopt these new nonsystems he offered them financial incentives and issued threats to their survival. Although they were warned that there might be uncomfortable adjustment periods, the caregivers were promised that the steep learning curves would level out and their professional lives would again be valued and productive.
Of course, the dictator is not a single person but a motley and disorganized conglomerate of user- and patient-unfriendly electronic health record nonsystems. Ask almost any nurse or physician for her feelings about computer-based medical record systems, and you will hear tales of long hours, disengagement, and frustration. Caregivers are unhappy at all levels, and patients have grown tired of their nurses and physicians spending most of their time looking at computer screens.
You certainly have heard this all before. But you are hearing it in hospital hallways and grocery store checkout lines as a low rumble of discontent emerging from separate individuals, not as a well-articulated and widely distributed voice of physicians as a group. To some extent this relative silence is because there is no such group, at least not in same mold as a labor union. The term “labor union” may make you uncomfortable. But given the current climate in medicine, unionizing may be the best and only way to effect change.
But organizing to effect change in the workplace isn’t part of the physician genome. In the 1960s, a group of house officers in Boston engaged in a heal-in to successfully improve their salaries and working conditions. But over the ensuing half century physicians have remained tragically silent in the face of a changing workplace landscape in which they have gone from being independent owner operators in control of their destinies to becoming employees feeling powerless to improve their working conditions. This perceived impotence has escalated in the face of the challenge posed by the introduction of dysfunctional EHRs.
Ironically, a solution is at almost every physician’s elbow. In a recent New York Times opinion piece Theresa Brown and Stephen Bergman acknowledge that physicians don’t seem prepared to mount a meaningful response to the challenge to the failed promise of EHRs (“Doctors, Nurses and the Paperwork Crisis That Could Unite Them,” Dec. 31, 2019). They point out that, over the last half century, physicians have remained isolated on the sidelines, finding just enough voice to grumble. Nurses have in a variety of situations organized to effect change in their working conditions – in some cases by forming labor unions.
The authors of this op-ed piece, a physician and a nurse, make a strong argument that the time has come for nurses and doctors shake off the shackles of their stereotypic roles and join in creating a loud, forceful, and effective voice to demand a working environment in which the computer functions as an asset and no longer as the terrible burden it has become. Neither group has the power to do it alone, but together they may be able to turn the tide. For physicians it will probably mean venturing several steps outside of their comfort zone. But working shoulder to shoulder with nurses may provide the courage to speak out.
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.” Email him at pdnews@mdedge.com.
FDA issues public health warning recommending against cesium salt usage
The Food and Drug Administration has issued a public health alert warning consumers to avoid the use of dietary supplements that contain cesium chloride or any other cesium salt because of significant safety risks.
Cesium salts are sometimes advertised as an alternative treatment for cancer, the FDA said in the announcement, but these salts have never proved to be safe or effective at treating cancer or any other disease. Clinical case reports and nonclinical trials have shown that cesium salts are associated with a variety of adverse events, including cardiac arrhythmias, hypokalemia, seizures, syncope, and death.
The FDA warned health care providers that cesium salts presented a significant safety risk in compounding drugs in July 2018.
Health care providers should not recommend dietary supplements containing cesium salts to their patients, the FDA said, and if a patient experiences an adverse event while taking a supplement containing cesium salt, the event should be reported to the agency.
While there are few dietary supplements on the market that contain cesium salt, consumers should be aware of the risks and avoid these products. The FDA noted that “if claims sound too good to be true, they probably are.”
The Food and Drug Administration has issued a public health alert warning consumers to avoid the use of dietary supplements that contain cesium chloride or any other cesium salt because of significant safety risks.
Cesium salts are sometimes advertised as an alternative treatment for cancer, the FDA said in the announcement, but these salts have never proved to be safe or effective at treating cancer or any other disease. Clinical case reports and nonclinical trials have shown that cesium salts are associated with a variety of adverse events, including cardiac arrhythmias, hypokalemia, seizures, syncope, and death.
The FDA warned health care providers that cesium salts presented a significant safety risk in compounding drugs in July 2018.
Health care providers should not recommend dietary supplements containing cesium salts to their patients, the FDA said, and if a patient experiences an adverse event while taking a supplement containing cesium salt, the event should be reported to the agency.
While there are few dietary supplements on the market that contain cesium salt, consumers should be aware of the risks and avoid these products. The FDA noted that “if claims sound too good to be true, they probably are.”
The Food and Drug Administration has issued a public health alert warning consumers to avoid the use of dietary supplements that contain cesium chloride or any other cesium salt because of significant safety risks.
Cesium salts are sometimes advertised as an alternative treatment for cancer, the FDA said in the announcement, but these salts have never proved to be safe or effective at treating cancer or any other disease. Clinical case reports and nonclinical trials have shown that cesium salts are associated with a variety of adverse events, including cardiac arrhythmias, hypokalemia, seizures, syncope, and death.
The FDA warned health care providers that cesium salts presented a significant safety risk in compounding drugs in July 2018.
Health care providers should not recommend dietary supplements containing cesium salts to their patients, the FDA said, and if a patient experiences an adverse event while taking a supplement containing cesium salt, the event should be reported to the agency.
While there are few dietary supplements on the market that contain cesium salt, consumers should be aware of the risks and avoid these products. The FDA noted that “if claims sound too good to be true, they probably are.”
How much exercise is needed for maximum heart benefit?
SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’m not telling you to run marathons. said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.
He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.
One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).
“That’s a very impressive result for modest physical activity,” the cardiologist commented.
Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.
“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.
In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).
All activity counts
Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).
Don’t just sit there – stand!
The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).
And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).
“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
Get strong
Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).
“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
For the time constrained
Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).
Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).
The same principle is applicable to the nonathlete interested in physical activity for heart health.
“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
High-volume exercise is safe, even with high coronary calcium
A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).
Cardiac rehab
Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.
“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”
A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).
“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.
Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
Yoga
For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.
Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.
SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’m not telling you to run marathons. said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.
He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.
One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).
“That’s a very impressive result for modest physical activity,” the cardiologist commented.
Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.
“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.
In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).
All activity counts
Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).
Don’t just sit there – stand!
The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).
And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).
“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
Get strong
Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).
“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
For the time constrained
Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).
Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).
The same principle is applicable to the nonathlete interested in physical activity for heart health.
“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
High-volume exercise is safe, even with high coronary calcium
A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).
Cardiac rehab
Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.
“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”
A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).
“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.
Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
Yoga
For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.
Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.
SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’m not telling you to run marathons. said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.
He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.
One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).
“That’s a very impressive result for modest physical activity,” the cardiologist commented.
Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.
“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.
In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).
All activity counts
Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).
Don’t just sit there – stand!
The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).
And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).
“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
Get strong
Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).
“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
For the time constrained
Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).
Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).
The same principle is applicable to the nonathlete interested in physical activity for heart health.
“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
High-volume exercise is safe, even with high coronary calcium
A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).
Cardiac rehab
Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.
“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”
A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).
“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.
Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
Yoga
For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.
Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.
EXPERT ANALYSIS FROM ACC SNOWMASS 2020