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FDA approves first generics of pregabalin
The generics were approved to manage neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia, as well as neuropathic pain associated with spinal cord injury, and as an adjunctive therapy for the treatment of partial-onset seizures in patients aged 17 years and older. Approvals were granted to Alembic Pharmaceuticals, Alkem Laboratories, Amneal Pharmaceuticals, Dr. Reddy’s Laboratories, InvaGen Pharmaceuticals, MSN Laboratories, Rising Pharmaceuticals, Sciegen Pharmaceuticals, and Teva Pharmaceuticals.
The most common adverse events associated with pregabalin include dizziness, somnolence, dry mouth, swelling, blurred vision, weight gain, and abnormal thinking. Pregabalin must be dispensed with a patient Medication Guide containing a guide to the drug’s uses and risks. Angioedema, hypersensitivity reactions, increased seizure frequency, increased suicidal behavior, and peripheral edema are all possible.
“Today’s approval of the first generics for pregabalin, a widely used medication, is another example of the FDA’s long-standing commitment to advance patient access to lower-cost, high-quality generic medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release.
The generics were approved to manage neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia, as well as neuropathic pain associated with spinal cord injury, and as an adjunctive therapy for the treatment of partial-onset seizures in patients aged 17 years and older. Approvals were granted to Alembic Pharmaceuticals, Alkem Laboratories, Amneal Pharmaceuticals, Dr. Reddy’s Laboratories, InvaGen Pharmaceuticals, MSN Laboratories, Rising Pharmaceuticals, Sciegen Pharmaceuticals, and Teva Pharmaceuticals.
The most common adverse events associated with pregabalin include dizziness, somnolence, dry mouth, swelling, blurred vision, weight gain, and abnormal thinking. Pregabalin must be dispensed with a patient Medication Guide containing a guide to the drug’s uses and risks. Angioedema, hypersensitivity reactions, increased seizure frequency, increased suicidal behavior, and peripheral edema are all possible.
“Today’s approval of the first generics for pregabalin, a widely used medication, is another example of the FDA’s long-standing commitment to advance patient access to lower-cost, high-quality generic medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release.
The generics were approved to manage neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia, as well as neuropathic pain associated with spinal cord injury, and as an adjunctive therapy for the treatment of partial-onset seizures in patients aged 17 years and older. Approvals were granted to Alembic Pharmaceuticals, Alkem Laboratories, Amneal Pharmaceuticals, Dr. Reddy’s Laboratories, InvaGen Pharmaceuticals, MSN Laboratories, Rising Pharmaceuticals, Sciegen Pharmaceuticals, and Teva Pharmaceuticals.
The most common adverse events associated with pregabalin include dizziness, somnolence, dry mouth, swelling, blurred vision, weight gain, and abnormal thinking. Pregabalin must be dispensed with a patient Medication Guide containing a guide to the drug’s uses and risks. Angioedema, hypersensitivity reactions, increased seizure frequency, increased suicidal behavior, and peripheral edema are all possible.
“Today’s approval of the first generics for pregabalin, a widely used medication, is another example of the FDA’s long-standing commitment to advance patient access to lower-cost, high-quality generic medicines,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release.
Medication overuse prevalent among U.S. migraine patients
PHILADELPHIA – according to findings from an analysis of 16,789 people with migraine.
About 18% of the people identified with migraine in the study cohort reported a drug consumption pattern that met the prespecified definition of “medication overuse,” Todd J. Schwedt, MD, and his associates reported in a poster at the annual meeting of the American Headache Society. Supplying each migraine patient with a “comprehensive treatment plan” along with “improved acute treatment options ... may help reduce the prevalence and associated burden of medication overuse,” said Dr. Schwedt, a professor of neurology at the Mayo Clinic in Phoenix. The analysis also showed that medication overuse (MO) significantly linked with several markers of worse clinical status.
If patients have “an effective preventive treatment that reduces headaches and migraine attacks then they will, in general, use less acute medications. Many people with migraine never even get diagnosed, and patients who qualify for preventive treatment never get it,” Dr. Schwedt noted in an interview. He described a comprehensive treatment plan as a management strategy that includes lifestyle modifications, a migraine-prevention agent, and the availability of an effective acute treatment for a patient to use when a migraine strikes along with clear instructions on how to appropriately self-administer the medication. Only a small fraction of U.S. migraine patients currently receive this complete package of care, he said.
The analysis he ran used data collected in the CaMEO (Chronic Migraine Epidemiology and Outcomes) study, which used an Internet-based survey to collect data from a representative 58,000-person sample of U.S. residents, which included 16,789 who met the applied migraine definition, with 91% having fewer than 15 headaches/month and the remaining 9% with a monthly headache average of 15 or more (Cephalagia. 2015 Jun;35[7]:563-78).
The researchers defined overuse of a single medication as use 15 times or more a month of an NSAID, aspirin, or acetaminophen, or use at least 10 times a month of a triptan, ergotamine, or opioid. They also had a prespecified definition of multidrug overuse that applied similar monthly thresholds. The patients averaged about 41 years old, three-quarters were women, and 85% were white. Patients identified with MO had a substantially higher rate of headaches per month: an average of nearly 12, compared with an average of about 4 per month among those without overuse. Almost two-thirds of the patients with MO reported having been formally diagnosed as having migraine headaches, compared with 41% of those without overuse.
Among the 13,749 patients (82%) on some headache medication, 67% were on a nonopioid analgesic, including 61% on an NSAID. MO among all people on nonopioid analgesics was 16%, and 12% among those who used NSAIDS. The most overused drug in this subgroup were combination analgesics, overused by 18% of those taking these drugs.
The drug class with the biggest MO rate was opioids, used by 12% of those on any medication and overused by 22% of those taking an opioid. Triptans were taken by 11%, with an MO rate of 11% among these users. Ergotamine was used by less than 1% of all patients, and those taking this drug tallied a 19% MO rate.
“Opioids were the class most often overused, more evidence that opioids should rarely if ever be used to treat migraine,” Dr. Schwedt said.
The analysis also showed that patients who had MO has multiple signs of worse clinical status. Patients with MO had a significantly higher rate of diagnosed depression, 54%, compared with 28% in those without MO; anxiety, 49% compared with 26%; migraine-associated disability, 73% compared with 32%; migraine-associated functional impairment (Migraine Interictal Burden Scale), 65% compared with 32%; and emergency department or urgent care use, 13% compared with 3%. All these between-group differences were statistically significant.
CaMEO was funded by Allergan. Dr. Schwedt has been a consultant to Allergan, and also to Alder, Amgen, Cipla, Dr. Reddy’s, Ipsen, Lilly, Novartis, and Teva. He has stock ownership in Aural Analytics, Nocira, and Second Opinion, and he has received research funding from Amgen.
SOURCE: Schwedt TJ et al. Headache. 2019 June;59[S1]:83-4, Abstract P92.
PHILADELPHIA – according to findings from an analysis of 16,789 people with migraine.
About 18% of the people identified with migraine in the study cohort reported a drug consumption pattern that met the prespecified definition of “medication overuse,” Todd J. Schwedt, MD, and his associates reported in a poster at the annual meeting of the American Headache Society. Supplying each migraine patient with a “comprehensive treatment plan” along with “improved acute treatment options ... may help reduce the prevalence and associated burden of medication overuse,” said Dr. Schwedt, a professor of neurology at the Mayo Clinic in Phoenix. The analysis also showed that medication overuse (MO) significantly linked with several markers of worse clinical status.
If patients have “an effective preventive treatment that reduces headaches and migraine attacks then they will, in general, use less acute medications. Many people with migraine never even get diagnosed, and patients who qualify for preventive treatment never get it,” Dr. Schwedt noted in an interview. He described a comprehensive treatment plan as a management strategy that includes lifestyle modifications, a migraine-prevention agent, and the availability of an effective acute treatment for a patient to use when a migraine strikes along with clear instructions on how to appropriately self-administer the medication. Only a small fraction of U.S. migraine patients currently receive this complete package of care, he said.
The analysis he ran used data collected in the CaMEO (Chronic Migraine Epidemiology and Outcomes) study, which used an Internet-based survey to collect data from a representative 58,000-person sample of U.S. residents, which included 16,789 who met the applied migraine definition, with 91% having fewer than 15 headaches/month and the remaining 9% with a monthly headache average of 15 or more (Cephalagia. 2015 Jun;35[7]:563-78).
The researchers defined overuse of a single medication as use 15 times or more a month of an NSAID, aspirin, or acetaminophen, or use at least 10 times a month of a triptan, ergotamine, or opioid. They also had a prespecified definition of multidrug overuse that applied similar monthly thresholds. The patients averaged about 41 years old, three-quarters were women, and 85% were white. Patients identified with MO had a substantially higher rate of headaches per month: an average of nearly 12, compared with an average of about 4 per month among those without overuse. Almost two-thirds of the patients with MO reported having been formally diagnosed as having migraine headaches, compared with 41% of those without overuse.
Among the 13,749 patients (82%) on some headache medication, 67% were on a nonopioid analgesic, including 61% on an NSAID. MO among all people on nonopioid analgesics was 16%, and 12% among those who used NSAIDS. The most overused drug in this subgroup were combination analgesics, overused by 18% of those taking these drugs.
The drug class with the biggest MO rate was opioids, used by 12% of those on any medication and overused by 22% of those taking an opioid. Triptans were taken by 11%, with an MO rate of 11% among these users. Ergotamine was used by less than 1% of all patients, and those taking this drug tallied a 19% MO rate.
“Opioids were the class most often overused, more evidence that opioids should rarely if ever be used to treat migraine,” Dr. Schwedt said.
The analysis also showed that patients who had MO has multiple signs of worse clinical status. Patients with MO had a significantly higher rate of diagnosed depression, 54%, compared with 28% in those without MO; anxiety, 49% compared with 26%; migraine-associated disability, 73% compared with 32%; migraine-associated functional impairment (Migraine Interictal Burden Scale), 65% compared with 32%; and emergency department or urgent care use, 13% compared with 3%. All these between-group differences were statistically significant.
CaMEO was funded by Allergan. Dr. Schwedt has been a consultant to Allergan, and also to Alder, Amgen, Cipla, Dr. Reddy’s, Ipsen, Lilly, Novartis, and Teva. He has stock ownership in Aural Analytics, Nocira, and Second Opinion, and he has received research funding from Amgen.
SOURCE: Schwedt TJ et al. Headache. 2019 June;59[S1]:83-4, Abstract P92.
PHILADELPHIA – according to findings from an analysis of 16,789 people with migraine.
About 18% of the people identified with migraine in the study cohort reported a drug consumption pattern that met the prespecified definition of “medication overuse,” Todd J. Schwedt, MD, and his associates reported in a poster at the annual meeting of the American Headache Society. Supplying each migraine patient with a “comprehensive treatment plan” along with “improved acute treatment options ... may help reduce the prevalence and associated burden of medication overuse,” said Dr. Schwedt, a professor of neurology at the Mayo Clinic in Phoenix. The analysis also showed that medication overuse (MO) significantly linked with several markers of worse clinical status.
If patients have “an effective preventive treatment that reduces headaches and migraine attacks then they will, in general, use less acute medications. Many people with migraine never even get diagnosed, and patients who qualify for preventive treatment never get it,” Dr. Schwedt noted in an interview. He described a comprehensive treatment plan as a management strategy that includes lifestyle modifications, a migraine-prevention agent, and the availability of an effective acute treatment for a patient to use when a migraine strikes along with clear instructions on how to appropriately self-administer the medication. Only a small fraction of U.S. migraine patients currently receive this complete package of care, he said.
The analysis he ran used data collected in the CaMEO (Chronic Migraine Epidemiology and Outcomes) study, which used an Internet-based survey to collect data from a representative 58,000-person sample of U.S. residents, which included 16,789 who met the applied migraine definition, with 91% having fewer than 15 headaches/month and the remaining 9% with a monthly headache average of 15 or more (Cephalagia. 2015 Jun;35[7]:563-78).
The researchers defined overuse of a single medication as use 15 times or more a month of an NSAID, aspirin, or acetaminophen, or use at least 10 times a month of a triptan, ergotamine, or opioid. They also had a prespecified definition of multidrug overuse that applied similar monthly thresholds. The patients averaged about 41 years old, three-quarters were women, and 85% were white. Patients identified with MO had a substantially higher rate of headaches per month: an average of nearly 12, compared with an average of about 4 per month among those without overuse. Almost two-thirds of the patients with MO reported having been formally diagnosed as having migraine headaches, compared with 41% of those without overuse.
Among the 13,749 patients (82%) on some headache medication, 67% were on a nonopioid analgesic, including 61% on an NSAID. MO among all people on nonopioid analgesics was 16%, and 12% among those who used NSAIDS. The most overused drug in this subgroup were combination analgesics, overused by 18% of those taking these drugs.
The drug class with the biggest MO rate was opioids, used by 12% of those on any medication and overused by 22% of those taking an opioid. Triptans were taken by 11%, with an MO rate of 11% among these users. Ergotamine was used by less than 1% of all patients, and those taking this drug tallied a 19% MO rate.
“Opioids were the class most often overused, more evidence that opioids should rarely if ever be used to treat migraine,” Dr. Schwedt said.
The analysis also showed that patients who had MO has multiple signs of worse clinical status. Patients with MO had a significantly higher rate of diagnosed depression, 54%, compared with 28% in those without MO; anxiety, 49% compared with 26%; migraine-associated disability, 73% compared with 32%; migraine-associated functional impairment (Migraine Interictal Burden Scale), 65% compared with 32%; and emergency department or urgent care use, 13% compared with 3%. All these between-group differences were statistically significant.
CaMEO was funded by Allergan. Dr. Schwedt has been a consultant to Allergan, and also to Alder, Amgen, Cipla, Dr. Reddy’s, Ipsen, Lilly, Novartis, and Teva. He has stock ownership in Aural Analytics, Nocira, and Second Opinion, and he has received research funding from Amgen.
SOURCE: Schwedt TJ et al. Headache. 2019 June;59[S1]:83-4, Abstract P92.
REPORTING FROM AHS 2019
Large genetic cohort supports NfL as Alzheimer’s biomarker
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.
REPORTING FROM AAIC 2019
When’s the right time to use dementia as a diagnosis?
Is dementia a diagnosis?
I use it myself, although I find that some neurologists consider this blasphemy.
The problem is that there aren’t many terms to cover cognitive disorders beyond mild cognitive impairment (MCI). Phrases like “cortical degeneration” and “frontotemporal disorder” are difficult for families and patients. They aren’t medically trained and want something easy to write down.
“Alzheimer’s,” or – as one patient’s family member says, “the A-word” – is often more accurate, but has stigma attached to it that many don’t want, especially at a first visit. It also immediately conjures up feared images of nursing homes, wheelchairs, and bed-bound people.
So I use a diagnosis of dementia with many families, at least initially. Since, with occasional exceptions, we tend to perform a work-up of all cognitive disorders the same way, I don’t have a problem with using a more generic blanket term. As I sometimes try to simplify things, I’ll say, “It’s like squares and rectangles. Alzheimer’s disease is a dementia, but not all dementias are Alzheimer’s disease.”
I don’t do this to avoid confrontation, be dishonest, mislead patients and families, or avoid telling the truth. I still make it very clear that this is a progressive neurologic illness that will cause worsening cognitive problems over time. But many times families aren’t ready for “the A-word” early on, or there’s a concern the patient will harm themselves while they still have that capacity. Sometimes, it’s better to use a different phrase.
It may all be semantics, but on a personal level, a word can make a huge difference.
So I say dementia. In spite of some editorials I’ve seen saying we should retire the phrase, I argue that in many circumstances it’s still valid and useful.
It may not be a final, or even specific, diagnosis, but it is often the best and most socially acceptable one at the beginning of the doctor-patient-family relationship. When you’re trying to build rapport with them, that’s equally critical when you know what’s to come down the road.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Is dementia a diagnosis?
I use it myself, although I find that some neurologists consider this blasphemy.
The problem is that there aren’t many terms to cover cognitive disorders beyond mild cognitive impairment (MCI). Phrases like “cortical degeneration” and “frontotemporal disorder” are difficult for families and patients. They aren’t medically trained and want something easy to write down.
“Alzheimer’s,” or – as one patient’s family member says, “the A-word” – is often more accurate, but has stigma attached to it that many don’t want, especially at a first visit. It also immediately conjures up feared images of nursing homes, wheelchairs, and bed-bound people.
So I use a diagnosis of dementia with many families, at least initially. Since, with occasional exceptions, we tend to perform a work-up of all cognitive disorders the same way, I don’t have a problem with using a more generic blanket term. As I sometimes try to simplify things, I’ll say, “It’s like squares and rectangles. Alzheimer’s disease is a dementia, but not all dementias are Alzheimer’s disease.”
I don’t do this to avoid confrontation, be dishonest, mislead patients and families, or avoid telling the truth. I still make it very clear that this is a progressive neurologic illness that will cause worsening cognitive problems over time. But many times families aren’t ready for “the A-word” early on, or there’s a concern the patient will harm themselves while they still have that capacity. Sometimes, it’s better to use a different phrase.
It may all be semantics, but on a personal level, a word can make a huge difference.
So I say dementia. In spite of some editorials I’ve seen saying we should retire the phrase, I argue that in many circumstances it’s still valid and useful.
It may not be a final, or even specific, diagnosis, but it is often the best and most socially acceptable one at the beginning of the doctor-patient-family relationship. When you’re trying to build rapport with them, that’s equally critical when you know what’s to come down the road.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Is dementia a diagnosis?
I use it myself, although I find that some neurologists consider this blasphemy.
The problem is that there aren’t many terms to cover cognitive disorders beyond mild cognitive impairment (MCI). Phrases like “cortical degeneration” and “frontotemporal disorder” are difficult for families and patients. They aren’t medically trained and want something easy to write down.
“Alzheimer’s,” or – as one patient’s family member says, “the A-word” – is often more accurate, but has stigma attached to it that many don’t want, especially at a first visit. It also immediately conjures up feared images of nursing homes, wheelchairs, and bed-bound people.
So I use a diagnosis of dementia with many families, at least initially. Since, with occasional exceptions, we tend to perform a work-up of all cognitive disorders the same way, I don’t have a problem with using a more generic blanket term. As I sometimes try to simplify things, I’ll say, “It’s like squares and rectangles. Alzheimer’s disease is a dementia, but not all dementias are Alzheimer’s disease.”
I don’t do this to avoid confrontation, be dishonest, mislead patients and families, or avoid telling the truth. I still make it very clear that this is a progressive neurologic illness that will cause worsening cognitive problems over time. But many times families aren’t ready for “the A-word” early on, or there’s a concern the patient will harm themselves while they still have that capacity. Sometimes, it’s better to use a different phrase.
It may all be semantics, but on a personal level, a word can make a huge difference.
So I say dementia. In spite of some editorials I’ve seen saying we should retire the phrase, I argue that in many circumstances it’s still valid and useful.
It may not be a final, or even specific, diagnosis, but it is often the best and most socially acceptable one at the beginning of the doctor-patient-family relationship. When you’re trying to build rapport with them, that’s equally critical when you know what’s to come down the road.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Surprise medical billing legislation advances to the House floor
Legislation to end surprise medical billing cleared the House Energy and Commerce Committee and is headed to the House floor, but it contains a somewhat controversial arbitration mechanism that allows physicians and hospitals to seek higher payments within 30 days.
The bill, which was tacked on to H.R. 2328, passed the committee by voice vote on July 17. The amendment on arbitration also passed the committee via voice vote.
“Our most important task today is to protect patients from the unreasonable and unacceptable practice of surprise billing,” Rep. Frank Pallone (D-N.J.), chairman of the Energy and Commerce Committee, said just prior to the votes being taken by the committee. “Under the [legislation], providers would no longer be able to balance bill patients for out-of-network emergency services or for scheduled services from providers the patient was not aware would be in their treatment.”
Out-of-network providers would receive a benchmark payment for the services they provided under the legislation.
Rep. Pallone described the legislation as taking patients out of the middle of disputes between payers and providers.
He went on to describe the arbitration amendment, introduced by Rep. Raul Ruiz, MD, (D.-Calif.) and Rep. Larry Bucshon, MD, (R-Ind.), as creating an independent dispute resolution process for physicians and hospitals to file a claim in the event that they don’t think they were adequately paid for their services.
“The amendment would allow providers to have 30 days within which to file an appeal of the benchmark payment with the insurer,” Rep. Pallone said. “The insurer would then have 30 days to adjudicate the appeal, after which the provider could initiate independent dispute resolution.”
The amendment limits appeals to extenuating circumstances so that only complex cases would qualify, and it limits the variables that can be considered during arbitration to the quality of care that was provided to the patient, according to Rep. Pallone.
“Most importantly to me, it bars arbitrators from considering billed charges, which are unilaterally set by providers,” Rep. Pallone said. “Provider charges are often double or triple Medicare rates, and in some cases for some large physician staffing companies, it is around 500% of Medicare rates. If Congress sends this signal to arbiters that provider charges are to be considered, we would be creating a significantly higher standard for payment, decreasing incentives for providers to be in network and putting upward pressure on health care premiums.”
Rep. Michael Burgess, MD, (R-Texas) praised the inclusion of the arbitration amendment and said the surprise billing legislation would not be able to be passed without its inclusion.
Rep. Janice Schakowsky (D-Ill.) offered a dissenting voice to the amendment. “Arbitration, in my view, which is used as the backstop, will not lower the health care costs,” she said. “Arbitration actually comes with additional administrative costs and complexities, which could then be passed on to consumers in the form of higher premiums. Even as a backstop, I think that binding arbitration leaves a public interest, public health decision, up to an unaccountable private decision maker, and I don’t think that is a very progressive way to be dealing with the issue of pricing.”
The American Medical Association praised the inclusion of an appeals process for resolving out-of-network payment disputes. “This addition represents progress,” Patrice Harris, MD, president of the AMA, said in a statement. “While we continue to have concerns with elements of the legislation, we remain committed to working with all committee members to secure further improvements to protect patients, preserve access, and foster fair payments for out-of-network services.”
America’s Health Insurance Plans, which represents health insurers, voiced its opposition to the arbitration provision. “We strongly oppose the inclusion of arbitration because it does not solve the problem of surprise medical bills,” AHIP President and CEO Matt Eyles said in a statement. “It increases the financial burden on everyone with coverage, increasing patient premiums and driving up the cost of health care. The arbitration proposal allows private-equity firms and certain providers to price gouge patients and then shifts the final decision to a ‘third party.’ This process introduces new bureaucracy and red tape into the system, with costs to hardworking taxpayers exceeding $1 billion.”
Benedic Ippolito, research fellow in economic policy studies at the American Economic Institute, further criticized the use of arbitration in this process.
“This concept that arbitration is a backstop doesn’t really make a lot of sense,” he said during a July 17 panel discussion hosted by the Bipartisan Policy Center on surprise billing. “The arbiter has to do the same thing any sort of rate setter has to do.” He noted that if they are doing “baseball-style” arbitration, they have to choose between two offers placed in front of the arbiter, based on what the arbiter believes to be closer to whatever the reasonable rate is.
This process will eventually lead to either a system that favors the payer, the provider, or ends up being exactly what the benchmark is that has been set. “If it is better for one or the other, somebody is going to have an incentive to just trigger this thing the whole time,” Mr. Ippolito said.
Loren Adler, associate director of the USC-Brookings Schaeffer Initiative for Health Policy, said during the panel discussion that “there is no policy reason to have arbitration. There is nothing it adds for policy value.”
Mr. Adler called the arbitration amendment “a provider giveaway bill,” adding that if there has to be an arbitration option, it should have a very high threshold to be triggered.
Legislation to end surprise medical billing cleared the House Energy and Commerce Committee and is headed to the House floor, but it contains a somewhat controversial arbitration mechanism that allows physicians and hospitals to seek higher payments within 30 days.
The bill, which was tacked on to H.R. 2328, passed the committee by voice vote on July 17. The amendment on arbitration also passed the committee via voice vote.
“Our most important task today is to protect patients from the unreasonable and unacceptable practice of surprise billing,” Rep. Frank Pallone (D-N.J.), chairman of the Energy and Commerce Committee, said just prior to the votes being taken by the committee. “Under the [legislation], providers would no longer be able to balance bill patients for out-of-network emergency services or for scheduled services from providers the patient was not aware would be in their treatment.”
Out-of-network providers would receive a benchmark payment for the services they provided under the legislation.
Rep. Pallone described the legislation as taking patients out of the middle of disputes between payers and providers.
He went on to describe the arbitration amendment, introduced by Rep. Raul Ruiz, MD, (D.-Calif.) and Rep. Larry Bucshon, MD, (R-Ind.), as creating an independent dispute resolution process for physicians and hospitals to file a claim in the event that they don’t think they were adequately paid for their services.
“The amendment would allow providers to have 30 days within which to file an appeal of the benchmark payment with the insurer,” Rep. Pallone said. “The insurer would then have 30 days to adjudicate the appeal, after which the provider could initiate independent dispute resolution.”
The amendment limits appeals to extenuating circumstances so that only complex cases would qualify, and it limits the variables that can be considered during arbitration to the quality of care that was provided to the patient, according to Rep. Pallone.
“Most importantly to me, it bars arbitrators from considering billed charges, which are unilaterally set by providers,” Rep. Pallone said. “Provider charges are often double or triple Medicare rates, and in some cases for some large physician staffing companies, it is around 500% of Medicare rates. If Congress sends this signal to arbiters that provider charges are to be considered, we would be creating a significantly higher standard for payment, decreasing incentives for providers to be in network and putting upward pressure on health care premiums.”
Rep. Michael Burgess, MD, (R-Texas) praised the inclusion of the arbitration amendment and said the surprise billing legislation would not be able to be passed without its inclusion.
Rep. Janice Schakowsky (D-Ill.) offered a dissenting voice to the amendment. “Arbitration, in my view, which is used as the backstop, will not lower the health care costs,” she said. “Arbitration actually comes with additional administrative costs and complexities, which could then be passed on to consumers in the form of higher premiums. Even as a backstop, I think that binding arbitration leaves a public interest, public health decision, up to an unaccountable private decision maker, and I don’t think that is a very progressive way to be dealing with the issue of pricing.”
The American Medical Association praised the inclusion of an appeals process for resolving out-of-network payment disputes. “This addition represents progress,” Patrice Harris, MD, president of the AMA, said in a statement. “While we continue to have concerns with elements of the legislation, we remain committed to working with all committee members to secure further improvements to protect patients, preserve access, and foster fair payments for out-of-network services.”
America’s Health Insurance Plans, which represents health insurers, voiced its opposition to the arbitration provision. “We strongly oppose the inclusion of arbitration because it does not solve the problem of surprise medical bills,” AHIP President and CEO Matt Eyles said in a statement. “It increases the financial burden on everyone with coverage, increasing patient premiums and driving up the cost of health care. The arbitration proposal allows private-equity firms and certain providers to price gouge patients and then shifts the final decision to a ‘third party.’ This process introduces new bureaucracy and red tape into the system, with costs to hardworking taxpayers exceeding $1 billion.”
Benedic Ippolito, research fellow in economic policy studies at the American Economic Institute, further criticized the use of arbitration in this process.
“This concept that arbitration is a backstop doesn’t really make a lot of sense,” he said during a July 17 panel discussion hosted by the Bipartisan Policy Center on surprise billing. “The arbiter has to do the same thing any sort of rate setter has to do.” He noted that if they are doing “baseball-style” arbitration, they have to choose between two offers placed in front of the arbiter, based on what the arbiter believes to be closer to whatever the reasonable rate is.
This process will eventually lead to either a system that favors the payer, the provider, or ends up being exactly what the benchmark is that has been set. “If it is better for one or the other, somebody is going to have an incentive to just trigger this thing the whole time,” Mr. Ippolito said.
Loren Adler, associate director of the USC-Brookings Schaeffer Initiative for Health Policy, said during the panel discussion that “there is no policy reason to have arbitration. There is nothing it adds for policy value.”
Mr. Adler called the arbitration amendment “a provider giveaway bill,” adding that if there has to be an arbitration option, it should have a very high threshold to be triggered.
Legislation to end surprise medical billing cleared the House Energy and Commerce Committee and is headed to the House floor, but it contains a somewhat controversial arbitration mechanism that allows physicians and hospitals to seek higher payments within 30 days.
The bill, which was tacked on to H.R. 2328, passed the committee by voice vote on July 17. The amendment on arbitration also passed the committee via voice vote.
“Our most important task today is to protect patients from the unreasonable and unacceptable practice of surprise billing,” Rep. Frank Pallone (D-N.J.), chairman of the Energy and Commerce Committee, said just prior to the votes being taken by the committee. “Under the [legislation], providers would no longer be able to balance bill patients for out-of-network emergency services or for scheduled services from providers the patient was not aware would be in their treatment.”
Out-of-network providers would receive a benchmark payment for the services they provided under the legislation.
Rep. Pallone described the legislation as taking patients out of the middle of disputes between payers and providers.
He went on to describe the arbitration amendment, introduced by Rep. Raul Ruiz, MD, (D.-Calif.) and Rep. Larry Bucshon, MD, (R-Ind.), as creating an independent dispute resolution process for physicians and hospitals to file a claim in the event that they don’t think they were adequately paid for their services.
“The amendment would allow providers to have 30 days within which to file an appeal of the benchmark payment with the insurer,” Rep. Pallone said. “The insurer would then have 30 days to adjudicate the appeal, after which the provider could initiate independent dispute resolution.”
The amendment limits appeals to extenuating circumstances so that only complex cases would qualify, and it limits the variables that can be considered during arbitration to the quality of care that was provided to the patient, according to Rep. Pallone.
“Most importantly to me, it bars arbitrators from considering billed charges, which are unilaterally set by providers,” Rep. Pallone said. “Provider charges are often double or triple Medicare rates, and in some cases for some large physician staffing companies, it is around 500% of Medicare rates. If Congress sends this signal to arbiters that provider charges are to be considered, we would be creating a significantly higher standard for payment, decreasing incentives for providers to be in network and putting upward pressure on health care premiums.”
Rep. Michael Burgess, MD, (R-Texas) praised the inclusion of the arbitration amendment and said the surprise billing legislation would not be able to be passed without its inclusion.
Rep. Janice Schakowsky (D-Ill.) offered a dissenting voice to the amendment. “Arbitration, in my view, which is used as the backstop, will not lower the health care costs,” she said. “Arbitration actually comes with additional administrative costs and complexities, which could then be passed on to consumers in the form of higher premiums. Even as a backstop, I think that binding arbitration leaves a public interest, public health decision, up to an unaccountable private decision maker, and I don’t think that is a very progressive way to be dealing with the issue of pricing.”
The American Medical Association praised the inclusion of an appeals process for resolving out-of-network payment disputes. “This addition represents progress,” Patrice Harris, MD, president of the AMA, said in a statement. “While we continue to have concerns with elements of the legislation, we remain committed to working with all committee members to secure further improvements to protect patients, preserve access, and foster fair payments for out-of-network services.”
America’s Health Insurance Plans, which represents health insurers, voiced its opposition to the arbitration provision. “We strongly oppose the inclusion of arbitration because it does not solve the problem of surprise medical bills,” AHIP President and CEO Matt Eyles said in a statement. “It increases the financial burden on everyone with coverage, increasing patient premiums and driving up the cost of health care. The arbitration proposal allows private-equity firms and certain providers to price gouge patients and then shifts the final decision to a ‘third party.’ This process introduces new bureaucracy and red tape into the system, with costs to hardworking taxpayers exceeding $1 billion.”
Benedic Ippolito, research fellow in economic policy studies at the American Economic Institute, further criticized the use of arbitration in this process.
“This concept that arbitration is a backstop doesn’t really make a lot of sense,” he said during a July 17 panel discussion hosted by the Bipartisan Policy Center on surprise billing. “The arbiter has to do the same thing any sort of rate setter has to do.” He noted that if they are doing “baseball-style” arbitration, they have to choose between two offers placed in front of the arbiter, based on what the arbiter believes to be closer to whatever the reasonable rate is.
This process will eventually lead to either a system that favors the payer, the provider, or ends up being exactly what the benchmark is that has been set. “If it is better for one or the other, somebody is going to have an incentive to just trigger this thing the whole time,” Mr. Ippolito said.
Loren Adler, associate director of the USC-Brookings Schaeffer Initiative for Health Policy, said during the panel discussion that “there is no policy reason to have arbitration. There is nothing it adds for policy value.”
Mr. Adler called the arbitration amendment “a provider giveaway bill,” adding that if there has to be an arbitration option, it should have a very high threshold to be triggered.
Exposure to synthetic cannabinoids is associated with neuropsychiatric morbidity in adolescents
according to data published online July 8 ahead of print in Pediatrics. The results support a distinct neuropsychiatric profile of acute synthetic cannabinoid toxicity in adolescents, wrote the investigators.
Synthetic cannabinoids have become popular and accessible and primarily are used for recreation. The adverse effects of synthetic cannabinoid toxicity reported in the literature include tachycardia, cardiac ischemia, acute kidney injury, agitation, first episode of psychosis, seizures, and death. Adolescents are the largest age group presenting to the emergency department with acute synthetic cannabinoid toxicity, and this population requires more intensive care than adults with the same presentation.
A multicenter registry analysis
To describe the neuropsychiatric presentation of adolescents to the emergency department after synthetic cannabinoid exposure, compared with that of cannabis exposure, Sarah Ann R. Anderson, MD, PhD, an adolescent medicine fellow at Columbia University Irving Medical Center in New York, and colleagues performed a multicenter registry analysis. They examined data collected from January 2010 through September 2018 from adolescent patients who presented to sites that participate in the Toxicology Investigators Consortium. For each patient, clinicians requested a consultation by a medical toxicologist to aid care. The exposures recorded in the case registry are reported by the patients or witnesses.
Eligible patients were between ages 13 and 19 years and presented to an emergency department with synthetic cannabinoid or cannabis exposure. Dr. Anderson and colleagues collected variables such as age, sex, reported exposures, death in hospital, location of toxicology encounter, and neuropsychiatric signs or symptoms. Patients whose exposure report came from a service outside of an emergency department and those with concomitant use of cannabis and synthetic cannabinoids were excluded. For the purpose of analysis, the investigators classified patients into the following four categories: exposure to synthetic cannabinoids alone, exposure to synthetic cannabinoids and other drugs, exposure to cannabis alone, and exposure to cannabis and other drugs.
Dr. Anderson and colleagues included 348 patients in their study. The sample included 107 patients in the synthetic cannabinoid–only group, 38 in the synthetic cannabinoid/polydrug group, 86 in the cannabis-only group, and 117 in the cannabis/polydrug group. Males predominated in all groups. The one death in the study occurred in the synthetic cannabinoid–only group.
Synthetic cannabinoid exposure increased risk for seizures
Compared with the cannabis-only group, the synthetic cannabinoid–only group had an increased risk of coma or CNS depression (odds ratio, 3.42) and seizures (OR, 3.89). The risk of agitation was significantly lower in the synthetic cannabinoid–only group, compared with the cannabis-only group (OR, 0.18). The two single-drug exposure groups did not differ in their associated risks of delirium or toxic psychosis, extrapyramidal signs, dystonia or rigidity, or hallucinations.
Exposure to synthetic cannabinoids plus other drugs was associated with increased risk of agitation (OR, 3.11) and seizures (OR, 4.8), compared with exposure to cannabis plus other drugs. Among patients exposed to synthetic cannabinoids plus other drugs, the most common class of other drug was sympathomimetics (such as synthetic cathinones, cocaine, and amphetamines). Sympathomimetics and ethanol were the two most common classes of drugs among patients exposed to cannabis plus other drugs.
Synthetic cannabinoids may have distinctive neuropsychiatric outcomes
“Findings from our study further confirm the previously described association between synthetic cannabinoid–specific overdose and severe neuropsychiatric outcomes,” wrote Dr. Anderson and colleagues. They underscore “the need for targeted public health messaging to adolescents about the dangers of using synthetic cannabinoids alone or combined with other substances.”
The investigators’ finding that patients exposed to synthetic cannabinoids alone had a lower risk of agitation than those exposed to cannabis alone is not consistent with contemporary literature on synthetic cannabinoid–associated agitation. This discordance may reflect differences in the populations studied, “with more severe toxicity prompting the emergency department presentations reported in this study,” wrote Dr. Anderson and colleagues. The current study also may be affected by selection bias, they added.
The researchers acknowledged several limitations of their study. For example, the registry lacked data for variables such as race or ethnicity, concurrent illness, previous drug use, and comorbid conditions. Another limitation was that substance exposure was patient- or witness-reported, and no testing to confirm exposure to synthetic cannabinoids was performed. Finally, the study had a relatively small sample size and lacked information about patients’ long-term outcomes.
Dr. Anderson and colleagues described future research that could address open questions. Analyzing urine to identify the synthetic cannabinoid used and correlating it with the presentation in the emergency department could illuminate specific toxidromes associated with particular compounds, they wrote. Longitudinal data on the long-term effects of adolescent exposure to synthetic cannabinoids would be valuable for understanding potential long-term neurocognitive impairments. “Lastly, additional investigations into the management of adolescent synthetic cannabinoid toxicity in the emergency department is warranted, given the health care cost burden of synthetic cannabinoid–related emergency department visits,” they concluded.
The study was not supported by external funding, and the authors had no relevant disclosures.
SOURCE: Anderson SAR et al. Pediatrics. 2019 Jul 8. doi: 10.1542/peds.2018-2690.
according to data published online July 8 ahead of print in Pediatrics. The results support a distinct neuropsychiatric profile of acute synthetic cannabinoid toxicity in adolescents, wrote the investigators.
Synthetic cannabinoids have become popular and accessible and primarily are used for recreation. The adverse effects of synthetic cannabinoid toxicity reported in the literature include tachycardia, cardiac ischemia, acute kidney injury, agitation, first episode of psychosis, seizures, and death. Adolescents are the largest age group presenting to the emergency department with acute synthetic cannabinoid toxicity, and this population requires more intensive care than adults with the same presentation.
A multicenter registry analysis
To describe the neuropsychiatric presentation of adolescents to the emergency department after synthetic cannabinoid exposure, compared with that of cannabis exposure, Sarah Ann R. Anderson, MD, PhD, an adolescent medicine fellow at Columbia University Irving Medical Center in New York, and colleagues performed a multicenter registry analysis. They examined data collected from January 2010 through September 2018 from adolescent patients who presented to sites that participate in the Toxicology Investigators Consortium. For each patient, clinicians requested a consultation by a medical toxicologist to aid care. The exposures recorded in the case registry are reported by the patients or witnesses.
Eligible patients were between ages 13 and 19 years and presented to an emergency department with synthetic cannabinoid or cannabis exposure. Dr. Anderson and colleagues collected variables such as age, sex, reported exposures, death in hospital, location of toxicology encounter, and neuropsychiatric signs or symptoms. Patients whose exposure report came from a service outside of an emergency department and those with concomitant use of cannabis and synthetic cannabinoids were excluded. For the purpose of analysis, the investigators classified patients into the following four categories: exposure to synthetic cannabinoids alone, exposure to synthetic cannabinoids and other drugs, exposure to cannabis alone, and exposure to cannabis and other drugs.
Dr. Anderson and colleagues included 348 patients in their study. The sample included 107 patients in the synthetic cannabinoid–only group, 38 in the synthetic cannabinoid/polydrug group, 86 in the cannabis-only group, and 117 in the cannabis/polydrug group. Males predominated in all groups. The one death in the study occurred in the synthetic cannabinoid–only group.
Synthetic cannabinoid exposure increased risk for seizures
Compared with the cannabis-only group, the synthetic cannabinoid–only group had an increased risk of coma or CNS depression (odds ratio, 3.42) and seizures (OR, 3.89). The risk of agitation was significantly lower in the synthetic cannabinoid–only group, compared with the cannabis-only group (OR, 0.18). The two single-drug exposure groups did not differ in their associated risks of delirium or toxic psychosis, extrapyramidal signs, dystonia or rigidity, or hallucinations.
Exposure to synthetic cannabinoids plus other drugs was associated with increased risk of agitation (OR, 3.11) and seizures (OR, 4.8), compared with exposure to cannabis plus other drugs. Among patients exposed to synthetic cannabinoids plus other drugs, the most common class of other drug was sympathomimetics (such as synthetic cathinones, cocaine, and amphetamines). Sympathomimetics and ethanol were the two most common classes of drugs among patients exposed to cannabis plus other drugs.
Synthetic cannabinoids may have distinctive neuropsychiatric outcomes
“Findings from our study further confirm the previously described association between synthetic cannabinoid–specific overdose and severe neuropsychiatric outcomes,” wrote Dr. Anderson and colleagues. They underscore “the need for targeted public health messaging to adolescents about the dangers of using synthetic cannabinoids alone or combined with other substances.”
The investigators’ finding that patients exposed to synthetic cannabinoids alone had a lower risk of agitation than those exposed to cannabis alone is not consistent with contemporary literature on synthetic cannabinoid–associated agitation. This discordance may reflect differences in the populations studied, “with more severe toxicity prompting the emergency department presentations reported in this study,” wrote Dr. Anderson and colleagues. The current study also may be affected by selection bias, they added.
The researchers acknowledged several limitations of their study. For example, the registry lacked data for variables such as race or ethnicity, concurrent illness, previous drug use, and comorbid conditions. Another limitation was that substance exposure was patient- or witness-reported, and no testing to confirm exposure to synthetic cannabinoids was performed. Finally, the study had a relatively small sample size and lacked information about patients’ long-term outcomes.
Dr. Anderson and colleagues described future research that could address open questions. Analyzing urine to identify the synthetic cannabinoid used and correlating it with the presentation in the emergency department could illuminate specific toxidromes associated with particular compounds, they wrote. Longitudinal data on the long-term effects of adolescent exposure to synthetic cannabinoids would be valuable for understanding potential long-term neurocognitive impairments. “Lastly, additional investigations into the management of adolescent synthetic cannabinoid toxicity in the emergency department is warranted, given the health care cost burden of synthetic cannabinoid–related emergency department visits,” they concluded.
The study was not supported by external funding, and the authors had no relevant disclosures.
SOURCE: Anderson SAR et al. Pediatrics. 2019 Jul 8. doi: 10.1542/peds.2018-2690.
according to data published online July 8 ahead of print in Pediatrics. The results support a distinct neuropsychiatric profile of acute synthetic cannabinoid toxicity in adolescents, wrote the investigators.
Synthetic cannabinoids have become popular and accessible and primarily are used for recreation. The adverse effects of synthetic cannabinoid toxicity reported in the literature include tachycardia, cardiac ischemia, acute kidney injury, agitation, first episode of psychosis, seizures, and death. Adolescents are the largest age group presenting to the emergency department with acute synthetic cannabinoid toxicity, and this population requires more intensive care than adults with the same presentation.
A multicenter registry analysis
To describe the neuropsychiatric presentation of adolescents to the emergency department after synthetic cannabinoid exposure, compared with that of cannabis exposure, Sarah Ann R. Anderson, MD, PhD, an adolescent medicine fellow at Columbia University Irving Medical Center in New York, and colleagues performed a multicenter registry analysis. They examined data collected from January 2010 through September 2018 from adolescent patients who presented to sites that participate in the Toxicology Investigators Consortium. For each patient, clinicians requested a consultation by a medical toxicologist to aid care. The exposures recorded in the case registry are reported by the patients or witnesses.
Eligible patients were between ages 13 and 19 years and presented to an emergency department with synthetic cannabinoid or cannabis exposure. Dr. Anderson and colleagues collected variables such as age, sex, reported exposures, death in hospital, location of toxicology encounter, and neuropsychiatric signs or symptoms. Patients whose exposure report came from a service outside of an emergency department and those with concomitant use of cannabis and synthetic cannabinoids were excluded. For the purpose of analysis, the investigators classified patients into the following four categories: exposure to synthetic cannabinoids alone, exposure to synthetic cannabinoids and other drugs, exposure to cannabis alone, and exposure to cannabis and other drugs.
Dr. Anderson and colleagues included 348 patients in their study. The sample included 107 patients in the synthetic cannabinoid–only group, 38 in the synthetic cannabinoid/polydrug group, 86 in the cannabis-only group, and 117 in the cannabis/polydrug group. Males predominated in all groups. The one death in the study occurred in the synthetic cannabinoid–only group.
Synthetic cannabinoid exposure increased risk for seizures
Compared with the cannabis-only group, the synthetic cannabinoid–only group had an increased risk of coma or CNS depression (odds ratio, 3.42) and seizures (OR, 3.89). The risk of agitation was significantly lower in the synthetic cannabinoid–only group, compared with the cannabis-only group (OR, 0.18). The two single-drug exposure groups did not differ in their associated risks of delirium or toxic psychosis, extrapyramidal signs, dystonia or rigidity, or hallucinations.
Exposure to synthetic cannabinoids plus other drugs was associated with increased risk of agitation (OR, 3.11) and seizures (OR, 4.8), compared with exposure to cannabis plus other drugs. Among patients exposed to synthetic cannabinoids plus other drugs, the most common class of other drug was sympathomimetics (such as synthetic cathinones, cocaine, and amphetamines). Sympathomimetics and ethanol were the two most common classes of drugs among patients exposed to cannabis plus other drugs.
Synthetic cannabinoids may have distinctive neuropsychiatric outcomes
“Findings from our study further confirm the previously described association between synthetic cannabinoid–specific overdose and severe neuropsychiatric outcomes,” wrote Dr. Anderson and colleagues. They underscore “the need for targeted public health messaging to adolescents about the dangers of using synthetic cannabinoids alone or combined with other substances.”
The investigators’ finding that patients exposed to synthetic cannabinoids alone had a lower risk of agitation than those exposed to cannabis alone is not consistent with contemporary literature on synthetic cannabinoid–associated agitation. This discordance may reflect differences in the populations studied, “with more severe toxicity prompting the emergency department presentations reported in this study,” wrote Dr. Anderson and colleagues. The current study also may be affected by selection bias, they added.
The researchers acknowledged several limitations of their study. For example, the registry lacked data for variables such as race or ethnicity, concurrent illness, previous drug use, and comorbid conditions. Another limitation was that substance exposure was patient- or witness-reported, and no testing to confirm exposure to synthetic cannabinoids was performed. Finally, the study had a relatively small sample size and lacked information about patients’ long-term outcomes.
Dr. Anderson and colleagues described future research that could address open questions. Analyzing urine to identify the synthetic cannabinoid used and correlating it with the presentation in the emergency department could illuminate specific toxidromes associated with particular compounds, they wrote. Longitudinal data on the long-term effects of adolescent exposure to synthetic cannabinoids would be valuable for understanding potential long-term neurocognitive impairments. “Lastly, additional investigations into the management of adolescent synthetic cannabinoid toxicity in the emergency department is warranted, given the health care cost burden of synthetic cannabinoid–related emergency department visits,” they concluded.
The study was not supported by external funding, and the authors had no relevant disclosures.
SOURCE: Anderson SAR et al. Pediatrics. 2019 Jul 8. doi: 10.1542/peds.2018-2690.
FROM PEDIATRICS
Statins crush early seizure risk poststroke
BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.
Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.
This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.
He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.
Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.
Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.
In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.
Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.
The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).
As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.
Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.
He reported having no financial conflicts regarding the study, conducted free of commercial support.
SOURCE: Matsubara S et al. IEC 219, Abstract P002.
BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.
Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.
This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.
He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.
Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.
Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.
In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.
Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.
The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).
As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.
Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.
He reported having no financial conflicts regarding the study, conducted free of commercial support.
SOURCE: Matsubara S et al. IEC 219, Abstract P002.
BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.
Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.
This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.
He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.
Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.
Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.
In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.
Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.
The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).
As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.
Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.
He reported having no financial conflicts regarding the study, conducted free of commercial support.
SOURCE: Matsubara S et al. IEC 219, Abstract P002.
REPORTING FROM IEC 2019
Transdermal estradiol may modulate the relationship between sleep, cognition
LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.
In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.
“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”
Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.
Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*
Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.
The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.
“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.
The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.
The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.
The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.
“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”
By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.
Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.
Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).
Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).
“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.
Dr. Zeydan had no financial disclosures.
*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.
LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.
In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.
“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”
Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.
Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*
Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.
The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.
“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.
The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.
The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.
The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.
“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”
By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.
Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.
Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).
Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).
“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.
Dr. Zeydan had no financial disclosures.
*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.
LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.
In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.
“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”
Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.
Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*
Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.
The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.
“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.
The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.
The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.
The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.
“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”
By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.
Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.
Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).
Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).
“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.
Dr. Zeydan had no financial disclosures.
*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.
REPORTING FROM AAIC 2019
Gum bacteria and Alzheimer’s: A hypothesis inches forward
LOS ANGELES – Scientists testing an unusual hypothesis about the pathogenesis of Alzheimer’s disease say that use of an experimental antimicrobial drug to target a common oral infection was associated with biomarker improvements in people with the disease.
At the Alzheimer’s Association International Conference, Michael Detke, MD, PhD, of Cortexyme in South San Francisco, Calif., presented findings from a small cohort (n = 9) of people with mild to moderate Alzheimer’s disease (AD).
Six patients, mean age 72, were randomized to 4 weeks’ treatment with an agent called COR388, which inhibits toxic proteases produced by Porphyromonas gingivalis, a bacterium that colonizes the mouth and gums and has been found in the brains and cerebrospinal fluid of people with AD more than in non-AD patients. Another three subjects were randomized to placebo.
At 28 days, the CSF levels of an Alzheimer’s-associated apolipoprotein E (ApoE) fragment and serum levels of RANTES, a chemokine associated with chronic inflammation, were reduced from baseline by about one-third in treated subjects, compared with placebo subjects (P less than .05).
“In AD, ApoE is known to be fragmented and the fragments are known to be neurotoxic,” Dr. Detke, the lead study author, said in an interview. “We hypothesized that these P. gingivalis proteases may be acting on ApoE cleavage – so if you bind the proteases you should reduce the fragments. We saw in this study that ApoE fragment was reduced by 30%, or back to about normal levels.”
It is difficult to eradicate P. gingivalis infection using conventional antibiotics. The experimental agent COR388 “does not kill the bacteria but rather neutralizes it by binding to the proteases it produces, making the bacteria benign,” Dr. Detke said.
While hypotheses involving infectious causes of Alzheimer’s remain on the periphery of dementia research, Dr. Detke and his colleagues will soon be able to test theirs in a more meaningful way. At the conference, Dr. Detke presented detailed plans for a phase 2/3, placebo-controlled, clinical trial of COR388 in 570 patients aged 55-80 with mild to moderate AD.
Patients in the study are currently being randomized to 48 weeks of treatment with one of two doses, or placebo, with cognitive and biomarker endpoints planned, including for amyloid-beta, tau, and serum, plasma, and CSF markers of neuroinflammation.
Dr. Detke is an employee of Cortexyme, as are another 8 of the study’s 11 authors.
LOS ANGELES – Scientists testing an unusual hypothesis about the pathogenesis of Alzheimer’s disease say that use of an experimental antimicrobial drug to target a common oral infection was associated with biomarker improvements in people with the disease.
At the Alzheimer’s Association International Conference, Michael Detke, MD, PhD, of Cortexyme in South San Francisco, Calif., presented findings from a small cohort (n = 9) of people with mild to moderate Alzheimer’s disease (AD).
Six patients, mean age 72, were randomized to 4 weeks’ treatment with an agent called COR388, which inhibits toxic proteases produced by Porphyromonas gingivalis, a bacterium that colonizes the mouth and gums and has been found in the brains and cerebrospinal fluid of people with AD more than in non-AD patients. Another three subjects were randomized to placebo.
At 28 days, the CSF levels of an Alzheimer’s-associated apolipoprotein E (ApoE) fragment and serum levels of RANTES, a chemokine associated with chronic inflammation, were reduced from baseline by about one-third in treated subjects, compared with placebo subjects (P less than .05).
“In AD, ApoE is known to be fragmented and the fragments are known to be neurotoxic,” Dr. Detke, the lead study author, said in an interview. “We hypothesized that these P. gingivalis proteases may be acting on ApoE cleavage – so if you bind the proteases you should reduce the fragments. We saw in this study that ApoE fragment was reduced by 30%, or back to about normal levels.”
It is difficult to eradicate P. gingivalis infection using conventional antibiotics. The experimental agent COR388 “does not kill the bacteria but rather neutralizes it by binding to the proteases it produces, making the bacteria benign,” Dr. Detke said.
While hypotheses involving infectious causes of Alzheimer’s remain on the periphery of dementia research, Dr. Detke and his colleagues will soon be able to test theirs in a more meaningful way. At the conference, Dr. Detke presented detailed plans for a phase 2/3, placebo-controlled, clinical trial of COR388 in 570 patients aged 55-80 with mild to moderate AD.
Patients in the study are currently being randomized to 48 weeks of treatment with one of two doses, or placebo, with cognitive and biomarker endpoints planned, including for amyloid-beta, tau, and serum, plasma, and CSF markers of neuroinflammation.
Dr. Detke is an employee of Cortexyme, as are another 8 of the study’s 11 authors.
LOS ANGELES – Scientists testing an unusual hypothesis about the pathogenesis of Alzheimer’s disease say that use of an experimental antimicrobial drug to target a common oral infection was associated with biomarker improvements in people with the disease.
At the Alzheimer’s Association International Conference, Michael Detke, MD, PhD, of Cortexyme in South San Francisco, Calif., presented findings from a small cohort (n = 9) of people with mild to moderate Alzheimer’s disease (AD).
Six patients, mean age 72, were randomized to 4 weeks’ treatment with an agent called COR388, which inhibits toxic proteases produced by Porphyromonas gingivalis, a bacterium that colonizes the mouth and gums and has been found in the brains and cerebrospinal fluid of people with AD more than in non-AD patients. Another three subjects were randomized to placebo.
At 28 days, the CSF levels of an Alzheimer’s-associated apolipoprotein E (ApoE) fragment and serum levels of RANTES, a chemokine associated with chronic inflammation, were reduced from baseline by about one-third in treated subjects, compared with placebo subjects (P less than .05).
“In AD, ApoE is known to be fragmented and the fragments are known to be neurotoxic,” Dr. Detke, the lead study author, said in an interview. “We hypothesized that these P. gingivalis proteases may be acting on ApoE cleavage – so if you bind the proteases you should reduce the fragments. We saw in this study that ApoE fragment was reduced by 30%, or back to about normal levels.”
It is difficult to eradicate P. gingivalis infection using conventional antibiotics. The experimental agent COR388 “does not kill the bacteria but rather neutralizes it by binding to the proteases it produces, making the bacteria benign,” Dr. Detke said.
While hypotheses involving infectious causes of Alzheimer’s remain on the periphery of dementia research, Dr. Detke and his colleagues will soon be able to test theirs in a more meaningful way. At the conference, Dr. Detke presented detailed plans for a phase 2/3, placebo-controlled, clinical trial of COR388 in 570 patients aged 55-80 with mild to moderate AD.
Patients in the study are currently being randomized to 48 weeks of treatment with one of two doses, or placebo, with cognitive and biomarker endpoints planned, including for amyloid-beta, tau, and serum, plasma, and CSF markers of neuroinflammation.
Dr. Detke is an employee of Cortexyme, as are another 8 of the study’s 11 authors.
FROM AAIC 2019
Systolic, diastolic BP each tied to adverse CV outcomes
Both systolic and diastolic hypertension independently predict myocardial infarction and strokes, but systolic blood pressure is more strongly linked to adverse outcomes.
That’s according to a study of more than 1 million patients and 36 million outpatient blood pressure measurements published in the New England Journal of Medicine.
Systolic and diastolic hypertension predicted adverse outcomes at cutpoints of 140/90 and 130/80 mm Hg in the large retrospective cohort study, supporting the recent guideline changes that made blood pressure targets more stringent for higher-risk patients, said lead investigator Alexander C. Flint, MD, of Kaiser Permanente Northern California (KPNC) in Oakland.
“While systolic does count for more, in the fact that it is a stronger driver of the risk of heart attack and stroke, diastolic absolutely does as well, and it does so independently. So we ignore our diastolic hypertension at our own peril,” Dr. Flint said in an interview.
Systolic hypertension began to overshadow diastolic after the Framingham Heart Study and others that suggested it is a more important predictor of adverse cardiovascular outcomes, Dr. Flint and coauthors said in a report on their study.
Those findings caused some to say diastole should be abandoned, and led to a “near-exclusive focus” on systolic hypertension in a 2000 advisory statement from the National High Blood Pressure Education Program, they say in their report.
While current guidelines emphasize the importance of both systolic and diastolic targets, many clinicians today often assign little importance to diastolic blood pressure values, the report adds.
“The pendulum needs to swing back, right down in the middle,” Dr. Flint said in the interview.
The study by Dr. Flint and colleagues comprised a cohort of approximately 1.3 million outpatients from KPNC who had at least one baseline blood pressure reading in during 2007-2008, and two or more follow-up measurements between 2009 and 2016, for a total of about 36.8 million data points.
Systolic hypertension burden was linked to the composite of MI or stroke, with a hazard ratio of 1.18 (95% confidence interval, 1.17-1.18; P less than .001) per unit increase in z score, according to results of a multivariable regression analysis. Likewise, diastolic hypertension burden was linked to those adverse outcomes, with a hazard ratio of 1.06 (95% CI, 1.06-1.07; P less than .001).
Put in terms of estimated risk of MI or stroke, patients with a systolic blood pressure around 160 mm Hg – 3 standard deviations from the mean – was 4.8%, compared to a predicted risk of just 1.9% for a systolic blood pressure near 136 mm Hg, the investigators said in their report.
Similarly, predicted risk was 3.6% for a diastolic pressure of about 96 mm Hg, also 3 standard deviations from the mean, and 1.9% for a diastolic BP near 81 mm Hg.
“The two are not that separate,” Dr. Flint said of the risks associated with systolic and diastolic hypertension at that 3-standard-deviation point. Beyond that, increased systolic blood pressure is associated with more risk relative to increased diastolic blood pressure, the logistic regression modeling shows.
Taken together, findings from this large cohort study emphasize the importance of making lifestyle modifications and adjusting medication to ensure that both systolic and diastolic targets are met, according to Dr. Flint.
“Rises in systolic blood pressure count for more in influencing the risk of heart attack and stroke,” he said, “but diastolic independently counts for quite a lot. It’s a close second.”
Dr. Flint reported no disclosures. Senior author Deepak L. Bhatt, MD, MPH, reported disclosures with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.
SOURCE: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.
Both systolic and diastolic hypertension independently predict myocardial infarction and strokes, but systolic blood pressure is more strongly linked to adverse outcomes.
That’s according to a study of more than 1 million patients and 36 million outpatient blood pressure measurements published in the New England Journal of Medicine.
Systolic and diastolic hypertension predicted adverse outcomes at cutpoints of 140/90 and 130/80 mm Hg in the large retrospective cohort study, supporting the recent guideline changes that made blood pressure targets more stringent for higher-risk patients, said lead investigator Alexander C. Flint, MD, of Kaiser Permanente Northern California (KPNC) in Oakland.
“While systolic does count for more, in the fact that it is a stronger driver of the risk of heart attack and stroke, diastolic absolutely does as well, and it does so independently. So we ignore our diastolic hypertension at our own peril,” Dr. Flint said in an interview.
Systolic hypertension began to overshadow diastolic after the Framingham Heart Study and others that suggested it is a more important predictor of adverse cardiovascular outcomes, Dr. Flint and coauthors said in a report on their study.
Those findings caused some to say diastole should be abandoned, and led to a “near-exclusive focus” on systolic hypertension in a 2000 advisory statement from the National High Blood Pressure Education Program, they say in their report.
While current guidelines emphasize the importance of both systolic and diastolic targets, many clinicians today often assign little importance to diastolic blood pressure values, the report adds.
“The pendulum needs to swing back, right down in the middle,” Dr. Flint said in the interview.
The study by Dr. Flint and colleagues comprised a cohort of approximately 1.3 million outpatients from KPNC who had at least one baseline blood pressure reading in during 2007-2008, and two or more follow-up measurements between 2009 and 2016, for a total of about 36.8 million data points.
Systolic hypertension burden was linked to the composite of MI or stroke, with a hazard ratio of 1.18 (95% confidence interval, 1.17-1.18; P less than .001) per unit increase in z score, according to results of a multivariable regression analysis. Likewise, diastolic hypertension burden was linked to those adverse outcomes, with a hazard ratio of 1.06 (95% CI, 1.06-1.07; P less than .001).
Put in terms of estimated risk of MI or stroke, patients with a systolic blood pressure around 160 mm Hg – 3 standard deviations from the mean – was 4.8%, compared to a predicted risk of just 1.9% for a systolic blood pressure near 136 mm Hg, the investigators said in their report.
Similarly, predicted risk was 3.6% for a diastolic pressure of about 96 mm Hg, also 3 standard deviations from the mean, and 1.9% for a diastolic BP near 81 mm Hg.
“The two are not that separate,” Dr. Flint said of the risks associated with systolic and diastolic hypertension at that 3-standard-deviation point. Beyond that, increased systolic blood pressure is associated with more risk relative to increased diastolic blood pressure, the logistic regression modeling shows.
Taken together, findings from this large cohort study emphasize the importance of making lifestyle modifications and adjusting medication to ensure that both systolic and diastolic targets are met, according to Dr. Flint.
“Rises in systolic blood pressure count for more in influencing the risk of heart attack and stroke,” he said, “but diastolic independently counts for quite a lot. It’s a close second.”
Dr. Flint reported no disclosures. Senior author Deepak L. Bhatt, MD, MPH, reported disclosures with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.
SOURCE: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.
Both systolic and diastolic hypertension independently predict myocardial infarction and strokes, but systolic blood pressure is more strongly linked to adverse outcomes.
That’s according to a study of more than 1 million patients and 36 million outpatient blood pressure measurements published in the New England Journal of Medicine.
Systolic and diastolic hypertension predicted adverse outcomes at cutpoints of 140/90 and 130/80 mm Hg in the large retrospective cohort study, supporting the recent guideline changes that made blood pressure targets more stringent for higher-risk patients, said lead investigator Alexander C. Flint, MD, of Kaiser Permanente Northern California (KPNC) in Oakland.
“While systolic does count for more, in the fact that it is a stronger driver of the risk of heart attack and stroke, diastolic absolutely does as well, and it does so independently. So we ignore our diastolic hypertension at our own peril,” Dr. Flint said in an interview.
Systolic hypertension began to overshadow diastolic after the Framingham Heart Study and others that suggested it is a more important predictor of adverse cardiovascular outcomes, Dr. Flint and coauthors said in a report on their study.
Those findings caused some to say diastole should be abandoned, and led to a “near-exclusive focus” on systolic hypertension in a 2000 advisory statement from the National High Blood Pressure Education Program, they say in their report.
While current guidelines emphasize the importance of both systolic and diastolic targets, many clinicians today often assign little importance to diastolic blood pressure values, the report adds.
“The pendulum needs to swing back, right down in the middle,” Dr. Flint said in the interview.
The study by Dr. Flint and colleagues comprised a cohort of approximately 1.3 million outpatients from KPNC who had at least one baseline blood pressure reading in during 2007-2008, and two or more follow-up measurements between 2009 and 2016, for a total of about 36.8 million data points.
Systolic hypertension burden was linked to the composite of MI or stroke, with a hazard ratio of 1.18 (95% confidence interval, 1.17-1.18; P less than .001) per unit increase in z score, according to results of a multivariable regression analysis. Likewise, diastolic hypertension burden was linked to those adverse outcomes, with a hazard ratio of 1.06 (95% CI, 1.06-1.07; P less than .001).
Put in terms of estimated risk of MI or stroke, patients with a systolic blood pressure around 160 mm Hg – 3 standard deviations from the mean – was 4.8%, compared to a predicted risk of just 1.9% for a systolic blood pressure near 136 mm Hg, the investigators said in their report.
Similarly, predicted risk was 3.6% for a diastolic pressure of about 96 mm Hg, also 3 standard deviations from the mean, and 1.9% for a diastolic BP near 81 mm Hg.
“The two are not that separate,” Dr. Flint said of the risks associated with systolic and diastolic hypertension at that 3-standard-deviation point. Beyond that, increased systolic blood pressure is associated with more risk relative to increased diastolic blood pressure, the logistic regression modeling shows.
Taken together, findings from this large cohort study emphasize the importance of making lifestyle modifications and adjusting medication to ensure that both systolic and diastolic targets are met, according to Dr. Flint.
“Rises in systolic blood pressure count for more in influencing the risk of heart attack and stroke,” he said, “but diastolic independently counts for quite a lot. It’s a close second.”
Dr. Flint reported no disclosures. Senior author Deepak L. Bhatt, MD, MPH, reported disclosures with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.
SOURCE: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: .
Major finding: Systolic and diastolic hypertension burden were linked to the composite endpoint with hazard ratios of 1.18 and 1.06 per unit increase in z score, respectively.
Study details: A retrospective cohort study of roughly 1.3 million outpatients with 36.8 million BP measurements.
Disclosures: The senior author of the study reported disclosures with Amarin, AstraZeneca, Bristol Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.
Source: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.